[Senate Hearing 109-75]
[From the U.S. Government Publishing Office]
S. Hrg. 109-75
ENSURING DRUG SAFETY: WHERE DO WE GO FROM HERE?
=======================================================================
HEARING
OF THE
COMMITTEE ON HEALTH, EDUCATION,
LABOR, AND PENSIONS
UNITED STATES SENATE
ONE HUNDRED NINTH CONGRESS
FIRST SESSION
ON
EXAMINING THE FOOD AND DRUG ADIMINISTRATION'S PROCESS OF ENSURING DRUG
SAFETY
__________
MARCH 3, 2005
__________
Printed for the use of the Committee on Health, Education, Labor, and
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COMMITTEE ON HEALTH, EDUCATION, LABOR, AND PENSIONS
MICHAEL B. ENZI, Wyoming, Chairman
JUDD GREGG, New Hampshire EDWARD M. KENNEDY, Massachusetts
BILL FRIST, Tennessee CHRISTOPHER J. DODD, Connecticut
LAMAR ALEXANDER, Tennessee TOM HARKIN, Iowa
RICHARD BURR, North Carolina BARBARA A. MIKULSKI, Maryland
JOHNNY ISAKSON, Georgia JAMES M. JEFFORDS (I), Vermont
MIKE DeWINE, Ohio JEFF BINGAMAN, New Mexico
JOHN ENSIGN, Nevada PATTY MURRAY, Washington
ORRIN G. HATCH, Utah JACK REED, Rhode Island
JEFF SESSIONS, Alabama HILLARY RODHAM CLINTON, New York
PAT ROBERTS, Kansas
Katherine Brunett McGuire, Staff Director
J. Michael Myers, Minority Staff Director and Chief Counsel
(ii)
C O N T E N T S
__________
STATEMENTS
THURSDAY, MARCH 5, 2005
Page
Enzi, Hon. Michael B., Chairman, Committee on Health, Education,
Labor, and Pensions, opening statement......................... 1
Kennedy, Hon. Edward M., a U.S. Senator from the State of
Massachusetts, opening statement............................... 3
Woodcock, Janet, M.D., Acting Deputy Commissioner for Operations,
U.S. Food and Drug Administration.............................. 4
Woodcock, Dr. Janet, and Dr. Kweder, joint prepared statement 17
Wilson, Cecil B., M.D., member, American Medical Association
Board of Trustees, Winter Park, FL; Keith L. Carson, chairman,
the Williamsburg Bioprocessing Foundation, Virginia Beach, VA;
Raymond Woosley, M.D., PhD, president, the Critical Path
Institute, professor of medicine and pharmacology, University
of Arizona, Tucson, AZ; and Bruce M. Psaty, M.D., PhD,
professor of medicine, Epidemology and Health Services,
codirector, Cardiovascular Health Research Unit, University of
Washington, Seattle, WA........................................ 25
Prepared statement of Dr. Wilson............................. 26
Prepared statement of Mr. Carson............................. 32
Prepared statement of Dr. Woosley............................ 35
Prepared statement of Dr. Psaty.............................. 42
ADDITIONAL MATERIAL
Statements, articles, publications, letters, etc.:
Clinton, Hon. Hillary Rodham, a U.S. Senator from the State
of New York, prepared statement............................ 54
Questions of Senator Clinton for Janet Woodcock, M.D......... 54
American Medical Association (Docket No. 2004D-0188)......... 55
American Medical Association (Docket No. 02N-0528)........... 59
American Society of Health-System Pharmacists, prepared
statement.................................................. 64
Grassley, Hon. Charles E., a U.S. Senator from the State of
Iowa, prepared statement................................... 67
Response to questions of Senator Enzi by Janet Woodcock, M.D. 69
Response to questions of Senator Hatch by Janet Woodcock,
M.D........................................................ 71
Response to questions of Senator Gregg by Janet Woodcock,
M.D........................................................ 72
Response to questions of Senator Kennedy by Janet Woodcock,
M.D........................................................ 74
Response to questions of the HELP Committee by Dr. Wilson:
Response to questions of Senator Enzi.................... 79
Response to questions of Senator Hatch................... 81
Response to questions of Senator Kennedy................. 83
Response to questions of Senator Enzi by Keith L. Carson..... 83
Response to questions of Senator Hatch by Keith L. Carson.... 85
Response to questions of the HELP Committee by Raymond L.
Woosley, M.D.:
Response to questions of Senator Enzi.................... 85
Response to questions of Senator Hatch................... 86
Response to questions of Senator Kennedy................. 90
Response to questions of Senator Enzi by Bruce M. Psaty, M.D. 92
Response to questions of Senator Hatch by Bruce M. Psaty,
M.D........................................................ 94
Response to questions of Senator Kennedy by Bruce M. Psaty,
M.D........................................................ 96
(iii)
ENSURING DRUG SAFETY: WHERE DO WE GO FROM HERE?
----------
THURSDAY, MARCH 3, 2005
U.S. Senate,
Committee on Health, Education, Labor, and Pensions,
Washington, DC.
The committee met, pursuant to notice, at 10:02 a.m., in
room 106, Dirksen Senate Office Building, Senator Enzi,
chairman of the committee, presiding.
Present: Senators Enzi, Burr, Isakson, Kennedy, Murray, and
Reed.
Opening Statement of Senator Enzi
The Chairman. I will call the hearing to order. Good
morning, and welcome to the second in a series on prescription
drug safety.
On Tuesday we received a number of recommendations from the
Food and Drug Administration and from outside experts on ways
that the FDA can improve its process for weighing the benefits
and risks of prescription drugs.
Today we are going to look to the future and consider the
implications for drug safety, development and regulation. As I
mentioned Tuesday, we have made major changes to the drug
approval process over the past dozen years. Congress has passed
a series of bills with overwhelming bipartisan support to bring
more consistency, transparency and accountability to the drug
approval process, but we have reached a critical juncture in
the long history of the FDA. We need new and better ways to
predict the safety and efficacy of the new drugs before they
enter widespread use. We also need new and better ways to
communicate with patients and physicians regarding the benefits
and risks of new drugs. And we need the FDA, industry,
physicians and patients to be vigilant and to work together to
ensure the continued safety of prescription drugs once they are
approved and on the market.
Doing nothing to address the current controversies is not
an option. However, overreacting to recent events could be just
as dangerous as doing nothing. With all due respect to the
press, we should not be making policy to make headlines, or in
response to the headlines. This issue is too important for
that. We must take extraordinary care to find the right
approach.
We have had and want to have the world's best example of
drug safety. I have convened these hearings because I am
concerned about the FDA and drug safety. All of us here today
are aware of the recent controversies that have raised
questions about the safety of our prescription drugs and
whether the FDA's process for reviewing and approving drugs is
working.
Tuesday we heard about some of the immediate steps the FDA
is taking to maintain the public's confidence in the Agency. We
also heard about some steps that Congress may need to take. But
as we consider how to deal with the questions raised by these
recent controversies, we must also be focused on the future. As
I said Tuesday, we should not sacrifice safety in order to
speed drugs to the market, but we do not want to return to the
days of the drug lag when desperate American patients waited
for drugs that were available for months or even years in
Europe, especially now that we stand on the cusp of tremendous
medical advances based on new scientific insights.
Just in the past decade we have sequenced the human genome
and doubled the NIH's budget. This has resulted in an explosion
of basic scientific knowledge and the promise of an avalanche
of new therapies. But despite that increase in scientific know-
how many threatening diseases and conditions still lack
effective treatment. More than a million Americans will have a
heart attack this year. Some 600,000 Americans will suffer a
stroke, and close to 500,000 women worldwide will die from
breast cancer. The advances in biomedical knowledge have not
been advanced by advances in new therapeutics. In fact the
number of submissions to the FDA for new drugs and biologics
each year has actually decreased since the completion of the
human genome sequence.
Part of the problem is that science is racing far ahead of
our current regulatory regime. For instance, most of the tools
we use to test the toxicity of a drug are decades old. One-
third of all drugs fail during preclinical or clinical trials
due to the toxic nature of the compounds being tested. If we
were better able to predict these failures before trials even
began, we could both improve drug safety and save billions of
dollars spent on research and development that leads nowhere.
We need to match our investment in biomedical research through
the NIH with new thinking, new methods and new resources to
improve and streamline the regulatory process at the FDA.
But that raises three questions. First, how do we use new
scientific knowledge to improve the medical product development
process? Second, can we also use this knowledge to improve drug
safety? And finally, how do we communicate new information
about safety and risk more effectively within the Agency and to
patients and to physicians?
I look forward to hearing the testimony of our witnesses. I
trust they will be able to help us to begin to answer these
questions. I know I speak for myself and Senator Kennedy when I
say that the Nation is looking to us, the members of this
committee, to ensure that drugs approved for use by the FDA are
safe when used as intended, and do not pose an unreasonable
risk to the public. And when we act to improve our drug
approval system and to get the FDA ready for the future, we
will act through this committee in a bipartisan and
comprehensive fashion.
After Senator Kennedy makes his opening statement, we will
hear from Dr. Janet Woodcock, the Acting Deputy Commissioner
for Operations at FDA.
I will recognize Senator Kennedy for his statement.
Opening Statement of Senator Kennedy
Senator Kennedy. Thank you very much, Mr. Chairman, and I
want to thank you and commend you for calling a second hearing
on the safety of prescription drugs, and look forward to
working with you to pass the legislation needed to correct the
glaring drug safety problems identified in these hearings.
We learned a great deal on Tuesday's hearing about the
problem. FDA obviously needs the authority from Congress to
order drugs on the market to be relabeled when clear safety
concerns arise. It is disgraceful it took nearly 2 years to
relabel Vioxx after the so-called VIGOR trial. And Dr. Kweder
of the FDA said such authority over relabeling would have
helped, and that should be part of any legislation we propose.
We also know from Tuesday's hearing that FDA needs
additional funds to monitor the safety of drugs on the market,
and Congress needs to make room in the budget for this
important priority.
Another major defect in the current law is that FDA lacks
the authority to require manufacturers to conduct a further
drug safety study after the drug has been approved and goes on
the market. It is essential for FDA to be able to order such
trials. Such authority may be the only way to ensure that the
safety problems discovered after approval are studied it
effectively in clinical trials.
The problems of Vioxx and Celebrex were discovered in
voluntary clinical trials to study potential new uses for the
drugs after they first came on the market. Those trials showed
conclusively that these drugs could cause heart attack or
stroke in some patients. If Merck and Pfizer had not
voluntarily conducted these studies millions might still be at
risk from using these drugs. Most of the witnesses, including
Dr. Kweder of FDA, said this additional authority would help
the Agency respond to drug safety problems.
We have concerns about how FDA acts on drug safety issues.
Although a warning was belatedly added to the Vioxx label as to
cardiovascular risk, Dr. Kweder told us that the warning had
little effect in encouraging safer use of drugs. We need to
understand why.
Dr. Alistair Wood, who chaired the FDA's Advisory Committee
meeting on Vioxx and related drugs, has said that the
precaution was essentially meaningless. Some experts question
whether relabeling is ever effective. FDA may well need better
ways to encourage or even require safe use of drugs.
Still another issue is direct to consumer advertising,
which encourages wide use of new drugs before we know enough
about their safety. Vioxx and Celebrex were heavily promoted
through direct consumer advertising. We have all seen the TV
ads for these drugs with people skating and playing golf. These
drugs were developed in the hope that they would reduce stomach
bleeding, a risk faced by perhaps 5 percent of those who needed
pain medications. Yet these ads did not say if you are at risk
for stomach bleeding, this drug may be for you; ask your
physician. Instead they peddled the drugs to everybody. A
recent study found that large numbers of patients who used
these drugs were not at risk for stomach bleeding. These ads
almost certainly encouraged the unnecessary use of these drugs.
Patients saw an ad, asked their doctor about them, and started
taking them even though another drug might have been just as
effective. How many of these patients suffered a stroke or
heart attack or died because of it?
Those drugs increase the risk of heart attack and stroke,
perhaps doubling the risk. They were used widely by as many as
50 million people for more than 5 years before the risk was
finally discovered. We will probably never know how many
thousands suffered because of it. All prescription drugs carry
some risk, and we are clearly not doing enough to minimize
them. FDA needs better ways to do so, and I look forward to
working with our chairman to enact more effective drug
legislation.
Again I commend our chairman for his leadership, and I
welcome our witnesses today and look forward to their
testimony.
The Chairman. Thank you for your comment and insights. You
add a lot of history to the committee.
I welcome our first witness which would be Janet Woodcock.
Dr. Woodcock, the Acting Deputy Commissioner for Operations at
the U.S. Food and Drug Administration. She has served as the
Director of the Center for Drug Evaluation and Research at the
FDA. The center is responsible for regulating prescription,
over-the-counter and generic drugs. She has had close
interactions with diverse constituencies including the clinical
and scientific community, members of Congress, the
administration, national media, patient and consumer advocacy
groups, the international drug regulatory community, the
pharmaceutical industry, and representatives of Federal and
State agencies.
She was selected as the Director for CDER in 1994 and under
her leadership the regulatory decisionmaking has been made more
open and transparent to the public, and we congratulate you on
your Acting Deputy Commissioner position now and look forward
to your testimony, Dr. Woodcock.
STATEMENT OF JANET WOODCOCK, M.D., ACTING DEPUTY COMMISSIONER
FOR OPERATIONS, U.S. FOOD AND DRUG ADMINISTRATION
Dr. Woodcock. Thank you. Mr. Chairman and distinguished
members of the committee, I thank you for the opportunity to
testify on the important issue of drug safety.
Five years ago this committee held hearings on adverse drug
reactions. At that time the discussion focused on the estimated
100,000 deaths per year, as well as hundreds of thousands of
hospitalizations and economic losses estimated in the billions
of dollars. This is a longstanding and serious problem that I
have worked on over many years of my professional life at FDA.
Since that hearing FDA has taken many important steps to
enhance drug safety, but while drugs bring profound benefit to
our population, we must continue to work together to mitigate
their harm. Safety findings with antidepressants and the COX-2
inhibitors again illustrate how much more work needs to be
done. FDA has taken additional steps as discussed at today's
hearing to improve management and transparency around major
drug safety issues.
Additional ideas for identifying drug side effects have
been put forth by many parties. While these ideas are part of
the solution, you should know that they are not the whole
answer. Why not? Because all drugs have side effects. Radically
restricting drug availability would clearly reduce the number
of side effects, but would also greatly diminish the treatments
available to doctors and to patients.
Our long-term goal cannot simply be detection and
restriction. It must focus on prevention and good management,
and unlike the situation in 2000 there is now hope we can do
just that, hope from new science and new technology.
What is this new science? Right now at the time a drug is
approved, we know it works in some people and we know the
safety results for those people. What we do not know is who it
works in and who is at risk for a side effect, and we rarely
know how to monitor people taking the drug to check if a side
effect is developing and to intervene to prevent it.
Why is this? Not for lack of trying. By the time a drug is
approved usually hundreds of millions of dollars have been
spent on development and animal and human testing, but until
recently we lacked the scientific tools to predict individual
response to therapy. Today that is changing. New science such
as pharmacogenomics, proteomics, advanced imaging technologies
and computer modeling are making prediction possible.
FDA's Critical Path Initiative, launched last spring, is
focused on modernizing the process for drug development to
rapidly incorporate new scientific methods. These methods will
help individualize therapy, select patients who will respond to
treatment, and avoid people at high risk for side effects. This
is not a futuristic dream. As I speak today, tests are being
done in real patients in real medical practice to target
therapy and avoid side effects.
In December FDA approved the first commercial
pharmacogenetic test that allows patients and doctors to
predict whether a person will be overdosed or underdosed by
many common drugs. Once this test is done it is valid for a
lifetime. So your relative, someone you know who may carry a
gene that makes them metabolize drugs slowly and causes them to
have many more adverse events from drugs, will know that they
should start on lower doses.
And in the treatment of cancer, some targeted therapies are
currently making a difference in people's lives. Many more are
on the way. Targeting helps select people who have a good
chance of a positive response to therapy. This improves safety
because people who cannot respond do not get the drug.
As part of the Critical Path Initiative FDA will work to
incorporate these new tools into drug development as rapidly as
possible. For example, we will issue our final pharmacogenomic
guidance very soon. This establishes processes for moving new
scientific techniques into the drug development and regulatory
process. Modernization will take time and scientific effort,
but at the end of the day, having new tools to decide who
should take a drug, who should not take a drug, and to monitor
for side effects will bring about a new era in drug safety.
At the same time, new technology, information technology
holds great promise for improving drug safety. With the help of
electronic data linking medication use with health outcomes we
can find rare side effects that were not seen before approval.
At the same time there are new ways to rapidly inform patients
and prescribers about emerging safety data using electronic
media. And equally important, computer-based interventions to
provide support to prescribers has been repeatedly shown to
reduce side effects and reduce hospitalization.
In summary, of course we must develop better ways to detect
drug side effects, but detection is not enough. We must improve
the science of therapeutics and make sure that that new
information is in the hands of those who need it. These are the
advances that will radically improve drug safety in this
country.
Thank you.
The Chairman. Thank you. We always appreciate the
additional information, and I want to assure you and all of the
other people who will be testifying today that their entire
statement will be made a part of the record.
In the way of questions, we heard the suggestion Tuesday
that the FDA needs greater authority to require drug labeling
changes. After hearing that I asked my staff if they would look
to see what the present authority is. It says that if the
labeling of such drug is false or misleading in any particular
and it was not corrected within a reasonable time after receipt
of written notice, that it can be pulled off the market by the
FDA. That seemed to me to be quite a bit of authority. Is it
sufficient authority?
I noticed with Vioxx that the timeline evidently began with
discussions in October of 2001 and there was continued analysis
and data from various studies, and then the FDA and Merck
agreed to a new labeling on April of 2002. That is a six-month
time span. Is that the amount of time that is usually required
to make major labeling changes?
Dr. Woodcock. No, that is an unusually long amount of time.
And actually the data from the VIGOR trial that we are talking
about the safety data on Vioxx was available earlier than that.
And currently with the recent changes that FDA has made in
information dissemination we are now, as we announced several
weeks ago, planning to put information directly out to the
public on emerging safety issues. This will reach directly to
the prescribers and the patients.
Part of the problem with label changes, even if a label
change is made, that is a paper document. The old labels are in
distribution and take a while to be changed over and so forth.
So this new mechanism that FDA is proposing really should deal
with this problem very effectively which is getting the
information directly out to the people who need it in a timely
manner.
The Chairman. Will there be negotiation before this data is
put out to the public or is this just basic information, and
then the labeling would change?
Dr. Woodcock. That is correct. What is proposed--and there
is going to be time for public discussion of how this actually
occurs--what is proposed is that FDA will put out the factual
information about the finding before the label is actually
changed.
The Chairman. Thank you. Tuesday we also talked about drug
ads and how they need to be made clear, consistent and honest.
Patients and physicians deserve to have as much information as
possible about medical conditions and how to treat them, but
the information also needs to be of high quality. Do you
consider the current direct to consumer advertising to be high
quality? Are there changes Congress or the FDA needs to
consider making regarding regulation of these ads?
Dr. Woodcock. Clearly direct to consumer advertising is a
double-edged sword. It has benefits in informing people about
treatments that they may not have been aware for their
condition. Our surveys show that doctors find that it improves
and increases the amount of conversation they have with their
patients about treatment options. On the other side though, it
may, direct to consumer advertising in some cases may increase
awareness of a drug, such as in the Vioxx situation, and people
may not have a full understanding of the risks of that
medication.
The direct to consumer advertising regulation takes into
account the fact that patients must go to a physician to obtain
a prescription for a drug, and so it is intended simply to
allow that certain information be provided to the patient, but
not complete information. The direct to consumer advertising is
supposed to be balanced and not misleading. Those are the
standards.
The Chairman. Thank you. Some have suggested that
accelerating the drug approval through PDUFA has caused the FDA
to decrease its focus on drug safety. Could you comment on this
assessment?
Dr. Woodcock. The pre-market review, which is what is done
under the PDUFA program, has about 50 percent of its focus on
drug safety, and the use fee program enhanced that. To use a
simple analogy, FDA is like the building inspectors. Someone
else builds the building according to code. FDA does the code,
writes the code, and then FDA comes in at the end and that is
the review time under the user fee program, and we inspect the
results and make sure they are up to code. What PDUFA did is
help us add civil engineers or mechanical engineers. In our
case it helped us add more scientific experts so that we could
do that assessment quickly, and we could make sure that the
standards for drug approval are kept up to date in current
scientific standards.
So we feel there has been a tremendous focus on safety
during the user fee years, and people have to recognize that
the development of drugs, the clinical development, is done
before the application is sent to FDA, and the PDUFA clock has
to do with how long the FDA takes to review that information.
The Chairman. I want to thank you for your concise answers
and great examples. My time has expired.
Senator Kennedy.
Senator Kennedy. Thank you very much.
Just on the advertising issue, currently the manufacturer
is allowed to flood the airways with ads for a drug on the day
it is approved, and they can send salespersons to every
doctor's office in the country to sway them to prescribe the
new pill. It is hard to deny that the massive ad campaign led
millions of patients who did not need them to take the COX-2
drugs, with tragic results.
I suppose the question that some of us would ask is, could
this be happening with other drugs? Would it not be better to
take a more cautious approach with advertising with newly
approved drugs, and do you think people are taking the
medicines that are not suitable for them as a result of the ad
campaign?
Dr. Woodcock. We have looked into how physicians treat
direct to consumer advertising, their attitudes toward direct
to consumer advertising. We asked them if they prescribe drugs
that they would not have otherwise prescribed because the
patients came in and asked for them. And in some cases that
does happen. There is no doubt about it.
The construct that we are working under is that the
physicians will be learned intermediaries and will decide after
a conversation with the patient whether or not a particular
drug is appropriate for that condition and that patient.
Senator Kennedy. Have we gotten rid of these incentives?
You mentioned the hearings that we had 5 years ago. I remember
them, where we had all of these very incredible incentives to
both the doctors and the ad people in terms of trips, tickets,
just about everything under the sun. I was just wondering, just
quickly, have those practices come back now or are we pretty
free from all of those?
Dr. Woodcock. No, those practices are still going on, and I
think most of us in the medical profession believe that the
detailing and, for example, physicians on average have six
visits per month of detail persons to their office. We believe
that that has more influence on prescribing patters than direct
to consumer advertising, and certainly the budget is much
larger.
Senator Kennedy. I was thinking of the incentives that were
given both to the doctors for the use of these drugs. You
probably remember those hearings. As I say, I do not want to
take a lot of time, but most of the abuses that we identified
during that period of time, have they been dealt with pretty
effectively or are some of them creeping back in. You can
answer later on, whatever you want to do.
Dr. Woodcock. I will be happy to answer more fully later
on, but I believe they still continue.
Senator Kennedy. I would be interested if you could let us
know, but I thank you.
On Tuesday Dr. Kweder acknowledged several FDA lapses in
relabeling and informing physicians about the risks of Vioxx.
In your view what were the other mistakes or missed
opportunities that resulted in the Vioxx drug disaster? Can you
assure the American people that these kind of lapses will not
happen again?
Dr. Woodcock. The lapses that we identified were the fact
that a communication about the findings of the VIGOR trial were
not effective in reaching the prescribers and the patients
despite a label change that was made. For example, most
prescribers really did not know about this finding, and so we
are making much greater efforts now to communicate, as I said
earlier, directly to prescribers and to patients so that they
are aware of these findings. Everyone needs to recognize that
today we know more about drug safety than ever before. One of
the consequences of that is that we find out things that are
bad. We find out more about adverse events of drugs.
A good example is the estrogens. A very large trial was
done at NIH, and it was found that postmenopausal use of
estrogens increase several serious conditions including heart
disease and breast cancer. This drug had been on the market for
45 years. It is not a cause for dismay that we are learning
these things. It means that we are making medical progress and
we finally have the means to understand these problems. What we
need to do is move forward in that area and continue to learn
more about drug side effects and how to avoid them.
Senator Kennedy. I think it is a good thing to get that
information out to the public as quickly as possible. At the
Tuesday hearing we heard the FDA lacked the ability to require,
not just to request, labeling changes to drugs already on the
market. I am sure much of the public simply assumed that FDA
had the basic authority to assure the safety of the medicines
that they take. Maybe equally shocking for the public is to
realize the FDA cannot require manufacturers to conduct follow-
up safety studies on drugs already on the market. The Chairman
pointed out that you have the power, you can withdraw it, so
you have the heavy hand. But withdrawing a drug disregards the
value that a particular drug, even I think the COX-2 drugs,
would have for some patients on it, and withdrawal is a very
dramatic step. Do you not think that relabeling authority would
be helpful in avoiding safety problems and also do you not
think FDA should be able to require safety studies of approved
drugs if there is a public health need to do so?
Dr. Woodcock. I think there are tradeoffs there and I think
that is something that has been debated a long time and that
Congress will debate. I do believe the steps we have taken to
have information directly from FDA to the public, to the
practitioners and to the patients will help deal with some of
these problems. If there is a need for an additional study to
be done it is going to become quite apparent as we communicate
this safety information.
Senator Kennedy. My time is up, Mr. Chairman. Thank you.
The Chairman. Thank you.
Senator Burr.
Senator Burr. Thank you, Mr. Chairman.
Welcome, Dr. Woodcock. It is great to see you. Thank you
for what you do. Let me just ask you very plainly, can
manufacturers go to market on a new drug that has been approved
where the FDA has not agreed to the labeling on that original
package?
Dr. Woodcock. No.
Senator Burr. So no product that is approved by the FDA can
be placed on the market unless a manufacturer has had a sign-
off by the FDA on the original labeling?
Dr. Woodcock. That is correct.
Senator Burr. I think individuals have suggested that
either somebody hid something or the FDA's process is in fact
broken. Do you believe that the FDA is approving dangerous
drugs to go on the market today?
Dr. Woodcock. I believe on the basis of my professional
experience, which is very extensive, and that my knowledge of
approvals in past decades, we have the strongest and most
detailed scientific evaluation of drugs that has ever occurred
anywhere in the world today.
Senator Burr. So our approval process is not broken?
Dr. Woodcock. No. It is stronger than it has ever been.
Senator Burr. Can we all agree that it could get better?
Dr. Woodcock. It has got to get better.
Senator Burr. Can you tell me how many labels Vioxx has
had?
Dr. Woodcock. No. [Laughter.]
Senator Burr. It was approved in May of 1999 I believe. I
think with material changes, it is either two or three. I would
ask the chairman for unanimous consent that the committee allow
the labels that have been available for Vioxx to be included as
part of the record, if I could get the chairman's attention for
one second. [Laughter.] Mr. Chairman? Mr. Chairman, if I could
get your attention for 1 minute, I would ask unanimous consent
that the labels that Vioxx has carried on its packaging since
May of 1999 be included as part of the record.
The Chairman. Without objection.
Senator Burr. Thank you.
[The Vioxx labels follow:]
[Editors Note-Due to the high cost of printing, previously
published materials submitted by witnesses may be found in the files of
the committee.]
Senator Burr. I think it is important because it is my
understanding that the original labeling for Vioxx included
under adverse events heart attack, stroke, congestive heart
failure, high blood pressure. It was not black-boxed, it was
not something that was emphasized, but it was an indication
that had been discovered in the clinical trials. Is that your
understanding?
Dr. Woodcock. I do not know about myocardial infarction of
heart attack. These other ones that you mention are true for
all the anti-inflammatory agents.
Senator Burr. So there is a common thread that runs through
these and one would expect physicians to be fairly well aware
of that.
Dr. Woodcock. Most are.
Senator Burr. Let me ask you, there are some that suggest,
I think all suggest we need a more robust postapproval
surveillance process. Some suggest that that has to be outside
of the FDA. Can I ask you for your professional opinion on
whether it needs to be inside the FDA or outside the FDA first?
Dr. Woodcock. There are two issues. One issue is a robust
surveillance system, and that means more active surveillance,
better access to the data that is out there about the use of
drugs in this country. That needs to be enhanced. It does not
need I think to be one place or another. It needs to be
enhanced.
Senator Burr. Let me stop you there if I could because I
want you to clarify another thing for the committee. Some have
suggested that the clinical data should be made available not
just to the physician world, but to the general public. In your
professional opinion do you believe that the general public can
disseminate clinical data in a way that it would be useful to
their decision process?
Dr. Woodcock. Can you clarify which clinical data you are
referring to?
Senator Burr. It would be the clinical trials.
Dr. Woodcock. We have highly-trained scientists. We have to
train--and they have all gone to medical school or gotten their
PhD's--we have to train them additionally once they arrive at
the FDA to analyze the raw data on clinical trials, and we are
extremely expert at that, but we can always improve.
That said, it is not something that the general public
really could evaluate. Before we had electronic data we would
get this in a tractor-trailer coming to the FDA. It is a very
large amount of data that is involved. We have already said we
believe summaries of information and results should be made
available to the public.
Senator Burr. If you could finish the answer that I
interrupted you on.
Dr. Woodcock. Yes. As far as who should make decisions
around drug safety, that is the second part. First we need a
strong surveillance system in this country. Then the question
is who makes the decisions. Some people have said they believe
that members of the FDA who were involved in the decisionmaking
have some sort of bias, an intellectual bias or whatever
against removing the drug. For that reason FDA has proposed
that we put together a board composed of qualified experts from
both within the FDA and external, none of whom would have been
involved in the decision to approve that drug, to address that
specific issue.
But in general, in my professional opinion, it is very
important to have people involved in decisionmaking who
actually treat patients with that condition, because if you
only look at risk we would not have any drugs. It would not be
sensible to have any drugs because they all cause harm. Even
acetaminophen very common drug, over-the-counter, number one
cause of drug-induced liver failure in the United States. If
you took that fact in isolation what you would say is that
should not be on the market. So you have to have the benefit
side right in front of you when you are evaluating the safety
problems of drugs.
Senator Burr. My time has run out, but you do uphold the
FDA's proposal that that be housed within the FDA but with
outside individuals, outside experts, outside docs coming in
and participating in the review process?
Dr. Woodcock. That is correct.
Senator Burr. Thank you.
Thank you, Mr. Chairman.
The Chairman. Thank you, Senator Burr.
Senator Murray.
Senator Murray. I believe Senator Reed was ahead of me.
The Chairman. Oh, I am sorry. Senator Reed?
Senator Reed. Thank you, Mr. Chairman.
Thank you, doctor, for your testimony. Let me continue a
point that Senator Burr raised, the issue of two standards that
you have to apply when reviewing a drug: safety and efficacy,
and also the standard of risk benefit analysis. Those standards
seem in some cases contradictory or at least have to be
balanced. Can you elaborate on how you are doing that in a
practical situation?
Dr. Woodcock. The FDA is charged with making sure that
drugs on the market are safe and effective. We interpret that
safety to mean that the benefits of the drug in the intended
population outweigh its risk, because there is really no way
that we can approve drugs that are absolutely without risk. So
when we say drugs are effective and safe, we mean that their
proven demonstrated benefits from the clinical trials outweigh
the risks of the drug for the people that it is indicated for.
Senator Reed. Has that always been the regulatory standard
or is this something that had evolved over the last several
years. Has there been any recent change that we should note
here?
Dr. Woodcock. That has always been the regulatory standard.
The change over the past decades is now drugs are studied in
more people before they are put on the market, and we know more
about them.
Senator Reed. Let me turn to another topic, clinical
trials. We acknowledge that every drug goes on the market with
a clinical trial, but I think we also acknowledge that all
clinical trials are not equal. Some are testing the best
hypotheses, some might not have the best hypotheses. Some might
have a long longitudinal survey. Some might be very quick.
Practically speaking, I think you would acknowledge that there
are differences in clinical trials. How do you deal with
different kinds of trials in terms of making a decision about
putting a drug on the market?
Dr. Woodcock. That is a good question, and I used earlier
the analogy of the building inspectors and the building code.
Not only does FDA do the building inspection, we look at the
results at the end, we write the code, so we say what the
standards are for showing safety and what the standards in the
clinical trials would be for showing effectiveness. So we would
say, ``You have to test these patients in this manner for 3
months, 6 months, whatever we say, and show these endpoints for
effectiveness, and you have to do it twice. You have to
replicate the results in another trial.'' So we set those
standards and then when we are doing the review, we are
reviewing against the standards that have been established.
Senator Reed. And there is a constant process of evaluating
how good you are in setting these standards internally.
Dr. Woodcock. Yes. We try to revise our guidance as we
learn from things that have gone wrong, from things that have
gone right in the clinical trials and post marketing.
Senator Reed. Without elaborating in detail on the latest
situation with Vioxx, have you reevaluated the standards you
set and the trial dynamics that you put in place?
Dr. Woodcock. Yes. When we discussed with our advisory
committee a couple weeks ago, one of the issues that was raised
is that drugs that are intended to treat symptomatic
conditions, say arthritis, typically if they are just for
symptoms, those drugs have not been studied for a long time in
the clinical trials, 3 months, 5 months, something like that.
That has increased over time. In other words we require much
more study than we used to 10 years ago, 15 years ago.
Nevertheless it was clear that there probably, even though
Vioxx and Celebrex had more patients than any other anti-
inflammatory drug had had before they got on the market, it
still was not enough people and enough time to detect these
particular problems. So we have to continue to evaluate how to
deal with that.
Senator Reed. A final question since I have very little
time left. That is, we have passed the PDUFA bill. We have
passed the FDA Modernization Act. Part of that is to streamline
the delivery of drugs to the marketplace, but inherent in that
is at least the issue of whether or not the streamlining has
curtailed clinical trials, curtailed judgment about putting
drugs in the marketplace. Very, very briefly, what is your
conclusion?
Dr. Woodcock. Well, again, I think that you have to
separate the time and the standards for doing the clinical
trials which occurs before they are sent to FDA from what is
the subject of the user fee legislation which has to do with
how fast the FDA reviews those results once they are in house.
What the user fee program has also given us is more experts who
can work on setting the standards during the clinical trials,
and although we have not advanced as much as I would like in
the clinical outcome area, we have made tremendous advances in
clinical pharmacology in many of the underlying specialties,
and these have improved drug safety quite a bit.
Senator Reed. Is it fair to say that these legislative
initiatives have basically changed the response of FDA, but not
the requirements of the investigators to pursue these
investigations, and has not materially in your view affected
the standards for clinical trials or for evaluation?
Dr. Woodcock. No. I think the clinical standards have
remained the same. There have been many additional safety
standards added over the past decade as we have learned more.
You can ask the pharmaceutical companies about this because
they are constantly saying, look, you now have to test
electrophysiologic parameters for the heart and certain other
types of drug metabolism and so forth. So these things have
been added. The overall standards have not been lowered, but we
can review drugs faster because we have more experts.
Senator Reed. Thank you very much.
Thank you, Mr. Chairman.
The Chairman. Senator Murray.
Senator Murray. Thank you, Mr. Chairman. I really
appreciate your having these hearings. I think it is really
giving us some good insight and information and will help us
move forward to some possible legislative solutions.
I do want to recognize a witness from the second panel who
is with us from the University of Washington, Dr. Bruce Psaty.
He is a professor of medicine, epidemiology and health services
at the University of Washington, and I appreciate him traveling
all the way out here to participate.
Let me just begin, Dr. Woodcock, with we have heard a lot
about the FDA approval process and the potential conflict of
interest that may be there because of the PDUFA fee. Can you
tell us if you can the number of new drug applications and the
number of new drugs that have been approved versus how many
have been disapproved?
Dr. Woodcock. I cannot tell you the numbers out of my head.
Senator Murray. Percentage perhaps?
Dr. Woodcock. Traditionally I think about 25 to 30 percent
are not approved. I do not believe that number has changed much
over time, over the decades.
Senator Murray. So even with the PDUFA fee, the number
disapproved is about the same percentage.
Dr. Woodcock. I would like to say though that although that
means perhaps we have not decreased our standards, it is a
failure of the enterprise. Those 20 percent of drugs that are
turned down, many patients were exposed to those drugs during
development and gave their time and effort to trying to see
whether they were safe and effective. We need to do better on
prediction. That is not a good number really.
Senator Murray. What is the average length of time for new
drug approval today?
Dr. Woodcock. For priority drugs that are felt to bring a
public health advance or an advance in therapy of some kind, it
is about 6 months for FDA to review those, and for the standard
drugs it is about 13.
Senator Murray. About 13 months, okay. I want to follow up
on what Senator Reed was asking you about in terms of clinical
trials and working with the manufacturers. Do you work with
them to make sure that they are not just focusing on whether a
drug is effective or whether or not there are risks attached to
that drug?
Dr. Woodcock. One of the innovations in the user fee
program, which I support highly, is greater interaction of the
regulators with the drug companies while they are doing the
clinical, the human experimentation phase. What we do, we tell
them we are going to expect, say, you to have 500 patients
exposed for this amount of time, and we would expect you to do
these kind of safety tests during the clinical trials. So there
is an opportunity for the FDA to intervene and explain its
expectations on safety and effectiveness during the trials.
Senator Murray. So you are not just looking at whether the
drug is effective, you are working with them to make sure that
we are looking at risks?
Dr. Woodcock. We just did an internal survey of how much
effort we spend on safety versus effectiveness, and we found
for the whole center we spend 50 percent of our time on safety.
Senator Murray. You were also asked by Senator Burr about
this independent office on drug safety. I think you answered
him that you did not think it was necessary. I would like to
ask a few questions about that. Are the same FDA employees
reviewing the new drug applications and the postmarket adverse
events data, do you know?
Dr. Woodcock. Not the data. The way the structure is set
up, the Office of New Drugs continues to follow a drug
throughout its life cycle until it becomes generic, in which
case the Officer of Generic Drugs takes over some of that. The
postmarketing surveillance system which gets our MedWatch
information, which is called our Ayres database, is operated by
the Office of Drug Safety. They run the surveillance system,
and so they are looking at that data as it comes in.
Senator Murray. So the manufacturer is not working with the
same employee throughout the entire----
Dr. Woodcock. Not necessarily on the MedWatch data, but
they are working with the same division on their label all the
way through the life cycle of the drug.
Senator Murray. What kind of processes do you have in place
to protect against any conflict of interest?
Dr. Woodcock. We have a team approach to review. We have a
large number of individuals who are involved in a hierarchical
approach to review so that supervisors also look at the work of
the primary reviewers, and that is all brought together in a
team process.
Senator Murray. Is there a concern about conflict of
interest or do you feel that you have enough employees?
Dr. Woodcock. The individuals reviewing all this
information are physicians. They are at the Agency rather than
out in private practice or industry because of their public
health orientation. And there may be a concern about this
intellectual bias because people were involved in approving a
drug, and that is what I have heard.
Whenever we have a serious drug safety issue, more people
are involved in looking at that, people who had no involvement
in the pre-market decision. And the new procedures that have
been put in place will even open up that more. So that should
take care, in my mind, of the issue of is there some bias by
those who were actually involved in the beginning.
Senator Murray. What would the drawbacks be of having an
independent office?
Dr. Woodcock. Can you define ``independent?''
Senator Murray. As I am hearing it defined by people who
are suggesting it, separate from FDA looking at the post
market.
Dr. Woodcock. I think people do not understand totally the
drug life cycle. Medications are often approved for very narrow
indications. The FDA remains involved as new trials are done.
Say, cancer drugs, they are often approved for the most
desperate cases, and then additional trials are done to see
what the real use of that cancer drug would be in the wider
population. Pediatric trials are done and so forth. So all the
time after the drug has been approved, there is a very active
process going on with new indications being added, new
warnings. It is really a continuum before the pre-market and
the postmarket. It is by no means that we sort of forget this
drug after it is approved.
So you need the input of all the experts on the drug and
the tremendous amount of expertise they have gained about that
drug and maybe that class of drugs before marketing, in the
postmarket period as well.
