[Senate Hearing 109-850]
[From the U.S. Government Publishing Office]
S. Hrg. 109-850
BUILDING A 21ST CENTURY FDA: PROPOSALS TO IMPROVE DRUG SAFETY AND
INNOVATION
=======================================================================
HEARING
OF THE
COMMITTEE ON HEALTH, EDUCATION,
LABOR, AND PENSIONS
UNITED STATES SENATE
ONE HUNDRED NINTH CONGRESS
SECOND SESSION
ON
EXAMINING PROPOSALS TO IMPROVE DRUG SAFETY AND INNOVATION, AND S. 3807,
TO AMEND THE PUBLIC HEALTH SERVICE ACT AND THE FEDERAL FOOD, DRUG, AND
COSMETIC ACT TO IMPROVE DRUG SAFETY AND OVERSIGHT
__________
NOVEMBER 16, 2006
__________
Printed for the use of the Committee on Health, Education, Labor, and
Pensions
Available via the World Wide Web: http://www.gpoaccess.gov/congress/
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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, NOVEMBER 16, 2006
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............................... 4
Prepared statement........................................... 5
Burke, Sheila P., Co-Chair, Committee on the Assessment of the
U.S. Drug Safety System, Institute of Medicine................. 7
Prepared statement........................................... 9
Hatch, Hon. Orrin G., a U.S. Senator from the State of Utah...... 14
Murray, Hon. Patty, a U.S. Senator from the State of Washington.. 17
Reed, Hon. Jack, a U.S. Senator from the State of Rhode Island... 18
Isakson, Hon. Johnny, a U.S. Senator from the State of Georgia... 20
Clinton, Hon. Hillary Rodham, a U.S. Senator from the State of
New York....................................................... 20
Thompson, Diane E., Vice President, Public Policy and
Communications, Elizabeth Glaser Pediatric AIDS Foundation;
Steven E. Nissen, M.D., Chairman, Department of Cardiovascular
Medicine, Cleveland Clinic Foundation; Adrian Thomas, M.D.,
Vice President, Benefit-Risk Management, Johnson & Johnson
Pharmaceutical Group; Jim Guest, President and Chief Executive
Officer, Consumers Union; and Greg Simon, President,
FasterCures.................................................... 24
Prepared statements of:
Diane E. Thompson........................................ 26
Adrian Thomas, M.D....................................... 32
Jim Guest................................................ 40
Greg Simon............................................... 58
ADDITIONAL MATERIAL
Statements, articles, publications, letters, etc.:
Advanced Medical Technology Association (ADVAMED)............ 69
American Society of Health-System Pharmacists (ASHP)......... 70
National Association of Chain Drug Stores (NACDS)............ 72
Response to questions of Senators Enzi, Kennedy, Murray, and
Clinton
by:
Sheila Burke............................................. 74
Diane E. Thompson........................................ 76
Steven E. Nissen, M.D.................................... 80
Response to questions of Senators Enzi, Kennedy, and Murray
by Adrian Thomas, M.D. 85
Response to questions of Senators Enzi, Kennedy, Murray, and
Clinton by Jim Guest....................................... 90
Response to questions of Senators Enzi, Kennedy, and Murray
by Greg Simon.............................................. 95
(iii)
BUILDING A 21ST CENTURY FDA: PROPOSALS TO IMPROVE DRUG SAFETY AND
INNOVATION
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THURSDAY, NOVEMBER 16, 2006
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 SD-426, Dirksen Senate Office Building, Hon. Michael B.
Enzi, chairman of the committee, presiding.
Present: Senators Enzi, Isakson, DeWine, Hatch, Kennedy,
Murray, Reed and Clinton.
Opening Statement of Senator Enzi
The Chairman. Good morning and welcome to today's hearings
on ideas and proposals for reforming our Nation's regulatory
framework for reviewing and approving prescription drugs. For
decades, the United States has been the standardbearer in
bringing new drugs and medications to the world market.
However, in the past few years there have been some concerns
that caused the public to lose confidence in our drug safety
system.