Senator Murray. I appreciate that very much. Thank you.
Thank you, Mr. Chairman.
The Chairman. Thank you.
Senator Isakson.
Senator Isakson. Thank you, Mr. Chairman.
I apologize that I am late and did not hear your testimony
and might be redundant in my questions, so be very brief or
tell me I am redundant and to look it up in the book.
I think following up on the previous question, your opinion
on this external review, just real quickly, what is your take
on that or the need for it?
Dr. Woodcock. I think of course the FDA is open to various
approaches and suggestions, but people need to have the
correct--say in medicine you have to have the correct diagnosis
before you move into treatment. I think people really need to
think about what problem are they trying to address before
thinking about what treatment to apply.
As I was just saying, the postapproval phase for a drug is
a very active one where more clinical trials are going on, the
label is being changed, the drug is being studied in additional
populations. So the involvement of the medical team in the drug
also continues throughout that time, and generally these are
subspecialists. We have neurosurgeons, neurologists,
gastroenterologists and so forth all across the medical
subspecialties. They have very deep and profound knowledge of
their particular area and the use of therapeutics in that area.
So it would be difficult to imagine moving that process to
some other unit, but perhaps people mean something else by what
they are saying with the independent safety board.
Senator Isakson. So within FDA following the approval of a
drug there is an ongoing tracking of the effects of that--or
any effects that are reported by physicians prescribing that
drug, and that comes to FDA?
Dr. Woodcock. Yes. That part comes to the Office of Drug
Safety, but all the clinical trials and oversight of those
clinical trials and the safety of the subjects and how the
trials are designed and so forth, those are done by the medical
divisions.
Senator Isakson. How does that come back to FDA, that
information, on paper and pencil or----
Dr. Woodcock. It is normally electronic, and these
additional studies have to be done under an IND because human
subjects are being exposed in experimental conditions. So the
FDA has a great deal of interaction and oversight into those
ongoing trials.
Senator Isakson. Are you one that subscribes to a belief
that I am coming to believe, and that is, one of the greatest
things we could do in health care overall is get technology
involved so this information flows seamlessly and accurately
from physician and pharmacist and patient, and there is an
integration of that information so it can be pulled out
quickly?
Dr. Woodcock. You are reflecting my testimony. I totally
agree with that, and we have been working very hard at the FDA
to do our part to make that happen.
Senator Isakson. Are you familiar with a company by the
name of Greenway?
Dr. Woodcock. No.
Senator Isakson. After the hearing I will give you a note.
There is some development on that end that is now actually out
in practice in my home State of Georgia that is showing great
promise in terms of information technology, patient, doctor,
pharmacist.
Last I just have a comment. You all take a lot of knocks
lately and there has been a lot of criticism. I would like to
just tell a story for the sake of the chairman and the
committee. On the 12th of September in 2001 a pharmaceutical
company in my district contacted me, Solvay. They had a burn
treatment known as Flamazine, which was in its final--I do not
know if I am using the right word but I remember they kept
using the word ``protocol''--before issuance. New York City had
run out of the only other approved ointment of this type, and
obviously we had a serious, tragic--I just want everybody to
know that FDA's response that day and the ability to get those
badly-needed medicines to New York City in a time of great
crisis was nothing short of unbelievable, which I do not think
portends that you only do timely work in an emergency, I might
add, but you do good work all the time. I appreciate what you
do.
That is all of my questions and comments, Mr. Chairman.
The Chairman. Thank you. That reminds me that I refer to
this hearing room as the reassurance room. Following September
11th, while most of the Senators were up in New York looking at
Ground Zero, those of us in the Banking Committee were in this
room holding hearings with the stock market people to reassure
America that the stock market was still working, that it would
open on the following Monday, and that everything would be
fine, and that there was plenty of backup.
Part of what we are doing with these hearings is giving
some reassurance on the condition of FDA in getting their
insight and others' insights into the kinds of things we can do
to do the job even better.
I thank you very much for your testimony. We will keep the
record open for another 10 days. That will give you a chance if
you want to expand on anything that you have answered today,
and Senator Kennedy had one particularly difficult one to
answer just on the spur of the moment in the timeframe that we
have, and also give members of the panel an opportunity to
address additional questions that may be more technical than
the general public might be interested in, but that would be
helpful to our decisions. Thank you very much for testifying
today.
[The joint prepared statement of Dr. Woodcock and Dr.
Kweder follows:]
Joint Prepared Statement of Dr. Woodcock and Dr. Kweder
INTRODUCTION
Mr. Chairman and members of the committee, I am Dr. Sandra Kweder,
Deputy Director of the Office of New Drugs at the Center for Drug
Evaluation and Research (CDER), United States Food and Drug
Administration (FDA or the Agency). I am pleased to be here today to
discuss drug safety and the drug approval process.
Because of the importance of these issues, you are holding two
hearings over the course of 3 days. Dr. Janet Woodcock, FDA's Acting
Deputy Commissioner for Operations, will appear at your hearing on
March 3. We have one written statement to address both hearings.
SAFETY IS A HIGH PRIORITY
Let me begin with a few words about safety, and I will return to
this issue throughout our written testimony. Modern drugs provide
unmistakable and significant health benefits. FDA's drug review process
is recognized worldwide as a gold standard. Indeed, we believe that FDA
maintains the highest standards for drug approval. There have been
significant additions to those standards during the last several
decades, in response to advances in medical science. Currently, FDA
approves drugs after they are studied in many more patients and undergo
more detailed safety evaluation than ever before. FDA grants approval
to drugs after a sponsor demonstrates that their benefits outweigh
their risks for a specific population and a specific use, and that the
drug meets the statutory standard for safety and efficacy. However, no
amount of study before marketing will ever elucidate all the
information about effectiveness or all the risks of a new drug.
Therefore, post-marketing surveillance is extremely important.
Adverse effects that are not detected during clinical trials are
identified after approval through post-marketing clinical trials,
spontaneous reporting of adverse events, or observational studies based
on more widespread use of the product following approval. That is why
Congress has supported and FDA has created a post-market drug safety
program designed to collect and assess adverse events identified after
approval for all drugs we regulate.
This program serves as a complement to the pre-market safety
reviews required for approval of prescription drugs in the U.S. FDA
also evaluates and responds to adverse events identified in ongoing,
post-market clinical trials that test approved drugs for other
indications. We also evaluate and respond to events reported by
physicians, their patients, or drug manufacturers. With this
information, we make label changes and take other regulatory action as
needed.
It is important to emphasize that all approved drugs pose some
level of risk, such as the risks identified in clinical trials and
listed on the labeling of the product. Unless a new drug's demonstrated
benefit outweighs its known risks for its intended population, FDA will
not approve the drug. However, we cannot anticipate all possible
effects of a drug based on data from the clinical trials that precede
approval.
NEW FDA INITIATIVES TO STRENGTHEN DRUG SAFETY
November 2004 Five-Step Plan
At FDA, we are constantly striving to improve our processes and
methods, and thereby better serve the public health. Recent
developments have prompted us to refocus our drug safety efforts and
take additional steps to identify drugs that may have unacceptable risk
profiles.
On November 5, 2004, Acting Commissioner Crawford announced a five-
step plan to strengthen FDA's drug safety program. First, it called for
FDA to sponsor an Institute of Medicine (IOM) study to evaluate the
current drug safety system. An IOM committee will study the
effectiveness of the U.S. drug safety system, with an emphasis on the
post-marketing phase, and assess what additional steps FDA could take
to learn more about the side effects of drugs as they are actually
used. We will ask IOM to examine FDA's role within the health care
delivery system and recommend measures to enhance the confidence of
Americans in the safety and effectiveness of their drugs.
Second, Dr. Crawford announced that CDER would implement a program
for addressing differences of professional opinion. I am pleased to
report that CDER recently put this program into effect. Currently, in
most cases, free and open discussion of scientific issues among review
teams and with supervisors, managers and external advisers, leads to an
agreed course of action. Sometimes, however, a consensus decision
cannot be reached, and an employee may feel that his or her opinion was
not adequately considered. Such disagreements can have a potentially
significant public health impact.
In an effort to improve the current process, CDER has formalized a
program to help ensure that the opinions of dissenting scientific
reviewers are formally addressed and transparent in its decision-making
process. An ad hoc panel, including FDA staff and outside experts not
directly involved in disputed decisions, will have 30 days to review
all relevant materials and recommend to the Center Director an
appropriate course of action.
Third, CDER will conduct a national search to fill the currently
vacant position of Director of the Office of Drug Safety (ODS), which
is responsible for overseeing the post-marketing safety program for all
drugs. CDER is seeking a candidate who is a nationally recognized drug
safety expert with knowledge of the basic science of drug development
and surveillance, and a strong commitment to protecting the public
health. CDER is working with the Office of Personnel Management on this
search.
Fourth, in the coming year CDER will conduct additional workshops
and advisory committee meetings to discuss complex drug safety and risk
management issues. Most recently, for example, the Agency conducted a 3
day Advisory Committee meeting that examined COX-2 selective non-
steroidal anti-inflammatory drugs and related medicines. The committee
held its meeting on February 16-18, 2005, and heard presentations from
more than 25 experts. At the end of the meeting, the Advisory Committee
issued recommendations that the Agency is promptly and carefully
reviewing before taking further action.
Finally, FDA intends to publish final versions of three guidances
that the Agency developed to help pharmaceutical firms manage risks
involving drugs and biological products. These guidances should assist
pharmaceutical firms identify and assess potential safety risks not
only before a drug reaches the market but also after a drug is already
on the market. FDA expects to publish the final guidances in the second
quarter of 2005.
February 2005 Drug Safety Announcement
On February 15, 2005, HHS Secretary Leavitt and Acting Commissioner
Crawford unveiled a new, emboldened vision for FDA that will promote a
culture of openness and enhanced oversight within the Agency. As part
of this vision, FDA will create a new independent Drug Safety Oversight
Board (DSB) to oversee the management of drug safety issues, and will
improve transparency by providing emerging information to health
providers and patients about the risks and benefits of medicines.
Under this proposal, FDA will enhance the independence of internal
deliberations and decisions regarding risk/benefit analyses and
consumer safety by creating an independent DSB. The DSB will oversee
the management of important drug safety issues within CDER. The DSB
will be comprised of individuals from FDA who were not involved in the
initial review of the drug, as well as medical experts from other HHS
agencies and government departments (e.g., the National Institutes of
Health and Department of Veterans Affairs). CDER's Deputy Director will
serve as the Chair of the DSB. The DSB also will consult with other
medical experts and representatives of patient and consumer groups.
FDA will also increase the transparency of the Agency's decision-
making process by establishing new and expanding existing communication
channels to provide drug safety information to the public. These
channels will help ensure that established and emerging drug safety
data are quickly available in an easily accessible form. The increased
openness will enable patients and their health care professionals to
make better-informed decisions about individual treatment options. The
Agency is also proposing a new Drug Watch web page that will include
emerging information about possible serious side effects or other
safety risks for previously and newly approved drugs. This resource
will contain valuable information that may alter the benefit/risk
analysis for a drug or affect patient selection or monitoring
decisions. The web resource may also contain information about measures
that patients and practitioners can take to prevent or mitigate harm.
This information resource will significantly enhance public knowledge
and understanding of safety issues by discussing emerging or potential
safety problems even before FDA has reached a conclusion that would
prompt a regulatory action. As always, FDA is committed to maintaining
patient privacy as it implements these measures.
As FDA develops these communication formats, the Agency will
solicit public input on how FDA should manage potential concerns
associated with disseminating emerging information prior to regulatory
action. The Agency will also issue draft guidance on procedures and
criteria we will use to identify drugs and information that will appear
on the Drug Watch web page. In addition, FDA will actively seek
feedback from health care professionals, patients and consumers on how
best to make this information available to them.
Increased Funding for the Office of Drug Safety
FDA has a longstanding commitment to provide a strong resource base
for ODS. As the graph set forth below demonstrates, we have steadily
increased the financial and human resources dedicated to post-market
drug safety over the past decade.
The budget for fiscal year 2006 continues this commitment. The
President has proposed a 24 percent increase for FDA's post-market
safety program to help further ensure that America's drug product
supply is safe and effective, and of the highest quality. Under this
proposal, CDER's ODS would receive increased funding to expand the
Agency's ability to rapidly survey, identify and respond to potential
safety concerns for drugs on the market. ODS will hire additional staff
to manage and lead safety reviews, will increase the number of staff
with expertise in critical areas such as risk management, risk
communication and epidemiology, and will increase access to a wide
range of clinical, pharmacy and administrative databases. The
Administration's proposed budget for ODS will increase by $6.5 million,
including $1.5 million in user fees, for a total fiscal year 2006 ODS
funding level of $33.4 million. PDUFA resources will represent nearly
one-third of the ODS budget for the coming year. Our commitment to
increase resources available for post-market safety will enhance the
structural changes we are proposing to advance drug safety.
THE DRUG APPROVAL PROCESS
Pre-Approval Focus on Safety
FDA's focus on safety begins at the earliest stages of drug
development, when we review a product under an investigational new drug
(IND) application. During the IND period, products must complete three
phases of clinical (human) trials. Phase I studies involve the initial
introduction of an IND drug into humans to assess the most common acute
adverse effects and examine the size of doses that patients can take
safely without a high incidence of side effects. However, before
beginning human trials, the sponsor must perform extensive animal
toxicity studies. Researchers closely monitor these studies. They may
conduct Phase I trials in patients, but often rely on healthy volunteer
subjects. In general, these studies yield initial safety data and
useful information to establish the appropriate dose of the drug.
Phase II includes the early controlled clinical studies conducted
to obtain additional information on appropriate dosing, as well as
preliminary data on the effectiveness of the drug for a specific
indication in patients with the disease or condition. This phase of
testing also helps identify short-term side effects and risks possibly
associated with the drug. Phase II studies are typically well
controlled, closely monitored and conducted in studies that usually
involve several hundred patients. In these studies, researchers compare
results of patients receiving the drug with those who receive a
placebo, a different dose of the test drug, and/or another active drug.
At the conclusion of these studies, FDA and the sponsor meet to
determine if the drug's development should advance to Phase III and how
to design and conduct further trials.
Finally, researchers design Phase III trials for a larger number of
patients and build on the data gained from the first two phases of
trials. These studies provide the additional information about safety
and effectiveness needed to evaluate the overall benefit-risk
relationship of the drug. Phase III studies also provide the basis for
extrapolating the results to the general population and provide
essential information for the package labeling. Once the results of all
the clinical trials are available, the sponsor of the application
(usually the manufacturer of the product) analyzes all the data and
submits a new drug application (NDA) or biologics license application
to FDA for review.
Post-Approval Risk Assessment
Once FDA approves a drug, the post-marketing monitoring stage
begins. The sponsor (typically the manufacturer) is required to submit
periodic safety updates to FDA on their drug. Also during this period,
we continuously receive adverse event reports through our MedWatch
system from other sources such as health care providers and patients.
Safety experts review and analyze the reports to establish the
frequency and seriousness of the adverse events. Our response to
information from this ongoing surveillance depends on an evaluation of
the aggregate public health benefit of the product compared to its
evolving risk profile. FDA carefully considers the seriousness and the
frequency of reported adverse events as well as the estimated number of
patients who benefit from the drug. The occurrence of a rare event,
even a serious event, may or may not, by itself, be sufficient to take
a drug product off the market. Adverse event reports do not solely
provide all the data necessary to identify any potential risks that may
be associated with a specific product or class of products; however,
over time, they provide us with another piece to a complex puzzle.
If the public health benefit of the product outweighs its known
risks for the intended population and intended use, FDA allows the
continued marketing of the drug. Often, as more becomes known about the
potential risks or benefits of a product, its label will be revised so
that it better reflects information on appropriate use. For example,
FDA may ask the manufacturer to revise the labeling to add information
on adverse reactions not previously listed, to add new warnings
describing conditions under which the drug should not be used, or to
add new precautions advising doctors of measures to minimize risk. FDA
often issues Public Health Advisories and information sheets for health
care providers and patients that discuss the new safety information. In
the event of reports of death or life-threatening injury, FDA and the
sponsor may consider restricting the distribution of the product or
removing it from the market. Our action will depend on the frequency of
the reports, the seriousness of the diseases or conditions for which
the drug provides a benefit, the availability of alternative therapy,
and the consequences of not treating the disease.
The issue of how to detect and limit adverse reactions can be
challenging. How to weigh the impact of these adverse drug reactions
against the benefits of these products on individual patients and the
public health is multifaceted and complex, and involves scientific as
well as public health issues.
STATUTORY CHANGES TO DRUG APPROVAL AT FDA
FDA was founded in response to concerns about safety, and attention
to safety pervades everything that we do. In the Federal Food, Drug and
Cosmetic Act of 1938, Congress gave FDA the authority to review the
evidence that a drug was safe for its intended use. In 1962, Congress
added a requirement that drug sponsors also demonstrate that a drug is
effective, using adequate and well controlled studies. Thus, drug
safety means that the demonstrated benefits of a drug outweigh its
known and potential risks for the intended population and use. In
recent years, Congress has enacted legislation that provides
significant additional tools to improve our focus on safety: the
Prescription Drug User Fee Act (PDUFA) and the Food and Drug
Administration Modernization Act (FDAMA).
In 1992, Congress enacted PDUFA. This landmark legislation provided
significant resources for FDA to hire more medical and scientific
reviewers to conduct pre-market reviews, to hire support personnel and
field investigators to speed the application review process for human
drug and biological products, and to acquire critical information
technology infrastructure to support our review process.
In 1997, following the success of PDUFA I, Congress reauthorized
the program for an additional 5 years when it enacted FDAMA of 1997.
With PDUFA II came higher expectations for product reviews and
additional goals designed to reduce drug development times.
In 2002, Congress reauthorized PDUFA for a third time. PDUFA III
places great emphasis on ensuring that user fees provide a sound
financial footing for FDA's new drug and biologic review process and,
for the first time, gives FDA authority to expend PDUFA resources on
risk management and drug safety activities during the approval process
and during the first 2 to 3 years following drug approval. Mr.
Chairman, your Committee played a significant role in creating and
reauthorizing PDUFA, and on behalf of my colleagues at FDA and
countless patients throughout America who benefit from the therapies
approved under the PDUFA process, I thank you for your efforts.
One of the primary goals of PDUFA was to address the significant
delay in U.S. patients' access to new medicines. The objective was to
increase benefits to patients, without increasing risks. Before PDUFA,
drug lag was a serious concern for U.S. patients and practitioners.
Life-saving drugs were available to patients in other countries months
and sometimes years before they were available in the U.S. Because of
the additional resources and process improvements implemented since
PDUFA I became law, the average FDA drug review time has declined by
more than 12 months.
It is important to emphasize that an recent study by Berndt, et al.
of the National Bureau of Economic Research found no significant
differences in the rates of safety withdrawals for drugs approved
before PDUFA compared to drugs approved during the PDUFA era. This
research confirms FDA's analysis on the same subject. In addition, we
are now adding black box warnings sooner than we did before PDUFA. This
indicates that PDUFA has been successful in both speeding access and
preserving safety.
In general, PDUFA authorizes FDA to collect fees from companies
that produce certain human drug and biological products. When a sponsor
seeks FDA approval for a new drug or biologic product, it must submit
an application accompanied by a fee to support the review process. In
addition, companies pay annual fees for each manufacturing
establishment and for each prescription drug product marketed. Before
PDUFA, taxpayers alone paid for product reviews through budgets
provided by Congress. Under the PDUFA approach, industry provides
additional funding in return for FDA's efforts to meet drug-review
performance goals that emphasize timelines but do not alter or
compromise our commitment to ensuring that drugs are safe and effective
before they are approved for marketing.
PDUFA III--GREATER EMPHASIS ON DRUG SAFETY
PDUFA fees are essential to our efforts to improve drug safety. Our
trained health professionals work to help ensure and improve drug
safety using a process of scientific review, monitoring, and analysis
throughout the life cycle of the drugs we approve for marketing. A
focus on safety initiates during the pre-marketing phase, when the
earliest work on drug discovery begins. As the drug development process
continues, we evaluate the safety of the therapeutic compound over a
number of years during pre-clinical testing, clinical trials involving
humans and eventually, with the submission of an NDA for FDA review.
Thanks to PDUFA, we are able to commit far greater resources to our
important safety responsibilities.
Under PDUFA III, Congress granted authority for FDA to expend user
fees for post-market safety review. FDA made this a top priority during
our PDUFA negotiations. Beginning with PDUFA III, for drugs approved
after October 1, 2002, we can spend PDUFA resources on ``collecting,
developing, and reviewing safety information on drugs, including
adverse event reports'' for up to 3 years after the date of approval.
The initiative to address drug safety for PDUFA III products helps FDA
better understand a drug's risk profile, provide risk feedback to the
sponsors and provide essential safety information to patients and
health practitioners.
From October 1, 2002, through December 31, 2004, FDA reviewed 63
risk management plans for drug and biologic products. Twenty-eight of
these related to applications submitted after PDUFA III took effect. We
also conducted pre-approval safety conferences, risk management plan
reviews, drug safety meetings, and meetings with sponsors to discuss
proposed drug supplements.
In response to PDUFA III, FDA held a public meeting in April 2003
to discuss risk assessment, risk management, and pharmacovigilance
practices. On May 5, 2004, based on the valuable information generated
through the meeting process, we published three draft guidances on
these important drug safety topics. FDA received extensive comments on
these documents, and we expect to publish all three final guidances in
the second quarter of 2005.
SAFETY ADVANCES IN FDAMA
Enacted in 1997, FDAMA has been an important addition to FDA's
legal framework. FDAMA passed following a thorough Congressional
examination of the Agency's policies and programs. It instituted a
number of comprehensive changes, reaffirmed the Agency's vital role in
protecting the public health and served as the vehicle for enacting
PDUFA II.
Pediatric Exclusivity and Safer Use of Drugs in Children
For decades, children were prescribed medications that had not been
studied for safety and efficacy in pediatric populations. As a
component of FDAMA, Congress provided incentives to sponsors to conduct
pediatric clinical trials. Section 111 of FDAMA authorized FDA to grant
an additional 6 months of marketing exclusivity (known as pediatric
exclusivity) to pharmaceutical manufacturers that conduct studies of
certain drugs in pediatric populations. The objective of section 111
was to promote pediatric safety and efficacy studies of drugs. With the
valuable information generated by these studies, the product labeling
can then be updated to include appropriate information on use of the
drug in the pediatric population. To qualify for pediatric exclusivity,
sponsors must conduct pediatric studies according to the terms of a
Written Request issued by FDA and submit the results of those studies
in an NDA or supplement.
In 2002, Congress renewed this authority when it enacted the Best
Pharmaceuticals for Children Act (BPCA). BPCA also mandates that FDA
report to the Pediatric Advisory Committee, in a public forum, any
safety concerns during the 1 year period after we grant pediatric
exclusivity. To date, we have reported safety concerns on 34 drugs at
six separate public advisory meetings.
Finally, BPCA contains important, new disclosure requirements.
Outside of BPCA, the Agency generally may not publicly disclose
information contained in an IND, unapproved NDA, or unapproved
supplemental NDA. Once FDA approves an NDA or supplemental NDA, the
Agency can make public certain summary information regarding the safety
and effectiveness of the product for the approved indication.
However, section 9 of BPCA gives FDA important new disclosure
authority. BPCA requires that, no later than 180 days after the
submission of studies conducted in response to a Written Request, the
Agency must publish a summary of FDA's medical and clinical
pharmacology reviews of those studies. Moreover, we must publish this
information regardless of whether our action on the pediatric
application is an approval, approvable, or not-approvable action. Thus
under FDAMA, information on pediatric studies conducted in response to
Written Requests was not available until after the supplemental
application was approved. In contrast, under BPCA, a summary of FDA's
medical and clinical pharmacology reviews of pediatric studies is
publicly available regardless of the action taken on the application.
Since 2002, FDA has posted the summaries of these reviews for 41
products submitted in response to a Written Request on FDA's website
at: (http://www.fda.gov/cder/pediatric/Summaryreview.htm). This
information provides a rich source of valuable safety information to
allow pediatricians to make more informed decisions about whether and
how to use these drugs in their patients.
Post-Marketing Safety Studies
On April 30, 2001, FDA's regulations implementing section 130 of
FDAMA, which requires sponsors of approved drugs and biologics to
report annually on the status of post-marketing commitments, became
effective. These regulations modified existing reporting requirements
for NDA drug studies and created a new reporting requirement for
biologic products.
FDA may request that the sponsor conduct post-marketing studies to
provide additional important information on how a drug works in
expanded patient populations or to identify safety issues that occur at
very low frequency or in special patient populations. The post-
marketing safety study obligations in section 130 are of keen interest
to patient and consumer advocates who track the completion of post-
marketing commitments and FDA's efforts to review study results and
modify drug labeling. The regulations implementing section 130 provide
FDA with a mechanism to monitor study progress through the annual
submission of study status reports. FDA posts the status of post-
marketing studies on its public website and publishes an annual summary
of industry's progress in fulfilling post-marketing commitments in the
Federal Register.
CRITICAL PATH
On March 16, 2004, FDA released a report addressing the recent
slowdown in innovative medical therapies submitted to FDA for approval:
``Innovation/Stagnation: Challenge and Opportunity on the Critical Path
to New Medical Products.'' The report describes options to modernize
the medical product development process to try to make it more
predictable and less costly. The report focuses on ways that FDA could
collaborate with academic researchers, product developers, patient
groups, and other stakeholders to make the critical path much faster,
predictable, and less costly.
Enhancing the Safety of Medical Products
During drug development, safety issues should be detected as early
as possible. However, because of limitations of current methods, safety
problems are often uncovered only during clinical trials or,
occasionally, after marketing. Despite efforts to develop better
methods, some tools used for toxicology and human safety testing are
outdated. Clinical testing, even if extensive, often fails to detect
important safety problems, either because they are uncommon or because
the tested population was not representative of eventual recipients.
Conversely, some models create worrisome signals that may not be
predictive of a human safety problem.
There are opportunities for developing tools that can more reliably
and efficiently determine the safety of a new medical product. To meet
this challenge, FDA has called for a new focus on modernizing the tools
that applied biomedical researchers and product developers use to
assess the safety and effectiveness of potential new products. Many of
these tools--diagnostics such as pharmacogenomic tests and imaging
techniques--would also be used after marketing to monitor safety in the
real world clinical setting. The Critical Path report describes
opportunities for FDA, working with academia, patient groups, industry,
and other government agencies, to embark on a collaborative research
effort. The goal is to create new performance standards and predictive
tools that will provide better answers about the safety and
effectiveness of investigational products, to do this faster and with
more certainty, and to enhance the safety of these products in the
clinic.
In addition to improved safety tools, Critical Path also focuses on
tools that will help individualize therapy. We enhance safety when the
target population does not include individuals who cannot benefit from
the treatment. For these individuals, drug exposure is all risk. Better
tools for individualized therapy will help to identify patients who
will respond to therapy. New science has provided the basic knowledge
to make these tools a reality.
Critical Path is not a fundamental departure for FDA, but rather
builds on the Agency's proven ``best practices'' for expediting the
availability of promising medical technologies. While the report
touches on all aspects of medical product development, identifying new
tools to address drug safety challenges would represent a giant step
down the Critical Path.
CONCLUSION
At FDA, providing the American public with safe and effective
medical products is our core mission. We base decisions to approve a
drug or to keep it on the market if new safety findings surface on a
careful balancing of risk and benefit to patients. This is a
multifaceted and complex decision process, involving scientific and
public health issues. The recent initiatives we have announced will
improve our current system to assess drug safety. Moreover, as we
strive for continuous improvement, we will continue to evaluate new
approaches to advance drug safety. As always, we value input from
Congress, patients and the medical community as we develop and refine
these drug safety initiatives.
Once again, thank you for the opportunity to testify before the
Committee today. I am happy to respond to questions.
The Chairman. As the next panel takes their place, I will
go ahead with introductions. On the next panel we have Dr.
Cecil B. Wilson, who is an internist from Winter Park, FL and a
member of the AMA Board of Trustees since 2002. Dr. Wilson has
been in private practice of internal medicine in Central
Florida for 30 years. He is board certified in internal
medicine and a member of the American College of Physicians.
Dr. Wilson will discuss the impact on prescribers of changes in
the way FDA communicates.
Also I have Mr. Keith L. Carson, Chairman of the
Williamsburg BioProcessing Foundation. Mr. Carson started the
foundation in 1994 and currently serves as the organization's
chairman. He edits BioProcessing Journal, a print journal that
features articles adapted from selected presentation given at
the foundation's conferences. Mr. Carson will discuss the
impact of new technologies on drug safety and how FDA can
improve its processes, including through the developing of
reference materials.
Dr. Raymond Woosley is a pharmacologist whose research has
been published in over 250 publications, and has investigated
the basic and clinical pharmacology of drugs for the drug
treatment of arrhythmias and the cardiac toxicity of drugs. In
January of 2005 he assumed the position of the President of the
Critical Path Institute, C-Path, a nonprofit corporation formed
by the Food and Drug Administration, SRI International and the
University of Arizona to accelerate the developing of safe
innovative medicines. Dr. Woosley will discuss his ideas on how
to increase the industry capabilities to develop innovative
methods for accelerated drug discovery and development and how
the FDA may have to change to adapt to these new methods.
We have Dr. Bruce Psaty. Dr. Bruce Psaty is a Professor of
Medicine and Epidemiology and Co-Director of the Cardiovascular
Health Research Unit at the University of Washington in
Seattle. A practicing general internist at Harbor View Medical
Center, he is a cardiovascular disease epidemiologist with
interest and expertise in pharmacoepidemiology,
pharmacogenetics and drug safety. He will discuss his
recommendations for improving FDA's drug safety process.
I thank the panel and we will begin then with the testimony
of Dr. Wilson.
STATEMENTS OF CECIL B. WILSON, M.D., MEMBER, AMERICAN MEDICAL
ASSOCIATION BOARD OF TRUSTEES, WINTER PARK, FL; KEITH L.
CARSON, CHAIRMAN, THE WILLIAMSBURG BIOPROCESSING FOUNDATION,
VIRGINIA BEACH, VA; RAYMOND WOOSLEY, M.D., PhD, PRESIDENT, THE
CRITICAL PATH INSTITUTE, PROFESSOR OF MEDICINE AND
PHARMACOLOGY, UNIVERSITY OF ARIZONA, TUCSON, AZ; AND BRUCE M.
PSATY, M.D., PhD, PROFESSOR OF MEDICINE, EPIDEMIOLOGY AND
HEALTH SERVICES, CO-DIRECTOR, CARDIOVASCULAR HEALTH RESEARCH
UNIT, UNIVERSITY OF WASHINGTON, SEATTLE WA
Dr. Wilson. Good morning, Chairman Enzi and members of the
committee. My name, as you have heard, is Cecil Wilson. I am a
member of the American Medical Association's Board of Trustees
and a practicing internist in Winter Park, FL.
On behalf of the AMA I would like to thank you for holding
today's hearings and for inviting us to participate. Today I
will discuss how FDA decisions regarding drug approval
postmarketing surveillance, product labeling, off-label use and
risk management impact practicing physicians like myself. I
will also discuss the AMA's recommendations to improve drug
safety and minimize the impact on physicians' ability to
practice medicine.
Our recommendations include more active approaches to
postmarketing surveillance, a final FDA rule on package
inserts, the preservation of off-label prescribing, and
continued collaboration between the FDA, the pharmaceutical
industry and physicians to develop better risk communication
tools. Approving a prescription drug or biologic for marketing
is a primary way in which the FDA affects physician practice.
Since PDUFA was passed in 1992 new drugs are getting to
market faster and importantly, and as you heard earlier,
studies have shown that this has been accomplished without
increasing the number of drug withdrawals. The AMA hopes that
any new efforts to enhance drug safety can be accomplished
without reversing this trend. As more drugs become available,
the AMA recognizes the need to improve postmarketing
surveillance. Such efforts would enhance our ability to
identify rare but potentially serious adverse events in a
timely fashion. So the AMA supports active approaches to
postmarketing surveillance. For example, well-designed studies
on newly marketed drugs would help to quickly assess the risk
of these drugs once they are in actual clinical use.
Another primary way in which FDA decisions affect
physicians is through product labeling, especially the package
insert. The package insert is designed and intended to inform
physicians about risk and benefits of a drug. Unfortunately,
today's package insert has become a long and complicated really
legal document rather than a useful resource for physicians.
In my own practice when a patient presents who is on a new
drug from another physician or when I simply want to check or
double check the dosage of a particular drug, I, as well as
other physicians, look up a drug's package insert. The problem
we encounter is that the package insert contains so much
information that it makes it difficult to find what we really
need. So information such as dosage, contraindications, major
risk and potential drug interactions are often varied within
the highly technical text of the document.
In the year 2000 the FDA issued a proposed rule to make the
package insert more user friendly for physicians. The AMA
supports this effort and urges the FDA to finalize this rule.
Further, the FDA should ensure that physicians' ability to
prescribe drugs off label not be impeded. In some instances
prescribing a product off label is the most appropriate therapy
based on the latest and best scientific evidence, and for some
patient populations it may be the only treatment.
Finally, Mr. Chair, over the past few years the FDA has
opposed a number of risk management tools to enhance drug
safety. Some of these tools may be useful, but some could lead
to unintended consequences such as decrease patients' access to
valuable medical treatments. For the vast majority of
prescription drugs the patient insert, combined with effective
postmarketing surveillance should constitute the risk
management plan. Additional risk management tools such as
patient agreements, enrollment programs or tools that create
special rules for prescribing should be used only as a last
resort to keep products with unique and important benefits on
the market.
Thank you, Mr. Chairman.
[The prepared statement of Dr. Wilson follows:]
Prepared Statement of Cecil B. Wilson, M.D.
The American Medical Association (AMA) appreciates the opportunity
to present its views on ways to ensure drug safety in this country and
the implications for practicing physicians. We commend the Chairman and
Members of this Committee for holding this important hearing. The AMA
shares a common goal with Congress and the Food and Drug Administration
(FDA) to optimize the benefit/risk balance of drug therapy and minimize
the risks of prescription drug and biologic products.
As our Nation's drug regulatory agency, the FDA ensures that
beneficial drug products are made available to the public with labels
that contain adequate information about the product's risks and
benefits, and protects the public from false claims. While the FDA's
approval process is considered the ``gold standard'' around the world,
the FDA's determination that a product is safe and effective is not
meant to signal an absence of risk. Drug and biologic products, by
their very nature, carry with them certain risks, some of which are
discovered after approval. Pharmaceutical manufacturers, the FDA,
physicians and patients all play essential roles in minimizing those
risks and enhancing the benefits of prescription drugs and biologics.
The AMA supports the FDA's proposals to improve the format and
content of the package insert, which is the portion of a drug product's
labeling directed primarily to physicians. We have also been a
proponent of more widespread use of the MedWatch program (FDA's adverse
event reporting system) by encouraging physicians to participate. More
recently, the AMA provided testimony and commentary on specific FDA
initiatives related to the risk management of prescription drugs,
including their concept paper on ``Risk Management Programs'' and their
draft guidance for industry on the ``Development and Use of Risk
Minimization Action Plans'' (Attachments 1 & 2).
This statement will focus on how FDA decisions impact practicing
physicians through the drug approval process; postmarketing
surveillance efforts; product labeling developed to guide physicians in
the appropriate use of medications; policies on unlabeled uses; and
risk management. In addition, we make recommendations to improve drug
safety and minimize the impact on physicians' ability to practice
medicine, including: more active approaches to post marketing
surveillance; final FDA rules on the format and content of package
inserts; the preservation of physicians' ability to prescribe
medications for unlabeled uses; and collaboration between the FDA,
pharmaceutical industry, and physicians to develop better risk
communication tools.
FDA DECISIONS AFFECTING PHYSICIAN PRACTICE
Drug Approval
The FDA's decision to approve a prescription drug or biologic
product for marketing moves that product from an investigational status
to an approved product available for widespread use. Approving a
prescription drug or biologic for marketing is the primary way in which
the FDA affects physician practice. Over the years, the FDA approval
process has resulted in access to a wide array of prescription drug and
biologic products for use by physicians in the care of their patients.
Fifteen years ago, a primary complaint about the FDA was that the
drug approval process was too slow. The problem was referred to as a
``drug lag'' because at the time, the United States stood well behind
other industrialized countries in getting needed drugs to market. After
numerous complaints, the government began to focus its attention on
improving FDA drug review timelines. In 1992, Congress passed the
Prescription Drug User Fee Act (PDUFA), which authorized the FDA to
collect user fees from companies that produce drug and biologic
products. Under PDUFA, these fees were provided in exchange for an FDA
agreement to meet drug-review performance goals, which emphasized
timeliness. PDUFA was reauthorized by the Food and Drug Administration
Modernization Act (FDAMA) of 1997 (PDUFA II) and again by the Public
Health Security and Bioterrorism Preparedness and Response Act of 2002
(PDUFA III).
These acts required the FDA to: (1) speed agency review of New Drug
Applications (NDAs) and Biologic Licensing Applications (BLAs); (2)
improve the efficiency of drug development before submission of new
drug or biologic applications; and (3) further improve the quality and
efficiency of drug development, review, and risk management for newly
approved products--all without compromising safety. According to the
FDA, before PDUFA, the agency approved about 40 percent of the new
drugs introduced on the world market either first or within 1 year of
their introduction in another country. After PDUFA and through 2002,
this percentage had nearly doubled. Additionally, the median total
review time for new drugs and biologics decreased from approximately 23
months to 12 months, with even shorter median approval times for drugs
designated for priority review.
Concern has been expressed about the number of drugs approved under
PDUFA that have been withdrawn for safety reasons. However, an FDA
analysis showed the rate of withdrawal for safety reasons of ``new
molecular entities'' pre-PDUFA was 2.7 percent, while the rate post-
PDUFA was 2.5 percent. This is not a significant difference. Thus, it
appears as if the FDA has met its obligations under PDUFA to increase
the efficiency of the drug review process without compromising the
safety of approved drug products. Therefore, the AMA and its physician
members hope that any new efforts to improve drug safety can be
accomplished without reversing the improvements that have occurred in
the drug approval process.
Postmarketing Surveillance
If formal postmarketing studies are not conducted by manufacturers
or clinical investigators to obtain safety information, observational
data collected by physicians, other health professionals, and patients
are the cornerstone for evaluating and characterizing a drug's risk
profile in actual clinical use. Currently, the FDA maintains an adverse
event reporting system termed MedWatch, which incorporates both a
mandatory adverse event reporting system for manufacturers subject to
the Agency's postmarketing safety reporting regulations, and a
voluntary, adverse event reporting system for health care
professionals, consumers, and patients. MedWatch can be an effective
tool for detecting signals suggesting that a drug may be associated
with a rare, but serious, adverse event.
However, the MedWatch program is a passive system and it is limited
by its reliance on voluntary reporting, which inevitably leads to under
reporting. Under reporting and uncertainty about the actual extent of
drug exposure, make it difficult to estimate true rates of occurrence
of drug-induced adverse events. Because of their observational nature,
spontaneous reports also are limited in their ability to establish
causality. Given the limitations of spontaneous reporting systems,
concerns have been raised about the FDA's ability to detect serious
adverse events that occur during the postmarketing phase of a drug
product's life cycle. Thus, as efforts are devoted to improving drug
safety, attention should be directed toward enhancing postmarketing
surveillance by using more active approaches. For example, well
designed pharmacoepidemiologic studies on newly marketed drugs could
enhance our ability to more accurately determine a drug's adverse event
profile in a timely manner.
Recently, the FDA announced its intent to create an independent
Drug Safety Oversight Board comprised of FDA staff as well as medical
experts from other Department of Health and Human Services agencies and
other government departments to oversee the management of important
drug safety issues. The AMA has not taken a position on this issue.
In addition, the FDA pledged to ``expand existing communication
channels and create new ones to ensure that established and emerging
drug safety data are quickly available to the public (and physicians)
in an easily accessible form with the intent of enabling patients and
their health care professional to make better-informed decisions about
individual treatment options.'' One of these proposed channels would be
a new ``Drug Watch'' Web page for emerging data and risk information,
and the AMA applauds these efforts to enhance transparency. However,
the FDA must provide clear advice when it disseminates emerging or
preliminary information prior to taking regulatory action.
Product Labeling
Product labeling decisions are made by the FDA in collaboration
with the drug sponsor, usually the manufacturer. The product labeling
includes the materials and language that comprise the product's
packaging, label and package insert. The package insert is that portion
of the approved labeling that is directed primarily to physicians to
inform them about a product's risks and benefits, and to provide
guidance on the conditions of appropriate use. However, today's package
insert has become a barrier to effective risk communication, serving
more as a legal document rather than a resource of useful information
for practicing physicians. The FDA has recognized this problem and in
December 2000, it issued a proposed rule to modify the format and
content of the package insert with the goal of making the information
more useful and user-friendly to physicians. Their recommendations
included a more simplified, ``Highlights of Prescribing Information''
section within the package insert. The AMA continues to strongly
support FDA efforts to make package inserts more useful and user-
friendly for physicians and encourages the FDA to issue a final rule to
that effect.
Unlabeled/Off-Label Uses
In an effort to strengthen drug safety, the FDA recently announced
its commitment to sponsoring an Institute of Medicine study on drug
safety systems with an emphasis on the postmarketing phase, including
the study of unlabeled (also known as off-label) use. Unlabeled uses
are defined as the use of a drug product for indications or in patient
populations, doses, or routes of administration that are not included
in FDA-approved labeling. Under the Federal Food, Drug, and Cosmetic
(FD&C) Act, a drug approved by the FDA for marketing may be labeled,
promoted, and advertised by a manufacturer for only those uses for
which the drug's safety and efficacy have been established. The
manufacturer submits data to the FDA demonstrating substantial evidence
of efficacy and safety for each labeled indication. Even though PDUFA
has reduced the review time for efficacy supplements (i.e.,
Supplemental New Drug Applications or SNDAs), manufacturers are not
required to and may choose not to seek FDA approval for all useful
indications. One major reason for not submitting an SNDA is because the
expense of regulatory compliance may be greater than the eventual
revenues expected (e.g., if patent protection for the drug product has
expired, or if the patient population affected by the new use is very
small). A sponsor also may not seek FDA approval because of
difficulties in conducting controlled clinical trials (e.g., for
ethical reasons, or due to the inability to recruit patients).
A physician may choose to prescribe a drug for uses, in treatment
regimens, or in patient populations that are not part of the FDA-
approved labeling. The decision to prescribe a drug for an unlabeled
use is made by the physician in light of all information available and
in the best interest of the individual patient. Prescribing for an
unlabeled use requires the physician to use the same judgment and
prudence as exercised in medical practice for it to conform to accepted
professional standards. Given the prevalence of unlabeled uses and the
fact that in many clinical situations such use may represent the most
appropriate treatment, the prescribing of FDA-approved drugs for
unlabeled uses is often necessary for optimal patient care. Therefore,
the AMA has had longstanding policy:
``That a physician may lawfully use an FDA approved drug product
for an unlabeled indication when such use is based upon sound
scientific evidence and sound medical opinion (Policy 120.988, AMA
Policy Compendium).''
The position of the FDA on physician prescribing of unlabeled uses
supports that of the AMA. The FDA's published statement that addresses
the appropriateness and legality of prescribing FDA-approved drugs for
unlabeled uses includes the following:
``The Food, Drug and Cosmetic Act does not limit the manner in
which a physician may use an approved drug. Once a product has been
approved for marketing, a physician may prescribe it for uses or in
treatment regimens or patient populations that are not included in
approved labeling. Such ``unapproved'' or, more precisely,
``unlabeled'' uses may be appropriate and rational in certain
circumstances, and may, in fact, reflect approaches to drug therapy
that have been extensively reported in medical literature (FDA Drug
Bulletin. 1982; 12:4--5).''
It is important to emphasize that the AMA strongly supports the
SNDA process to add new uses for drugs to FDA-approved labeling.
However, given the disparity between the actual submission of SNDAs and
the evolution of evidence-based medical practice, physician prescribing
for unlabeled uses should not be impeded by any actions taken to
improve drug safety.
Risk Management of Prescription Drug Products
In 1999, an FDA Task Force published ``Managing the Risks from
Medical Product Use.'' Subsequently, in the context of PDUFA III, the
FDA agreed to provide guidance for the regulated industry on risk
management activities for drug and biological products. In addition to
conducting a Part 15 Hearing on risk management in 2002, the FDA issued
three Concept Papers (``Premarketing Risk Assessment,'' ``Risk
Management Programs,'' and ``Risk Assessment of Observational Data.'')
for comment in 2003, and then released three ``draft`` Guidances for
Industry, (``Premarketing Risk Assessment,'' ``Development and Use of
Risk Minimization Action Plans [RiskMAPs],'' and ``Good
Pharmacovigilance Practices and Pharmacoepidemiologic Assessment'') in
2004. A RiskMAP is a strategic safety program designed to meet specific
goals and objectives in minimizing known risks of a product while
preserving its benefits.
Routine risk minimization measures include use and revision of the
package insert, combined with postmarketing surveillance. These
measures should constitute the risk management plan for the vast
majority of drug and biologic products. The draft guidance on RiskMAPs
identified several additional tools that could be considered in
designing risk minimization plans when reliance on the package insert
as the primary tool may be inadequate. These tools can generally be
placed under the following three categories:
Targeted education and outreach (e.g., physician letters;
training programs for physicians or patients; medication guides);
Reminder system, processes or forms (e.g., patient
agreements or acknowledgement forms; certification programs for
physicians; enrollment of physicians and/or patients in special
educational programs; specialized systems or records that attest to
safety measures having been satisfied); and
Performance-linked access systems (e.g., prescription can
be ordered only by specially certified physicians; use of compulsory
fulfillment systems; product dispensing only to patients with evidence
of lab tests results or other documentation).
Implications for Physicians. In government's efforts to improve
drug safety, there may be a desire to use, more routinely, those risk
minimization tools that extend beyond targeted education and outreach
to include a more pervasive use of tools associated with reminder
systems and/or performance-linked access systems. A number of these
approaches would directly manage or restrict physician prescribing and
may have unintended consequences.
These unintended consequences include:
(1) preventing some patients (who would benefit from higher risk
drugs) from having access to them because of added burdens on the
prescriber;
(2) prescribing of less effective, less studied, and even less safe
alternative drugs that are not subject to restrictions because they are
simply much easier to use;
(3) employing multiple and complex risk management tools that may
be confusing to both physician and patient and, potentially result in
unintended medication errors;
(4) creating administrative burdens for physicians that would
likely result in the drug not being prescribed at all (unless the
restricted drug is truly innovative); and
(5) possibly adversely impacting pharmaceutical company research
and development in promising areas where restrictive risk management of
drugs is anticipated.
Rather than focus on restrictions, the AMA believes that the FDA,
the pharmaceutical industry, and physician organizations must
collaborate and identify innovative ways to communicate new risk
information about a drug or biological product to physicians so they
will be aware of it, remember it and act on it when prescribing a drug.
The AMA previously proposed potential ways to improve risk
communication about drugs to physicians in its comment letters to FDA
on risk management (see Attachments 1 & 2).
High level risk minimization tools, such as performance-linked
access systems and some reminder systems, should be used only as a last
resort to keep high-risk drug products with unique and important
benefits on the market. The AMA encourages the FDA and the product
sponsor to work with relevant physician organizations to assure that
the minimum number and least intrusive RiskMAP tools are selected to
achieve the risk minimization objective.
Recommendations
The AMA is pleased to offer the following recommendations to the
Committee. We believe these recommendations will both improve drug
safety and not adversely impact how physicians practice medicine. The
recommendations are as follows:
1. Improved postmarketing surveillance for potential adverse events
can be achieved without slowing down the premarket drug approval
process. The AMA supports the use of more active approaches to enhance
postmarketing surveillance.
2. The FDA should issue a final rule, as soon as possible,
implementing modifications to the format and content of the package
insert with the goal of making the information more useful and user-
friendly to physicians.
3. Physician prescribing for unlabeled uses should not be impeded
because prescribing of FDA-approved drugs for unlabeled uses is often
necessary for optimal patient care.
4. The package insert, combined with effective postmarketing
surveillance, should constitute the risk management plan for the vast
majority of drug and biologic products. When this is insufficient to
ensure an appropriate level of drug safety, then effective risk
communication to physicians should be the primary means to reduce risks
of drugs. The AMA urges the FDA and the pharmaceutical industry to
collaborate with physician organizations to develop better risk
communication vehicles and approaches. High level risk minimization
tools, such as performance-linked access systems, should be used only
as a last resort to keep high-risk products with unique and important
benefits on the market.
The AMA once again, commends the Committee for holding today's
hearing, and we thank the chairman for the opportunity to present our
views. We look forward to working together on this important issue.
Attachments
1. AMA Letter 7/6/04 to FDA RE: Draft Guidance for Industry on
``Development and Use of Risk Minimization Action Plans'' [Docket No.
2004D-0188]
2. AMA Letter 4/29/03 to FDA RE: Risk Management [Docket No. 02N-
0528]
The Chairman. Thank you very much, and I very much
appreciate your concise testimony. Your entire testimony will
be a part of the record, and that gives us more time for
questions too.
Mr. Keith Carson.
Mr. Carson. Mr. Chairman, members of the committee, I want
to thank you for inviting me to come talk to you today.
I am a chemical engineer, different than a number of your
panelists in my discipline and background, actually trained as
a process engineer, and have been working for over 25 years in
helping companies scale up and produce biological products at
large scale, including vaccines, antibodies, recombinant
proteins, and even some of the newer products that are now
coming out. So I will give you I hope a slightly different
perspective.
In my organization, again, I started 10 years ago, we find
ourselves in a fairly unique position I believe, and at times
being a neutral party that can work with both FDA and with
industry since we really have no affiliation with either, and
that is a position we have been in several times in helping to
develop what are called reference materials.
Biological products are very, very difficult to not only
manufacture but to characterize and understand exactly what
they are or to compare one product to another. This is where
reference materials come in. By being able to establish a well-
characterized reference material, then the manufacturers can
compare their products to this one standard or this reference
material.
So the most successful project to date is one where an
adenovirus was produced and is now currently being stored at
ATCC. It is being used throughout the world as a reference
material for validating internal reference materials and their
assays.
I cannot tell you enough how difficult some of these
products are not only to manufacture but to regulate. They are
all different. Most of the discussions here are about drugs or
chemically formulated products, but when you get into biologics
it becomes incredibly more complex. We have a group that are
now known or being called ``well-characterized biologics,''
including the monoclonal antibodies, recombinant antibodies,
recombinant proteins. But beyond that then you have viral
products, viral vaccines, bacterial vaccines. And then on top
of that the cellular products, the cell therapy products are
incredibly difficult to product and to produce on a consistent
basis. The lot to lot variability is very, very difficult to
maintain.
One reason I am bringing this up is the people that we have
there at FDA are not only receiving more and more submissions,
they are having to work on more and more complex products all
the time, products that they are just now trying to get their
arms around and figure out the best way to try to regulate
them, and even figure out what questions to ask.
The U.S. is considered to be the world leader in this
technology. We certainly lost our edge in many other
manufacturing and technology areas, but throughout the world we
are considered the technology source for biotechnology and for
biological processing. Our meetings that we hold in Europe and
in Asia, they still want us to bring 70 percent of our speakers
from North America. So we have a leadership role in the world
here and we are highly respected, not only from a processing
standpoint and technology standpoint, but from a regulatory
standpoint. These other countries harmonize their regulations
to a great extent around what has been done here and developed
here by the FDA.
All of these products have risks, as Dr. Woodcock
mentioned, even Tylenol as she mentioned. She did not use the
generic name, but--or the marketed name, but all of these
products have risk. The important thing is to try to define the
patients that can tolerate these products the best and give
them these products and then identify the patients that would
have adverse events, and that is where I think we will talk
about some of these new technologies that might help us move in
that direction.
Thank you.
[The prepared statement of Mr. Carson follows:]
Prepared Statement of Keith L. Carson
I am a chemical engineer with over 25 years experience in the
biopharmaceutical industry. My training is as a process engineer, and
my focus has been on the large-scale production of biological products
including viral vaccines, antibodies, recombinant proteins, viral gene
vectors, and cellular therapies.
I also received an MBA in marketing from George Washington
University in Washington, DC, and lived on Capitol Hill from 1981 to
1993.
I helped found the Virginia Biotechnology Association and have
served as a board member for 7 years, plus one term as the
association's president. I currently serve as an advisor to the board,
and provide advice on biotech business development for the State and
Hampton Road area.
In 1994, I founded the Williamsburg BioProcessing Foundation, or
``WilBio,'' in Virginia Beach, Virginia. WilBio is a biotech
information company that publishes the BioProcessing JournalTM, and
organizes 12 international conferences on the development and
production of biological products for human health care.
Our mission is to help develop safe and effective biological
products, and our objectives are to make product development less
costly, provide a trained workforce for the biotech industry, and
improve communication between FDA and industry, and the academic
processing centers.
Since 2000, WilBio has signed several FDA Co-Sponsorship Agreements
for the development of viral reference materials. Our role has been to
serve as a facilitator and coordinator for Working Groups, which manage
the development of these materials and are made up of representatives
from FDA, industry, and academia. In 2002, the first project resulted
in the production of a well-characterized adenovirus, which is now used
by product sponsors throughout the world to validate assays and
internal reference materials.
Also through a Co-Sponsorship agreement, this is the 3rd year that
WilBio has helped organize and manage the Annual FDA Science Forum,
which is held at the DC Convention Center in May. With approximately
2,000 attendees from government, industry, and academia; this unique
meeting offers the best opportunity to learn about the scientific
interests and activities at FDA, and how science is used to help
formulate policy and regulate products.
I have just completed a lengthy analysis of FDA's Critical Path
Initiative, and have written a review article for our publication. A
copy of this article has been submitted to the committee, and
additional copies are available upon request. As you will note, key
concepts for this initiative include: well-characterized reference
materials, standardized analytical methods, shared characterization and
clinical data, and improved regulatory guidelines. I have proposed that
working groups be formed to tackle these issues in a fashion similar to
the one taken for the highly successful adenoviral reference material
project.
Today, I am here to testify about Drug Safety, and specifically the
impact that new technologies could have on drug discovery, development,
and approval. While these technologies appear to offer tremendous
potential, their use and implementation are still in a very early
stage; and a number of technical, logistical, and ethical issues must
be resolved.
Technological advances in sensors, analytical methods,
instrumentation, and computing power are happening so quickly that it
is very difficult to know how they can best be applied, or understand
what the information they generate actually means. Some breakthroughs
are occurring, but many years will be required to devise the
correlations needed to make the data useful.
To keep up with these technological advances and use them in the
regulatory process, FDA must be properly funded to staff and equip
their labs, plus train their personnel. Product reviewers must be
familiar with these technologies and how to apply them, as well as
comprehend the sponsor data that is submitted.
The Agency also needs a permanent Commissioner who can provide
consistent leadership, policy, and direction.
Executive Summary
I am here to testify about Drug Safety, and specifically the impact
that new technologies could have on drug discovery, development, and
approval. While these technologies appear to offer tremendous
potential, their use and implementation are still in a very early
stage; and a number of technical, logistical, and ethical issues must
be resolved. The technologies receiving the most attention include:
microarray technology, in silico models, datamining, and proteomics.
Technological advances in sensors, analytical methods,
instrumentation, and computing power are happening so quickly that it
is very difficult to know how they can best be applied, or understand
what the information they generate actually means. Some breakthroughs
are occurring, but years will be required to devise the correlations
needed to make most of this data useful.
To utilize the technologies, patient samples are analyzed for
differences in genetic markers, or in the application of proteomics,
differences in expressed proteins that can be linked with genetic
markers. In particular, researchers are looking for genetic markers
that could be associated with the uptake of a particular drug, or even
its metabolism. In other applications, specific genetic markers could
be related to potential adverse events.
Personalized medicine is based on matching drug treatments with the
patient-specific genetic markers that could predict a more favorable
outcome. With this approach, a higher chance of success could be
predicted with certain treatments, and adverse events could hopefully
be avoided.
However, there are a number of technical, logistical, and ethical
issues involved with the use of these techniques. First, a patient must
submit to having his genetic profile determined and analyzed, and many
individuals are concerned about how this data might be used. Certain
genes have already been linked to a predisposition for various
diseases, and the patient could be barred from insurance or certain
types of employment if this information were accessible.
In addition, very large computing power will be needed to hold the
vast amount of data that will be generated. Then when numerous product
sponsors want to share their data, the hardware requirements become
even greater, and patient confidentiality could be further compromised.
And if correlations are developed, the reasons for any relationships
may not be known for many years.
To keep up with these technological advances and use them in the
regulatory process, FDA must be properly funded to staff and equip
their labs, plus train their personnel. Product reviewers must be
familiar with these technologies and how to apply them, as well as
comprehend the sponsor data that is submitted.
The Chairman. Thank you.
Dr. Woosley.
Dr. Woosley. Chairman Enzi and members of the committee,
as I was introduced, I am the President of a newly formed
nonprofit organization created to facilitate innovations in
drug development. Our goal is to create a forum for drug
development that does not exist where scientists from the FDA,
academia and the drug industry can bring innovations into drug
development, innovations that will give patients the earliest
possible access to the safest possible medications.
We believe that such a forum can spawn innovation from
scientific interchange by serving as a neutral territory, free
of the regulatory environment that limits most interactions of
the FDA with the industry.
I am also Director of the Center for Education and Research
on Therapeutics called CERT, and interdisciplinary center
funded by AHRQ. Our CERT is one of 7 centers authorized by
Congress in FDMA, the Food and Drug Modernization Act, to work
with the FDA to improve the medical outcomes from therapeutics.
Drug safety is included in that. In my testimony today I will
recommend changes in drug development, drug regulation and drug
surveillance that address a crisis, and I do not use that word
lightly. I took it out of my testimony probably three times,
but I want to emphasize that I have thought about this a great
deal and I do believe there is a crisis and I hope I can
convince that that word is not hyperbole.
I think this crisis in drug development translates into a
crisis in the future in public health. My concern is for the
long-term viability of the pharmaceutical industry and the
likelihood that without change patients will have even less
access to new medical therapies in the future. There are
numerous signals of this crisis and they are listed in my
written testimony. The following are a few that I hope will
convince you that I am not over-using that word.
The pharmaceutical industry now spends an average of 12 to
15 years and almost a billion dollars for each drug that it
successfully develops. Yet with all of that investment of time
and money, too often it fails to detect serious adverse effects
of its products until they have been on the market usually for
years and millions of patients have been exposed to harm. Also
these unnecessarily long billion dollar development programs
leave only 2 to 5 years of market time before generic
competition begins. This short amount of time to make back a
billion dollars plus large profits and lack of competition from
other products results in unacceptably high drug prices, prices
so high that Americans are going to other countries to buy
their medicines.
Over the last 10 years what has happened? The
pharmaceutical industry has increased its investment in R&D by
250 percent. But what has happened from that 250 percent? The
number of products, significant new products submitted to the
FDA for review has fallen by 50 percent. Drug failures during
testing have doubled, tens of billions of dollars in
development dollars were lost when 17 drugs were removed from
the market. Many patients suffered serious injury, and hundreds
of class action lawsuits now threaten the very existence of
some of our Nation's most successful companies.
So while the issue of drug safety must be addressed--and I
am very pleased you are having these hearings--I encourage you
to do so in the context of this broader crisis in which the
wrong action, as you, Chairman Enzi, did mention earlier, could
really have unintended consequences and could further threaten
the future viability of the U.S. pharmaceutical industry, and
therefore, the availability of vital new medicines.
For example, adding a requirement for Phase IV studies to
our broken system without other important changes could be
catastrophic. Any changes to the system must really
simultaneously correct the flaws that are in our current system
that leads to 12 to 15 years of development and billions of
dollars expended, and it must create an efficient, effective
postmarketing drug surveillance system.
Other recommendations are in my testimony, but the
following are my two major points. The FDA needs more options
for regulatory action. I recommend creating an optional new
process of stages approval of drugs, and it is described in
this article which I would like, if you would, to add to the
record. The details are there, and I would be glad to answer
questions about that.
The Chairman. Without objection.
[The article follows:]
[Editors Note-Due to the high cost of printing, previously
published materials submitted by witnesses may be found in the files of
the committee.]
Dr. Woosley. This track would not result in earlier
marketing, but more close surveillance of all drugs.
My second recommendation is that the FDA should be
adequately funded to carry out its mission. The budget should
include funds for FDA's Critical Path Initiative that was
mentioned by Dr. Woodcock. That is a very important addition to
this because it will improve the process to accelerate the
development of safe drugs.
Because a major part of drug safety is safe use of drugs,
FDA and AHRQ should be given adequate funds to create together
a comprehensive multifaceted safety surveillance system. We
have to create something new that does not exist, and in my
written testimony I describe the characteristics of an
important community-based safety network that is needed for the
early detection and quantification of drug adverse events,
something that is not going to be available by data dredging
and data mining of the currently available databases.
In summary, drug safety problems are only a symptom of a
flawed system of drug development. In the Critical Path
Initiative the FDA has offered to be part of the solution to
this serious problem. The Critical Path Initiative is a great
investment because it has the potential to improve drug safety,
facilitate drug development and to substantially reduce the
future costs of medications, especially the $720 billion
estimated for a Medicare prescription drug benefit.
Thank you.
[The prepared statement of Dr. Woosley follows:]
Prepared Statement of Raymond L. Woosley, M.D., Ph.D
Senator Enzi and members of the committee, I am Dr. Raymond
Woosley, President of The Critical Path Institute, a non-profit
organization created to facilitate innovations in drug development. Our
goal is to create a forum for drug development scientists from the FDA,
academia and the pharmaceutical industry to evaluate innovations in
drug development; innovations that will give patients the earliest
possible access to the safest possible medications. We believe that
such a forum, i.e. a neutral territory, is essential to bring about
needed changes in the ways drugs are developed. The Institute is
working closely with the FDA Commissioner's office and other scientists
at the FDA, The University of Arizona and SRI International (formerly
Stanford Research Institute) to develop a formal arrangement for this
collaboration. I am also the Director of the Center for Education and
Research on Therapeutics (CERT), a Center at the University of Arizona
funded by the Agency for Healthcare Research and Quality. CERT is one
of seven centers in the Nation authorized by Congress to improve the
medical outcomes from therapeutics. After 30 years of research and
teaching in medical schools at Vanderbilt University, Georgetown
University and most recently the University of Arizona, I will leave my
academic position in July to lead the CERT and The Critical Path
Institute. This will enable me to focus my efforts on what I believe is
a crisis in pharmaceutical development.
A CRISIS IN DRUG DEVELOPMENT
This crisis can best be appreciated by looking at recent events and
the following data:
1. The pharmaceutical industry spends 12-15 years and almost a
billion dollars for each drug that is successfully developed. Yet, in
spite of such an investment in time and dollars, this process still
fails to detect serious adverse effects of products until they are on
the market, often for years, and millions of Americans have been
exposed to potential harm.
2. Pharmaceuticals have been one of our Nation's most successful
industries. However, over the last 10 years, the industry increased its
investment in research and development by 250 percent but the number of
new products submitted for FDA review has fallen by 50 percent.
3. The proportion of drugs that fail during development has doubled
in the last 10 years.
4. In the last 8 years, over half of the 15 drugs removed from the
market because of safety concerns were, in fact, safe when used as
directed in the labeling. Warning labels did not prevent drugs from
being used in ways that resulted in harm to patients. Tens of billions
of research and development dollars were wasted and many patients
suffered serious injury.
5. Personalized medicines, the promise of human genome research,
are only rarely being developed because of the high cost of drug
development relative to the potential market size.
6. The protracted and costly development of drugs, combined with
the limited time in the market before generic competition begins,
results in unacceptably high drug costs and drug re-importation from
countries that employ price controls.
7. Skyrocketing estimates for the cost of a Medicare prescription
drug benefit have prompted consideration of policies and pricing
negotiations that would limit access to new medicines and threaten
future research and development of medicines that are needed by
patients with chronic and debilitating diseases.
8. In addition to concern for the patients harmed by drugs, there
is another societal concern. The removal of drugs from the market has
resulted in hundreds of class action law suits that threaten the very
existence of some of our Nation's most successful companies.
So, while the issue of drug safety must be addressed, we must do so
in the context of a broader crisis in which the wrong action(s) could
further threaten the future viability of the pharmaceutical industry
and the availability of vital new medicines. For example, adding a
requirement for phase IV monitoring to our broken system without other
changes would be catastrophic. At the same time, the absence of an
effective drug safety program is one of the major contributors to the
delays in drug development that adds to high costs and delayed access
to important new medicines. Two-thirds of the FDA medical reviewers
recently surveyed expressed concern that the post-marketing
surveillance system at the FDA was inadequate. I have no doubt that
this concern must have a negative influence the reviewers' willingness
to assist the industry in accelerated development of even the most
important new medicines. Therefore, it is essential and timely that we
discuss how to improve the development of drugs and assure their safe
use.
BASIC ``FACTS OF LIFE'' FOR PHARMACEUTICALS
A critical first principle is that there is no such thing as a
``safe drug''. Even the title of these hearings, ``Ensuring drug
safety'' is an impossible goal. No one can ensure drug safety; we can
only expect the FDA to identify drugs with an acceptable risk/benefit
ratio, inform the public, and develop methods to maximize benefit and
minimize harm. FDA approval will never mean that a drug is ``safe.''
Instead it signifies that the available evidence indicates that a drug
should be ``relatively safe when used as directed.'' All medicines that
have pharmacologic effects must be assumed to have the potential for
harm. This is a message that must be better appreciated by the public
so that they are not surprised when newly marketed drugs are found to
have adverse effects.
THE FDA MUST BE GIVEN ADEQUATE NUMBERS OF PEOPLE AND RESOURCES
Over the last 20 years I have served as a frequent advisor to the
FDA, usually on issues of drug safety. In this capacity, I learned
first hand the limitations that exist in the FDA's legal authority as
well as the FDA's limited resources. It doesn't appear in their budgets
but information technology and computer allocations have been slashed
in recent years. The agency that handles some of the most complex and
vital data in the world relies upon information handling systems that
were discarded decades ago in most corporations. Only 109 scientists
monitor the safety data from over 3,000 prescription drugs. Where a
complete system of drug safety surveillance is needed, the FDA is
forced to rely on its voluntary reporting system for adverse events.
THE FDA LACKS ADEQUATE LEGAL AUTHORITY TO EFFECTIVELY REGULATE DRUGS
Once a drug is marketed, the FDA has no control over the way it is
used in clinical practice. Relatively safe drugs are often used in
unsafe ways (e.g. in combination with other interacting drugs or in
excessive dosage or duration). As is the case in Canada and other
countries, the FDA should be given the authority to restrict or suspend
access to drugs when serious questions arise about their safety.
The FDA also lacks any authority to demand further research on
marketed drugs. Warning labels, though commonly required by the FDA,
are known to be ineffective. The only effective tools that the FDA has
to protect the public are, (1) to keep a drug off the market or, (2)
once on the market, try to take it off. Because of its limited
resources, the FDA rarely attempts legal action to remove drugs from
the market. In almost every case, drugs are voluntarily removed by the
manufacturer because of pressure from the FDA and not deliberate legal
action by the FDA.
A BETTER TOOL BOX
The FDA needs more options for action. The FDA could better perform
its responsibility if it had a broader range of options with which it
can respond to the ever broadening spectrum of drug information that is
generated over the pharmaceutical life of a drug.
A PROPOSAL FOR STAGED APPROVAL OF NEW DRUGS
Because more information than ever before is being generated about
the value and risks of new drugs and because time is required for this
information to be assimilated into the practice of medicine, there is a
need for earlier approval followed by tightly controlled and more
gradually increasing usage of new medications. Figure 1 demonstrates an
alternative path for new drugs that I believe should be considered,
debated and evaluated. It proposes an earlier approval but more gradual
growth in use of a prescription drug combined with a comprehensive
safety assessment in the marketplace. As can be seen, there is an
earlier and more gradual rise in the number of patients treated in this
model. This allows time for more complete safety testing and
assimilation of the drug into the practice of medicine before millions
are exposed to the drugs.
The first change suggested is in phase II, which would be expanded
to include more complete characterization of the drug's dose-response
relationship in the intended population and sub-populations (e.g. the
very elderly, those with renal insufficiency, co-morbid conditions,
etc) and for completion of any necessary targeted drug interaction
studies. These latter studies should be those based on in vitro
predictions, e.g. cytochrome P450 or drug transporter interaction
studies. Phase II should include modern computing techniques such as in
silico simulation of trials, enrichment using biomarkers, adaptive
trial design and others suggested in the FDA's Critical Path
Initiative.
Market-I: At the end of a more comprehensive and informative phase
II requiring approximately 4 years, the drug could be approved for
marketing to a carefully defined population of patients (Market-I in
figure 1). This is very similar to the way AIDS drugs were developed in
2-4 years without taking dangerous shortcuts.
A Safety System: To make the early release of a drug feasible and
rationale, it will be essential to have an intensive plan for post-
marketing safety assessment and risk management. Academic programs such
as the Centers for Education and Research on Therapeutics
(competitively funded by the Agency for Healthcare Research and Quality
to improve outcomes from medical therapies) can help develop risk
management programs and conduct outcomes research on large databases
and registries to confirm the efficacy and safety predicted from phase
II. As they evaluate the safety of the drug, they can also use similar
methods to confirm efficacy for initial indications and evaluate the
potential efficacy of the drug in new indications. In most cases, the
new drug should initially be given under observed conditions, using a
system like the yellow card system in the U.K. in which physicians
report the outcome of therapy in each patient receiving a specific drug
on a ``yellow card.'' Modern electronic medical record systems make it
possible to have a system like the U.K.'s General Practitioner's
Network which tracks the outcome of every patient they treat with a new
drug. Also, modern electronic registries can detect adverse event
signals earlier and compare the safety of new and older drugs in a
class. The CERTs could play a role similar to the pharmacovigilance
centers in France and monitor drug outcomes in the community. The FDA
and the pharmaceutical sponsor would have to agree to the use of
measures to assure that the drug is used as directed in labeling.
Sponsors could be encouraged to follow the lead of at least one
innovative company that paid commissions to sales representatives based
upon how well doctors in their region used the company's drug instead
of how often the drug was prescribed. Effective risk management
programs have been successfully developed in the past for drugs with
the potential for serious toxicity, e.g. clozapine. Because this
antipsychotic drug can cause fatal bone marrow toxicity in 1 percent
patients per year of treatment, proof of monitoring of white blood
count is required before the drug can be dispensed. This has reduced
the incidence of fatal toxicity by 60 percent.
A Novel System: In Arizona, The Critical Path Institute and the
CERT are exploring the feasibility of developing an innovative
community based safety surveillance system. This system would resemble
programs in the UK and France in that it would prospectively gather
data on the outcomes of new medicines and submit it directly to the
FDA. I believe that such a system must be developed de novo because the
information needed to address drug safety cannot be gleaned from
currently available databases. Data mining only works when the
information you need is somewhere in the system. For the same reason,
linking databases will never give adequate information. The system must
be relatively inexpensive, should not interfere with the practice of
medicine or pharmacy and should be flexible enough to detect suspected
and unsuspected adverse events of any newly marketed drug. It should be
able to quantify the rate of adverse event occurrences and even answer
questions of relative safety by comparing the outcomes with selected
comparator drugs. It should provide positive feedback to physicians in
order to prevent future adverse events and improve drug outcomes. If
the system were effective, even drugs with the potential for serious
adverse events might be able to remain on the market. For this or any
program to be successful, the FDA must be given the staff and resources
to participate in the design and implementation of this system and then
to monitor the data that are gathered from this system.
The staged approval model would allow a pharmaceutical company to
begin marketing its product earlier with a lower total capital
investment and at a time when much more of the patent life is still in
effect. It should also make it possible to detect any serious life-
threatening problems earlier before millions have been exposed,
reducing the frequency of litigation and class action law suits. Also,
for companies using this track, serious consideration should be given
to offering indemnification from law suits filed for adverse events in
return for the sponsor paying for any medical expenses resulting from
such adverse reactions. This would provide patients and the drug
sponsor some protection from the potential harm from a new drug.
Market II: If after a period of careful observation on the market,
the drug appears safe and effective, it could be given approval for an
expanded market with fewer or no restrictions to its use (Market II on
the diagram). Market II is effectively the same as the current market
in which any licensed physician can prescribe a marketed drug for any
indication, as long as the physician has evidence that such use has a
scientific basis.
Pharmacist Assisted Care (PAC) and OTC: If a marketed prescription
drug is found to be relatively safe and used for a condition that can
be self-diagnosed by the patient, it has been customary for it to be
given non-prescription status, often called ``over-the-counter'' or
OTC. This may or may not be attractive to the pharmaceutical sponsor
depending upon many economic and market factors. In some cases the
sponsor would like to expand the market by having the drug available
OTC. However in many cases such as the statin drugs for lowering
cholesterol, some aspect of a drug's use requires medical supervision
and the FDA is reluctant to approve its use without medical
supervision. In these cases, there is no alternative now available but
to deny approval of OTC status. However, in Canada and many other
countries there is another option. The drug can be given ``behind the
counter'' status. ``Behind the counter'' means that the drug is
available in pharmacies for patients who ask for the medication but
only after consultation with a pharmacist. The pharmacist can perform
any pre-screening or counseling that could make it more likely that the
drug will be used safely. This additional step, ``Pharmacist Assisted
Care'' (PAC), could widen the therapeutic benefit to patients, better
utilize the important role of pharmacists and minimize the risk of
therapy. After a period of safe use in the PAC category, a drug may be
recommended for full OTC status when justified.
THE NEED FOR INNOVATIONS IN THE PROCESS OF DRUG DEVELOPMENT
To address the increasing delays and failures in drug development,
the leadership of the FDA has proposed the ``Critical Path
Initiative''. This proposal includes efforts to optimize drug
development and identify new ways to test medicines that will give
greater assurance of safety and effectiveness than we have now.
However, this plan will require new partners and new resources for the
FDA. A recent report from former Secretary of Health and Human Services
(HHS), Tommy Thompson, pointed out the need for partnering between FDA
and the NIH, CMS and CDC. But to do this collaborative work, it must
have resources that are not provided in the current budget. Also, the
fact that the FDA budget is under the Department of Agriculture and not
under the full control of the Secretary of HHS is an impediment to
forming these partnerships.
The FDA's Critical Path Initiative calls for academic partnerships
to develop innovations that improve drug development. Forming these
will also require that the Agency have the staff and resources to
participate. Just as the Moffet Center in Illinois was established by
the FDA to address food safety, academic sites can be ``neutral
ground'' where scientists can share their knowledge and expertise in
drug development and drug safety without commercial conflicts of
interest. These public/private partnerships can enable scientists from
the FDA, academia and industry to develop methods to increase the
efficiency and informativeness of the drug development process.
The Critical Path Institute that I lead was created for this
purpose. Out of serious concern over the relative safety and
availability of new medicines, the citizens of Tucson and Southern
Arizona have committed over $9 million to seed the initial work of the
Institute.
We believe that an investment that enables the FDA to facilitate
the development of safe drugs is a good investment, especially at this
time. Medicare estimates that its prescription drug benefit will cost
over $720 billion in its first 10 years. That estimate surely assumes
that new drug costs will continue to rise at its current rapid rate. If
we are ever going to have less expensive new drugs, we must shorten the
development time, increase the number of drugs successfully developed
in order to stimulate competition in the marketplace and improve the
safety information about these drugs. Increased numbers of drugs for a
specific disease enable competition to yield lower drug prices. Larger
numbers of drugs with different actions will better meet the needs of
our biologically diverse population. ``One size'' does not ``fit all.''
Furthermore, adequately studied drugs and the safe use of drugs can
result in lower healthcare costs and improved health.
Lowering drugs costs by accelerating the development of safer
medications is a far better alternative than ``re-importation'' of
drugs which is just an indirect means to use foreign price controls to
lower our consumers' drug costs. It would be preferable to give the FDA
the resources it needs to help improve the process of developing drugs.
SUMMARY OF RECOMMENDATIONS
1. Permanent experienced leadership for the FDA is essential.
Acting Commissioner Lester Crawford, Acting Deputy Commissioner Janet
Woodcock and many others working with them are experienced leaders who
can, with the proper resources, lead positive change at the FDA.
2. The FDA should be adequately funded to carry out its mission.
This support should include funds for the Critical Path Initiative and
an effective safety surveillance system.
3. The ``user fee'' system should be replaced with a system in
which industry support is not directly linked to the FDA's work and
performance.
4. Determination of drug safety requires an assessment of both risk
and benefit and should remain the purview and responsibility of the
FDA, and not of a separate agency as I and others have previously
suggested. However, the on-going safety evaluations of marketed drugs
should be made by FDA scientists who were not responsible for the
original approval recommendation.
5. The FDA should develop a comprehensive post-marketing assessment
program for drugs using inter-agency collaborative programs and public-
private partnerships.
6. Just as the National Transportation Safety Board is responsible
for investigating all accidents and then makes recommendations for
safety, there should be an analogous independent body to conduct in-
depth review of the process used to detect serious issues/events in
drug development and the response to those events by the FDA and
industry. This body could assess the roles played by consumers,
healthcare providers, health professions educators, the FDA, the
pharmaceutical industry, the press and even Congress.
7. The FDA should be given the authority to release drugs in stages
that are appropriate for the drugs' level of development and the
information that is known at the time.
I am extremely grateful for the opportunity to provide testimony at
this hearing. I hope you find my perspective of value as you review the
FDA's drug safety system.
The Chairman. Thank you very much.
Dr. Psaty. Thank you very much. Thank you for the
opportunity to testify. My name is Bruce Psaty and, as you
indicated, I am a general internist and a cardiovascular
disease epidemiologist. I have broad interests in public health
and drug safety.
The COX-2 inhibitors, a new class of nonsteroidal anti-
inflammatory drugs, were supposed to have fewer serious side
effects than other available nonsteroidals. After more than 5
years on the market, an increased risk of heart attack, stroke
were confirmed for Vioxx, Celebrex and Bextra. Some of the 20
million Vioxx users and 27 million Celebrex users were injured.
Indeed, the integrity of the American Drug Safety System has
been called into question. How can this problem be prevented in
the future?
Recommendations:
No. 1. Give balanced attention to risks and benefits in the
FDA decisions. To use a drug wisely, patients and physicians
need to know about both risks and benefits. The design of the
preapproval trials of the COX-2 inhibitors minimized the
possibility of uncovering evidence of cardiovascular harm. Some
of the trials with unfavorable results went unpublished. If
manufacturers do not address the potential risks, as well as
benefits, with equal scientific rigor, then, in the interests
of public health, the FDA must insist that they do so, both
before and after approval.
No 2. Require large long-term trials. The limited
preapproval of the evaluation of the COX-2 inhibitors was not
adequate. Medicines that will be used by millions of Americans
for long periods of time are best evaluated in large, long-term
clinical trials that are started as early as possible in the
approval process. These trials need not delay the approval.
This approach used for the lipid-lowering statin drugs has
benefited patients, physicians and the pharmaceutical industry.
No. 3. Create an independent Center for Drug Safety within
the FDA to oversee drugs after marketing. In a commentary,
entitled, ``Postmarketing surveillance--lack of vigilance, lack
of trust,'' the editors of JAMA write, ``It is unreasonable to
expect that the same agency that was responsible for approval
of drug licensing and labeling would also be committed to
actively seek to prove itself wrong.'' Other scientists and
former FDA officials have also advocated an independent Center
for Drug Safety.
No. 4. Invest the Center for Drug Safety with new authority
to regulate drugs that are on the market. Revisions to the
Vioxx product label took 2 years. The Center for Drug Safety
must be able to compel manufacturers in a timely fashion to
revise labels, to conduct patient education or physician
education, to limit advertising, to complete promised studies,
to conduct new studies, to suspend sales or to withdraw drugs.
The Center for Drug Safety should be responsible for
postmarketing evaluations, including the determinations of the
risks and benefits for drugs that are on the market.
No. 5. Provide the Center for Drug Safety with new
resources. America has become the drug safety testing ground
for new medications, such as COX-2 inhibitors. According to Dr.
David Kessler, former head of the FDA, ``PDUFA should have had
funding on the safety side from the beginning, but industry
refused to accept that. We wanted it. The industry said, no.''
Senator Enzi, you referred to the drug lag. And your
committee did terrific work in solving the drug lag. We now
have a safety lag, and I would encourage you to address the
safety lag. In the Office of New Drugs, more than 1,000
employees work to review a few dozen new drugs each year. In
the Office of Drug Safety, 109 employees work to evaluate the
safety of thousands of drugs that are currently on the market.
The FDA needs an independent center whose mission, vision and
values are geared toward evaluating and monitoring drugs that
are on the market.
No. 6. Strengthen postmarketing safety systems. The FDA's
MedWatch system, which has been characterized as a
fundamentally 1950s approach, lacks many of the features of
high-quality epidemiologic studies, including the ability to
validate events by standard criteria, the ability to identify
controls and so forth. The State of this system stands in stark
contrast to the enormous expansion of the pharmaceutical
industry during the past several decades. In 2004, the COX-2
inhibitors had combined sales of more than $6 billion. Several
new mechanisms to conduct postmarketing surveillance rapidly
and efficiently merit support.
In summary, regardless of the speed of approval, toxic
molecules occasionally make it to market as drugs. To protect
the health of the public, the most important recommendation is
an independent Center for Drug Safety with new authority and
funding. Ongoing congressional oversight of the FDA, of CDER,
and the new Center for Drug Safety would afford an important
opportunity for the public discussion of drug safety.
Thank you.
[The prepared statement of Dr. Psaty follows:]
Prepared Statement of Bruce M. Psaty, M.D., Ph.D.
Mr Chairman and members of the committee, thank you for the
opportunity to testify. My name is Bruce Psaty. As a practicing general
internist and cardiovascular-disease epidemiologist, I have broad
interests in public health and drug safety.
The COX-2 inhibitors, a new class of non-steroidal anti-
inflammatory drugs, were supposed to have fewer serious side effects
than other available non-steroidals. After more than 5 years on the
market, an increased risk of heart attack and stroke has been confirmed
for Vioxx, Celebrex, and Bextra (1-5). Some of the 20 million Vioxx
users and 27 million Celebrex users have been injured. Indeed, the
integrity of the American drug-safety system itself has been
questioned. How can this problem be prevented in the future?
RECOMMENDATIONS
1. Give balanced attention to risks and benefits in FDA decisions
(6-8). To use a drug wisely, patients and physicians need to know about
both risks and benefits. The design of the pre-approval trials of the
COX-2 inhibitors minimized the possibility of uncovering evidence of
cardiovascular harm. If manufacturers do not address the potential
risks and benefits with equal scientific rigor, then in the interests
of public health, the FDA must insist that they do so, both before and
after approval.
2. Require large long-term trials (9). The limited pre-approval
evaluation of the COX-2 inhibitors was not adequate. Medicines that
will be used by millions of Americans for long periods of time are best
evaluated in large long-term clinical trials that are started as early
as possible in the drug approval process. These trials need not delay
approval. This approach, used for the lipid-lowering statin drugs, has
benefited patients, physicians and the pharmaceutical industry.
3. Create an independent Center for Drug Safety within the FDA to
oversee drugs after marketing (10-14). In a commentary entitled,
``Postmarketing surveillance--lack of vigilance, lack of trust,'' the
editors of JAMA, write: ``It is unreasonable to expect that the same
agency that was responsible for approval of drug licensing and labeling
would also be committed to actively seek evidence to prove itself
wrong.'' Other scientists and former FDA officials have also advocated
a truly independent Center for Drug Safety.
4. Invest the Center for Drug Safety with new authority to regulate
drugs that are on the market (4,15). Revisions to the Vioxx product
label in 2002 took more than 2 years to negotiate. The CDS must be able
to compel manufacturers, in a timely fashion, to revise product labels,
to conduct patient or physician education, to limit advertising, to
complete promised studies, to conduct new studies, to suspend sales and
to withdraw drugs. The Center for Drug Safety should be responsible for
post-marketing evaluations, including determinations of the balance of
risks and benefits for drugs that are on the market.
5. Provide the Center for Drug Safety with new resources
(14,16,17). America has become the drug-safety testing ground for new
medications, such as the COX-2 inhibitors. According to Dr. David
Kessler, former head of the FDA, ``PDUFA should have had funding on the
safety side from the beginning, but the industry refused to accept that
. . . . We wanted it. The industry said no.'' Since 1992, FDA resources
for drug safety have dwindled. In the Office of New Drugs, more than
1,000 employees work to review a few dozen new drugs per year. In the
Office of Drug Safety, 109 employees work to evaluate the safety of
thousands of drugs currently on the market.
6. Strengthen US post-marketing safety systems (18-21). The FDA's
MedWatch system, which has been characterized as ``fundamentally a
1950s-era approach,'' lacks many of the features of high-quality
epidemiologic studies, including validation of events by standard
criteria, complete ascertainment of cases, population-based controls,
comparable assessment of drug use and risk factors, and so forth. The
state of this system stands in stark contrast to the enormous expansion
of the pharmaceutical industry during the past several decades. In
2004, the three COX-2 inhibitors alone had combined sales more than $6
billion dollars. Several new mechanisms to conduct post-marketing
surveillance rapidly and efficiently merit support.
Regardless of the speed of approval, toxic molecules occasionally
make it to market as drugs. To protect the health of the public, the
most important recommendation is an independent Center for Drug Safety
with new authority and funding. On-going congressional oversight of the
FDA, CDER, and the new Center for Drug Safety would afford an important
forum for the public discussion of drug safety. Thank you.
SUPPLEMENTARY INFORMATION
Post-marketing surveillance. When drugs are approved as ``safe and
effective'' for their intended use, the known benefits appear to
outweigh the known risks (20). At the time of regulatory approval for
most drugs, a number of issues remain unknown--the occurrence of rare
but serious adverse drug events, drug interactions, late events during
treatment or after the discontinuation of treatment, effects in
pregnancy or differential effects in subgroups that may be defined by
age, sex, race, or other factors. In contrast to the highly structured
pre-marketing evaluation, post-marketing surveillance has little
structure. According to Gale, ``the regulatory process creates an
evidence-free zone at the time of launch of new drugs'' (20).
Pharmaceutical companies often promise post-marketing clinical trials
as a condition of approval. In practice, however, more than half of
these promised studies, according to an FDA report, have not been
started (15). The FDA lacks authority to insist that these promised
studies be completed or to compel new post-marketing studies. The FDA
post-marketing regulations require only that pharmaceutical companies
collect, review and report to the FDA all suspected adverse drug
reactions (ADRs) thought to be associated with the drug (22,23). While
both companies and the FDA can analyze the ADR data and recommend
actions such as label changes, additional warnings, or new studies, the
FDA regulations largely focus on reporting procedures and thus leave
unclear who is required to initiate these actions.
U.S. post-marketing surveillance system. MedWatch, the FDA safety
information system and adverse event reporting program, encourages
physicians to report ADRs on a voluntary basis (18). Although the FDA
received 286,755 ADR reports in 2001 (24), these data have major well-
known limitations. The MedWatch ADR data are suitable only to identify
rare serious adverse drug events that occur early in treatment and that
are unrelated to the indication of the drug. For example, the lipid-
lowering statin drug, Baycol (cerivastatin), was withdrawn from the
market in 2001 because it was associated with high rates of
rhabdomyolysis, a breakdown of muscle cells that causes pain, kidney
failure and sometimes death (19,21,25). The MedWatch ADR data lack many
of the features of high-quality epidemiologic studies, including
validation of events by standard criteria, complete ascertainment of
cases, population-based controls, comparable assessment of drug use and
risk factors, and so forth. It would not have been possible to use the
MedWatch system to detect reliably, for instance, the increased risk of
cardiovascular events associated with the COX-2 inhibitors. One recent
commentator characterized the MedWatch system as ``fundamentally a
1950s-era approach'' (26).
Growth of drug sales. The lack of development in post-marketing
surveillance systems stands in stark contrast to the enormous expansion
of the pharmaceutical industry during the past several decades.
Although the costs of drug development are high, spending on
prescription drugs between 1997 and 2001 increased by about 18 percent
per year; and in 2001, the total prescription drug expenditures in the
U.S. reached $154.5 billion dollars (27). In 2004, despite the
withdrawal of Vioxx in September, the three COX-2 inhibitors alone--
Vioxx, Celebrex, and Bextra--had combined sales more than $6 billion
dollars, or an average of about $16 million per day (28). The recent
growth of the pharmaceutical industry has outstripped the safety
systems that were developed when the industry was young.
Epidemiologic studies and new opportunities. In the past, data
sources used to conduct high-quality observational studies of the risks
and benefits of drugs have included existing cohort studies (29),
administrative data from health maintenance organizations (30,31),
Medicaid data (32,33), Medicare data linked to cancer registries (34),
and international databases with drug data (35,36). In addition to
AHRQ-funded Centers for Education and Research in Therapeutics (26),
the FDA has had cooperative agreements with several institutions to
investigate drug safety, but the available funds have diminished in
recent years. Several new opportunities are on the horizon. First, data
from new Medicare drug benefit can be linked with hospital and
ambulatory care data to create a new resource for the study of drugs in
older adults. With appropriate protections for privacy, these data
should be available to the FDA and independent scientists interested in
drug safety. Secondly, as part of the NIH Roadmap Project, the HMO-
Research Network--Coordinated Clinical Studies Network will create an
infrastructure for conducting studies on substantial numbers of the
U.S. population, and the movement toward an EPICcare based electronic
record among the network members should soon provide the opportunity to
conduct post-marketing surveillance rapidly and efficiently.
Post-marketing clinical trials. The pharmaceutical industry
supports a number of post-marketing clinical trials, often for new
indications. The cardiovascular harm associated with the COX-2
inhibitors became apparent in studies that were conducted for new
indications such as the prevention of non-cancerous tumors in the colon
(1-3). For the lipid-lowering statin drugs, for instance, the large
long-term clinical trials have provided robust evidence about their
health benefits in preventing cardiovascular complications of high
levels of cholesterol (37-40). On the basis of this evidence, the
indications for the statin drugs have expanded, statin drug sales have
increased, and the health of the public has improved. Rapid publication
and widespread dissemination of favorable findings is standard
practice.
Failure to publish trials with unfavorable results. Unfavorable
results tend not to get published. In the manufacturer's trial of 1.6
mg of Baycol, about 12 percent of patients developed signs and symptoms
compatible with rhabdomyolysis (25). The high rate of adverse effects,
with a dose that was only twice as high as the approved dose of 0.8 mg,
``led to a consensus by the [company's communications] committee not to
publish the results of this study'' (25). Similarly, in 2000, Pfizer
completed a randomized trial of celecoxib in Alzheimer's patients, but
never published the unfavorable cardiovascular results and only made
them publicly available in January 2005 (41). The results of this
Alzheimer's study were not submitted to the FDA until June 2001,
several months after a safety review that established labeling for
Celebrex. Human subjects participate in studies to contribute to
science and public health. Failure to publish findings not only
violates their trust, but it also misrepresents the evidence about
risks and benefits for patients and physicians. Federal action to
assure that all clinical trials are registered and reported in a timely
fashion is important.
Prescription Drug Users Fee Act (PDUFA) of 1992. In the late 1980s
and early 1990s, the pressure from companies and patients alike was not
for additional safety evaluations, but for shorter approval times (42).
In response to the criticism that the FDA approval times were too long,
Congress introduced user fees in 1992. Pharmaceutical companies seeking
drug approvals paid fees that enabled the FDA to hire additional staff,
and the FDA was expected to meet new requirements for the timelines of
new-drug approvals (16). According to Dr. David Kessler, head of the
FDA from 1990 to 1997, ``PDUFA should have had funding on the safety
side from the beginning, but the industry refused to accept that . . .
. We wanted it. The industry said no'' (17). The 1992 user fee act and
its reauthorization in 1997 prohibited the agency from spending users
fees ``on post-marketing surveillance or other drug-safety programs''
(14). The reauthorization in 2003 included some provisions for safety.
During the period 1992 to 2003, this approach--more and faster new
approvals without additional funds for safety surveillance--relied
increasingly on the honesty, trustworthiness, and integrity of the
pharmaceutical industry in the conduct of its own post-marketing safety
evaluations.
PDUFA, review times, and funding for safety. The PDUFA act in 1992
and its reauthorizations in 1997 and 2003 reduced the time required for
review of a new drug application by the FDA from 33 months in 1992 down
to about 13 or 14 months in 2001 (17). As a result, the proportion of
new molecular entities that are first introduced in the U.S. has
increased from 2 to 3 percent in the early 1980s up to 60 percent in
1998 (43). New medicines are now indeed available to Americans more
quickly. At the same time, U.S. patients also became the first to
receive new medications, some of which, such as COX-2 inhibitors, are
subsequently discovered to have serious adverse effects. The Office of
Inspector General 2003 Report on the FDA's Review Process for New Drug
Applications has assessed the impact of the new review process at the
FDA (16). Funding for safety has also been affected. In 1992, 53
percent of the budget of the FDA Center for Drug Evaluation went to new
drug reviews, and the rest went to surveillance, laboratories and other
safety efforts. In 2003, 79 percent went to new drug reviews. Resources
available for safety have dwindled (44). Drug recalls following
approval increased from 1.56 percent in 1993-1996 up to 5.35 percent
for 1997-2001 (10).
Calls for an independent Center or Office of Drug Safety. In a
recent commentary, the JAMA editors advocate an independent center or
office of drug safety: ``It is unreasonable to expect the same agency
that was responsible for approval of drug licensing and labeling would
also be committed to actively seek evidence to prove itself wrong (ie,
that the decision to approve the product was subsequently shown to be
incorrect)'' (10). Other recent commentaries in JAMA (13) and the New
England Journal of Medicine have recommended the creation of an
independent drug-safety board ``to monitor drug safety, investigate
reports of drug toxicity, and recommend actions to minimize the risks
of drug therapy'' (14). The new Advisory Board on Drug Safety announced
by Michael O. Leavitt, secretary of Health and Human Services on
February 15 is not adequate. According to Dr. William Schultz, FDA
deputy commissioner for policy from 1994 to 1998, ``The FDA should
separate the monitoring of drugs after they have been approved from the
drug review function'' (12).
Need for additional authority in the Center for Drug Safety. In
March 2000, Merck was aware that compared with naproxen, Vioxx
increased the risk of heart attacks (45). In February 2001, an FDA
Advisory Committee reviewed the safety data, but revisions to the
``Precautions'' section of the VIOXX product label were delayed until
April 2002. The public health rationale for the 2 year delay in
revising the product label remains unclear. Although the FDA can call
Advisory Committee meetings or issue press releases, talk papers,
guidances, and requests to manufacturers, these powers are not adequate
to regulate drugs that are on the market. For an approved drug, the FDA
currently engages in protracted negotiations with manufacturers rather
than mandating manufacturers: to change a product label, to conduct
patient or physician education, to limit advertising to patients or
physicians, to modify approved indications, to restrict use to selected
patients, to complete post-marketing studies agreed upon at the time of
approval, to conduct additional post-marketing studies or trials, to
suspend marketing or withdraw a drug. At least one pharmaceutical
executive has advocated providing the FDA with additional authority to
mandate studies after drugs are approved (46). Moreover, provisional
approval for the first 2 or 3 years would provide an opportunity to re-
review the balance of risk and benefit.
Elements required to protect the health of the public. The failure
to pose a question often precludes the possibility of obtaining an
answer. Pharmaceutical companies generally lack enthusiasm for
aggressively pursuing questions about the safety of their drugs. In
science, only those questions that are investigated with well-designed
studies have a decent chance of producing a solid answer. If the
pharmaceutical industry does not pose critical questions about drug
safety, the FDA must do so in an effort to protect the health of the
public. Key elements related to the study of drug safety include: (1)
the generation of ideas about a drug's risks as well as its benefits;
(2) a sustained effort to investigate or document risks as well as
benefits; (3) the availability of high-quality surveillance systems or
the conduct of specifically designed studies to assess risks as well as
benefits; and (4) the willingness to publish findings about risks as
well as benefits. If manufacturers do not provide support for a
vigorous and balanced scientific evaluation of safety signals for drugs
that are already on the market, the Center for Drug Safety must do so
to protect the health of the public.
Activities of the Center for Drug Safety. At the time of approval
for each new drug and on the basis of information available in the NDA
and other studies, the Center for Drug Safety needs to identify a set
of studies required to address the key unanswered questions,
particularly the pursuit of potential safety ``signals'' or ``plausible
biologic hypotheses'' on behalf of the health of the public. Depending
on the drug, the indication and the known safety profile, the studies
may include Phase IV trials, epidemiologic studies, pharmacokinetic-
pharmacodynamic studies, close surveillance of ADR reports, or a
combination of several approaches. Specific post-marketing trials or
studies should be designed, conducted and completed in a timely
fashion. The Center for Drug Safety should be responsible for assessing
the balance of risk and benefit of drugs that are on the market.
References
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The Chairman. Thank you very much. I appreciate the
testimony of all of the witnesses. I have a huge number of
questions. I know I am not going to be able to get through all
of them. But as I mentioned before, we will be submitting some
in writing, particularly the more detailed ones.
I will begin with Dr. Wilson. One of our witnesses on
Tuesday said that patients are going to doctors and getting
drugs they should not because of direct-to-consumer
advertising. How would you respond to that? Could you comment
on the role of direct-to-consumer advertising in educating
patients and in the doctors' prescribing decisions?
Dr. Wilson. Yes, thank you, Mr. Chairman. The AMA supports
patients' increased access to drug information and, clearly,
direct-to-consumer advertising provides that. But let me just
say, as a practicing physician, I would echo the remarks that
you heard earlier this morning that it, also, exerts an
enormous pressure on the physician. And so our concern is the
impact direct-to-consumer advertising has on the physician-
patient relationship. It, obviously, is advertising that is
designed to sell a product, and we would suggest that it does
not present in the ads the kind of accurate and objective
information that patients need.
In 1993, the AMA published some guidelines or agreed to
some guidelines in consultation with the FDA which deal with
direct-to-consumer advertising. So we would urge the
pharmaceutical industry to use those guidelines.
The Chairman. Thank you.
Mr. Carson, you mentioned data mining in your testimony.
What are the potentials and limitations for data mining to
identify safety signals early? What are the hurdles to
developing a comprehensive database for use with validated
mining tools? Does the FDA have the computational resources it
would need to truly be able to use those databases?
Mr. Carson. Probably not, as far as the last part of your
question. The amount of data that is involved is phenomenal and
is rapidly growing. One of the biggest problems is in having
the data available or making it available, getting the
companies to make the data available unless they are required
to. There are some aspects where it is voluntary, some where it
is required, some where it is just not asked for at all or it
is not involved.
I think that industry needs to see the advantage of making
the data available and sharing it amongst themselves. And then
there is a lot of data available at the FDA that other
companies do not see, but a lot of it is proprietary. They have
to keep it confidential for the companies that have supplied
the data. So there would have to be agreement that this data
could be made available.
In addition to that, of course, is the confidentiality
issues surrounding the patient. There, of course, is a lot of
concern, and you see reports of this of people will be, many
people will be very reluctant to have these genetic screenings
done and to have that information in a database where they do
not know if it is controllable or not. Of course, there was the
story the other day in the paper about one of the major banks
losing a lot of information on their customers. Well, I think
that in general the public does not trust these large databanks
or people that control this data.
So I think getting the data is probably the biggest
problem. There would be ways to provide the computing
capability of the cooperation were there. That is probably the
easiest part, but does FDA have the resources right now? I
would probably think they do not. They probably need additional
funding for that.
The Chairman. Thank you.
Dr. Woosley, you indicate in your written testimony that
you no longer support the idea of a separate drug safety agency
and that you now believe that the determination of drug safety
requires an assessment of both risk and benefit and should
remain in FDA. What made you change your mind?
Dr. Woosley. Further information, and the kind of points
that were made by Dr. Woodcock this morning were compelling. I
think she, clearly, described the need for an ongoing
evaluation of the benefits and the safety. And that really does
need some memory, some corporate memory, of what the drug has
done.
But the other points she made is, also, very important, and
that is what the other drugs in that category might have done
because often the safety assessment of one drug really needs to
include the safety of all the other drugs around it and in that
class. Because predicting drug safety is often knowing what the
others did.
In fact, I went back and read our New England Journal
article a few years ago that we wrote, and it really, what we
were calling for was an oversight, like the NTSB, not that
actually does the drug safety analysis, but looks at drug use,
in general, and are the systems that we have in place
appropriate? Are drugs being developed, regulated, and are they
being used in the appropriate way, and are there places outside
the FDA that need to get involved?
For example, I have taught medical students for 30 years,
and I should be taking some blame when doctors misprescribe.
Only 15 percent of the medical schools in this country have
required courses in clinical pharmacology and therapeutics. We,
as medical educators, really need to be part of solving this
problem, also. AHRQ needs to be there, to be looking at the
drug use. They have the drug safety programs, the medical
errors programs, but it is not just the FDA that is involved.
They cannot control drug use.
So, again, to answer your question more specifically,i do
not support a separate, independent safety agency outside of
the FDA. I think the FDA needs to be involved in the changes
that they are making to bring the decisionmaking away from the
people who approved it into an environment where there will be
greater input, but still have the efficacy there is going to
make me very happy with the changes.
The Chairman. Thank you. And I think probably local
pharmacists appreciate your comments because it emphasizes the
role that they play in the whole process, too.
My time is expired.
Senator Isakson.
Senator Isakson. Thank you, Mr. Chairman.
Following up on that question, Dr. Psaty, I take it you
disagree with that.
Dr. Psaty. No. Actually, I have not advocated necessarily
that the independent office be outside the FDA. I think, in
many instances, the FDA has done terrific work. I would
question some of the decisions they have made. But the Office
of New Drugs currently dominates CDER, the drug review section,
and the current structure at the FDA is just what the industry
desires--a powerful engine to approve drugs and a weak effort
to investigate safety in the postmarketing setting.
What the American public needs and deserves, in addition to
the rapid approval of drugs, is a center whose mission is
devoted to postmarketing safety evaluations.
Senator Isakson. So your reference to independence was
independence of the original testing not independence of the
Agency.
Dr. Psaty. Yes, it was. And I said in my testimony an
independent center within the FDA.
Senator Isakson. I just wanted to make sure I understood
that.
Thank you.
Dr. Psaty. Yes, sir.
Senator Isakson. Dr. Wilson, is the insert that you have
difficulty reading the same one I am supposed to read in my
medicine bottle?
Dr. Wilson. Senator, I would assume that it is very
similar. [Laughter.] As a matter of fact, in that regard, I
frequently will move from the part I am supposed to read to the
part the patient is supposed to read, and I find them equally
unclear.
Senator Isakson. The only thing harder to read than the
insert in a medicine bottle is the doctor's signature on a
prescription. [Laughter.]
Dr. Wilson. And the better the doctor, the worse their
writing is.
Senator Isakson. And I would acknowledge that I am sure
legal liability plays a large role in what has to go in that
information, and I understand that, having been a businessman
for 33 years. And I do not like for the Government to get in
the business of starting to say how big letters ought to be,
and how short words ought to be and things like that, but I
would say that, from a standpoint of a patient's, that
information regards to warnings to a patient, which certainly
is what we ought to think about, giving what we are talking
about today, and that information a doctor needs with regard to
what they need to know vis-a-vis warnings the patient might
get, if it was a little larger or at least at the beginning of
that insert, it would sure be a help to me, and I take it, it
would be a help to you. I do not know if that is AMA's
recommendation, but that was just an independent advertisement.
Dr. Woosley, you read, and I am not sure I heard you say
it, but you read in your recommendations I read that the user
fee system should be replaced with a system in which industry
support is not directly linked to the FDA's work and
performance. Would you elaborate on that for a second.
Dr. Woosley. I applaud the willingness of the
pharmaceutical industry to help the Agency do its job in
reviewing drugs. But when you tie it, like piecework, to the
review of the drug, it really misses the real need that the
Agency has for something more than just reviewing that product.
When a new drug goes on the market, there are drug interactions
with other drugs that can affect the safety and the use of
other drugs. That is not paid for when you just pay for the
review. So, by having more drugs on the market, you create more
work for everybody and more surveillance.
So what I would suggest is that we come up with a way to
fund the Agency, ideally, without user fees. In a perfect
world, that would be the goal, but that may not be the reality.
So a compromise would be to find a way that the industry can
support the FDA's role in assisting them in the regulation of
their products. Now, that does not mean just reviewing the NDA.
It means all of the work for the FDA that the FDA needs to do
to improve the drug development process, to improve the drug
surveillance system. How that is done, I mean, that is what you
gentlemen and ladies are expert at, but I think the basic
principle of tying it like piecework to the product creates the
wrong environment.
It, also, because of the large amount of money coming into
the FDA for that part of it, and the lack of additional money
for the rest of the mission, I made the analogy to, if you open
up a restaurant and you sold all sorts of sandwiches, but
everybody bought the roast beef, then you become a roast beef
store. And that is what the FDA has become because there is so
much money now going for the review process and not for the
rest of its work, people think that it is beholding to the
industry. It is not beholding to the industry. It is just that
that part of it is well-funded. The rest of its mission needs
to be funded, also.
Senator Isakson. My time is almost up, but I want to make
sure I understand. You talked about the staged approval
process. Did that mean that there would be a stage at which
certain patients might get a drug before total approval took
place? Is that what that meant?
Dr. Woosley. That is what it means. It means that the drugs
would be used in people who have been tested, that it would
move into the community in a staged fashion, and as you learn
more about it, then it would be expanded into the broader
population.
Senator Isakson. Just to comment, Mr. Chairman. I think her
name, Mrs. Washington Ines, I think was her name, that
testified yesterday or the day before on behalf of cancer
patients. That is a particular census of patients where it
appears to me that would be a process well worth looking at. Is
that the kind of thing you are talking about?
Dr. Woosley. Exactly.
Senator Isakson. Thank you, Doctor. Thank you, Mr.
Chairman.
The Chairman. Thank you.
Senator Burr.
Senator Burr. Thank you, Mr. Chairman.
I thank all of you for your willingness to be here and for
the expertise that you bring.
Dr. Wilson, I have got to ask you about one thing. One, you
need to know I do not hold much confidence, and have not held
much confidence, in MedWatch. I think that the marketplace has
changed. I think it is an antiquated program. It worked at one
time, and the fact is that we cannot count too much on it
regardless of how it is structured, so I am not going to ask
you how to restructure it or your confidence in it.
I am concerned that in your written testimony you talked
about the FDA needing to spoon-feed physicians, and I think
that in the system that we have got, and certainly with the
ability for physicians to make off-label decisions about
prescriptions that they write, it is really incumbent on
physicians not necessarily to wait for pharmaceutical reps or
for the FDA or for some outside entity to share with them
either the original information of a new drug or the ongoing
revisions that might be learned in a postsurveillance process
or in the practice of medicine.
So I am going to ask you to elaborate, if you will, exactly
what you meant because I do not think I read it in the same
context.
Dr. Wilson. Thank you, Senator. And I hope I did not say
``spoon feed'' in the testimony.
Physicians have a significant responsibility to recognize
untoward effects and to take those known untoward effects of
drugs into account when they are counseling with patients, be
sure the patients understand both the risks and the benefits.
Having gone through a college and medical school, I believe
strongly that communication and education can change behavior.
So I think my observation about present methods of
communication, whether it is MedWatch or whether it is the drug
insert, which we have discussed, I would suggest that if it is
not working, it is not because communication and education
cannot work, it is because it is because it is not good
communication and education.
So I think we, as physicians, would suggest that we need to
look at ways to communicate, and people who know how to do that
do it very well. But I would not discard that because the
challenge in discarding it is to put regulations which
prescribe who can prescribe the medicine and under what
circumstance, which put requirements on patients in terms of
reporting and testing. Efforts which may well decrease adverse
side effects, I would suggest, very well will decrease access
to medication. So we are wedded to better communication, better
surveillance, better education.
Senator Burr. I agree with you wholeheartedly, and I think
communication is at the root of it. And just since 1997, when
FDMA was passed, technology has changed in such a way that you
no longer have a pharmaceutical reference book that you go to.
First, you go to your computer. It is a much faster, easier,
more complete analysis that one can receive.
There is only one problem. It has to be initiated either by
an individual or by a medical professional. They have to be
willing to go there and to look for the answer, but I think
that the answers are available. They are certainly not
available in the things that we do not know, and I encourage
everybody within the system to begin to look at how we not
mandate it, but continue to make it easier for individuals to
want to do that.
Dr. Woosley, welcome. It is great to see you again. I have
got to ask you, because I have got great pride in CERT, how is
it going? Can you give us an update?
Dr. Woosley. It is going great, and I really thank you, as
former Congressman Burr, for being one of the champions and the
visionaries that helped us create this CERT. There are seven of
them now. They are competing for creating four more.
I must say, though, the biggest limitation--remember, you
remember this I am sure--CERTS were created to work with the
FDA. The biggest failing of the CERTs is the lack of ability to
work with the FDA to the level that we need to. They do not
have the budgets to send people. They send one person to each
of our meetings every quarter. But day-to-day interactions with
the FDA needs to occur for us to be successful in our CERTs.
That is what I was saying earlier is that because safe
drugs means safe use of drugs, we need the people, like AHRQ
and CERT, to be part of the solution in drug safety.
Senator Burr. I think we have heard, in a pretty
coordinated fashion, both several days ago and then from this
panel, that the focus should not be on how we create something
new. What we have is a system that can work if you properly
fund it. If the emphasis is on making sure that you fill in the
holes and the gaps that exist, and I hope that, in fact, we are
going to do that, my hope, looking at the changes that have
just happened again since 1997, the creation of CERT, the
frustrations that I think more people share than just me with
MedWatch, are that we can design something that is better. It
can be within FDA. It can take the talents of professionals
that we have there. It can use the expertise in the outside
world of physicians and researchers across the country.
In addition to that, we now have the human genome mapping
complete, and our ability now to take this to another level,
whether that is within the FDA or within NIH or within HHS or
within academia in this country, to be able to look at the
current compounds that we have from a human genome standpoint
and begin to target where we might not have picked up something
that we might want to go back and look at or that raises a red
flag is available, but we have got to have the initiative to go
there.
So it may be that this conversation is not just about where
do we go on this particular incident, but where do we go down
the road based on more technology and based upon where our
knowledge allows us to go. And it is refreshing to think that
we could be at a point where we are not tasked with dealing
with a crisis, where we are actually a visionary committee, and
I think it is because of the chairman's willingness to do these
hearings that we are actually focused now and, hopefully, will
focus out a little bit further than just tomorrow.
Mr. Chairman, thank you.
The Chairman. Thank you.
I wish we had more time for going into this. I have about
another 20 questions that I came with, and I have got another
dozen questions that I have developed as a result of the things
that you said, that we will need more clarification on, but we
will get to those and would appreciate a response.
We have had some excellent testimony. I really appreciate
your interest, the information, your attendance. The hearings
that we have had on the FDA have made a great contribution I
think to the debate on drug safety. The witnesses have given us
the benefit of their vast and varied experience, and we have
had a tremendously varied panel in all instances. They have
brought us some serious and some innovative proposals to
improve the system and given us a lot to think about.
I look forward to working with my colleagues on both sides
of the aisle to develop a comprehensive response to the issues
that have been raised in these hearings. As I mentioned, there
will be further questions. Your full testimony will be in the
record. You will have an opportunity to expand on any of your
remarks or any of the questions that others were given as well,
and those will become a part of the record. The record will be
open for 10 days for that. So I thank you for your
participation, and this hearing is now adjourned.
[Additional Information follows:]
Additional Information
Prepared Statement of Senator Hillary Rodham Clinton
I would like to thank Senator Enzi and Senator Kennedy for
convening today's hearing, and I look forward to learning more
about the ways in which the FDA and private industry are using
technology to further the agency's mission of ensuring the
safety of medications for all Americans.
I am extremely interested in the opportunity to learn more
about the FDA's Critical Path Initiative, through which the
agency will identify and prioritize the most pressing drug
development problems facing our public health system.
This initiative will expedite the development of new
technologies that can improve the assessment of new products,
allow for the use of more targeted therapies, and improve post-
marketing safety monitoring.
The innovations that could result from such an initiative
would be invaluable to our health system. Not only could they
be used to improve the health status of Americans, but they
would improve the quality of care provided to consumers, and
could reduce the impact of medical errors upon the healthcare
system.
While First Lady, I began my work with the FDA on
developing the Pediatric Rule, which ensures that drugs
marketed to pediatric populations have first been tested on
children. And I've continued to work on these issues with my
colleagues, including Senators DeWine and Dodd, during my time
in the Senate. I know that my colleagues and I are interested
in the ways that the technologies we discuss today could be
used to further deliver clinically appropriate treatments to
pediatric populations.
For example, genetic markers may someday allow physicians
to determine how a specific patient will react to a given
medication, thus removing many of the dosing uncertainties that
exist in modern medicine.
I am pleased to learn that the FDA has already identified
the data collected through the Best Pharmaceuticals for
Children Act and the Pediatric Rule as the foundation for
development of medications that are increasingly safe and
efficacious for use in pediatric populations.
And I believe the lessons we learn from analyzing this
pediatric data will benefit all patient populations with
specific dosing and treatment needs--in short, all Americans.
Again, I would like to thank Senators Enzi and Kennedy for
convening today's hearing, and I look forward to working with
my colleagues on the HELP committee to developing some
practical, bipartisan solutions to encourage the development of
innovative and safe medications for American consumers.
Questions of Senator Clinton For Janet Woodcock, M.D.
Question 1. In the FDA's ``Innovation or Stagnation'' report, the
agency mentions the research possibilities associated with the body of
data collected by the FDA as a result of the Best Pharmaceuticals for
Children Act and the Pediatric Rule. Could you please elaborate on the
ways that the Critical Path Initiative might utilize this data to
perform a comprehensive analysis of pediatric pharmacology, safety and
efficacy?
Question 2. I was interested to learn that the technology
development initiatives supported by the FDA might allow clinicians to
target medications to very specific patient populations. Could you
please comment on the ways in which the targeting of medications might
enhance the delivery of clinical appropriate treatments to children
beyond the scope of what we are currently able to achieve with the
Pediatric Rule and Best Pharmaceuticals for Children Act?
______
American Medical Association
Chicago, Il 60610
July 6, 2004
Division of Dockets Management (HFA-305)
Food and Drug Administration
5630 Fishers Lane, Room 1061
Rockville, MD 20852
RE: Draft Guidance for Industry on ``Development and Use of Risk
Minimization Action Plans'' [Docket No. 2004D-0188]
The American Medical Association (AMA) is pleased to offer its
comments on the Food and Drug Administration's (FDA) May 2004 Draft
Guidance for Industry on ``Development and Use of Risk Minimization
Action Plans'' [Fed Reg. 2004;69:25130-25132]. The AMA's comments focus
principally on Sections II-V of the Draft Guidance, and generally are
consistent with AMA's previous comments of April 29, 2003 on the FDA's
Concept Paper, ``Risk Management Programs'' [Docket No. 02N-0528], and
of May 22, 2002 in testimony at FDA's Public Meeting on the Risk
Management of Prescription Drugs.
GENERAL COMMENTS ABOUT THE DRAFT GUIDANCE, DEVELOPMENT AND USE OF RISK
MINIMIZATION ACTION PLANS
The AMA shares a common goal with the FDA to optimize the benefit/
risk balance of drug therapy and to minimize the risks of drug and
biological products. However, the AMA remains concerned about the
number of Risk Minimization Action Plan (RiskMAP) tools described in
the Draft Guidance that would directly manage or restrict physician
prescribing. If these tools are expanded to more pharmaceutical
products, the potential for unintended consequences such as reduced
patient access to necessary drugs or reduced manufacturer investments
in innovative therapies is significant. Thus, the AMA continues to
recommend that higher level risk minimization tools, such as
performance-linked access systems and some reminder systems, should be
used only as a last resort to keep high-risk products with unique and
important benefits on the market.
On the other hand, the AMA commends the FDA for incorporating
changes into the Draft Guidance that respond to some of our criticisms
of the Agency's 2003 Concept Paper on this subject. In particular, the
AMA is pleased that the FDA is encouraging drug sponsors to:
Develop RiskMAPs only for products that pose an unusual
type or level of risk;
Use RiskMAPs judiciously to minimize risks without
encumbering drug availability or otherwise interfering with the
delivery of product benefits to patients;
Seek the input of other stakeholders, including
physicians, when planning risk minimization activities and when
selecting specific RiskMAP tools;
Apply objective criteria when determining whether a
RiskMAP is necessary for a particular product;
Select the minimum number of RiskMAP tools necessary to
minimize the risk, select tools based on available evidence of
effectiveness, and objectively evaluate the effectiveness of RiskMAPs
and their tools using evidence-based performance measures;
Adopt tools that facilitate the central role of the health
care practitioner in controlling the risks of medical product use; and
Consider unintended consequences of a RiskMAP, such as
reduced access, as part of the sponsor's Evaluation Plan.
The AMA offers the following comments on individual Sections II-V
of the Draft Guidance.
SECTION II: BACKGROUND
The AMA agrees with the FDA that ``when planning risk assessment
and risk minimization activities, sponsors should consider stakeholder
input (e.g., from consumers, pharmacists, physicians, third-party
payers).'' However, the AMA believes the FDA needs to put greater
emphasis on this important point in a Final Guidance.
The AMA continues to urge open communication and collaboration
among the FDA, the pharmaceutical industry, and national physician
organizations on the subject of risk management. Such communication and
collaboration is needed at the macro level so that the FDA's overall
risk management initiative achieves an appropriate balance between the
need to protect patients from harm and the need to avoid heavy-handed
regulations that interfere with medical practice. Furthermore,
collaboration among the FDA, a product sponsor, and relevant physician
organizations also is recommended for individual product RiskMAPs, as
described in the Draft Guidance, to ensure that the RiskMAP is
effective, feasible and acceptable in usual health care practices.
Furthermore, the FDA also may wish to consider establishing a
permanent advisory council of practicing physicians, representing a
large number of national medical specialty societies, that could advise
the Agency on issues like RiskMAPs on an ongoing basis.
SECTION III: THE ROLE OF RISK MINIMIZATION AND RISKMAPS IN RISK
MANAGEMENT
Determining an Appropriate Risk Minimization Approach. The AMA
strongly agrees with the FDA that the FDA-approved professional
labeling (Package Insert [PI]), updated from time-to-time to
incorporate information from routine postmarketing surveillance, is
sufficient to be the routine risk minimization plan for the vast
majority of drug and biological products. The information provided in
the PI, along with other information about a product (e.g., published
clinical trials), should remain the standard method of providing
benefit and risk information to physicians about the use of a drug or
biological product.
However, as previously communicated to FDA, the AMA believes that
the current PI for prescription drugs is a barrier to effective risk
communication because it has become a legal document rather than a
resource of useful information for busy practicing physicians. In
December 2000, the FDA issued a Proposed Rule to modify the format and
content of the PI with the goal of making the information more useful
and user-friendly to physicians. The AMA has supported this effort,
especially the proposed ``Highlights of Prescribing Information.'' The
AMA urges the FDA to issue a Final Rule implementing these changes to
the PI as soon as possible.
Furthermore, the FDA should promptly develop and make readily
available (e.g., via the Internet) a computerized database of the most
up-to-date prescription drug labeling for all products. Such a database
could have prominently placed safety alerts for new risk information on
selected drugs. Physicians need to be trained to use this database for
their professional labeling needs in lieu of the hard-copy Physicians
Desk Reference (PDR) that is both cumbersome and dated for certain
products.
Definition of Risk Minimization Action Plan (RiskMAP). The AMA
accepts the FDA's definition of a RiskMAP as ``a strategic safety
program designed to meet specific goals and objectives in minimizing
known risks of a product while preserving its benefits.'' Moreover, the
AMA agrees with the FDA that tools used to meet RiskMAP goals and
objectives do not apply to routine risk minimization plans, i.e., FDA-
approved professional labeling.
Determining When a RiskMAP Should be Considered. The AMA agrees
with the FDA that the decision to develop a RiskMAP needs to be
determined on a case-by-case basis. Moreover, the AMA supports the
FDA's recommendation to use objective criteria, such as type of risk,
magnitude of risk, frequency of risk, populations at greatest risk and/
or those likely to derive the most benefit, existence of alternative
treatments, reversibility of adverse events observed, preventability of
the adverse event, and probability of benefit, when considering whether
a RiskMAP is necessary. As previously discussed, the AMA encourages the
FDA and the product sponsor to seek the input of relevant physician
organizations in determining whether a RiskMAP is needed. This will
give further assurance to physicians that the process is equitable and
driven by good science.
SECTION IV: TOOLS FOR ACHIEVING RISKMAP GOALS AND OBJECTIVES
Relationship of RiskMAP Tools to Objectives and Goals. The AMA has
no specific comments on this section.
Categories of RiskMAP Tools. The AMA accepts the FDA's three
categories of RiskMAP tools, i.e., targeted education and outreach,
reminder systems, and performance-linked access systems.
Description of RiskMAP Tools. The AMA supports the establishment of
a RiskMAP Web site by FDA. At a minimum, this Web site should contain a
description of RiskMAP tools that have been used and all available
evidence on the effectiveness of each tool in achieving a risk
minimization objective and/or goal. The AMA believes this is necessary
to convince health care practitioners that a potentially burdensome
RiskMAP tool can effectively improve the benefit/risk balance for a
drug product.
Selecting and Developing the Best Tools. This is an especially
important section of the Draft Guidance, and the AMA commends the FDA
for its recommendations to product sponsors, that when selecting
RiskMAP tools, to:
Maintain the widest possible access to the product with
the least burden to the health care system that is compatible with
adequate risk minimization;
Identify the key stakeholders (e.g., physicians) who have
the capacity to minimize the product's risks and to define their roles;
Seek input from these stakeholders, including physicians,
on the feasibility of implementing and accepting a particular RiskMAP
tool in usual health care practices;
Use RiskMAP tools with the least burdensome effect on
physician-patient relationships;
Select tools based on available evidence of effectiveness
in achieving the specified objective; and
Consider, and seek to avoid, unintended consequences of
tool implementation that obstruct risk minimization and product
benefit.
The AMA also appreciates the FDA's recognition that physicians are
the most important managers of product risks once a drug is marketed
and, furthermore, that the FDA does not have the authority to control
prescribing decisions made by physicians for their patients. The AMA
strongly agrees with the FDA's view that product sponsors should
recognize this central role played by physicians in controlling the
risks of medical product use and should adopt tools that facilitate
this role.
Only time and experience will answer the question as to whether
drug product sponsors are implementing RiskMAPs that are consistent
with the recommendations put forth by the FDA in this section of the
Draft Guidance. The AMA is hopeful that this will be the case. When
RiskMAPs are considered necessary, the AMA encourages the FDA and the
product sponsor to work with relevant physician organizations to assure
that the minimum number and least intrusive RiskMAP tools are selected
to achieve the risk minimization objective. Whenever possible, targeted
education and outreach should be the RiskMAP tools selected, and the
AMA refers the FDA to our letter of April 29, 2003 to Docket No. 02N-
0528 for detailed comments on how risk communication to physicians can
be improved.
As stated earlier in this letter, the AMA continues to believe that
higher level risk minimization tools, such as performance-linked access
systems and some reminder systems, should be used only as a last resort
to keep high-risk products with unique and important benefits on the
market. As discussed in detail in our earlier letter of April 29, 2003,
a number of potential unintended consequences, including reduced access
to necessary therapies, substitution of less effective therapies that
are not subject to RiskMAPs, multiple burdensome and confusing RiskMAPs
that can lead to errors, and adverse effects on pharmaceutical
innovation, may result if RiskMAPs with high level risk minimization
tools are more commonly employed.
Mechanisms Available to the FDA to Minimize Risks. The AMA has no
specific comments on this section.
SECTION V: RISKMAP EVALUATION: ASSESSING THE EFFECTIVENESS OF TOOLS AND
THE PLAN
Rationale for RiskMAP Evaluation. The AMA is in strong agreement
with the FDA regarding the need for well-designed studies to
periodically evaluate the effectiveness of a RiskMAP. The AMA concurs
that the most important evaluation is of the overall performance of a
RiskMAP in achieving its targeted health outcomes and goals. However,
the AMA also agrees that separate assessments should be done for
individual tool performance and for acceptability of RiskMAP tools by
physicians.
Considerations in Designing a RiskMAP Evaluation Plan. The AMA is
in general agreement with the FDA on the details of this section. In
particular, the AMA supports the following FDA recommendations:
When possible, drug product sponsors should select well-
defined, evidence-based, and objective performance measures tailored to
the particular RiskMAP to determine whether the RiskMAP's goals or
objectives are being achieved.
Whenever feasible, drug product sponsors should design
evaluation plans to include at least two different, quantitative,
representative, and minimally biased evaluation methods for each
critical RiskMAP goal to compensate for the limitations of the other.
Drug product sponsors should periodically evaluate each
RiskMAP tool to ensure it is materially contributing to the achievement
of RiskMAP objectives and goals to eliminate ineffective tools and
concentrate resources on useful tools.
Drug product sponsors should evaluate RiskMAP tools prior
to implementation; this should include pilot testing to assess
comprehension, acceptance, feasibility, and other factors to determine
how readily RiskMAP tools will fit into everyday physician practices.
Formal evaluation plans are unnecessary for routine risk
minimization plans, i.e., FDA-approved professional labeling.
FDA Assessment of RiskMAP Evaluation Results. The AMA generally
supports this section on how the product sponsor reports a RiskMAP
evaluation to the FDA, and that FDA will perform its own assessment of
RiskMAP effectiveness.
Making Information from RiskMAP Evaluation Available to the Public.
As stated earlier in this letter, the AMA supports the establishment of
a RiskMAP Web site by FDA that would include descriptions of RiskMAP
tools and all available evidence on the effectiveness of these tools.
The AMA also believes that this Web site should contain results of
evaluations of RiskMAPs that have been previously implemented to inform
physicians and the public about the effectiveness of the program in
meeting its risk minimization objectives and goals. While the AMA
understands that some product sponsor information will remain
proprietary, we believe it is in the sponsor's and FDA's best interests
to be as transparent as possible about the effectiveness of a RiskMAP.
Such transparency will provide credible evidence to physicians and the
public that a particular RiskMAP either did or did not effectively
improve the benefit/risk balance for a drug product.
ADDITIONAL COMMENTS
In our letter of April 29, 2003, the AMA offered two additional
comments that have not been adequately addressed by the FDA in the
Draft Guidance. First, concern has been expressed by physicians and
pharmacists that it is difficult to remember the various risk
management programs (now called RiskMAPs), and especially the multiple
risk management (RiskMAP) tools, currently employed for various drug
products. This is because each risk management program has been
uniquely developed for a specific drug product and, therefore, all of
the current programs are different in their requirements. However, in
Section IV(D) of the Draft Guidance, FDA continues to suggest that the
best RiskMAP tool or tools be selected on a case-by-case basis.
To address this concern, the AMA encourages the FDA, in
collaboration with the pharmaceutical industry and other stakeholders
(e.g., physician organizations), to take a more systems-based approach
to RiskMAPs. Appropriate tools should be prospectively developed based
on evidence of effectiveness, and a standard set of tools for each
level of risk should be part of a standard ``toolbox'' of RiskMAP
tools. When a product meets the criteria for a RiskMAP at a certain
level, to the extent possible, a standard set of tools should be
employed in that product's RiskMAP. At a minimum, any given tool should
be consistent across products.
The AMA's other comment that was not addressed in the FDA's Draft
Guidance regards the incorporation of RiskMAPs for drug products into
more global quality assurance programs. The AMA believes that the FDA,
the pharmaceutical industry, physician organizations, and other
stakeholders need to consider the incorporation of risk management
(RiskMAPs) for drug and biological products into more global quality
assurance programs. As electronic health records (EHRs) and E-
prescribing become more common and they are electronically linked to
other aspects of care (e.g. lab test results), it should be possible to
effectively incorporate RiskMAPs, as part of overall quality assurance,
into the normal routine of physician practice. As an analogy, the
Physician Consortium for Performance Measurement, convened by the AMA,
is currently developing physician performance measures derived from
evidence-based practice guidelines. The AMA is working with physician
group practices that have EHRs to incorporate the performance measures
into their systems so that satisfying the performance criteria becomes
a routine part of medical practice.
CONCLUSION
In conclusion, the AMA appreciates the opportunity to comment on
the FDA's Draft Guidance for Industry on ``Development and Use of Risk
Minimization Action Plans.'' We hope that our insight into the issues
discussed in the Draft Guidance proves helpful for the FDA as it moves
to finalize this Guidance. We look forward to working with the Agency
as it continues its activities in this area.
Sincerely,
Michael D. Maves, M.D., MBA
______
American Medical Association
Chicago, Illinois 60610
April 29, 2003
Dockets Management Branch (HFA-305)
Food and Drug Administration
5630 Fishers Lane, Room 1061
Rockville, MD 20852
RE: Risk Management [Docket No. 02N-0528]
The American Medical Association (AMA) is pleased to offer its
comments on the Food and Drug Administration's (FDA) Notice on risk
management activities for drug and biological products that was issued
in the March 7, 2003 Federal Register. The AMA's comments focus
principally on Sections II-V of the FDA Concept Paper, ``Risk
Management Programs,'' and generally are consistent with the AMA's
testimony at the FDA's Public Meeting on the Risk Management of
Prescription Drugs on May 22, 2002. We further address the FDA's
question about improving the quality of spontaneously reported case
reports [of adverse events], which was part of the FDA Concept Paper,
`` Risk Assessment of Observational Data: Good Pharmacovigilance
Practices and Pharmacoepidemiologic Assessment.''
GENERAL COMMENTS ABOUT THE CONCEPT PAPER, RISK MANAGEMENT PROGRAMS
The AMA has had a longstanding commitment both to improving the
quality of medical care delivered by physicians to patients and to
promoting efforts to improve patient safety. In furtherance of this
goal, the AMA established the National Patient Safety Foundation in
1997 and has participated in a number of initiatives on clinical
quality improvement. The AMA also has been a partner and strong
supporter of MedWatch, the FDA's adverse event reporting program. As
such, the AMA shares a common goal with the FDA to optimize the
benefit/risk balance of drug therapy and to minimize the risks of drug
and biological products.
However, a number of the risk management tools described in the
FDA's Concept Paper would directly manage or restrict physician
prescribing. The AMA has serious concerns about the potential
unintended consequences if these tools were expanded to more
pharmaceutical products. We are particularly concerned that the use of
these risk management tools could prevent some patients who would
benefit from higher-risk drugs from having access to them, or that
potential restrictions on prescribing could serve as a deterrent to
manufacturer investments in innovative therapies. As expressed in our
testimony last year, the AMA is also concerned that the FDA, and drug
sponsors, may be attempting to regulate the practice of medicine
through some of these risk management tools in ways that exceed the
FDA's statutory authority.
Other than the AMA's testimony at the FDA Public Meeting in May
2002, we are unaware of any input from national medical specialty
societies on the FDA's risk management initiatives. The AMA believes it
is essential that there be open communication and collaboration among
the FDA, the pharmaceutical industry, and national physician
organizations on this subject. Such communication and collaboration is
needed at the macro level so that the FDA's overall risk management
initiative achieves an appropriate balance between the need to protect
patients from harm and the need to avoid heavy-handed regulations that
interfere with medical practice. Furthermore, collaboration among the
FDA, a product sponsor, and relevant physician organizations also is
recommended when a risk management program, as described in the Concept
Paper, is being contemplated for a specific drug or biological product.
SECTION II: IMPORTANT RISK MANAGEMENT CONCEPTS
The AMA strongly agrees with the FDA that the Package Insert (PI),
as defined in this section of the Concept Paper, combined with routine
postmarketing surveillance should constitute the risk management plan
for the vast majority of drug and biological products. The information
provided in the PI, along with other information about a product (e.g.,
published clinical trials), should remain the standard method of
providing benefit and risk information to physicians about the use of a
drug or biological product.
However, the AMA believes that the current PI for prescription
drugs is a barrier to effective risk communication because it has
become a legal document rather than a resource of useful information
for busy practicing physicians. In December 2000, the FDA issued a
proposed rule to modify the format and content of the PI with the goal
of making the information more useful and user-friendly to physicians.
The AMA has supported this effort, especially the proposed ``Highlights
of Prescribing Information.'' The AMA urges the FDA to issue a final
rule implementing these changes to the PI as soon as possible.
Furthermore, the FDA should promptly develop and make readily
available (e.g., via the Internet) a computerized database of the most
up-to-date prescription drug labeling for all products. Such a database
could have prominently placed safety alerts for new risk information on
selected drugs. Physicians need to be trained to use this database for
their professional labeling needs in lieu of the hard-copy Physicians
Desk Reference (PDR) that is both cumbersome and dated for certain
products.
SECTION III: WHEN WOULD AN RMP BEYOND THE PACKAGE INSERT BE
APPROPRIATE?
The AMA accepts the FDA's definition of a risk management program
(RMP) as ``a strategic safety program designed to decrease product risk
by using one or more interventions or tools beyond the package insert''
(see Section II of the Concept Paper). Thus, the remainder of the AMA's
comments will assume a drug or biological product requires a Level 2,
3, or 4 RMP, as defined in Section IV of the Concept Paper.
The AMA agrees with the FDA that the decision to develop an RMP for
a particular product, and the level of the RMP, needs to be determined
on a case-by-case basis. This will depend on the severity of the risks
when compared to the magnitude of the benefits for a drug or biological
product, and the likelihood that an RMP would lower the risks without
adversely affecting the benefits. As discussed above, the input of
relevant physician organizations in this decision-making should help
the FDA and the product's sponsor select the most appropriate RMP for
the product.
To help determine whether any drug or biological product needs an
RMP, as well as the level of the RMP, the AMA believes it would be
useful for the FDA, the pharmaceutical industry, and physician
organizations to collaborate on the development of objective criteria
for making this determination. Severity of risk, frequency of risk,
reversibility of risk by an effective RMP, importance of product
benefit to patient outcome, and availability and relative benefit/risk
of alternative therapies are among the factors that should be
considered in developing criteria for determining whether an RMP is
needed. This collaborative development of objective criteria to
determine the need for an RMP would give some assurance to all
stakeholders that the process is equitable and driven by good science.
SECTION IV: WHAT INTERVENTIONS OR TOOLS ARE AVAILABLE FOR USE IN
ACHIEVING RMP GOALS AND OBJECTIVES?
The AMA has a number of comments on this section of the Concept
Paper. In making our comments, we have assumed the Level 1--4
categorization scheme, as proposed by the FDA under Section IV(D), is
applicable.
Physician education (Level 2) should be the risk management tool
used for most drug and biological products that need an RMP.
The AMA believes that the FDA should promote physician education
through improved risk communication as the tool that should be used for
most drug and biological products that need an RMP. Level 3 and Level 4
RMPs should be used only as a last resort to keep high-risk products
with unique and important benefits on the market.
Based on our experience at the May 2002 Public Hearing, the AMA is
concerned that the FDA has a predetermined view that risk communication
to physicians is ineffective in modifying prescribing behavior to
minimize risk. For example, the FDA considers the effectiveness of
traditional ``Dear Doctor'' letters that are mailed to physicians when
new and important risks are discovered to be questionable. While this
may be true, it is an indication that more innovative and effective
approaches to physician education about risk need to be developed, not
an indication that Level 3 and 4 RMPs should be more frequently
employed. The AMA urges the FDA to work with all stakeholders to make
physician education through improved risk communication an effective--
and the preferred--RMP for most products.
The AMA believes that the FDA, the pharmaceutical industry, and
physician organizations must collaborate and identify innovative ways
to communicate new risk information about a drug or biological product
to physicians so they will be aware of it, remember it, accept it, and
act on it when prescribing a drug. At the May 2002 Public Meeting, the
AMA presented a number of potential ways to accomplish this goal. Most
of these options could be implemented immediately, including:
The FDA, the pharmaceutical industry, and physician
organizations should undertake a major CME initiative on risk
communication. Physicians need to be aware of labeling changes that
identify serious adverse events and that, in some cases, these serious
adverse events can be minimized by modifications in prescribing. The
AMA's recommendations that the FDA publish its final rule on the PI and
create a computerized database of up-to-date PIs, as discussed above,
should be implemented as part of this education initiative.
The FDA, in collaboration with physician organizations,
should work with major medical journals and medical society web site
editors to identify standard places for the dissemination of important
new risk information about drugs and biological products.
``Dear Doctor'' letters should be disseminated by
mechanisms other than hard-copy mail. Alternative mechanisms should
include publication in medical journals (possibly as paid
advertisements), placement on medical society web sites, and
transmission to individual physicians by blast fax, blast email, and
direct daily downloads to personal digital assistants (PDAs). Unlike
letters, electronic transmission is inexpensive, timely, and
repeatable. Thus, important risk information can be reinforced by more
than one transmission.
The content and format of ``Dear Doctor'' letters should
be changed to emphasize the need for action by the prescribing
physician. For example, a ``Dear Doctor'' letter should contain a bold-
faced opening paragraph that emphasizes the possible severe outcome
(e.g., permanent harm or death) to patients from the new adverse event,
that the adverse event is probably preventable if the drug is used
appropriately, and what necessary steps the physician must take to
prescribe the drug appropriately.
Pharmaceutical companies should be obliged to train and
send their sales forces to physicians to educate them on important new
risk information about company products. The company should provide
incentives to sales representatives to do this because the highest
priority of any company should be to prevent harm to patients who use
their products. The effectiveness of the 80,000 pharmaceutical sales
representatives in the United States in promoting the benefits of their
companies' products is well documented, and they could have similar
success in educating physicians about important product risks.
New information technologies, such as computerized
physician order entry (CPOE), offer enormous opportunities to
communicate important risk information about drug and biological
products. CPOE systems with well-designed decision support programs
potentially could communicate important new risk information to
physicians at the point of prescribing, i.e., at a time when the
information is most needed. As these new information technologies
become integrated into physician practice, the FDA, the pharmaceutical
industry, and physician organizations should work with database
providers and software vendors to incorporate the appropriate risk
information into these electronic systems.
The AMA encourages the FDA and the pharmaceutical industry
to work with physician organizations to optimize physician education
about the risks of drug and biological products through identification
and implementation of effective methods of risk communication. The AMA
also recommends that the Centers for Education and Research on
Therapeutics (CERTs) program be charged with developing a research
agenda in risk communication to help identify new and effective
educational strategies.
Level 3 and Level 4 RMPs should be used only as a last resort to
keep high-risk products with unique and important benefits on the
market.
The AMA has concerns about many of the tools that the FDA has
proposed under Level 3 and Level 4 RMPs including:
prescribing only by registered physicians (restricted
distribution);
certification programs for physicians;
enrollment of physicians in a safety program;
specialized systems or records that attest to safety
measures having been satisfied (e.g., stickers, physician attestation
of capabilities);
dispensing only to patients with evidence or other
documentation of safe use conditions (e.g., lab test results)
(restricted distribution); and
patient agreements/informed consent.
As discussed above, the AMA has general concerns about the FDA and
product sponsors managing or restricting physician prescribing. There
also are a number of other reasons why the AMA believes that Level 3
and Level 4 RMPs should be used only as a last resort to ensure that
high-risk products with unique and important benefits remain on the
market. These reasons include:
While Level 3 and Level 4 RMPs may reduce risk, such
programs most likely will also reduce access. Some patients who would
benefit from a product subject to a high-level RMP may not be
prescribed that product because of the added burdens on the prescriber.
A less effective, less studied, and even less safe
alternative drug or biological product not subject to a high-level RMP
may be prescribed instead of a product with a Level 3 or Level 4 RMP.
There is some anecdotal information to suggest that this may be
happening with drugs used to treat cardiac arrhythmias. Sotalol and
quinidine, neither subject to an RMP, may be prescribed instead of
dofetilide, which is subject to a high-level RMP, when dofetilide is
actually the preferred drug.
Level 3 and Level 4 RMPs that employ multiple tools are
complex and may be confusing to both the physician and patient. This
could result in unintended medication errors unrelated to adherence to
the RMP. This could be magnified in patients with multiple diseases who
are on multiple drug products with multiple high-level RMPs, all of
which could be different.
Many of the tools for Level 3 and Level 4 RMPs are
administrative burdens for physicians. Therefore, unless the product
provides a truly innovative therapy for a particular disease or for a
specific subset of patients with a disease, it is unlikely that
physicians will take the necessary time to prescribe the product.
It is unclear what the impact of Level 3 and Level 4 RMPs
will have on pharmaceutical company research and development plans. It
is possible that a company could cease development of a promising drug
because of the likelihood of a high-level RMP. High-level RMPs could
have an adverse effect on pharmaceutical innovation, which would
ultimately limit new drug discoveries.
For certain drugs subject to Level 3 and Level 4 RMPs,
patients may seek these products from alternative sources, such as
illegal foreign Internet sites. For example, if a patient knows about
the product but cannot find it easy to obtain in the United States,
then the patient may take direct action and purchase the drug
illegally. Also, a patient may be concerned about his or her privacy
and want to avoid a high-level RMP that mandates patient registration
with a pharmaceutical company.
For all of these reasons, the AMA believes the FDA must be highly
discriminating in requiring a drug or biological product to have a
Level 3 or Level 4 RMP. The serious nature of the risk must clearly be
validated. As discussed earlier, objective criteria, agreed to by all
stakeholders, should be developed to determine the need for such a
high-level RMP. In addition, the FDA and the company must take great
care in selecting the tools that will be employed in the RMP. Only the
minimum number of tools needed to effectively reduce the risk should be
employed in the RMP. Only those tools that have been shown to be
effective in reducing the risk should be used, and the tools should be
acceptable to other stakeholders (e.g., physicians).
An Integrated, Systems-Based Approach to Risk Management of Drug
and Biological Products is Preferred to Product-Specific RMPs.
As discussed above, the decision to develop a RMP for a particular
product, and the level of the RMP, needs to be determined on a case-by-
case basis using objective criteria. On the other hand, the RMPs for
any given level of risk should be as uniform as possible across
products. This is especially the case for Level 3 and Level 4 RMPs.
Currently, the FDA uses a product-by-product approach in developing
an RMP. Thus, every product has its unique RMP. For high-level RMPs,
which often employ multiple tools, this results in a number of complex,
administratively burdensome, and, in some cases, conflicting RMPs. As
discussed above, this can be confusing to both physicians and patients
and potentially could result in unintended medication errors.
Furthermore, it is unclear to the AMA whether any of the different
Level 3 or Level 4 RMPs for currently marketed drug products, or the
tools used in these high-level RMPs, have been thoroughly evaluated for
effectiveness. The AMA requests the FDA to be forthcoming with any
information about the effectiveness of current RMPs. The AMA also
questions the impact on patient care of certain tools, such as
requiring stickers to be placed on handwritten prescriptions, when
physicians or hospitals no longer use paper prescriptions.
The AMA encourages the FDA, in collaboration with the
pharmaceutical industry and other stakeholders (e.g., physician
organizations), to take a more systems-based approach to risk
management programs. Appropriate tools should be prospectively
developed based on evidence of effectiveness, and a standard set of
tools for each level of risk should be part of a standard ``toolbox''
of risk management tools. When a product meets the criteria for a RMP
at a certain level, to the extent possible, a standard set of tools
should be employed in that product's RMP. At a minimum, any given tool
should be consistent across products.
The AMA also believes that the FDA, the CERTs program, the
pharmaceutical industry, physician organizations, and other
stakeholders need to consider the incorporation of risk management for
drug and biological products into more global quality assurance
programs. As electronic medical records (EMRs) and CPOE become more
common and they are electronically linked to other aspects of care
(e.g. lab test results), it should be possible to effectively
incorporate drug risk management, as part of overall quality assurance,
into the normal routine of physician practice. As an analogy, the
Physician Consortium for Performance Measurement, convened by the AMA,
is currently developing physician performance measures derived from
evidence-based practice guidelines. The AMA is working with physician
group practices that have EMRs to incorporate the performance measures
into their systems so that satisfying the performance criteria becomes
a routine part of medical practice.
SECTION V: HOW AND WHEN CAN RISK MANAGEMENT PROGRAMS BE EVALUATED?
The AMA strongly supports the evaluation of RMPs for effectiveness.
In particular, we support the FDA's intent to require risk management
tools to be pretested prior to their implementation in an RMP. As part
of this pretesting, the FDA and the sponsor should seek the input of
physicians and other affected stakeholders to see if the particular
tool is acceptable. The AMA strongly concurs with the FDA that any RMP
also must be evaluated after implementation to determine whether the
program has met its desired objectives. As an important first step and
as discussed above, the AMA believes that the FDA and the relevant
sponsors of drug products with high-level RMPs currently should
evaluate those RMPs, and the tools used in the RMPs, for effectiveness.
The AMA concurs with the FDA's view that metrics which capture
actual health outcome data are preferred to those that measure a
surrogate event or a process. Metrics, preferably quantitative, should
be well-defined and validated. The AMA agrees with the FDA that two
different and complementary evaluation methods should be used for key
RMP goals or objectives. The AMA shares the FDA's view that spontaneous
adverse event data should not be used as an outcome measure for RMP
evaluation. The AMA also agrees with the FDA about the limitations of
administrative claims data for evaluation of RMPs.
SUMMARY COMMENTS ON CONCEPT PAPER, RISK MANAGEMENT PROGRAMS
In summary, the AMA shares a common goal with the FDA to optimize
the benefit/risk balance of drug therapy and to minimize the risks of
drug and biological products. The AMA concurs with the FDA that the PI,
combined with postmarketing surveillance, should constitute the risk
management plan for the vast majority of drug and biological products.
The AMA urges the FDA to publish its final rule on the PI and to
develop a computerized database of PIs that is publicly available.
The need for a RMP, and the level of the RMP, should be made on a
case-by-case basis using objective criteria that need to be developed
by the FDA, in collaboration with the pharmaceutical industry and
physician organizations. The AMA believes that the vast majority of
drug or biological products that require an RMP should fall into Level
2. Again, the AMA supports a collaborative effort among the FDA, the
pharmaceutical industry, and physician organizations to optimize
physician education about the risks of drug and biological products
through identification and implementation of effective methods of risk
communication.
The AMA has a number of concerns about Level 3 and Level 4 RMPs and
recommends that these high-level RMPs be used only as a last resort to
keep high-risk products with unique and important benefits on the
market. There needs to be a clear documented need for a high-level RMP
that is based on objective criteria. Furthermore, the FDA is encouraged
to use an integrated, systems-based approach to these high-level risk
management programs to make them more uniform and less intrusive to
physicians. While evaluation of the effectiveness of RMPs, and of their
risk management tools, is recommended for all levels of RMPs, this is
especially important for Level 3 and Level 4 RMPs.
The AMA also is concerned that the FDA and drug sponsors may be
attempting to regulate the practice of medicine through some of the
tools proposed for these high-level risk management programs. It has
been long established that the FDA is not authorized to control the
practice of medicine. American Pharmaceutical Association vs.
Weinberger 377 F. Supp. 824, 829 n. 9 (D.D.C. 1974), aff'd sub nom.
APhA v. Mathews 530 F.2d 1054 (D.C. Cir 1976).
HOW CAN THE QUALITY OF SPONTANEOUSLY REPORTED CASE REPORTS BE IMPROVED?
(from fda concept paper, risk assessment of observational data: good
pharmacovigilance practices and pharmacoepidemiologic assessment
Spontaneous adverse event reports serve an important purpose in
generating signals about serious adverse events that may be caused by
drug and biological products. Because physicians are the group best
able to observe and communicate information about adverse events, the
AMA has had longstanding policy that physicians have an obligation to
inform the FDA or product sponsors about potential serious adverse
events associated with drug and biological products.
For the above reasons, the AMA has been a proactive MedWatch
partner since the program's inception. For example, the AMA was a co-
sponsor of one of the first public meetings on MedWatch. Over the
years, the AMA has also worked with the FDA to educate physicians about
the importance of voluntary reporting, on what to report, about how to
make a meaningful report, and how to cooperate fully with follow-up
calls from sponsors or the FDA. The AMA reaffirms its commitment to the
MedWatch program and stands ready to work with the FDA and the
pharmaceutical industry to continue to educate physicians about the
importance of spontaneous reporting.
CONCLUSION
In conclusion, the AMA appreciates the opportunity to comment on
the FDA's risk management activities. We hope that our insight into the
issues discussed in the Concept Papers proves helpful for the FDA, and
we look forward to working with the Agency as it moves forward in this
area.
Sincerely,
Michael D. Maves, M.D., MBA
______
Statement of The American Society of Health-System Pharmacists
The American Society of Health-System Pharmacists (ASHP) is pleased
to present the United States Senate Health, Education, Labor and
Pensions Committee with comments on an issue of grave importance--the
safety of our drug supply. It is essential that the American public
have confidence in our Nation's drug approval and monitoring systems'
ability to maintain the integrity of our drug supply and protect
patients' health.
For more than 60 years, ASHP has helped pharmacists who practice in
hospitals and health systems improve medication use and enhance patient
safety. The Society's 30,000 members include pharmacists and pharmacy
technicians who practice in inpatient, outpatient, home-care, and long-
term-care settings, as well as pharmacy students.
ASHP has long taken a leadership role in efforts to improve
medication safety. Pharmacists are the health care professionals best
educated and positioned to monitor the safe and appropriate use of
medications, often serving as the final safety check before medications
reach the patient. ASHP keeps health-system pharmacists informed of
drug safety issues and helps them respond appropriately. ASHP publishes
drug information both for health professionals and consumers, promotes
evidence based medication use programs, disseminates FDA's MedWatch
notices, and maintains a drug shortage Web site that informs and offers
guidance to help pharmacists manage shortages.
In recent years, drug safety and the FDA approval and monitoring
process have come under intense scrutiny. With many important new drugs
entering the market each year, some of which have been fast-tracked
through the approval process, FDA's ability to monitor safety has been
questioned. The short duration and small number of participants in the
clinical drug trials required for FDA-approval dictates that the
toxicity of new products cannot be fully understood when a drug is
approved and initially marketed. FDA's postmarketing surveillance,
therefore, needs to be modernized and strengthened to provide ongoing
assessment of products on the market. Moreover, the FDA needs
sufficient resources to fully implement the depth of programs necessary
to prevent injury and save lives.
The FDA faces a difficult challenge--establishing a system of drug
approval and monitoring that maintains a balance between the benefits
of bringing a new, potentially life-saving drug to market quickly, and
the risks associated with widespread use of a new drug.
This testimony will walk through the drug approval and monitoring
process, examining opportunities to improve safety, while maintaining
this important balance.
ISSUES RELATED TO THE FDA DRUG APPROVAL PROCESS
Under the Federal Food, Drug, and Cosmetic (FD&C) Act, the FDA is
responsible for ensuring that all new drugs are safe and effective.
Before any drug is approved for marketing in the United States, the FDA
must make a determination that the drug is safe and effective for the
conditions of use in the drug's labeling and that the benefits of
approval outweigh the drug's risks.
According to a report by the Inspector General, new drug reviewers
in the FDA's Center for Drug Evaluation and Research (CDER) have
experienced shorter approval times and increased pressures to recommend
approval of a drug even if they have reservations about the drug's
safety or efficacy.\1\ This pressure is illustrative of the need to
better educate the American public about both the risks and the
benefits of new drugs. It also highlights the potential conflict that
arises by having FDA funding for the drug approval process relying
heavily on user fees.
---------------------------------------------------------------------------
\1\ FDA's Review Process for New Drug Applications: A Management
Review, Inspector General Report March 2003. (OEI-01-01-00590)
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ISSUES RELATED TO POSTMARKETING SURVEILLANCE
Regardless of the rigor of the premarket drug approval process,
postmarketing surveillance is essential to ensuring drug safety. The
more widespread, longer-term use of a product in the real world detects
adverse effects that often go undetected during clinical trials.
ASHP is pleased that on February 15, 2005, the FDA announced a plan
to improve the way the FDA manages drug safety information to make
FDA's review and decision-making processes more independent and
transparent. However, it is important to review FDA's authority to
monitor and examine drugs once they are on the market to ensure the FDA
has sufficient authority to develop an enhanced postmarketing
surveillance system necessary to meet today's needs.
Adverse Event Reporting Must be Encouraged. FDA's MedWatch program,
which provides for the reporting of adverse drug events, is essential
to detecting enhanced risk associated with medications. ASHP, through
its Web site, coordinates an effort to provide this information in a
timely manner to the pharmacy community. However, the MedWatch program
must be strengthened to encourage more reporting. The information
gathered from the MedWatch program must be acted upon in a timely
manner, by someone separate from the team that initially approved the
drug for marketing. Information must also be made available to patients
and providers in a timely manner. This may require the FDA being
granted additional authority to make labeling changes.
Authority Needed to Require Certain Postmarketing Safety Studies.
The FDA's ability to measure the ultimate safety of a drug once it has
entered the market is limited by the fact that the FDA cannot conduct
independent clinical trials, and it is unclear whether the FDA can
require manufacturers to conduct such studies. In order for the FDA to
fully understand side effects of an approved drug that may not have
surfaced in the limited premarket test group, it is essential that the
FDA be able to require these studies under certain circumstances.
Funding Needed for Postmarketing Clinical Effectiveness Studies.
There is also a significant need for studies comparing the clinical
effectiveness of medications on the market. Pharmacists, other members
of the health care team, patients, and private and public payers need
objective, authoritative, and reliable evidence in order to make the
best treatment decisions. Such research will contribute to the practice
of evidence-based patient care, good clinical decision-making, and
rational drug use. Since prescription drugs represent a significant
portion of health care costs, the need for such research is
increasingly important. Only the Federal Government has the ability to
support such independent comparative research, provide oversight to
safeguard the integrity of the research process, and disseminate the
findings.
We encourage committee members to support expanded funding for the
Agency for Healthcare Research and Quality (AHRQ) to sponsor this type
of research. Impartial private sector entities could supplement the
efforts of AHRQ, but the Federal Government needs to take the lead.
Clinical Trials Should be Disclosed in National Registry. While
expanded FDA authority to require postmarketing clinical trials is an
important start to building a stronger drug monitoring system, it will
have limited impact if this information is not made available to the
FDA and the public in some way. Disclosure is essential to creating a
system of transparency and accountability necessary to promote consumer
confidence.
ASHP supports the establishment of a mandatory registry established
and administered by the Department of Health and Human Services. This
registry should build upon the existing registry administered by the
National Institutes of Health for clinical trials dealing with the
effectiveness of treatments for serious and life-threatening
conditions, and it should cover all publicly and privately funded
clinical trials.
All clinical trials undertaken, but not yet completed, should be
added to the registry and, upon completion, the results should be
posted as quickly as possible after FDA approval but before marketing
commences. Strong enforcement mechanisms are necessary to ensure
compliance.
Any opposition raised regarding the disclosure of a company's
research action plan is outweighed by the public and individual
patient's right to know and critically examine all available studies
and their results.
Additional FDA Funding Needed for Postmarketing Surveillance.
Additional funding is needed by the FDA, particularly in the area of
postmarketing surveillance. Due to the fact that the Prescription Drug
User Fee Act (PDUFA) requires manufacturers to pay a user fee when they
submit a drug approval application, more resources are available for
drug approval review than for postmarketing monitoring.
Such funding is necessary in order for the FDA to conduct
postmarketing surveillance and establish a national clinical trial
registry.
OTHER INITIATIVES ESSENTIAL TO IMPROVING DRUG SAFETY
Legislation Needed to Encourage Medical Errors Reporting.
Legislation is needed to help create a culture of safety that would
entice individuals to report medical errors and ``near misses.'' The
Senate passed legislation last year, the Patient Safety and Quality
Improvement Act (S. 720), that would establish a system for reporting
and analyzing errors reports and establish peer review protections for
individuals reporting to the system. ASHP is encouraged that the
committee plans to move that legislation forward this year.
Congress Should Consider a New Category of Drugs to Help Balance
Safety and Access Concerns. There is a significant push to make more
products available over-the-counter. In order to balance access with
safety concerns, the Congress should consider making the appropriate
changes in Federal statutes and regulations to establish an
intermediate category of drug products that do not require a
prescription but are available only from pharmacists and licensed
health care professionals who are authorized to prescribe medications.
Pharmacists, who have the education, training, and expertise to
help patients make appropriate therapeutic decisions, would be able to
provide drugs in this new category directly to patients without a
prescription, on the basis of appropriate assessment and professional
consultation. This would enhance patient access, while addressing
safety concerns that prevent drugs from being dispensed over the
counter.
Current Drug Importation Laws Should be Enforced Vigorously Until A
System Can be Established to Maintain Current FDA Assurance of the
Safety and Authenticity. Working outside of the FDA's regulatory
framework to import drugs from other countries is counterproductive to
efforts to strengthen FDA's drug approval and monitoring processes.
Current importation efforts increase the risk that Americans will
receive drugs that do not meet the FDA's standards and are harmed as a
result.
ASHP believes that current laws and regulations related to
importation should be upheld and vigorously enforced until in order to
(1) maintain the integrity of the pharmaceutical supply chain to avoid
the introduction of counterfeit products into the United States; (2)
provide for continued patient access to pharmacist review of all
medications and preserves the patient-pharmacist-prescriber
relationship; and (3) provide adequate patient counseling and
education, particularly to patients taking multiple high-risk
medications.
Before any consideration is given to opening the United States
market to medications from abroad, systems should be put in place to
guarantee the integrity of any new distribution networks. Related to
this point, ASHP encourages stronger authority for the FDA and others
to control the prescribing and dispensing of medications via the
Internet. ASHP supports efforts that require pharmacy World Wide Web
sites to list the States in which the pharmacy and pharmacists are
licensed, and, if prescribing services are offered, requires that the
sites (1) ensure that a legitimate patient-prescriber relationship
exists (consistent with professional practice standards) and (2) list
the States in which the prescribers are licensed.
FDA Should Be Given Broader Authority to Notify Providers of Drug
Product Shortages. ASHP members and other health care providers have
increasingly experienced drug shortages. These shortages not only
affect access to care but, also due to the limited notice providers
receive of impending shortages, increase the cost of alternative care
and the likelihood of medication-related complications. ASHP strongly
believes that the Congress and the FDA should consider expanding the
definition of ``medically necessary'' drug products to enhance FDA's
authority to require pharmaceutical manufacturers to notify the
appropriate government body well in advance of voluntarily
discontinuing a product and put in place effective sanctions for
manufacturers that do not comply with this mandate.
Direct-to-Consumer Advertising of Specific Drugs Should be
Prohibited. Direct-to-Consumer (DTC) advertising has more than doubled
over the last 5 years. Despite this dramatic expansion in advertising,
FDA enforcement actions against ads that are in violation of FDA
standards have dropped. While the FDA can require DTC ads to be
scientifically accurate and provide a fair balance of risks and
benefits, the FDA lacks the necessary resources to assure that
companies comply.
ASHP is concerned about the impact DTC advertising for specific
drug products has had on fostering inappropriate prescribing and
supports a ban on such advertisements.
Drug Samples Should be More Carefully Regulated. ASHP also believes
that addressing drug safety is incomplete without considering safety
concerns that arise due to manufacturer samples that go through
distribution channels that (1) do not foster pharmacist oversight of
therapy, (2) result in poor drug control, allowing patients to receive
improperly labeled and packaged, deteriorated, out-dated, and
unrecorded drugs, (3) provide access to prescription drugs by
unauthorized, untrained personnel, (4) may encourage inappropriate
prescribing habits, or (5) may increase the cost of treatment for all
patients.
FDA should be encouraged to provide the additional guidance
necessary to ensure drug samples are distributed through channels
meeting these criteria.
Manufacturers Should be Required to Make Available Unit Dose
Packaging of Medications Commonly Dispensed in Hospital and Ambulatory
Health Care Settings. ASHP urges the FDA to require manufacturers to
provide all medications commonly used in hospitals and other ambulatory
health care settings in ready-to-use unit dose packaging. The FDA
issued a final regulation in February 2004 that requires pharmaceutical
manufacturers to apply bar codes to ``most prescription drugs'' and
``certain over-the-counter drugs that are commonly used in hospitals
and dispensed pursuant to'' a medication order. Currently, many drugs
are not available from manufacturers packaged as a single dose ready
for dispensing. In order for bar coding to have the greatest effect on
patient safety, bar coded packaging of medications must be available at
the unit-of-use level. Lack of availability of appropriate dosage forms
packaged for unit dose dispensing places the burden on hospital
pharmacy departments, who are not well situated to take on this role.
In the interest of patient safety, manufacturers should be required to
provide medications in dosage packaging commonly used in hospitals and
ambulatory health system settings.
Concluding Comments. ASHP is encouraged by the reasoned approach
the committee has taken to addressing drug safety concerns. The U.S.
has a solid record for drug safety that should not be overlooked. The
system, however, will benefit from a careful examination and
enhancements to address current weaknesses. We look forward to working
with the committee to develop balanced solutions to enhancing safe
medication use and moving any necessary legislation forward.
______
Prepared Statement of Senator Grassley
Chairman Enzi, I congratulate you on becoming chairman of the
Health, Education, Labor, and Pensions (HELP) Committee, and thank you
for your leadership in holding hearings on the Food and Drug
Administration (FDA) and drug safety. As you know, these issues have
been a central concern of mine during the past year. My staff on the
Finance Committee has been investigating serious allegations raised by
whistleblowers that call into question whether the FDA is fulfilling
its mission to protect the health and safety of Americans.
Indeed, the Food and Drug Administration has failed to put patient
safety first with respect to both SSRIs and COX-2 drugs. Last November,
the Finance Committee held an oversight hearing based on an
investigation of the withdrawal of Vioxx, Merck's blockbuster COX-2
drug. Red flags had been raised about the safety risks of Vioxx before
and after the drug had been approved by the FDA. The Vioxx hearing shed
some much needed light on how the Food and Drug Administration
regulated or rather failed to regulate Vioxx effectively.
The Finance Committee has a responsibility to more than 80 million
Americans who receive health care coverage, including prescription
drugs, under the Medicare and Medicaid programs. As Chairman of the
Finance Committee, Merck's withdrawal of Vioxx was of particular
interest because Medicaid paid over $1 billion for Vioxx while it was
on the market. Medicare and Medicaid beneficiaries rely on medicines
paid for with federal funds. The Finance Committee has a responsibility
to make sure that every federal dollar paid for drugs is not misspent
on unsafe drugs and drug companies who profit at the expense of
consumer safety.
Historically, the Food and Drug Administration has met its charge
to protect the health and safety of the American public. Those who work
at the agency are, by and large, committed to doing no harm. Even so,
the FDA has also stood watch over failures when it comes to drug safety
this past year. Consequently, public confidence has been shaken.
When the FDA approves a drug, it's considered a Good Housekeeping
seal of approval. Consumers should not have to second guess the safety
of what's in their medicine cabinets. When the FDA approves a drug,
Americans should be able to bank on its benefits outweighing its risks.
If a drug presents an unacceptable risk, the FDA should take it off the
market. This risk-benefit analysis should be non-negotiable. When it
comesto putting patient safety first there is no room at the table for
drug companies. The FDA should not be sitting down to negotiate with
drug companies whose priorities too often appear to lie with their
stockholders.A vital and pressing concern today is post-marketing
surveillance and the way FDA monitors the safety of prescription drugs.
Dr. Raymond Woolsey, a witness at today's hearing, stated in a
Frontline interview in November 2003 that ``the number of people hired
at the [FDA] to protect, to analyze data and drug safety, is criminal.
. . The teams that are needed to do drug safety are infinitely more
than what they've got right now. We don't have a safety system in this
country.''
One of my concerns is that the FDA has a relationship with drug
companies that is far too cozy. That's exactly the opposite of what it
should be. Despite findings from a Merck study that heart attacks were
five times higher for Vioxx patients than for patients on another drug,
nearly two years passed before label changes were made by the FDA.
Consumers and doctors remained largely unaware of the cardiovascular
risks while Merck continued to aggressively market Vioxx during that
time. The overriding concern of the FDA should have been the health and
safety of the American people.
Evaluating drug safety, of course, involves balancing the risks
against the benefits of each drug, and Vioxx is no different, but we
need to know what the risks are in order to make those risk-benefit
calculations. And in the case of Vioxx, doctors and patients did not
have that opportunity. What I also find disturbing is that Merck
negotiated with the FDA to place information about the cardiovascular
risks of Vioxx in the "Precautions" section of the label rather than
prominently displaying it as a "Warning."
Several witnesses at the Finance Committee's November hearing
believed the FDA should have required a black box warning for Vioxx,
the strongest label warning the FDA requires. FDA's own advisory
committees recently agreed. Less than two weeks ago, the FDA joint
advisory committee recommended black box warnings on all COX-2 labels.
FDA has also disregarded and downplayed important concerns and
warnings from its own best scientists. We saw evidence of that in the
way FDA treated Dr. Andrew Mosholder's findings on SSRIs and Dr. David
Graham's findings on Vioxx. The FDA even attempted to undermine the
publication of Dr. Graham's findings in The Lancet. According to Dr.
Graham's peer reviewed and published findings, an estimated 88,000-
140,000 excess cases of serious coronary heart disease are attributable
to Vioxx, with about half these cases being fatal. That means there may
be as many deaths attributable to Vioxx as the number of soldiers who
died during the Vietnam War. Information about the Vioxx disaster needs
to be shared with the public and shared in a timely manner.
This week I introduced the Fair Access to Clinical Trials Act of
2005 with Senator Dodd. I introduced this legislation as part of a
sustained effort to restore public confidence in the federal
government's food and drug safety agency. The FACT Act would expand
www.clinicaltrials.gov to create a publicly accessible national data
bank of clinical trial information comprised of a clinical trial
registry and a clinical trial results database.Enactment of this bill
would be a meaningful step toward greater transparency and
accountability in clinical trials and the scientific process.
In addition, Senator Dodd and I are working on a bill to establish
an independent office for drug safety within the FDA. The independence
of the office would not exist solely on an organizational chart. The
office would have an independent director and regulatory authority.
When it comes to drug safety, intra-agency community is indeed
essential. However, the Office of New Drugs is hampered by real and
perceived conflicts of interest. An independent drug safety office
would more effectively regulate drugs post market. It doesn't make
sense, from an accountability standpoint, to have the office that
reviews the safety of drugs that are already on the market to be under
the thumb of the office that puts the drugs on the market in the first
place.
As I continue with my Constitutional duties to conduct oversight as
Chairman of the Finance Committee, I look forward to working closely
with you, Mr. Chairman, to ensure that critical changes are made within
the FDA to keep the agency focused on its mission to protect public
health and safety. I look to your leadership and seek your support with
the legislation that is necessary to help get FDA back on the right
track. Again, I commend you for holding these hearings and look forward
to working with you.
______
Response to Questions of Senator Enzi by Janet Woodcock, M.D.
Hon. Mike Enzi,
Chairman,
Committee on Health, Education, Labor, and Pensions,
U.S. Senate,
Washington, D.C. 20510-6300.
Dear Chairman Enzi: Thank you for the facsimiles dated March 21,
2005, including questions for the record related to the Committee's
recent hearings, March 1 and 3, 2005, entitled, ``FDA's Drug Approval
Process: Up to the Challenge?'' We have repeated your questions below,
followed by the Food and Drug Administration's (FDA or the Agency)
response.
Question 1. Some witnesses at our Tuesday hearing emphasized that
clinical trials, because of their size and length, cannot always
predict fully the potential side effects of a drug. Would you explain
this in more detail?
Answer 1. The most recent actions concerning the drug Vioxx
(rofecoxib) illustrate the vital importance of the ongoing assessment
of the safety of a product once it is in widespread use. FDA grants
approval to drugs after a sponsor demonstrates that they are safe and
effective for a given indication. Experience has shown that the full
magnitude of some potential risks do not always emerge during the
mandatory clinical trials conducted before approval to evaluate these
products for safety and effectiveness. A new drug application (NDA)
typically includes safety data on several hundred to several thousand
patients. If a serious adverse event occurs in 1 in 5,000 or even 1 in
1,000 users, it might not occur in clinical trials of this size. When
the drug is used by many times that number of patients, that event
could show up as a serious risk. Occasionally, serious adverse effects
are identified after approval either in post-marketing clinical trials
or through spontaneous reporting of adverse events. That is why
Congress has supported, and FDA has created, a strong post-market drug
safety program designed to assess adverse events identified after
approval for all of the medical products it regulates as a complement
to the pre-market safety reviews required for approval of prescription
drugs in the United States.
Question 2. What technologies and processes are currently available
to predict potential adverse events during drug development and/or
identify post-marketing safety issues?
Answer 2. During the Pre-Market Phase, ODS works with OND at pre-
NDA and pre-Biologics Licensing Applications (BLA) meetings with
industry to review safety information and to discuss proposed risk
management plans and the need for any post-approval risk management
studies. During NDA and BLA review, ODS and OND work together in the
development and review of risk management programs. ODS provides
expertise in the review of proposed proprietary drug names, labeling,
and packaging to minimize medication errors, patient labeling and
Medication Guides, and Phase 4 safety studies. ODS staff are involved
in the preparation for and may present information at advisory
committee meetings involving safety issues and risk management for
pending applications and when post-marketing safety information is
available for similar products.
Under Title 21, Code of Federal Regulations (CFR) 314.80, Post-
Marketing Reporting of Adverse Drug Experiences, subsections (b)
(review of adverse drug experiences) and (c) (reporting requirements),
manufacturers are required to review and report to FDA all adverse drug
experience information obtained or otherwise received by the applicant
from any source, foreign or domestic. This includes information derived
from commercial marketing experience, post-marketing clinical
investigations, post-marketing epidemiological/ surveillance studies,
and reports in the scientific literature and unpublished scientific
papers. There is comparable language in 21 CFR 600.80 for biologics.
FDA recently published a proposed rule that would require drug
manufacturers to submit reports electronically. The rule, if finalized,
would help harmonize worldwide reporting of post-marketing safety
information and expedite detection of safety problems for marketed
drugs. The Agency is also expanding the reporting requirements for
manufacturers of biological products to include adverse event reports
from unlicensed blood banks and transfusion services.
In concert with industry's reporting requirements, the Food and
Drug Administration Modernization Act of 1997 (FDAMA) requires sponsors
of approved drugs and biological products report to FDA annually on the
progress of their post-marketing study commitments, both those that are
required and those that are agreed upon in writing. Under FDAMA, FDA is
obligated to track the progress of post-marketing study commitments,
make certain information about commitments available to the public, and
to report annually in the Federal Register on the performance of post-
marketing study commitments (PMC). This tracking and reporting allows
for FDA to monitor compliance of PMCs. The status of PMCs is published
on the CDER website at http://www.fda.gov/cder/pmc/default.htm.
During the Post-Market Phase, one of ODS' primary roles is to
provide expertise in the review of post-marketing safety data and to
maintain and coordinate CDER's post-marketing surveillance and risk
assessment program. This program includes the Adverse Event Reporting
System (AERS), a computerized information database designed to support
the FDA's post-marketing safety surveillance program for all approved
drug and therapeutic biologic products. Information in AERS comes from
required reporting by companies and through voluntary reports submitted
directly to FDA's MedWatch program by consumers and health
professionals, which together total more than 350,000 reports per year.
ODS review of AERS data may provide signals of safety issues that did
not appear during the drug development process as well as those that
appear more frequently or with a greater degree of severity after
approval than was seen in clinical trials. ODS review of AERS reports
may also detect product quality problems that are referred to the
Office of Compliance.
Individual reports may trigger further evaluation of similar
reports in the AERS database and could signal important safety concerns
prompting regulatory actions both in the U.S. and abroad. To further
investigate safety signals, ODS safety evaluators, epidemiologists and
drug utilization specialists perform research to define drug use,
background rates of the event in the treated population, and
epidemiological trends.
In addition to AERS, ODS staff are responsible for the acquisition,
analysis, and interpretation of information from contracted databases
on drug use in various populations, including in-patients, children,
and patients over time that help place safety signals into context and
inform regulatory decision-making. For newly approved products with
important safety concerns, ODS independently evaluates product
utilization to evaluate whether these products are being used in a safe
manner and works collaboratively and pro-actively with OND and industry
on related issues.
ODS' cooperative agreement program in pharmacoepidemiology provides
CDER with access to external experts with access to population-based
databases for the purpose of studying important post-marketing drug
safety questions. CDER works collaboratively with the cooperative
agreement partners to identify research areas and to design and conduct
studies to investigate suspected associations between specific drug
exposures and specific adverse events and to estimate risk. FDA is
revising this program to use contracts, rather than cooperative
agreements, to help focus on drug safety issues that are of the highest
priority and urgency to the Agency.
ODS also uses additional data sources as needed, such as the
National Electronic Injury Surveillance System: All Injury Program
(NEISS-AIP), an ongoing active surveillance system for the purpose of
collecting data on all injuries presented to a probability sample of
U.S. hospital emergency departments; the Drug Abuse Warning Network, a
public health surveillance system that monitors drug-related visits to
hospital emergency departments and drug-related deaths investigated by
medical examiners and coroners.
ODS reviews reports of medication errors that have occurred with
marketed products and recommends changes to product names, labeling,
and/or packaging to prevent future errors. ODS works with OND and the
Office of Generic Drugs to review risk management programs for approved
products to assess their implementation and effectiveness. ODS reviews
patient labeling and Medication Guides that are put in place to address
serious and significant public health concerns both pre-marketing and
when issues arise after a product is marketed. ODS assists the Office
of Training and Communication in the development of Consumer Drug
Information Sheets by assessing readability.
ODS' MedWatch program is an important tool in both acquiring and
disseminating safety information. In addition to receiving direct
reports of serious adverse events and problems related to drugs and
other medical products regulated by FDA from consumers and health
professionals, the MedWatch program also provides important and timely
clinical information on safety issues involving medical products,
including prescription and over-the-counter drugs, biologics, medical
and radiation-emitting devices, and special nutritional products (e.g.,
medical foods, dietary supplements and infant formulas). Medical
product safety alerts, recalls, withdrawals, and important labeling
changes that may affect the health of all Americans are disseminated to
the medical community and the general public via the MedWatch website
and the MedWatch E-list that provides e-mail updates to over 46,000
subscribers. MedWatch Partners are over 150 health care professional
organizations, consumer groups, and web-media groups that work with FDA
to help keep their members informed about medical product safety
information and reporting. Partners are encouraged to play an active
role in post-marketing surveillance.
FDA created an independent Drug Safety Oversight Board (DSB or the
Board) to enhance the independence of internal deliberations and
decisions regarding risk/benefit analyses and consumer safety. The DSB
will oversee the management of important drug safety issues within the
CDER. The DSB will be comprised of members from FDA and medical experts
from other HHS agencies and government departments (e.g., Department of
Veterans Affairs). The Board also will consult with other medical
experts and representatives of patient and consumer groups. CDER's
Manual of Policies and Procedures has been updated to reflect the
organization of the DSB; you may view this document by visiting: http:/
/www.fda.gov/cder/mapp/4151-3.pdf.
FDA recently asked the Institute of Medicine (IOM) to look at the
structure of our post-marketing surveillance program and to give FDA
their expert advice on whether additional changes are needed to the
Agency's approach to drug safety, which could include recommendations
for changes in the CDER's organizational structure.
______
Response to Questions of Senator Hatch by Janet Woodcock, M.D.
Question 1. I believe it is important for the FDA to look for ways
to address differences of opinion within the agency. I think that
[when] FDA officials have conflicting messages about the safety of
specific drugs, it is extremely confusing to the general public. How
would this program address disagreements among FDA scientists regarding
the safety of a specific drug? Would this program have the FDA speak
with one voice or would the public be given the opportunity to review
the concerns of all FDA scientists? How would the new independent Drug
Safety Oversight Board interact with the individuals involved with this
program?
Answer 1. In November 2004, Dr. Crawford announced that CDER was
establishing a new ``Differing Professional Opinions and Dispute
Resolution'' Program. For more information about this program, please
visit: http://www.fda.gov/bbs/topics/news/2004/new01131.html. CDER has
developed a Manual of Policies and Procedures describing how this
dispute resolution process will be managed. This process is available
to any individuals in the Center who wish to express their differing
professional opinions (DPOs) concerning any regulatory actions or
policy decisions with significant public health impacts in instances
when the normal procedures for resolving internal disputes are not
sufficient.
In most cases, free and open discussion of scientific issues among
review teams, and with supervisors, managers, and external advisors
leads to an agreed course of action. Sometimes, however, a consensus
decision cannot be reached, and an employee may feel his or her opinion
was not adequately considered. Such disagreements can have a
potentially significant public health impact. That is why CDER's new
program provides for a review of the involved differing professional
opinions by FDA and outside experts. An ad hoc panel, whose members
were not directly involved in the disputed decisions, will have 30 days
to review all relevant materials and recommend to the Center Director
an appropriate course of action.
In addition to this program for resolving individual disputes
regarding any regulatory matters or policies, CDER is establishing the
Drug Safety Oversight Board (DSB) to specifically address drug safety
issues and to assist in the resolution of disputes and differing
professional opinions between staff from the Office of New Drugs and
the Office of Drug Safety within the Center for Drugs. The membership
of the Board has been carefully balanced with equal representation from
both the Office of New Drugs and the Office of Drug Safety, along with
representatives from other offices within CDER, the Center for Biologic
Evaluation and Research, the Center for Devices and Radiological
Health, the National Cancer Institute and the Department of Veterans
Affairs. These organizational disputes will be addressed during
meetings of the Board, with a final recommendation reached through
achievement of consensus or through voting of the Board if no consensus
can be reached.
Question 2. I commend the FDA on its willingness to increase
communication with the public on drug safety. I believe that will make
a significant difference for both physicians and their patients when
they are making treatment decisions. Besides the internet, how will
this information be provided to the public so they may be able to
access information about pharmaceutical products?
Answer 2. As part of the vision announced on February 15, 2005, by
the Department of Health and Human Service's Secretary Leavitt and
FDA's Acting Commissioner Crawford, FDA will create a new independent
DSB to oversee the management of drug safety issues. The Agency plans
to improve transparency by providing emerging information to health
providers and patients about the risks and benefits of medicines.
We understand that many Americans still do not have access to the
Internet and that Internet communication is just one form of
communication. In addition to using the Internet as a communication
medium, FDA also uses trade and other press as well as other forms of
external communication to convey safety information. We routinely use
print media (periodicals) and coordinate with the press to publicize
information. We will continue to use magazine advertisements, press
releases, and other campaigns to inform the public.
FDA uses a very important means of communication, FDA-approved
patient labeling, which includes:
Patient Package Inserts. For some prescription medicines, FDA
approves special patient materials to instruct patients about the safe
use of the product. These materials may be given to patients by their
health care provider or pharmacist, and are considered part of FDA-
regulated product labeling.
Medication Guides. FDA may require distribution of Medication
Guides, FDA-approved patient information, for selected prescription
drugs that pose a serious and significant public health concern.
Medication Guides will be required if FDA determines that one or more
of the following circumstances exist:
Patient labeling could help prevent serious adverse effects;
The drug product has serious risk(s) (relative to benefits) of
which patients should be made aware because information concerning the
risk(s) could affect patients' decision to use, or to continue to use,
the product;
The drug product is important to health and patient adherence to
directions for use is crucial to the drug's effectiveness.
In addition, FDA will be creating a Drug Watch Web Page, which will
include emerging information for both previously and newly approved
drugs about possible serious side effects or other safety risks that
have the potential to alter the benefit/risk analysis of a drug, affect
patient selection or monitoring decisions, or that can be avoided
through measures taken to prevent or mitigate harm. FDA has recently
issued a draft guidance entitled; ``FDA's `Drug Watch' for Emerging
Drug Safety Information,'' which articulates the Agency's current
thinking on the topic. This draft guidance is open for public comment
and may be viewed by visiting: http://www.fda.gov/cder/guidance/
6657dft.pdf. Other new communication channels will also include:
Health care Professional Information Sheets. One-page information
sheets for health care professionals for all drugs on FDA's Drug Watch
and all drugs with Medication Guides (FDA-approved patient labeling)
containing the most important new information for safe and effective
product use, such as known and potential safety issues based on reports
of adverse events, new information that may affect prescribing of the
drug, and the approved indications and benefits of the drug.
Patient Information Sheets. One-page information sheets for
patients containing new safety information as well as basic information
about how to use the drug in a consumer friendly format for all
products on Drug Watch.
All of this information will be provided on the Internet.
______
Response to Questions of Senator Gregg by Janet Woodcock, M.D.
Question 1. During the hearings, when questioned about whether the
FDA needed additional authority to require label or labeling changes on
prescription drug products it appeared that Dr. Sandra Kweder and Dr.
Janet Woodcock--the FDA witnesses at each of the hearings--responded
differently to the question. Does FDA have adequate authority for the
drug approval and postmarket surveillance processes? Does FDA need any
additional authority to require label or labeling changes on drug
products, to require phase IV clinical trials, or to withdraw marketed
drug products? Does FDA need any additional authority to ensure the
safety and efficacy of new and marketed drugs?
Answer 1. We do not believe new statutory authority is needed. We
will use all existing regulatory authority and enforcement powers when
negotiating label changes with drug companies or when monitoring or
managing drug safety issues. In most cases, FDA and the sponsor are
able to reach agreement on the labeling text fairly quickly (a few
weeks). As Dr. Janet Woodcock testified on March 3, 2005, a key factor
in labeling changes is that once a label change is made, old labels in
paper form are still in distribution and it takes time to get newer
labels into circulation. Dr. Woodcock testified that the new strategy
of posting drug safety information sooner using the Drug Watch
mechanism will help alleviate that factor because it will enable FDA to
get information directly to the people who need it in a timely manner.
In addition to the Drug Watch web page, our February 15, 2005,
announcement included plans to create a new Drug Safety Oversight Board
(DSB) to provide independent oversight and advice on the management of
important drug safety issues and to manage the dissemination of certain
safety information through FDA's website to health care professionals
and patients. For more information on this initiative, please visit:
http://www.fda.gov/oc/factsheets/drugsafety.html. Also, FDA is
intensifying our current efforts to provide the public with the most
important information for the safe and effective use of drugs in
patient-friendly language. Two tools, Patient Information Sheets and
Health care Information Sheets, will allow FDA to deliver emerging
safety information to patients and health care providers.
To carry out these enhancements, the Agency's fiscal year 2006
budget request includes an increase of $5 million for the Office of
Drug Safety, bringing total funding to $22.9 million (a nearly 25
percent increase).
Question 2. Concerning the recent withdrawal of marketed drugs, I
understand that 12 of the 17 drugs taken off the market were used in
ways that were unsafe. What drugs were they? How were they used? Was
this use off-label? Did the companies involved withdraw the drug
products from the market or did FDA require the withdrawals?
Answer 2. We are providing a list below of safety-based drug
withdrawals associated with unsafe labeled or off-label use of the drug
product. All of these products were voluntarily withdrawn by the
manufacturer. Those drugs for which the company made the withdrawal
decision independent of FDA advice are indicated with an asterisk. In
all other cases, the decision was made jointly by FDA and the company
or by the company upon FDA recommendation.
Propulsid (cisapride), a drug to treat gastroesophageal symptoms,
was withdrawn in 2000. It was withdrawn due to adverse events
associated with labeled, contraindicated usage (concomitant use of
medications, which inhibit a certain metabolic pathway), which
continued despite the fact that the label included a boxed warning
about this interaction and several ``Dear Healthcare Provider'' letters
were sent out to practicing physicians as reminders.
Lotronex (alosetron), a drug to treat Irritable Bowel Syndrome in
women, was withdrawn in 2000 and reintroduced in 2002 under a
restricted distribution program. Lotronex was withdrawn because of the
occurrence of ischemic colitis in patients taking the drug, many of
whom were prescribed the drug for unapproved indications.
Duract (bromphenac), a drug to treat acute pain, was withdrawn in
1998. The drug was found to have a very high rate of liver toxicity
when used for longer than a few weeks. Despite several label changes,
including a boxed warning and several ``Dear Health Care Provider''
letters advising use of the drug for no more than two weeks, cases of
severe liver toxicity continued to be reported in patients taking the
drug for prolonged periods.
Seldane (terfenadine), a drug to treat seasonal allergic rhinitis,
withdrawn in 1998. Seldane caused an abnormal prolongation of heart
electrical pathways when used in combination with other drugs that
inhibited certain metabolic pathways. Despite a boxed warning and other
measures to educate prescribers, reports of serious cardiovascular
events, including death, continued due to Seldane and contraindicated
concomitant medicines.
*Hismanal (astemizole), a drug to treat seasonal allergic rhinitis,
was withdrawn in 1999. This drug was withdrawn under the same set of
circumstances that Seldane had been several months before.
Mibefradil, a drug to lower blood pressure, was withdrawn in 1998
because it caused a potentially fatal heart rhythm disturbance when
used in combination with some other drugs. Warnings and other
notifications were not successful in mitigating such use.
Voluntarily withdrawn from the market by the manufacturer, but not
due to use inconsistent with the label:
Bextra (valdecoxib), a drug to treat acute and chronic pain, was
withdrawn in 2005. It was withdrawn due to post-marketing data
regarding risk of CV safety associated with it and other anti-
inflammatory drugs, and a very high rate of serious skin reactions that
is not shared by other similar drugs.
*Vioxx (rofecoxib), a drug to treat acute and chronic pain, was
withdrawn in 2004. It was withdrawn due to concerns of an increased
risk of CV events.
Baycol (cerivastatin), a drug to treat high cholesterol, was
withdrawn in 2001. It was withdrawn due to reports of rhabdomyolysis
(severe and potentially serious muscle toxicity) that was found to be
far more common with Baycol than other similar drugs.
*Raplon (rapacuronium), a drug used to induce anesthesia, was
withdrawn in 2001 due to reports of serious bronchospasm associated
with its use.
Phenylpropanolamine, a nasal decongestant, was withdrawn in 2000.
Never approved by FDA, this very old drug was voluntarily removed from
numerous prescription and non-prescription products by manufacturers,
due to concerns that it might cause strokes.
Rezulin (troglitazone), a drug to treat diabetes, was withdrawn in
2000 at the time of introduction of newly approved products that could
serve as less toxic, adequate substitutes. Rezulin included labeling
warning of liver toxicity and the need for routine monitoring of
patients. Several ``Dear Healthcare Provider'' letters about this
toxicity and need for monitoring were issued.
*Rexar (grepafloxacin), an antibiotic, was withdrawn in 1999. It
was withdrawn by the company after the manufacturer observed a small
number of severe CV events.
Question 3. For several years, FDA has been implementing an
initiative to make product labels easier to use by consumers. For
example, FDA issued regulations to require that nonprescription drugs
carry clear, simple and readable labeling. FDA took this action to make
it easier for consumers to understand information about OTC drug
products, including the benefits and risks, and how the drugs should be
used most effectively. Does FDA intend to review prescription drug
labeling to see if it is possible to make it easier for consumers and
caregivers to find and understand important information about the
products?
Answer 3. FDA agrees that the current package insert format is
inadequate. Therefore, we have embarked on a major initiative to
improve it. In recent years, there has been an increase in the length,
detail and complexity of prescription drug labeling, making it harder
for health care practitioners to find specific information and to
discern the most critical information in product labeling. In the
Federal Register of December 22, 2000, (65 FR 81082) FDA issued a
proposed rule to revise its regulations governing the content and
format of labeling for human prescription drug products. Prior to
issuing the proposal, the Agency evaluated the usefulness of
prescription drug labeling for its principal audience to determine
whether, and how, its content and format could be improved. The Agency
used focus groups, a national physician survey, a public meeting and
written comments to develop multiple prototypes and to ascertain how
prescription drug labeling is used by health care practitioners, what
labeling information practitioners consider most important, and how
practitioners believed labeling could be improved. The Agency developed
a prototype based on this accumulated information as the model for the
proposed rule. FDA received many comments on the proposed rule and is
working to finalize it in the near future. Publication of this rule
will be accompanied by publication of four implementing guidance
documents.
______
Response to Questions of Senator Kennedy by Janet Woodcock, M.D.
Question 1. In your testimony, you and Dr. Kweder described how the
agency approves drugs under the statutory ``safe and effective''
standard, which the agency applies by comparing the known benefits of
the drug against the known risks and assessing whether the benefits
exceed the risks. Dr. Kweder and you explained, for example, how the
agency assessed benefit with respect to the disease or condition to be
treated, so that treating a tension headache, which goes away on its
own and is in no sense life-threatening, is considered to offer
considerably less benefit than treating a life-threatening cancer, and
the risks that may be tolerable are considerably higher.
Under section 515 of the statute, the agency approves pre-market
approval applications for medical devices if there is reasonable
assurance of safety and effectiveness. Does application of this
standard also involve comparing benefit and risk? If so, please explain
how the application is similar to, and differs from, the risk-benefit
assessment that the agency performs for a drug? If not, why not? Please
explain in detail, and with examples, how the agency applies the
standard of reasonable assurance of safety and effectiveness.
Answer 1. FDA wants to emphasize that all drugs and devices,
regardless of their approval mechanism, must have benefits that
outweigh risks.
For devices going through the pre-market approval application
process, there is a reasonable assurance that a device is safe when it
can be determined, based on valid scientific evidence, that the
probable benefits to health from use of the device for its intended
uses and conditions of use, when accompanied by adequate directions and
warnings against unsafe use, outweigh any probable risks (21 CFR
860.7(d)(1)). There is a reasonable assurance that a device is
effective when it can be determined, based on valid scientific
evidence, that in a significant portion of the target population, the
use of the device for its intended uses and conditions of use, when
accompanied by adequate directions for use and warnings against unsafe
use, will provide clinically significant results (21 860.7(e)(1)).
For devices, the mechanisms of assessing the benefits and the risks
are analogous to drugs. Assurance of safety is based upon
investigations using laboratory animals, investigations involving human
subjects, and non-clinical investigations including in vitro studies
(21 CFR 860.7(d)(2)). The valid scientific evidence to determine a
reasonable assurance of effectiveness of a device shall consist
principally of well controlled investigations (21 CFR 860.7(e)(2)). The
device regulations also allow for the consideration of other types of
studies as well (21 CFR 860.7(e)(2)).
The Center for Devices and Radiological Health (CDRH) similarly
assesses benefit with respect to the disease or condition to be
treated. For example, a device that uses shockwave therapy to treat a
pain associated with tendonitis, which may be treated with physical
therapy and is in no sense life-threatening, is considered to offer
less benefit than devices used to treat a life-threatening condition,
such as replacing a faulty heart valve. Further, the risks that would
be considered acceptable will be higher in the latter case.
FDA's analysis of VIOXX was based on our assessment of the
available data, the recommendations from the advisory committee, and
our best judgment of the potential benefits of the drugs compared to
the potential risks of the drug when used according to the
recommendations included in the revised labeling.
Question 2a. In the VIGOR trial, compared with naproxen, Vioxx at
50 mg increased the risk of heart attacks by a factor of 5. At that
dose, the approved indication was the short-term treatment of acute
pain. Do these risk-benefit analyses still seem reasonable to you?
Answer 2a. FDA carefully considered all the CV findings from the
VIGOR study, and available data from other trials, in assessing the
impact of the VIGOR data on the continued safe use of the drug. FDA
presented the results of the VIGOR study at a public Arthritis Advisory
Committee meeting on February 8, 2001. The GI, CV, and general safety
results of the VIGOR study were presented and discussed extensively.
The expert panel, which included two cardiologists, recommended that
both the positive GI information (reduced risk of serious
gastrointestinal bleeding versus naproxen) as well as the potential
increased risk of CV events (compared to naproxen) be included in the
label. The panel did not recommend withdrawal of the 50 mg dose from
the market.
Vioxx 50 mg was originally approved only for the short-term
management of acute pain. Based on the data available to FDA at that
time, we concluded that the potential risk of short-term use of VIOXX
50 mg did not outweigh the potential benefits. FDA did however,
implement changes to the VIOXX labeling that specifically stated that
the prolonged use of the 50 mg dose was not recommended and that the
maximum recommended dose for prolonged use in osteoarthritis and
rheumatoid arthritis was 25 mg daily.
FDA's analysis of VIOXX was based on our assessment of the
available data, the recommendations from the advisory committee, and
our best judgment of the potential benefits of the drugs compared to
the potential risks of the drug when used according to the
recommendations included in the revised labeling.
As you know, FDA convened a joint meeting of the Arthritis Advisory
Committee and the Drug Safety and Risk Management Advisory Committees
in February 2005 to discuss overall benefit to risk considerations,
including CV and GI safety concerns for COX-2 selective non-steroidal
anti-inflammatory drugs. The Advisory Committees analyzed all available
information from recent studies of Vioxx, Celebrex, Bextra, naproxen,
and other data for non-selective NSAIDs and COX-2 selective products.
Following the joint meeting, FDA scientists conducted a thorough
internal review of the available data regarding CV safety issued for
COX-2 selective and non-selective NSAIDs. It was determined that Bextra
was associated with an approximately two-fold increased risk of serious
CV events compared to placebo. On April 6, 2005, FDA completed a
``Decision Memo--Analysis and Recommendations for Agency Action--COX-2
Selective and Non-Selective NSAIDs'' based upon the internal review.
The Decision Memo stated that, based upon detailed conclusions, the
Agency should ask the manufacturer of Bextra, Pfizer Pharmaceuticals,
to voluntarily remove Bextra from the U.S. market. Pfizer agreed to do
so.
On April 7, 2005, FDA issued the enclosed Public Health Advisory,
indicating that the Agency had asked Pfizer to voluntarily remove
Bextra from the U.S. market. The Agency is also asking manufacturers of
all marketed prescription NSAIDs, including Celebrex (celecoxib) to
revise the labeling (package insert) for their products to include a
boxed warning, highlighting the potential for increased risk of CV
events and the well described, serious, potential life-threatening GI
bleeding associated with their use.
Further, manufacturers of non-prescription (over-the-counter)
NSAIDs are also being asked to revise their labeling to provide more
specific information about the potential CV and GI risks of their
individual products and remind patients of the limited dose and
duration of treatment of these products in accordance with the package
instructions. In addition, FDA advised the public to contact their
health care providers to see if other marketed NSAIDs may be helpful in
treating their pain. For more information on FDA's recent actions,
please visit: http://www.fda.gov/cder/drug/infopage/COX2/default.htm.
Question 2b. Some have attributed tens of thousands of deaths to
the use of Vioxx. Dr. Kweder has described these deaths as
``theoretical.'' Dr. Galson said they were based on ``junk science.''
Does the agency stand by these statements?
Answer 2b. Dr. Kweder's description of deaths as ``theoretical'' is
a reference to epidemiological studies that project the numbers of
deaths from adverse drug reactions. Epidemiology takes certain
information that is received and attempts to apply that information to
the entire population. Conclusions from this data are not conclusive,
but are merely estimates. Any epidemiological study that says a million
patients suffered adverse events is a theoretical estimation of the
total adverse drug reactions that is derived by extrapolating the
actual numbers observed to the population as a whole. Therefore, these
can be considered ``theoretical'' deaths. The accuracy of projection is
highly dependant on the accuracy of the information, methodology, and
assumptions used in the study. While theoretical deaths are estimates
and must be distinguished from confirmed deaths, this nevertheless
provides valuable information about potential outcomes, and FDA takes
this information very seriously in determining whether to revise the
risk/benefit profile for a particular drug.
The ``junk science'' quote comes from a conversation with a
Washington Post reporter that was taken out of context. The FDA
official interviewed was asked to respond to the reporter's question
about whether it was accurate to state that a certain number of
individuals in particular Congressional districts could be said to have
died of cardiovascular events because of Vioxx. It is not possible to
derive from risk estimates the cause of a particular individual's
death. This concept is complicated to explain, and FDA's official
reacted to it by characterizing the particular statement regarding
deaths of individuals in a Congressional district as ``junk science.''
Question 2c. Does the agency believe that Vioxx increases the risk
of heart attack and stroke? If not, why not?
Answer 2c. Following the February 16-18, 2005, joint meeting of
FDA's Arthritis Advisory Committee and the Drug Safety and Risk
Management Advisory Committee, FDA scientists conducted an internal
review, taking into consideration the recommendations of the Advisory
Committees, of the available data regarding CV safety for COX-2
selective and non-selective NSAIDs. On April 6, 2005, FDA completed a
document entitled, ``Decision Memo--Analysis and Recommendations for
Agency Action--COX-2 Selective and Non-Selective NSAIDs'' (located at:
http://www.fda.gov/cder/drug/infopage/COX2/NSAIDdecisionMemo.pdf). The
Decision Memo reflects the Agency's evaluation of the risk/benefit
profile of Vioxx, Celebrex, and Bextra, among others. The memo
concluded that ``these three approved COX-2 selective drugs are
associated with an increased risk of serious CV events, at least at
some dose, with reasonably prolonged use.''
Question 2d. If so, does the agency believe that some of the 20
million people who used Vioxx actually experienced heart attack or
stroke because of Vioxx? If not, why not? If so, how many heart attacks
and strokes does the agency believe Vioxx caused?
Answer 2d. Based on evidence from clinical trials, it is possible
that some of the patients who were treated with Vioxx may have
experienced a heart attack or stroke related to the use of Vioxx. We
cannot reliably state how many heart attacks and strokes were caused by
Vioxx alone, in part because the estimates vary depending on how you
assume Vioxx was used and at what time point you believe the CV risks
of Vioxx start.
In his presentation prepared for FDA's Advisory Committee meeting
on NSAIDs in February 2005, Dr. Robert O'Neill described the many
challenges and assumptions involved in making projections of harm
associated with Vioxx to the general population that might have been
exposed to Vioxx. To illustrate these challenges, he considered the
types of assumptions, often unverifiable, that have to be made to make
any projection. He illustrated an approach that emphasized the
importance of when during exposure the risk occurs, what is its time
pattern, and how many people are estimated to be chronically exposed
for various durations. The clinical trials available were used for some
estimates. The approach estimated the cumulative risk of confirmed
thrombotic events, myocardial infarction (MI) and sudden death for
Vioxx from two different clinical trials, VIGOR and APPROVe, trial
designs of different duration, with different patient populations, with
different doses, and with different control groups. He then estimated
and projected to the population sizes that would typically have been
exposed for different durations of chronic usage. For MI and sudden CV
death, the projections for the 25mg and 50mg combined were between
32,418 to 33,093 people, depending upon assumptions. For confirmed
thrombotic events occurring with 14 days of last study dose the
projection were between 47,710 and 49,440. Taking all the known and
unknown sources of variability as well as the statistical uncertainty
in the data, the estimates could be larger or smaller.
Question 3a. Please explain how the agency's response to the VIGOR
trial would have been different if Secretary Leavitt's recently
announced independent board had been in place at the time? What actions
would have occurred?
Answer 3a. FDA's experience with Vioxx and other recent drug safety
events are the impetus behind our forming the Drug Safety Oversight
Board. Had the Drug Safety Board existed at the time FDA became aware
of the results of the VIGOR trial, we believe that CDER staff would
have identified the trial results and concerns as an issue that would
have warranted deliberation by the Board. It is difficult to speculate
exactly what would have happened, but we feel that the Board as it is
currently conceptually proposed would have made its best scientific
judgments and recommendations based on all of the safety information
available.
Question 3b. Is there reason to think its analysis of the VIGOR
data and recommendations stemming from it would have been different
from those of the FDA reviewers at the time? What authority would they
have had to take corrective actions?
Answer 3b. Again, it is difficult to speculate what would have
happened in this case had the Board existed at the time the VIGOR trial
results became known. However, whatever recommendations the Board may
have made would have been presented to the Center Director who would
have made the final determination on how to proceed. It then would have
been the responsibility of the appropriate CDER program offices to
carry out the decision of the Center Director.
Question 3c. Does the agency believe that use of the drug would
have been different? In particular, would significantly fewer people
have experienced heart attack and stroke? If not, please explain why
the recent FDA proposals are an adequate response to the Vioxx
disaster.
Answer 3c. Again, it is difficult to speculate with confidence the
level of influence the Drug Safety Oversight Board's involvement would
have made in the VIOXX case. We are confident, however, that the
actions that have been announced recently including the formation of
the DSB, the introduction of the ``Drug Watch,'' increased involvement
of outside expertise, recent publication of risk management guidance,
and other activities are an appropriate proactive response to the
recent drug safety concerns. But we do not assume that these actions
alone are adequate. We are continuing to proactively discuss and seek
advice and feedback from internal and external sources on possible
additional actions we can take. For example, we look forward to the
Institute of Medicine's report on the drug safety system in the U.S.
While we would not characterize the Vioxx situation as a
``disaster,'' we have openly conceded the fact that there is room for
improvement in our post-marketing drug surveillance program and that is
why we have acted quickly to improve our drug safety processes and our
internal and external communication of drug safety issues. We agree
that discussions with the company to change the labeling for Vioxx were
lengthy. However, in the future, we expect that the Drug Watch page
will provide a forum for informing the public sooner about emerging
safety issues.
Question 4. In January 2005, the data from an early clinical trial
of Celebrex indicating an increased risk of cardiovascular problems
were posted on a clinical registry database. The results from this
trial had never before been released to the public. Were these results
given to the FDA? When? In what form? Please explain in detail how the
agency assessed these data. Were they ever reflected in the labeling of
the drug? Did the agency do any sort of follow-up? Did this study play
any role in the agency's assessment of the heightened cardiovascular
risk from Vioxx shown by the VIGOR trial?
Answer 4. The sponsor gave these results to FDA. The report,
submitted on June 7, 2001, indicated that a number of patients (n=13)
who participated in the study had adverse events, which were listed
using the WHO preferred term ``cerebrovascular disorder.'' The Division
of Neuropharmacological Drug Products (DNDP) requested narratives be
submitted for all 13 patients. Upon review of the narratives all 13
appear to have unequivocally sustained either a stroke or transient
ischemic attack during or within 28 days of the study's termination.
The incidence of serious adverse events (including deaths), adverse
event discontinuations and all adverse events, when evaluating
individual adverse events as coded by specific preferred terms, did not
raise any safety concerns which warranted further action.
In October 2004, the Division again looked at the CV adverse event
data contained in the June 7, 2001, study report, focusing on
myocardial infarction, angina, and cerebrovascular disorder (since
myocardial infarction and stroke were the events of greater concern
with rofecoxib) and did not include atrial fibrillation, cardiac
failure and pulmonary edema. DNDP felt that no action was needed based
on these results, except to further evaluate the events that were
subsumed under the term ``cerebrovascular disorder.''
On October 22, 2004, after assessing the overall adverse event
profile for this study, DNDP asked the sponsor to provide clinical
narratives for patients who participated in the study and had adverse
events that were listed using the WHO preferred term ``cerebrovascular
disorder.'' The objective of this request was to clarify whether the
patients actually had strokes or transient ischemic attacks.
Based on the narratives provided and reviewed by DNDP, the deaths
in the study seem not to be primarily related to thrombotic vascular
events (many different presumed causes), and the difference between
drug and placebo in the incidence of vascular serious adverse events
(or non-serious adverse events in general) does not clearly indict the
drug.
Our conclusions that no action was needed was based on the fact
that the events were small in number in both treatment groups, not
uncommon in older individuals, not strikingly different in incidence
between the drug and placebo groups, and in some instances more common,
in fact, in the placebo group.
This study did not play role in the Agency's assessment of the
heightened CV risk from Vioxx shown by the VIGOR trial as it was an
Alzheimer's study and was not designed nor did it focus on those
endpoints.
Question 5. You mentioned in the Q&A that drug sales
representatives are still using egregious marketing techniques-such as
detailing, or shadowing of doctors in their offices, offering expensive
gifts and samples and honoraria for prescribing physicians-and that
those practices have a large effect on prescribing habits. Can FDA
encourage drug companies to use better educational techniques, such as
peer-reviewed communication of results, to get the word out about new
products? Would it help the FDA promote rational prescribing if the FDA
had the authority to limit such marketing for recently approved drugs,
whose risk-benefit profiles are still not fully understood? If not, why
not? How in your view should the concern about promotion to physicians
be addressed?
Answer 5. FDA does not regulate practices such as shadowing of
doctors in their offices or offering expensive gifts or honoraria for
prescribing physicians, and FDA does not regulate the practice of
medicine.
FDA's regulations do require that all promotional materials be
submitted to FDA on Form 2253 at the same time as they are used to
promote to healthcare professionals or to consumers. In other words,
FDA's review of promotional materials is generally intended to occur
post hoc. If FDA finds the materials to be inaccurate or unbalanced,
FDA may take enforcement actions requesting that sponsors stop using
violative materials. In some cases, FDA may request that sponsors run
corrective advertisements or issue corrective letters to correct
product misimpressions created by false, misleading, or unbalanced
materials.
CDER's Division of Drug Marketing, Advertising, and Communications
(DDMAC) is responsible for regulating prescription drug promotion.
DDMAC's mission is to protect the public health by helping to ensure
that prescription drug information is truthful, balanced, and
accurately communicated. This is accomplished through a comprehensive
surveillance, enforcement and education program, and by fostering
optimal communication of labeling and promotional information to both
health care professionals and consumers.
Promotional programs and materials performed and disseminated by
companies are subject to the labeling and advertising provisions of the
FD&C Act. The FD&C Act and regulations do not distinguish between
promotion to professional or consumer audiences. Section 502(n) of the
FD&C Act specifies that prescription drug advertisements must contain
``a true statement of . . . information in brief summary relating to
side effects, contraindications, and effectiveness'' of the advertised
product. The implementing regulations specify that prescription drug
advertisements cannot be false or misleading, cannot omit material
facts, and must present a fair balance between effectiveness and risk
information.
FDA regulates advertisements and other promotional material, called
``promotional labeling,'' disseminated by or on behalf of the
advertised product's manufacturer, packer or distributor. According to
the October 2002 GAO report entitled, Prescription Drugs: FDA Oversight
of Direct-to-Consumer Advertising Has Limitations, ``Promotion to
physicians accounted for more than 80 percent of all promotional
spending by pharmaceutical companies in 2001.'' Therefore, the bulk of
the Agency's time spent reviewing promotional material, is spent
reviewing materials produced for promotion to health care
professionals, such as detail aids used by manufacturer
representatives, convention displays, file cards, booklets, and
videotapes, which is distinct from advertising directed toward
consumers.
Thank you again for the opportunity to testify before the committee
on this important topic and also for the opportunity to submit these
answers for the hearing record. If there are further questions, please
let us know.
Sincerely,
Patrick Ronan,
Assistant Commissioner for Legislation.
______
Response to Questions of the HELP Committee by Cecil B. Wilson, M.D.
RESPONSE TO QUESTIONS OF SENATOR ENZI
Question 1. What does FDA do to get important new information about
drugs to doctors and patients, short of an actual label change? How
might FDA improve their communications?
Answer 1. The primary way by which the FDA communicates information
about a drug's risks and benefits to physicians is through the package
insert. However, when changing a product's labeling is not appropriate,
the FDA relies primarily on electronic means to communicate important
new drug or safety information, including the posting of public health
advisories directly on the FDA Web site. Approximately 46,000
individuals receive direct e-mail notices of safety alerts that are
posted on the MedWatch homepage. Additionally, approximately 160
MedWatch partners, including the AMA, assist in disseminating safety
alert information.
The FDA, the pharmaceutical industry, and physician organizations
must collaborate and identify innovative ways to communicate new risk
information about a drug or biological product to physicians so they
will be aware of it, remember it and act on it when prescribing a drug.
Potential collaborative activities include:
Undertaking a major CME initiative on risk communication;
Working with major medical journals and medical society
web site editors to identify standard places for the dissemination of
important new risk information about drugs and biological products;
Using alternative mechanisms to transmit ``Dear Doctor''
letters, which disseminate important prescribing information from the
pharmaceutical companies to physicians (e.g., publication in medical
journals, possibly as paid advertisements; placement on medical society
web sites; and transmission to individual physicians by blast fax,
blast e-mail, or direct daily downloads to personal digital assistants
[PDAs]);
Changing the content and format of ``Dear Doctor'' letters
to emphasize the need for action by the prescribing physician; and
Encouraging pharmaceutical companies to train and send
their sales forces to physicians to educate them on important new risk
information about company products.
Additionally, the FDA issued a proposed rule in December 2000 to
modify the format and content of the package insert with the goal of
making the information more useful and user-friendly to physicians.
Their recommendations included a more simplified, ``Highlights of
Prescribing Information'' section within the package insert. The AMA
continues to strongly support FDA efforts to make package inserts more
useful and user-friendly for physicians and encourages the FDA to issue
a final rule to that effect.
Question 2. We have heard that the voluntary and passive nature of
the adverse event reporting system may result in under-reporting of
safety issues. What can you suggest to this Committee as to how we
could improve that reporting? How might new technologies, such as
Electronic Medical Records be applied to the Adverse Event Reporting
System and what are the benefits one could expect to achieve?
Answer 2. As mentioned in our written testimony, if formal
postmarketing studies are not conducted by manufacturers or clinical
investigators to obtain safety information, observational data
collected by physicians, other health professionals, and patients are
the keys to evaluating and characterizing a drug's risk profile in
actual clinical use. Currently, the FDA maintains an adverse event
reporting system termed MedWatch, which incorporates both a mandatory
adverse event reporting system for manufacturers subject to the
Agency's postmarketing safety reporting regulations, and a voluntary,
adverse event reporting system for health care professionals,
consumers, and patients. MedWatch can be an effective tool for
detecting signals suggesting that a drug may be associated with a rare,
but serious, adverse event.
However, the MedWatch program is a passive system and it is limited
by its reliance on voluntary reporting, which inevitably leads to under
reporting. Under reporting and uncertainty about the actual extent of
drug exposure, make it difficult to estimate true rates of occurrence
of drug-induced adverse events. Because of their observational nature,
spontaneous reports also are limited in their ability to establish
causality. In order to enhance this program, better educational efforts
are needed to inform physicians and other health professionals on how,
when, and where to report suspected serious adverse events.
Additionally, attention should be directed toward enhancing
postmarketing surveillance by using more active approaches. For
example, well designed pharmacoepidemiologic studies on newly marketed
drugs could substantially enhance our ability to more accurately
determine a drug's adverse event profile in a timely manner.
Question 3. I know that there are questions about both quantity and
quality of adverse event reports. FDA already receives hundreds of
thousands of reports a year, and perhaps should be receiving more. How
do they separate the truly important events from the rest? What can
treating physicians do to improve the quality of reporting that you do
to the FDA?
Answer 3. Based on our understanding, the FDA defines adverse drug
events as those occurring: (1) in the course of use of a drug product
in professional practice; (2) from drug overdose, whether accidental or
intentional; (3) from drug abuse; (4) from drug withdrawal; and (5)
from any ``failure of expected pharmacological action.'' According to
the FDA, MedWatch is especially interested in receiving: (1) reports of
serious adverse event reports that are novel or not currently included
in the drug's labeling; (2) all serious events associated with new
drugs during their first 3 years on the market; and (3) previously
reported reactions if they are serious and occur in clusters.\1\
---------------------------------------------------------------------------
\1\ A serious adverse drug reaction is defined as one that results
in or prolongs hospitalization, is life-threatening, contributes to
significant disability, or results in the death of the patient.
---------------------------------------------------------------------------
To improve the quality of reporting to MedWatch, better educational
efforts are needed to inform physicians and other health professionals
on how, when, and where to report suspected serious adverse events.
Question 4. FDA evaluates the risk/benefit ratio of a drug for a
population, but doctors and patients evaluate it on an individual
basis. Could you comment on the value and limitations of off-label
prescribing? Would Federal restrictions on off-label use negatively
interfere with the doctor-patient relationship?
Answer 4. Unlabeled (off-label) uses are defined as the use of a
drug product for indications or in patient populations, doses, or
routes of administration that are not included in FDA-approved
labeling. Under the Federal Food, Drug, and Cosmetic Act, a drug
approved by the FDA for marketing may be labeled, promoted, and
advertised by a manufacturer for only FDA approved uses. Even though
the Prescription Drug User Fee Act (PDUFA) has reduced the review time
for Supplemental New Drug Applications or SNDAs, manufacturers are not
required to and may not choose to seek FDA approval for all useful
indications. This occurs because the expense of regulatory compliance
may be greater than the eventual revenues expected. A sponsor may also
not seek FDA approval because of difficulties in conducting controlled
clinical trials (e.g., for ethical reasons, or due to the inability to
recruit patients).
A physician may choose to prescribe a drug for uses, in treatment
regimens, or in patient populations that are not part of the FDA-
approved labeling. The decision to prescribe a drug for an unlabeled
use is made by the physician in light of all information available and
in the best interest of the individual patient. Prescribing for an
unlabeled use requires the physician to use the same judgment and
prudence as exercised in medical practice for it to conform to accepted
professional standards. Given the prevalence of unlabeled uses and the
fact that in many clinical situations such use may represent the most
appropriate treatment (and in some cases the only treatment), the
prescribing of FDA-approved drugs for unlabeled uses is often necessary
for optimal patient care.
The AMA also strongly supports the SNDA process. However, given the
disparity between the actual submission of SNDAs and the evolution of
evidence-based medical practice, physician prescribing for unlabeled
uses should not be impeded by any actions taken to improve drug safety.
Question 5. Could you comment on the value of FDA's new Web site,
announced by HHS Secretary Leavitt and Acting Commissioner Crawford, as
a step to make sure patients and doctors have the latest and best
information about the drugs they are using?
Answer 5. The AMA applauds HHS and FDA efforts to enhance the
transparency of the drug surveillance and risk communication processes
with the creation of the ``Drug Watch'' web page. However, the FDA must
provide clear advice when it disseminates emerging or preliminary
information prior to taking regulatory action.
RESPONSE TO QUESTIONS OF SENATOR HATCH
Question 1. I understood from your remarks that the FDA had over
the last several years increased the speed of drug approvals without
any decrements in drug safety. The observational data collected by
clinicians and patients that is used to evaluate and characterize a
drug's risk profile in actual clinical use has received a fair amount
of criticism lately. Would you please comment on the limitations and
benefits of the current system and any changes you would recommend?
Answer 1. As mentioned in our written testimony, if formal
postmarketing studies are not conducted by manufacturers or clinical
investigators to obtain safety information, observational data
collected by physicians, other health professionals, and patients are
the keys to evaluating and characterizing a drug's risk profile in
actual clinical use. Currently, the FDA maintains an adverse event
reporting system termed MedWatch, which incorporates both a mandatory
adverse event reporting system for manufacturers subject to the
Agency's postmarketing safety reporting regulations, and a voluntary,
adverse event reporting system for health care professionals,
consumers, and patients. MedWatch can be an effective tool for
detecting signals suggesting that a drug may be associated with a rare,
but serious, adverse event.
However, the MedWatch program is a passive system and it is limited
by its reliance on voluntary reporting, which inevitably leads to under
reporting. Under reporting and uncertainty about the actual extent of
drug exposure, make it difficult to estimate true rates of occurrence
of drug-induced adverse events. Because of their observational nature,
spontaneous reports also are limited in their ability to establish
causality. In order to enhance this program, better educational efforts
are needed to inform physicians and other health professionals on how,
when, and where to report suspected serious adverse events.
Additionally, attention should be directed toward enhancing
postmarketing surveillance by using more active approaches. For
example, well designed pharmacoepidemiologic studies on newly marketed
drugs could substantially enhance our ability to more accurately
determine a drug's adverse event profile in a timely manner.
Question 2. How would you recommend we enhance postmarketing
surveillance? What more active approaches do you see as promising? How
is it best to notify clinicians of changes in practice or new findings?
Passive means, such as having them log onto a Web site, are likely to
be less effective than more active methods--but what specifically do
you see as the best practices?
Answer 2. Well designed pharmacoepidemiologic studies on newly
marketed drugs could substantially enhance our ability to more
accurately determine a drug's adverse event profile in a timely manner.
Furthermore, the FDA, the pharmaceutical industry, and physician
organizations must collaborate and identify innovative ways to
communicate new risk information about a drug or biological product to
physicians so they will be aware of it, remember it and act on it when
prescribing a drug. Potential collaborative activities include:
Undertaking a major CME initiative on risk communication;
Working with major medical journals and medical society
web site editors to identify standard places for the dissemination of
important new risk information about drugs and biological products;
Using alternative mechanisms to transmit ``Dear Doctor''
letters, which disseminate important prescribing information from the
pharmaceutical companies to physicians (e.g., publication in medical
journals, possibly as paid advertisements; placement on medical society
web sites; and transmission to individual physicians by blast fax,
blast e-mail, or direct daily downloads to personal digital assistants
[PDAs]);
Changing the content and format of ``Dear Doctor'' letters
to emphasize the need for action by the prescribing physician; and
Encouraging pharmaceutical companies to train and send
their sales forces to physicians to educate them on important new risk
information about company products.
Question 3. I appreciate your educating us on the reasons why so
many patients are being properly treated by off-label uses of drugs. Do
you see the decision by a physician or other clinician to use a drug in
this way as an exercise in clinical judgment, in the same way that the
physician decides what diagnostic test to use, what diagnosis is the
most likely, whether the treatment plan is successful, and so on?
Answer 3. Unlabeled (off-label) uses are defined as the use of a
drug product for indications or in patient populations, doses, or
routes of administration that are not included in FDA-approved
labeling. Under the Federal Food, Drug, and Cosmetic Act, a drug
approved by the FDA for marketing may be labeled, promoted, and
advertised by a manufacturer for only FDA approved uses. Even though
the Prescription Drug User Fee Act (PDUFA) has reduced the review time
for Supplemental New Drug Applications or SNDAs, manufacturers are not
required to and may not choose to seek FDA approval for all useful
indications. This occurs because the expense of regulatory compliance
may be greater than the eventual revenues expected. A sponsor may also
not seek FDA approval because of difficulties in conducting controlled
clinical trials (e.g., for ethical reasons, or due to the inability to
recruit patients).
The decision to prescribe a drug for an unlabeled use is made by
the physician in light of all information available and in the best
interest of the individual patient. Prescribing for an unlabeled use
requires the physician to use the same judgment and prudence as
exercised in medical practice for it to conform to accepted
professional standards. In some instances, prescribing a product off-
label is the most appropriate therapy based on the latest, best
scientific evidence. In some patient populations, it may be the only
treatment option.
Question 4. We have heard several people recommend that the FDA be
able to ``control'' how drugs are used. Do you agree? Should the
government, through the FDA, decide how patients should be treated, or
is that a matter for the clinician who is caring for that individual
patient? Should we instead focus on improving educational outreach
programs and surveillance notifications to clinicians?
Answer 4. As stated in our testimony, FDA-approved drug product
labeling (i.e., the package insert) should be the primary means by
which the FDA communicates risks about drug products to physicians for
the vast majority of drugs. Higher level risk communication and risk
minimization tools that extend beyond the package insert, such as
performance-linked access systems and some reminder systems, should be
used only as a last resort to keep high-risk drug products with truly
unique and important benefits on the market.
In the government's efforts to improve drug safety, there may be a
desire to use, more routinely, risk minimization tools that extend
beyond not only the package insert, but also beyond targeted education
and outreach in an effort to improve drug safety. A number of these
approaches would directly manage or restrict physician prescribing and
may lead to unintended consequences.
Rather than focus on restrictions, the AMA believes that the FDA,
the pharmaceutical industry, and physician organizations must
collaborate and identify innovative ways to communicate new risk
information about a drug or biological product to physicians so they
will be aware of it, remember it and act on it when prescribing a drug.
The AMA encourages the FDA and the product sponsor to work with
relevant physician organizations to assure that the minimum number and
least intrusive tools are selected to achieve the risk minimization
objective.
The AMA believes that individual States should regulate the
practice of medicine. AMA policy provides that, ``the AMA and
interested physicians will continue to work with the Food and Drug
Administration to prevent the unnecessary intrusion of the government
and other regulatory bodies into the doctor-patient relationship,
especially as it concerns the prescription of medication.'' (AMA Policy
H-100.971).
RESPONSE TO QUESTIONS OF SENATOR KENNEDY
Question 1. Why do you believe that direct-to-consumer ads that
encourage patients already in treatment to ask their doctor about
prescribing a particular drug or switching them to a new drug are so
effective? Why are drug companies spending so much time and money
shadowing doctors, and showering them with gifts and honoraria and
samples, as part of their marketing? I assume that all of these
practices work in getting physicians to prescribe drugs they wouldn't
have otherwise. Is that beneficial?
Answer 1. The AMA supports patients' increased access to drug
information, but is concerned about the impact direct-to-consumer (DTC)
advertisements have on the physician-patient relationship. In
consultation with the FDA, the AMA developed guidelines (AMA Policy H-
105.988) in 1993 for acceptable DTC advertisements. These
advertisements should promote accurate, balanced information that can
provide educational benefit for consumers. The AMA policy also urges
the FDA and the pharmaceutical industry to conduct or fund
``independent'' research to study the effects of the DTC ads on the
physician-patient relationship, health outcomes and costs.
Regarding gifts given to physicians by pharmaceutical companies,
some gifts that reflect customary practices of the industry, may not be
consistent with the AMA Principles of Medical Ethics (AMA Code of
Medial Ethics E-8.061). These Principles were developed by the AMA's
Council on Ethical and Judicial Affairs and are designed to guide
physicians on the inappropriateness of accepting gifts from the
pharmaceutical industry.
Question 2. Besides asking for FDA help in getting better quality
information to doctors and patients, what is the American Medical
Association doing to ensure that doctor's prescribing habits are based
on peer-reviewed evidence, rather than on clever marketing to doctors
and patients? Are those strategies working? Does the FDA need to step
in and regulate communication between the drug industry and the public
or the promotional goods and services offered by the drug industry to
prescribing doctors?
Answer 2. The AMA supports activities designed to foster the
development and implementation of evidence-based, physician-level
clinical quality improvement efforts. The AMA convened the Physician
Consortium for Performance Improvement to identify and develop
performance measurement resources for physicians. The Consortium is
comprised of clinical content experts from more than 60 State and
medical specialty societies, methodological experts, the Agency for
Health Research Quality (AHRQ) and the Center for Medicare and Medicaid
Services (CMS).
Through publication of the Journal of the American Medical
Association (JAMA) and the Archive specialty journals, the AMA is the
world's leading medical organization in publishing peer-reviewed
articles intended to inform and guide evidence-based clinical practice.
Additionally, the AMA is a leader in providing Continuing Medical
Education (CME) activities. In 2004, the AMA sponsored more than 320
CME activities serving more than 43,000 physicians.
The AMA believes that individual States should regulate the
practice of medicine. AMA policy provides that, ``the AMA and
interested physicians will continue to work with the Food and Drug
Administration to prevent the unnecessary intrusion of the government
and other regulatory bodies into the doctor-patient relationship,
especially as it concerns the prescription of medication.'' (AMA Policy
H-100.971).
______
Response to Questions of Senator Enzi by Keith L. Carson
Question 1. Personalized medicine intrigues me. Each product is a
small market but the field overall has huge potential. How do we make
the drug development process efficient enough to make these products
worth pursuing?
Answer 1. Personalized Medicine will allow doctors and drug
companies to identify individuals who are genetically susceptible to
certain diseases, as well as those who have a propensity to either
respond well to, or experience an adverse event from, certain drugs.
With this information, doctors will have a better chance to prescribe
drugs to which a patient will respond well, an avoid drugs to which a
patient will have problems. The product manufacturers will also be able
to use this information in clinical trials to select patients who would
probably do well in the trial, and avoid patients who could have
adverse reactions.
Genetic mapping could therefore revolutionize medicine by making
drugs work better while avoiding undesirable reactions. Clinical trials
could be done with smaller patient populations and result in fewer
adverse events. The product development cost savings could be
tremendous, plus the welfare of the clinical trial participants would
be greatly improved.
Personalized Medicine would not necessarily result in small markets
for each product, but would improve the performance of products while
preventing harmful side-effects. If patients were identified as having
a higher probability of bad side effects with a product, no one would
want them to take it. The use of this technology could prevent a
tremendous amount of litigation costs and settlements that now result
from drug related adverse events and deaths.
The potential savings from smaller clinical trial populations and
fewer patient law suits are such that product developers
(biopharmaceutical companies) will eagerly adopt this new technology
and use it extensively.
Unfortunately, there are significant problems associated with
Personalized Medicine. Many patients will be reluctant to have their
genes mapped, since they don't know how the information will be used,
or by whom. In addition, very large databases will have to be built and
managed to share enough information for Personalize Medicine to be
effective. Doctors will have to do a far better job of sharing patient
response data, and product developers will have to share what they now
consider proprietary clinical data with the public and other companies.
Question 2. What other emerging technologies might be useful in
identifying at-risk patients or populations and/or predicting potential
adverse events? Are there processes in place for the use of these
technologies in regulatory decision-making? What are some of the
hurdles to validation, regulatory acceptance and broad application of
these technologies?
Answer 2. I'm not aware of technologies other than pharmacogenomics
(gene-mapping) that have this potential. However, gene-mapping
technology currently relies on the use of microarray technology, plus
datamining and in silico technology to establish the correlations
needed for it to be useful in Personalized Medicine.
I know that the FDA is trying to build up their technical
capabilities in this area, so that they can better understand the
technology and apply it. However, I'm sure they will need more funding
to do this properly.
FDA is the only entity that has access to all of the clinical trial
data that is submitted. They are in a unique position to manage this
data and make it available for correlations to patient gene-mapping.
However, such an endeavor will take massive data storage and computing
capability.
I suggest that Congress provide adequate funding so FDA can have
outside firms provide the necessary storage and analysis services. Such
services are becoming a commodity and prices are very competitive. FDA
doesn't have the internal expertise to build and maintain a state-of-
the-art capability, and they certainly don't have the hardware. They
should rely on outside contractors as much as possible.
Once a large enough database has been assembled, then FDA could use
the data to make comparisons between similar products, and help make
better regulatory decisions concerning the design and size of clinical
trials, plus the selection of specific patients for these trials. As
more clinical data became available for a particular product, the
Agency could even decide that the product should be licensed for
specific patient profiles, while other studies continued.
To validate or accept this technology, sufficient data will be
needed. Product response data is required to show which patients did
well or had problems with a certain drug. Adverse events will have to
be experienced to establish the correlations needed to predict which
patients could be susceptible to them. To get this data, product
developers must be more willing to share clinical data with the public
and other companies, and doctors must do a better job of reporting how
patients respond to new drugs.
In addition, patients will have to become more comfortable with
having their genes mapped. Many people are concerned about how this
information will be used. They are especially fearful of what insurance
companies and employers could do with the data. Systems must be devised
that provide adequate data encryption and controlled access.
Question 3. What one action could Congress take that would most
dramatically improve drug safety in the U.S.?
Answer 3. Congress could increase funding so that FDA can fully
utilize this new technology. In addition, Congress could work with AMA
to implement better electronic systems through which doctors can report
drug responses--good and bad.
______
Response to Questions of Senator Hatch by Keith L. Carson
Question 1. Do you believe that the lack of a modern IT
infrastructure at the FDA impairs the agency's ability to do its job
and hire the best people?
Answer 1. I believe that the lack of modern IT infrastructure will
severely impede FDA's ability to utilize new technologies such as
advanced data management, datamining, and in silico technology. FDA is
the only entity that has access to all the clinical trial data that is
submitted, and has a unique opportunity to make this data available for
use in Personalized Medicine.
To acquire adequate infrastructure, I suggest that much of it
should be obtained through services from outside contractors. However,
significant upgrades will still be needed for internal data management
capabilities that should not be outsourced.
I don't know if a lack of IT infrastructure is keeping FDA from
hiring the best people, but it could certainly prevent top-notch IT
people from joining the Agency.
However, FDA budget restrictions provide a far bigger impediment to
capturing the best people. The Agency is known for having a very tight
budget, where everything is difficult to justify and buy. Top technical
people will go where the resources are available for them to do the
best work.
Question 2. Is the FDA competitive when it comes to attracting new
staff? What do you believe that the FDA should do to attract the best
and brightest scientists?
Answer 2. I seriously doubt that FDA is competitive when it comes
to attracting new staff. FDA is constantly losing good people to
industry positions that pay far more money and provide vastly superior
resources. In addition, these industry positions don't involve the
political and bureaucratic hassles that an Agency job is known for. At
FDA, every decision must be scrutinized as to ethical and legal
implications, plus pass through multiple levels of management. Such an
environment stifles innovation and sound decision making.
To attract the best and brightest scientists, FDA must have the
resources to equip, supply, and staff their laboratories. Without
proper funding, good people would never put up with the bureaucratic
hassles and red tape that the Agency is known for.
The FDA does have some very talented and brilliant people, who are
truly dedicated public servants. I could not work under the pressures,
internal politics, and bureaucratic nightmares these folks endure on a
daily basis. Then, when their programs are drastically underfunded, I
don't know how they can take it. We should all be proud to have the
folks that are there, and Congress should do all it can to adequately
fund FDA's laboratories.
______
Response to Questions of the HELP Committee by Raymond L. Woosley, MD,
Ph.D.
RESPONSE TO QUESTIONS OF SENATOR ENZI
Question 1. In your testimony, you describe some initiatives for
tracking outcomes of treatment with new drugs, particularly the UK's
``yellow card'' system. The UK has a national health care system,
unlike the US. How do you envision setting up a physician-based
national drug safety evaluation system in the absence of a national
health care system?
Answer 1. I don't think such a system is the best approach for the
United States. The cost of reimbursing physicians would make it too
expensive to implement and it would compete with physician's time to
allocate for patient care. That is why I have suggested a pharmacy-
based system for drug safety. The expertise of pharmacy technicians,
pharmacists and clinical pharmacists are under-utilized and would cost
far less than a physician-driven system. The proposal described in my
written testimony would be community-based and focused on outpatient
healthcare. We would also need to have a hospital-based pharmacy
network. The principles would be the same.
We would give pharmacy technicians, pharmacists and clinical
pharmacists special training in drug safety surveillance using a
curriculum designed by the AHRQ-funded Centers for Education and
Research on Therapeutics (CERTs). They could receive the training
through distance learning (such as ``telemedicine''). The surveys
(questionnaires developed by the FDA and CERTs collaborators) would be
performed by pharmacy technicians. Specially trained pharmacists (for
outpatients) and clinical hospital pharmacists (for inpatients) could
address the interpretation of medical information and contact
physicians when necessary to obtain more detailed information.
The Quality Improvement Organizations (QIOs) funded by the Centers
for Medicare and Medicaid (CMS) could assist by abstracting medical
records, a function they now do under contract for CMS. The information
gained would not only improve outcomes (which both increases safety and
lowers cost to CMS), it would provide data for the FDA Office of Drug
Safety that is not now available.
The data would also be rapidly available so that the number of
people exposed to risks should be minimized. For the 15 drugs removed
from the market since 1997, it took an average of 5.9 years before the
harm was detected and final action taken. I envision a rapid response
system that saves lives and therefore limits liability for companies in
subsequent litigation.
Question 2. I am intrigued by your suggestion of a staged approval
process for new drugs. However, I'm concerned that there would be great
demand for a new drug as soon as it is approved. Patients who are
desperately ill want and need access to new treatments. Could you tell
me more about how you would restrict access to these drugs?
Answer 2. I hesitate to use the word ``restrict'' because I share
your concern for patients who need new medicines. I think we need a
process that makes the drug available as early as possible but only for
those patients who are representative of those for whom a new drug has
shown benefit. If a drug has only been tested in patients with a
certain type of cancer and patients with renal or liver disease have
never been studied, we should prohibit or at least strongly discourage
patients with renal disease from receiving the drug. Likewise, the very
elderly should be discouraged from taking a new drug if it has only
been studied in younger people. Perhaps, they could only get the drug
under a registry system so that we would know what happens when the
drug is used off label.
Every drug will be different and we need a system that is flexible
enough to rapidly response to patient needs. Once in place throughout
the country, the Community Based Pharmacy Safety Network described
above could perform this type of function.
While some may argue this system would limit the ability of doctors
to prescribe approved drugs for any use them deem appropriate, I
suggest it would provide a proper balance between the rights of medical
practitioners and the rights of patients to receive safe and effective
drugs for their particular medical issues.
Question 3. What one action could Congress take that would most
dramatically improve drug safety in the U.S.?
Answer 3. I agree with Acting Commissioner Lester Crawford in his
recent testimony that (and I paraphrase) the best way to address drug
safety is to enable the FDA to pursue the Critical Path Initiative
described in the white paper: ``Innovation or Stagnation, Challenge and
Opportunity on the Critical Path to New Medical Products.'' I recommend
that Congress provide the FDA with $50 million in funding for the
Critical Path Initiative to utilize the currently available mechanisms
to both enhance drug safety and enable the development and approval of
new drugs for serious medical conditions.
The drug safety problem cannot be solved by the FDA alone. These
funds would enable the FDA to work with its sister agencies (CMS, AHRQ,
CDC and NIH), the academic community and the industry to address drug
safety and the interrelated problems that result from the lack of
innovation in the process of drug development.
RESPONSE TO QUESTIONS OF SENATOR HATCH
Question 1a. You mention that the pharmaceutical industry spends
12-15 years and nearly a billion dollars on each drug that is
successfully developed. You also describe that the proportion of drugs
that fail during development has doubled in the last 10 years. Why is
that?
Answer 1a. The most complete answers to this question can be found
in the FDA's white paper that was released in March of 2004:
``Innovation or Stagnation, Challenge and Opportunity on the Critical
Path to New Medical Products.'' First, I should expand on my testimony:
Estimates range from $850 million to $1.7 Billion for the amount that
the industry must spend overall in order to get one drug approved. This
includes the cost of many drug failures. The amount spent on any one
drug that succeeds is actually less, probably about $400 million.
However, the cost of failures is a real cost and one that must be
accounted for. The rising number of drug failures, both before and
after marketing, adds tremendously to the cost of pharmaceutical
research and development. Since 1997, 17 major drug products were
removed from the market. The costs of their development were in the
billions of dollars and should be considered a loss from the standpoint
of ``opportunity costs.'' Removing these drugs from the market also is
associated with billions of dollars in losses due to litigation and
personal injury claims.
A short answer to your question is the following: Over the last
twenty years we have had a revolution in science that has created new
opportunities to learn more about the medicines that are being
developed. The FDA has required that drug companies add research
projects to the development process in order to know more about the
drugs and how to use them. For example, the FDA now asks companies to
identify which enzymes break down the drug because we know that some
people, due to their individual genetics, can fail to break down the
drug, which could build up in their bodies to cause harm.
We now know that two drugs can interact when taken together, so we
ask companies to do specific studies to test for drug interactions
before marketing. We now know that some drugs from every possible class
can have effects on the heart that result in potentially lethal heart
rhythm abnormalities. We now ask companies to conduct studies to screen
for this problem.
These are but a few of the many important new requirements that
have improved our understanding of how to use medicines more safely.
However, these requirements add time and expense to the development
process. On the other hand, there are opportunities to remove certain
requirements from the traditional process. For example, we still
require that all companies conduct studies to determine in two rodent
species (usually rats and mice) the dose of the new drug that kills
half of the animals. Often rodents don't have the same proteins as
humans so the studies may never be relevant. However, there is no
ongoing process for the FDA to meet with other scientists in drug
development and reach a consensus on what work should no longer be
required.
It will take a very special process that brings the very best
science and a willingness of all involved to share data and experience.
That does not now exist, but it is the kind of partnership called for
in the Critical Path Initiative (``Innovation or Stagnation, Challenge
and Opportunity on the Critical Path to New Medical Products'').
Question 1b. Do you know how many drugs are not brought to market?
In other words, how much money and time does the pharmaceutical
industry invest in research that does not result in a new marketable
drug?
Answer 1b. Estimates are that only 11 percent of drugs that enter
clinical testing are ever approved. Therefore, for every drug approved,
nine others fail. Since only about 30 new drugs are approved each year,
approximately 270 fail using these numbers for projection. The figure
below is taken from Nature Reviews: Drug Discovery, 3 (8): 711, 2004.
It shows the percentage of successful drugs in each class.
It is difficult to know how much the industry loses on drugs that
fail but it could be as high as 55 percent of their $40 billion annual
investment in research and development. I base this on current
estimates that a company must plan to spend about $400 million on a
successful drug and the fact that $875 million is the final cost per
drug including failures. Unfortunately our ability to predict failure
is getting worse, not better. Again the work proposed in the Critical
Path Initiative would help by developing ``biomarkers'' for many
indications that could more accurately predict the safety and
effectiveness of drugs.
Question 2. You testified that industry investment has increased by
250 percent over the last 10 years, but the number of new products
submitted for FDA review has fallen by 50 percent. Why is that?
Answer 2. I believe the rising cost and protracted development
times have deterred companies from taking more new drugs into
development. The consolidation of the pharmaceutical industry has also
been a major factor. Since 1980, 48 companies have collapsed into six
and with every merger or purchase a large number of drugs have been
taken out of development. Also, since 1995, the number of failures
during development has risen and only half as many drugs now succeed to
reach market.
Question 3a. You mention that over half of the 15 drugs that were
removed from the market for safety concerns over the last 8 years were
in fact safe when used as directed. Should these drugs not have been
removed?
Answer 3a. If we had an effective means to assure their safe use
(i.e., in which use is limited to those conditions where safety and
efficacy have been proven), these drugs could have remained on the
market. This is why the FDA must partner with CMS and AHRQ and others
to find ways to better inform healthcare providers in ways that result
in safe medication use. The Centers for Education and Research on
Therapeutics (CERTs) were authorized by Congress with this task.
However, the CERTs have been too small in number and inadequately
funded to accomplish this task. Also the FDA has not had sufficient
staff or resources to work on this with AHRQ and the CERTs. CMS and
other insurers are the financial benefactors if this can be
accomplished.
When terfenadine was removed from the market, the generic form of
the drug had just been approved by the FDA. However, when it was
removed, it left only the very expensive brand named non-sedating
antihistamines. Billions of dollars spent on these antihistamines
(Claritin, Allegra and Zyrtec) could have been saved if generic
terfenadine could have remained on the market and used safely, i.e. in
a way in which it was not taken with drugs such as erythromycin that
interacted and made its use dangerous.
Question 3b. If they were effective when used according to their
indications, did not their removal harm those patients who had been
using them properly and receiving benefit from them?
Answer 3b. Indeed. For some of these drugs, there was no
alternative therapy and patients and doctors lost the benefit of
effective therapy. For some, there were alternatives but, as mentioned
above for terfenadine, the alternatives were very expensive and caused
financial hardship for patients. Vioxx is another example where it was
intended for patients at risk for gastrointestinal bleeding. Now, they
do not have access to this safer drug and may be harmed by the
available agents. By removing Vioxx from the market, the underlying
issues of why Vioxx and other Cox 2 inhibitors were developed and
approved have not gone away.
Question 4. Is the problem in drug development the lengthy,
extensive, and yet inadequate approval process which costs so much, or
is it the limited time the company is allowed to recoup its R&D costs
before generic competition? Or is it the litigious environment in which
we live that leads to the industry's heightened fears about labeling or
lawsuits?
Answer 4. These are all contributors to the problem. However, I
would not favor extending the patent coverage. This would only
encourage and reward further inefficiency. We should focus on improving
(i.e., shortening) the process. AIDS drugs were developed in an average
of 3 years without risk to patients. That should be the model for all
drugs.
Question 5a. You mention that ``once a drug is marketed, the FDA
has no control over the way it is used in clinical practice.'' Should
the FDA control this?
Answer 5a. No, I do not think the FDA should control the practice
of medicine. This should be controlled by professional societies.
However, we must encourage better prescribing in every way possible.
One way that is being addressed by Dr. Mark McClellan, the head of CMS,
which involves the way we reimburse caregivers. He believes that payors
like CMS should reward evidenced-based practices. We do not do that
today. We pay the same for a visit in which a drug was prescribed
inappropriately as we do for a visit in which the drug was prescribed
in ways proven to be safe and effective. By rewarding evidenced-based
practices, CMS can help FDA be sure the drugs they approve are used
safely.
Question 5b. Or should clinicians? Isn't there a partnership
between the FDA and practitioners?
Answer 5b. I don't think there is such a partnership. The FDA
writes labels for drugs that do not result in safe practice. The FDA
has to resort to removing drugs from the market because its ``Dear
Doctor'' letters are too often ignored, both by doctors and by
pharmacists.
Question 5c. Isn't it the role of continuing medical education--and
in a worst case scenario our malpractice system--to ensure that
practitioners are using drugs appropriately?
Answer 5c. Research has shown that conventional continuing medical
education (CME) programs do not effectively improve the practice of
medicine. CME when provided by pharmaceutical companies yields
increased use of a medicine but that is not always the best practice of
medicine. Vioxx is again a great example, where it was promoted through
CME programs that resulted in its overuse, i.e., use in patients
without risk of gastrointestinal bleeding.
Yes, physicians fear malpractice claims and that fear affects the
way they practice medicine but not always in ways that we would prefer.
For example, physicians order unnecessary lab tests to guard against
claims that are unlikely to occur. They often prescribe unnecessary
medicines because they are afraid they will be accused of doing nothing
to help the patient. Healthcare providers want to prescribe the very
best medicines for their patients. When they fail to do so, it is often
the ``system'' that has failed them. For example, many times drug
interactions occur because the physician is unaware of medicines
prescribed by other doctors.
Question 6a. If the FDA receives the authority to demand further
research on marketed drugs, does this also imply they will have the
responsibility to fund the research as well?
Answer 6a. I would not recommend giving the FDA the authority to
require companies to do research after a drug is marketed. Instead, I
suggest that the FDA, NIH and AHRQ work with the drug company sponsor
to agree upon what research is needed. The FDA and NIH or AHRQ should
conduct the agreed upon studies with funding from user fees paid by the
sponsor. Since the studies would be conducted by NIH and/or AHRQ, there
would be less concern about the validity of the research. While such
research is being conducted, the FDA should be given the authority to
change the way the drug is marketed and distributed. It should be
allowed to suspend direct to consumer advertising. It could work with
AHRQ and insurers to prohibit payment for off label prescription if the
use is possibly dangerous or of unproven value. For example, if a drug
is considered potentially unsafe for very elderly patients and safety
studies have not been conducted in this population, CMS and other
insurers should not provide payment for the drug in those patients. If
these limitations are inadequate to protect the public, the FDA should
also be given the authority to suspend marketing. During this
suspension, every effort should be made to make the drug available to
those for whom there are no alternative therapies of serious illnesses.
Question 6b. If they are not going to fund it, will the companies?
And what will happen to those patients who are benefiting from the drug
if the company decides that it is more cost effective to remove the
drug from the market rather than do additional studies?
Answer 6b. The drug companies will resist changes in post marketing
research and surveillance because they will want to retain control over
the research on their products. It is unlikely that they would conduct
research projects unless they agree upon the methods to be used. It
will be difficult for NIH or AHRQ to conduct research on drugs unless
the manufacturer is not in agreement. The company will have to provide
the medications for the study and they often control the manufacturing
process. Therefore, I think it is important that this research be
mutually agreed upon. The FDA will need leverage in order to see that
the research is done in the best way to protect the public. For this
reason, the FDA must have the authority to suspend direct to consumer
ads, suspend sales, etc.
Compared to the potential profits from a marketed drug, the cost of
most studies is only a small fraction. I do not think a company will
choose to remove a drug from the market because of the need for more
studies. The incentive of having a larger market or less legal
liability should encourage a company to collaborate in the necessary
research.
Question 7. How should we replace the ``user fee'' system so as to
avoid linking industry support to the FDA's work and performance while
simultaneously ensuring that the FDA has the funds it needs to carry
out its mission?
Answer 7. The funds that are needed to support the FDA should be
provided by all companies and based on a fraction of sales. The funds
should pay for all of the activities of the FDA, not just review of new
drugs and/or devices. I recognize that these charges could lead to
higher prices for consumers (although market forces can limit pricing,
especially in a world where more efficient and faster safe drug
development is practiced). However, even if some prices are higher,
patients and the public health will be better served by having the FDA
adequately funded to perform its mission.
RESPONSE TO QUESTIONS OF SENATOR KENNEDY
Question 1. Could you please elaborate on why the post approval
drug safety surveillance system needs to be enhanced? Please describe
the components of a robust system for post approval safety monitoring,
including your community pharmacy safety net project?
Answer 1. Although some tout the current safety system for its
ability to detect rare adverse events, it is dangerously inefficient
and slow to respond. The 15 drugs removed from the market over the last
seven years were on the market for an average of 5.9 years before they
were detected by the spontaneous reporting system and removed from the
market. One of the major limitations of the current system is the lack
of ability to detect rare events quickly and to estimate the frequency.
Another weakness is the inability to conduct comparative safety
analyses.
Therefore, the ideal system would have the following
characteristics:
1. Ability to detect rare adverse events very early after
marketing.
2. Ability to accurately quantify the incidence of rare adverse
events.
3. Ability to compare the safety of alternative therapies.
4. Ability to detect adverse events that are restricted to special
populations, e.g., children, the very elderly, patients with renal or
liver disease, etc.
5. Ability to detect adverse events under special conditions of
use, e.g., nursing homes, hospitals, hospices, etc.
6. Ability to identify risk factors associated with the adverse
event, e.g., presence of other illnesses, biological sex, concomitant
medicines, etc. (This information will be essential in the design of
methods to prevent or minimize future occurrences of the adverse
event.)
7. Ability to focus on potential adverse events identified by FDA
medical reviewers during review of a new drug application.
8. Ability to address specific questions that arise after the drug
is on the market.
The community pharmacy safety net would address many but not all of
these requirements. The following is a plan that The C-Path Institute
is developing for a pilot project to be conducted in community
pharmacies:
The Community Pharmacy Safety Network (CPSN)
A Community-Based National Medications Safety Program
The most effective means of maximizing the benefit and
minimizing the risk of harm from medicines is to have every
member of the healthcare team, including patients and their
families, fully informed in how to use medicines safely. The
current healthcare delivery system fails to adequately inform
patients how to use medications optimally and fails to provide
the U.S. Food and Drug Administration (FDA) with adequate
information about the outcomes of medication usage. This is a
proposal for the creation of a novel community-based network of
individuals trained to help patients maximize the benefits of
their medications and also trained to obtain reliable data for
the FDA on the beneficial and adverse outcomes of medicines.
This is information not currently available in any database.
A pilot demonstration program for the nation will be conducted
in Southern Arizona by the CPSN. The Critical Path Institute
and the Arizona Center for Education and Research on
Therapeutics (AzCERT) will develop two special curricula for
certificate programs in the Pharmacy Technician training
program at Pima Community College and the College of Pharmacy
at the UA. This curriculum will enable Certified Pharmacy
Technicians (CPTs) and certified pharmacists to aid patients in
the safe use of new medications and medications in general.
CPTs will also maintain a log of patients receiving pre-
specified medicines and obtain baseline and follow-up
information from those patients to determine the outcome of
their therapies. Scientists in the Arizona CERT will
participate in the development of the curriculum and the
evaluation of the effectiveness of the program. Scientists from
CERT, C-Path and the FDA will collaborate to identify medicines
to be monitored, define comparator cohorts and prepare survey
questions to define outcome parameters for each cohort of
patients. The CPTs will enter the survey results into a web-
based database for analysis by the Office of Drug Safety at the
FDA. When complex medical events are detected by the CPT
survey, a Certified Pharmacist with special training in drug
safety will gather information and submit a report to the FDA
using standardized MedDRA terminology. The Pharmacist will also
report to the prescribing physicians informing them how their
patients responded to their therapies and provide summary
information from the FDA so they can benchmark their practice
to the experience of other physicians and patient populations.
The CERT will evaluate the impact of the CPSN on patient safety
by comparing the outcomes of patients who were given special
training in the safe use of their medicines by CPTs to the
outcomes in a matched control group receiving routine
conventional care. If this pilot is successful, the overall
cost of medical therapies should be reduced justifying future
payment by insurers for CPSN services.
When operational, this system will be able to conduct
prospective post-marketing surveillance for drugs. Unlike
current systems, it will be able to determine the denominator
(number exposed) for adverse events and, when comparator drugs
are available, comparative safety of drugs will be determined.
The CPSN will be able to determine how drugs are being
prescribed and if there is evidence of their effectiveness in
new diseases or uses. Because CPSN will provide greater
assurance that drug safety will be effectively monitored and
adverse events detected earlier, it will be possible for the
FDA to accelerate the approval of new drugs without
compromising the public safety. The CPSN will also enable
patients to play an active role in the management of their
therapies reducing the risk of preventable adverse events and
hastening the detection of unanticipated adverse reactions.
Question 2. Please describe how our responses to bioterrorism and
to drug safety might overlap and complement one another?
Answer 2. Because of the almost unlimited number of biologicals
that can be used in bioterrorism, it will be necessary to have the
capacity to develop a broad range of preventative or therapeutic drugs
quickly. It is unlikely that there will be adequate time to test the
drugs completely, so it will be essential that we have a work force
prepared and trained in drug safety analysis and surveillance to
participate in the evaluation of any new agents employed in the
response to bioterrorist attacks. The Community Based Pharmacy Network
and other needed programs can be essential elements in a plan for being
prepared for safety surveillance. The same curriculum used to certify
pharmacists and pharmacy technicians can be used to train members of
the military to conduct safety assessment of any new drugs being
developed for bioterrorism.
______
Response to Questions of Senator Enzi From Bruce M. Psaty, M.D.
Question 1. You support creating an independent Office of Drug
Safety. This could result in an office that only looks at problems.
Isn't it more appropriate for risks and benefits to be considered
together?
Answer 1. It is appropriate, even essential, for the new
independent Center for Marketed-Drug Evaluation and Research (CMDER) to
consider both risks and benefits. The FDA needs to be reorganized to
achieve this new division of labor: (1) the Office of New Drugs (OND)
in the Center for Drug Evaluation and Research (CDER) reviews New Drug
Applications (NDAs) or supplemental NDAs (sNDAs) and assesses the risks
and benefits of drugs before approval; and (2) the new CMDER reviews
and assesses the risks and benefits of prescription drugs after
approval. Consultation and coordination between CDER and CMDER around
the time of drug approval will be important. At the time of approval,
authority to regulate the new drug will pass from CDER to CMDER.
Reorganization of the FDA to achieve this new division of labor--pre-
marketing evaluations by CDER and post-marketing evaluations by CMDER--
will eliminate the conflict of interest that OND currently has in
evaluating the post-marketing safety of drugs that OND had approved in
the first place.
CDER's OND is effective at reviewing and approving new drugs, and
many of the FDA reviewers there are skilled in conducting the pre-
approval reviews. But when drugs go on the market, they are used by
large numbers of people, many of whom would not have been eligible for
the pre-approval trials. What the American public needs and deserves,
in addition to the rapid approval of drugs, is a new FDA CMDER whose
primary mission, vision and values are geared toward monitoring and
assessing the safety and efficacy of drugs that are on the market.
Post-marketing surveillance is a different mission, and needs to be a
separate but equal partner with CDER's pre-approval evaluation. The new
CMDER will need the skills of public health scientists, epidemiologists
and ethicists to evaluate the risks and benefits to the population as a
whole. Provided with new authorities, the independent CMDER can pursue
aggressively key safety questions that industry would sometimes prefer
to ignore and protect the health of the public by considering not only
the risks but also the benefits in the populations that actually use
the new drugs. Regular congressional oversight can help to assure the
quality of FDA efforts at both CDER and CMDER and provide an important
forum for the discussion of drug efficacy and safety.
Question 2. You have indicated that the Office of Drug Safety is
underfunded. Could you comment on the adequacy of the President's
proposed fiscal year 2006 budget for FDA, which includes a 24 percent
increase for FDA's post-market safety program? If this figure is not
adequate, how much funding would it take?
Answer 2.The proposed increase of $6.5 dollars (24 percent
increase) for the FDA's post-marketing safety program in fiscal year
2006 is not adequate. The first 10 years of PDUFA, between 1992 and
2002, did not permit user fees to be used for drug safety activities.
According to the General Accounting Office report on the effects of
user fees: \1\ ``The implementation of PUDFA has been successful in
bringing new drugs and biologics to the U.S. market more rapidly than
before. However, maintaining adequate funding for approving new drugs
and biologics has had the unintended effect of reducing the share of
funding and staffing for other activities'' including drug-safety-
related activities. ``According to FDA officials,'' the GAO report
continues, \1\ ``safety problems not detected in clinical trials are
more likely to be found first among U.S. patients because they are
increasingly first to have access to new drugs.'' In 1992, when America
began to serve as a major drug-safety testing ground, there was little
or no attention to enhancing drug safety efforts. According to Dr David
Kessler, \2\ former head of the FDA, ``PDUFA should have had funding on
the safety side from the beginning, but the industry refused to accept
that . . . . We wanted it. The industry said no.'' The development of
infra-structure, described in response to Senator Hatch's first
question, remains a major unmet need and will require considerable
investment.
In the preparation of the March 2003 report, ``FDA's Review Process
for New Drug Applications,'' \3\ the Office of the Inspector General
conducted a survey of 401 CDER reviewers. Fully ``66 percent of FDA
respondents indicated on our survey that they were somewhat or not at
all confident that the FDA adequately monitors the safety of
prescription drugs once they are on the market.'' \3\ The lack of trust
and confidence in the FDA post-marketing surveillance system, expressed
by FDA reviewers, is shared by many independent scientists. The FDA's
meager post-marketing surveillance system is further stressed by the
mounting challenges. In the 8-year period between 1995 and 2003, the
number of post-marketing adverse event reports received by the FDA
MedWatch adverse-event reporting system increased by 137 percent, from
156,477 in 1995 to 370,887 in 2003.\4\ \5\ In the 4 year period between
1997 and 2001, retail spending on prescription drugs almost doubled,
increasing from $78.9 billion in 1997 to $154.5 billion in 2001.\6\
Over the same time period, the 50 percent increase in the FTE at the
Office of Drug Safety lagged far behind the huge increase in the
exposure of the U.S. population to prescription drugs.
The current needs of the new Center for Marketed Drug Evaluation
and Research represent not just ``current needs'' but also an array of
previously unmet needs, some of which have accumulated for more than a
decade. A serious effort to improve drug safety in America will require
a substantial investment. Infrastructure and collaborations for safety
studies that have been ignored for a decade need to be developed. In
order to protect the health of the public, the budget for the new CMDER
will need to move, over the next several years, close to the level of
the budget for the OND. Required funding levels will depend in part on
the existence of new authorities. If the CMDER cannot compel the
pharmaceutical industry to conduct key post-marketing studies and if
CMDER has to fund the conduct of independent studies, the funding
requirements for drug safety would be especially large.
Question 3. You support a mandatory Federal registry of clinical
trials. How would you set up a results database so that the information
is actually useful for patients and providers?
Answer 3. The International Committee of Medical Journal Editors
has called for clinical trial registration and for ``full transparency
with respect to the performance and reporting of clinical trials.'' \7\
The rationale is important. To use drugs wisely, patients and
physicians need to know about risks and benefits. Risk-benefit analyses
need complete and accurate information about all relevant studies. The
primary purpose of a Federal clinical trials registry is to assure that
all randomized trials are fully reported. In the absence of a mandatory
registry of clinical trials, the pharmaceutical industry occasionally
finds it difficult to resist the marketing instinct to conceal studies
with unfavorable findings. In a study of Alzheimer's patients, for
instance, Pfizer's Celebrex (celecoxib) increased the risk of
cardiovascular events.\8\ Although the study was completed in 1999, its
results were not submitted to the FDA until June 2001, several months
after a safety review that established new labeling for Celebrex. The
findings, which were never published, were finally posted on an
industry website in January 2005.\8\ This selective-non-publication
approach creates a distorted knowledge base so that risk-benefit
analyses of Celebrex cannot take into account the cardiovascular harm
detected in this study.
For these reasons, the results database of the Federal clinical
trials registry will be most useful to scientists who want to conduct
reviews and meta-analyses of all the existing studies of a particular
drug. The available data and the data structures must be adequate for
and useful to these scientists. To make each entry in the database
useful for patients and providers, the trial results should include a
clear statement of the original hypotheses, its study population, the
primary findings in quantitative terms, secondary analyses and safety
analyses. The findings from one trial, however, are not adequate to
make informed treatment decisions. Instead, treatment decisions should
be based on the totality of the evidence about a drug's safety and
efficacy. In other words, patients and providers would do well to seek
out independent reviews and meta-analyses of the studies conducted on
the drug of interest. Journals often make some of these major high-
quality reviews available on their websites without cost to non
subscribers. In December 2004, moreover, Consumer's Union launched
``Consumer's Reports Best Buy Drugs,'' which is ``a major new public
education program that is designed to provide unbiased information
about the comparative effectiveness and cost-effectiveness of
prescription drugs.'' \9\ This service is ``provided free to
consumers.'' The effort to integrate information on the safety and
efficacy of new drugs in an independent and unbiased fashion is also an
important role for the new CMDER. It is these integrated independent
reviews, and not individual entries in the clinical-trials database,
that will be most useful to providers and patients.
Question 4. It seems to me that achieving the right balance between
the benefit and risk is the key challenge both of approving a new drug
and of deciding whether to keep it on the market. What would you
suggest could (or should) be done differently so that benefit-risk
decision can be made in the best possible way?
Answer 4. The best possible way to make risk-benefit decisions is
to have available good scientific evidence from randomized clinical
trials that assess the risks and benefits with equal scientific rigor.
The pharmaceutical industry expends enormous energy in the effort to
demonstrate a drug's efficacy. For the purpose of evaluating efficacy,
industry studies are generally well designed and adequately powered.
But the industry efforts to identify and quantify risks of a drug are
modest or less. To an independent scientist, for instance, the known
biologic effects of the COX-2 inhibitors would suggest two different
hypotheses--the possibility of benefit to the stomach and the
possibility of injury to the heart. While many Vioxx (rofecoxib)
studies were well designed to assess the potential benefits of pain
relief or protection of the stomach, these same studies often minimized
the chances of finding any cardiovascular harm. In general, they were
small, lasted a few weeks or months, excluded patients with heart
disease or patients who used aspirin, and paid little specific
attention to cardiovascular events. The evidence provided by this
efficacy-driven marketing-focused approach to science--well-studied
benefits and ill-defined risks--undermines the validity of a genuine
risk-benefit analysis.
The FDA has two major opportunities to help industry address these
deficiencies. In the pre-approval stage, the OND can insist that
clinical trials examine adequately risks as well as benefits. In
addition to the traditional collection of adverse event reports,
specific safety outcomes can be defined in advance and assessed in a
standardized fashion. Large long-term trials of chronic-disease
medicines should be started as early as possible in the drug-approval
process. The OND can also insist that patients included in the pre-
approval studies are representative of those who will actually use the
new drugs. In the post-marketing setting, the new CMDER can address the
key questions that remained unanswered at the time of approval.
Although 6-week studies may be adequate to demonstrate that drugs such
as Vioxx reduce the pain of arthritis in the knee or hip, pain
medicines do not cure osteoarthritis, and large numbers of patients
with arthritis will take these drugs for many years. Osteoarthritis is
common in older adults, many of whom have cardiovascular disease and
take aspirin. Under these circumstances, for instance, CMDER can insist
on the conduct of post-marketing studies or clinical trials that
evaluate the new drug in the patients who actually take them and in the
way that these patients actually take the new drugs. In the post-
marketing setting, CMDER needs at once to assure that the evaluations
of marketed drugs match the way that the marketed drug is used in the
U.S. population and, at the same time, to work with physicians and
patients to limit the use of the marketed drug to the approved
indications and populations. In short, the FDA needs to take an pro-
active role in assuring the quantity and quality of the data for risk-
benefit analyses, both before and after approval.
______
Response to Questions of Senator Hatch by Bruce M. Psaty, M.D.
Question 1. Do you think that the current post-marketing
evaluations are adequate? Could you suggest some specific ways in which
they should be improved?
Answer 1. The current MedWatch program is adequate for only one
minor, though important, drug-safety effort.\10\ This voluntary
reporting system is suitable to identify rare serious adverse drug
events that occur early in treatment and that are unrelated to the
indication of the drug. For example, the lipid-lowering statin drug,
Baycol (cerivastatin), was withdrawn from the market in 2001 because it
was associated with high rates of rhabdomyolysis, a breakdown of muscle
cells that causes pain, kidney failure and sometimes death.\11\ \12\
\13\ It would not have been possible to use the MedWatch system to
detect reliably, for instance, the increased risk of cardiovascular
events associated with the COX-2 inhibitors.
The MedWatch adverse drug-reaction data--recently characterized as
``fundamentally a 1950s-era approach'' \14\ lack many of the features
of high-quality epidemiologic studies, including validation of events
by standard criteria, complete ascertainment of cases, population-based
controls, comparable assessment of drug use and risk factors, and so
forth. In short, the current post-marketing surveillance systems are
not adequate to meet the new surveillance challenges posed by the rapid
approval of new drugs. Several opportunities deserve to be cultivated.
First, data from new Medicare drug benefit can be linked with hospital
and ambulatory care data to create a new resource for the study of
drugs in older adults. With appropriate protections for privacy, these
data should be available to the FDA and independent scientists
interested in drug safety. Secondly, as part of the NIH Roadmap
Project, the HMO-Research Network--Coordinated Clinical Studies Network
will create an infrastructure for conducting studies on substantial
numbers of the U.S. population, and the movement toward an EPICcare
based electronic record among the network members should soon provide
the opportunity to conduct post-marketing surveillance rapidly and
efficiently.
The development of these ``research resources'' needs to be
complemented by a new public-health vision and sense of mission at the
FDA. As indicated in the response to Senator Enzi's questions,
pharmaceutical companies sometimes lack enthusiasm for pursuing
questions about the safety of their drugs. Although the risk-benefit
analysis may appear favorable in the well persons typically recruited
to the pre-approval trials, the populations who take new drugs include
many groups such as the elderly and those with other serious health
conditions. As a result, the risk-benefit assessments may differ
markedly in the post-marketing setting from those of the pre-approval-
trials setting.
At time of approval, the new independent CMDER should review the
NDA and all available data, published and unpublished, to identify the
set of studies required to address the key unanswered questions,
particularly the pursuit of potential safety ``signals'' or ``plausible
biologic hypotheses'' on behalf of the health of the public. The
current FDA risk-management approach places on the manufacturer the
responsibility for defining the safety questions of interest and
designing the studies to answer those questions. Rather than serve as
simply a reviewer of industry's proposals, the FDA's CMDER should
actively select the questions, the studies, and the designs that merit
attention. CMDER's work in this regard should be peer-reviewed by
independent scientists to assure that the key questions are properly
identified and that the studies required to address them are properly
designed. Depending on the drug, the indication and the known safety
profile, the studies may include Phase IV trials, epidemiologic
studies, pharmacokinetic-pharmacodynamic studies, close surveillance of
ADR reports, or a combination of several approaches. Specific post-
marketing trials or studies should be designed, conducted and completed
in a timely fashion. Provisional approval may be another useful
approach. The CMDER should be responsible for assessing the balance of
risk and benefit of drugs that are on the market.
Question 2. In your testimony, you state that since 1992 funding
for drug safety has dwindled. Yet in her testimony, Dr. Sandra Kweder
of FDA stated that resources devoted to drug safety, both human and
financial, have steadily increased over the past decade. For instance,
the ODS budget increased from around $7 million in fiscal year 1996 to
a proposal of more than $33 million in fiscal year 2006. Likewise, ODS
employment has increased during that time from 52 FTEs in fiscal year
1996 to 137 FTEs in fiscal year 2006. Moreover, PDUFA III authorized
FDA to use some of its user fee money for risk management activities,
and PDUFA resources will represent nearly one third of the ODS budget
for the coming fiscal year. Doesn't this increased funding--both from
PDUFA and otherwise--evidence a strong and continuing commitment to
drug safety?
Answer 2. As I have indicated in responses to the questions from
Senator Enzi, the efforts since 1992 to increase the speed of approval
for new drugs have not been accompanied by commensurate improvements on
the drug safety side. According to the General Accounting Office
report, ``FDA reduced staffing levels for non-PUDFA activities each
year, leaving the agency fewer resources to perform its other
responsibilities,'' including safety-related activities.\1\ The old
system not only produced a ``drug lag'' that kept new medicines from
U.S. patients, but it also provided a ``safety buffer'' that protected
U.S. patients. New drugs would first come to market in Europe; safety
problems would be identified there; and the problematic drugs--
practolol and thalidomide are examples--would never come to market in
the U.S. . Now, with America as the new drug-safety testing ground, the
``safety buffer'' has been replaced by a ``safety lag.'' Today, U.S.
patients remain at risk of large-scale injuries such as the tens of
thousands of heart attacks and strokes caused by Vioxx. The U.S. drug
safety systems were not originally upgraded to meet the new challenges
of PUDFA in 1992; infra-structure and collaborations have not been
developed to conduct new studies rapidly or efficiently; and in recent
years, the spending on prescription drugs and the reporting of adverse
events have expanded much faster than the resources provided to ODS.
The budget increases thus remain inadequate.
Question 3. In the supplementary information provided with your
testimony, you suggest that pharmaceutical companies are not complying
with their obligations to conduct Phase IV studies. Yet in a recently
published report on the performance of drug and biologic firms in
conducting post-marketing (Phase IV) studies, FDA finds that, of the
studies concluded between October 1, 2003 and September 20, 2004, no
studies were identified where the commitment was not met. Likewise, the
study indicates that only 1 percent of the pending studies for NDAs and
ANDAs were delayed. Doesn't this report indicate that pharmaceutical
firms are doing a good job meeting their post-marketing study
commitments in a timely manner?
Answer 3. Under the Food and Drug Modernization Act (FDAMA) of
1997, the FDA is required to report annually in the Federal Register on
the status of postmarketing study commitments made by manufacturers of
approved drug and biological products. The most recent report includes
information available through September 30, 2004.\15\ The following
table summarizes the status of the open post-marketing commitments for
New Drug Applications (NDA) and Abbreviated NDAs (ANDA).
Table. Open Post-Marketing Commitments
------------------------------------------------------------------------
Status NDA/ANDA
------------------------------------------------------------------------
Pending (study not yet initiated, not delayed)......... 812 (68%)
Ongoing (proceeding on schedule)....................... 219 (18%)
Delayed (behind schedule).............................. 15 (1%)
Terminated (study ended, no final report submitted).... 2 (<1)
Submitted (study ended, final report submitted)........ 143 (12%)
Total number of open commitments....................... 1191 (100%)
------------------------------------------------------------------------
The number of open post-marketing commitments, currently at 1191,
remains large (Table). Although 143 (12 percent) were submitted and
another 234 (19 percent) were ongoing or delayed, a total of 812 (68
percent) have not yet been initiated. It appears that if these
``pending studies'' had no ``original schedule'' at the time of the
original agreement to conduct them, they can never be delayed, and some
may remain in the ``pending'' category in perpetuity. The large number
of ``pending'' studies is a concern.
The tardiness with post-marketing commitments can be most clearly
illustrated by the accelerated approval mechanism, where the post-
marketing studies are essential to defining what, if any, clinical
benefit may derive from drugs approved on the basis of surrogate end
points. In testimony before the Senate Health, Education, Labor and
Pensions Hearing on the ``FDA's Drug Approval Process: Up to the
Challenge?'' on March 1, 2005 and in a recent article, \16\ Dr Fleming
raised concerns about the quality and the timing of post-marketing
commitments associated with the accelerated approval (subpart H)
regulatory process. ``One of the more disturbing facts revealed in that
meeting (ODAA, March 2003),'' writes Fleming, ``was that the average
time between the granting of marketing through AA [accelerated
approval] and the completion of on-going validation trials for these
eight products was projected to be 10 years . . . . Furthermore, after
receiving authorization to market the product, the sponsor often has a
loss of the sense of urgency that in the premarketing settings is a
powerful driving force for the sponsor to obtain timely evaluation of
the benefit-to-risk profile of the intervention.'' \16\ Dagher and
colleagues discuss some of the same accelerated-approval cancer drugs
in their review.\17\ For the 15 cancer drugs that were granted
accelerated approval between 1992 and 2004, postmarketing studies that
used a clinical outcome were required for full approval, and to date,
only 6 (40 percent) of the 15 have met their post-marketing
requirements.\17\ This leisurely approach to completing post-marketing
commitments is not adequate.
______
Response to Questions of Senator Kennedy by Bruce M. Psaty, M.D.
Question 1. Pharmaceutical manufacturers must pay attention to risk
and benefit when designing drugs and deciding what to take to market.
Is it appropriate to give them the responsibility for drug safety after
marketing?
Answer 1. This approach assigns the fox to guard the hen house. In
the case of Baycol (cerivastatin), a lipid-lowering statin drug, the
manufacturer was unable to overcome the inherent conflict of interest
in interpreting and responding to the adverse event reports that
appeared soon after the drug was launched.\13\ Several opportunities
were missed to protect patients and prevent injuries. The manufacturer
was slow to respond to signals, failed to conduct key safety studies in
a timely fashion, decided not to publish a high-dose study with
unfavorable findings, and ignored the safety recommendations of its own
scientists and epidemiologists.
Soon after the Baycol was on the market, Bayer scientists conducted
excellent analyses of the FDA's MedWatch data. They identified
rhabdomyolysis as a major adverse effect of Baycol, used either alone
or in combination with Lopid (gemfibrozil). According to a memo from
Bayer scientists in March 2000, ``The findings [of internal analyses]
indicate that in patients receiving monotherapy, cerivastatin
substantially elevates risk for rhabdomyolysis compared with other
statins. In combination with gemfibrozil, cerivastatin patients were
also found to be at a remarkable disadvantage compared with patients
receiving gemfibrozil with another statin.'' \13\ This information was
not, however, communicated to patients, physicians or the FDA.
These safety findings were reported to David Ebsworth, who headed
Bayer AG's Pharmaceuticals Business Group. In a memorandum and order
regarding the Bayer AG Securities Litigation, District Judge William H.
Pauley III summarizes the response to these safety concerns: ``On
August 2, 2000, senior members of Bayer's Global Drug Safety team and
consultants met with Plischke to discuss the accumulation of adverse
event reports. A consensus emerged that the data concerning Baycol's
dangers `was putting the brand at risk.' When that conclusion was
communicated to Ebsworth, he dismissed the reservations of the safety
experts and instructed his marketing team `to promote the hell out of
this product.''' \12\ Baycol remained on the market for another year.
By 2000, annual drug sales for Baycol were supposed to be several
hundred million dollars and were soon expected to reach block-buster
proportions of $1 billion per year. Ebsworth's one-sided attention to
drug sales rather than drug safety delayed the withdrawal of the Baycol
and harmed patients. Hence, the need for a strong Center for Marketed-
Drug Evaluation and Research to protect the health of the public.
Question 2. You have advocated a separate Center for Drug Safety,
within the FDA, for post-market assessments. Why do you feel a separate
center is needed? Some seem concerned that a separate safety center
would make decisions strictly based on determinations of safety,
without considering the benefits of drugs. Is that a valid concern? How
might we ensure that all decisions made are both unbiased and based on
a weighing of risk against benefit?
Answer 2. The Office of New Drugs dominates CDER. In the last year,
safety concerns about antidepressants and COX-2 inhibitors did not find
an open forum for expression at the FDA. The report by the Office of
the Inspector general points to the fact that ``21 percent of FDA
respondents indicated that the work environment allowed for the
expression of differing scientific opinions to a small or no extent.''
\3\ The current structure and culture at the FDA is just what industry
desires--a powerful engine to approve drugs and a weak effort to
investigate safety in the post-marketing setting. What the American
public needs and deserves, in addition to the rapid approval of drugs,
is a Center whose mission is devoted to post-marketing evaluations of
the safety and efficacy of marketed drugs.
In a recent commentary, the JAMA editors point out the inherent
conflict of interest when the OND reviews its own approval decisions:
``It is unreasonable to expect the same agency that was responsible for
approval of drug licensing and labeling would also be committed to
actively seek evidence to prove itself wrong (ie, that the decision to
approve the product was subsequently shown to be incorrect).'' \18\
Although a new CMDER would still be within the FDA, the separation of
the CMDER from CDER is necessary to assure the independent review of
drug safety questions. William Schultz, the FDA's deputy commissioner
for policy from 1994 to 1998, agrees: ``FDA should separate the
monitoring of drugs after they have been approved from the drug review
function . . . . The post-market function should be separated from the
drug review function.'' \19\
Several key FDA leadership positions have been vacant in recent
years. In public statements, some FDA officials have occasionally
seemed to lack a public-health perspective on the balance of risks and
benefits. For instance, two senior CDER officials called epidemiologic
estimates of Vioxx injuries ``junk science'' \20\ and claimed that the
deaths caused by Vioxx were ``not real deaths.'' \20\ As the FDA
Advisory Committee indicated in mid February, the COX-2 inhibitors do
increase the risk of heart attack and stroke. Tens of thousands of
patients were injured, and many died. The CDER leadership has yet to
offer an explanation for why the cardiovascular risks of the COX-2
inhibitors remained undetected for so many years. The studies designed
by Merck for the approval of Vioxx were individually sound. But as a
group, they minimized the possibility of finding cardiovascular harm,
which was biologically plausible on the basis of the known actions of
Vioxx. The FDA missed an opportunity to protect the health of the
public by failing to insist at several stages that the company attend
carefully to potential risks as well as benefits. Without an
appreciation for the opportunities for prevention that may have been
missed, it is not clear that the CDER leadership can avoid future
Vioxx-like drug disasters. To protect the health of the public, the FDA
needs an independent CMDER whose primary mission, vision and values are
geared toward monitoring and assessing the safety and efficacy of drugs
that are on the market. Passing the responsibility from CDER to CMDER
at the time of approval also avoids the potential conflict of interest
mentioned by the JAMA editors.
Question 3. Has the FDA done a good job in assessing risk versus
benefit for new drugs? How about for approved drugs in the post-
marketing setting? Can you explain any similarities or differences?
Answer 3. In the pre-approval setting, the FDA often does a good
job of assessing what is reported by the company about the risks and
benefits of new drugs. On the basis of the pre-approval studies,
however, the FDA often has limited data on the risks and benefits of
drugs that will be used long term for chronic conditions such as
arthritis. People use arthritis pain medications for many years, but
before Vioxx was approved, several thousand patients received the drug
usually in small trials that were designed to assess pain relief over
the course of a few weeks or months.\21\ Only about 750 patients
received usual doses of Vioxx, 12.5 mg or 25 mg per day, for a year or
longer. Even though the FDA medical officer observed a three-fold
increase in the risk of ``thromboembolic events'' in short-term
studies, \22\ Vioxx was approved and eventually used by many patients--
those with heart disease and those taking aspirin--who had often been
excluded from the pre-approval trials. Large long-term clinical trials
of drugs that will be used by millions of Americans for many years are
best started as early as possible in the drug-approval process. This
public-health approach, which need not slow the drug approval process,
recognizes and anticipates how the drugs will be used in the population
once they are approved.
In the post-marketing setting, some OND decisions seem more
industry-friendly than public-health friendly. For instance, in
clinical trials of the 0.8 mg supplemental NDA for Baycol, the findings
suggested a high likelihood of harm to about 7 percent of thin elderly
women.\23\ Although the manufacturer needed this dose to compete with
Lipitor (atorvastatin), the public-health rationale for approving the
0.8 mg dose, given the known risks, was not clear. Within a year,
Baycol was withdrawn from the market because of rhabdomyolysis, a
serious adverse event that was especially common at high doses. A
second example is Rezulin (troglitazone), a diabetes drug, that was
associated with episodes of liver failure and death soon after
marketing. The drug was withdrawn from the market rapidly in the United
Kingdom.\24\ In the United States, the FDA and the manufacturer
experimented with a series of recommendations and label-revisions that
did not work.\25\ \26\ Rezulin was eventually withdrawn from the U.S.
market in 2000.\1\ Finally, in the VIGOR trial, \27\ 50 mg dose of
Vioxx was associated with a five-fold higher risk of heart attack than
naproxen. With the large number of effective low-risk pain medications
then available, it is not clear how the FDA's formal risk-benefit
analysis could have favored keeping the 50 mg dose of Vioxx on the
market for the indication of acute pain relief.
The issue is not just weighing risk versus benefit but also the
quantity and quality of evidence about risk and benefit. In the post-
marketing setting, industry tends to do studies that generate good news
for the marketing departments. Those studies, which focus on benefits,
are often cleverly designed to generate little useful information about
risk. This asymmetry in evidence--well-studied benefits and ill-defined
risks--undermines the validity of the knowledge base. In the post-
marketing setting, the FDA needs a strong and independent CMDER to
pursue aggressively key safety questions that industry would sometimes
prefer to ignore. I have not seen this sense of mission from CDER
leadership in recent years.
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[Whereupon, at 11:44 a.m., the committee adjourned.]