At the beginning of the 109th Congress last year, Senator
Kennedy and I pledged to work together with the Food and Drug
Administration and its policies and procedures for bringing new
drugs to the marketplace. In fact, two of the very first HELP
Committee hearings in this Congress were focused exclusively on
drug safety. Overall we've had 10 hearings on issues involving
the FDA. We incorporated the witnesses' recommendations and
comments from a series of stakeholder meetings into the
development of the Enhancing Drug Safety and Innovation Act, S.
3807.
We also took the extra step of posting the draft of the
Enzi-
Kennedy drug safety bill on the HELP Committee Website so the
public could comment, and we received dozens of comments from
consumer groups, from patient advocates, industry, and other
members of the public, and we've incorporated as many as
possible of those into the introduced bill.
Just like the bipartisan effort that led to the
Prescription Drug User Fee Act and the Food and Drug
Administration Modernization Act, now's the time for our
bipartisan legislation to bring more consistency, transparency,
and accountability to the drug approval process. This
legislation would create a more structured framework, leverage
advances in science and technology to build a more effective
and efficient FDA. This is further evidenced by the fact that
many of the recommendations made by the recent Institute of
Medicine report on drug safety were already part of the bill
well before the release of the report.
Now, throughout our oversight process we heard repeatedly
that all drugs have risks and the risks and benefits must be
weighed together, not separately. We also learned that the FDA
has considerable existing statutory authority. However, the
application of that authority can often be too blunt an
instrument for the situations currently faced by the agency.
Perhaps that's because we do not have a confirmed commissioner.
Witness after witness recommended that the agency be
granted a variety of intermediate authorities so that the
agency can more finely calibrate its actions to match the
problem and challenges presented to it. For example, granting
FDA special authority for label changes, post-marketing
studies, or delays in direct-to-consumer advertising.
However, rather than enact a series of solutions to
accommodate each and every potential situation, we must look at
a way to accommodate any needed change in the drug approval
process and post-market monitoring. Under our legislation the
FDA would begin to approve drugs and biologics and new uses for
these products with risk evaluation and mitigation strategies,
otherwise known as REMS. The REMS are designed to be an
integrated, flexible mechanism to acquire and adapt to new
safety information about a drug. The drug company sponsor and
the FDA would assess and review an approved REMS at least
annually for the first 3 years, as well as during review of
applications for a new use for the drug, when the sponsor
suggests changes, or when the FDA requests a review based on
new safety information.
Another significant problem faced by the FDA is that the
development of tools to evaluate medical products has not kept
pace. New tools are needed to better predict safety and
effectiveness of drugs, which in turn would increase the speed
and efficiency of applied biomedical research. Our bill would
spur innovation by establishing a new public-private
partnership at the FDA to advance what's known as the Critical
Path Initiative. This is the FDA's effort to improve the
sciences of developing, manufacturing, and evaluating the
safety and effectiveness of drugs, devices, biologics, and
diagnostics. We can accelerate and assure its continued
vitality by creating a permanent locus at the FDA, which we're
calling the Reagan-Udall Institute for Applied Biomedical
research.
Our bill also establishes a central clearinghouse for
information about clinical trials and their results to help
patients, providers, and researchers access these materials so
they can make more informed healthcare decisions.
Finally, the act would make great improvements to the FDA's
screening process for advisory committee members.
When we began our hearings early last year, the FDA asked
the Institute of Medicine to conduct a study covering the
agency and the U.S. drug safety system. That report was
released in late September of this year. I've been struck by
how closely the Institute of Medicine's exhaustive report
recommendations parallel provisions in S. 3807. I look forward
to hearing more today from Ms. Sheila Burke, Chair of the
Institute of Medicine Committee on the Assessment of the U.S.
Drug Safety System about those recommendations as well as the
other findings and recommendations in the report. I'm also very
interested to hear the reaction of our second panel to the
recommendations raised in the IOM report and pending
legislative proposals. I'm confident we can continue with the
open process we've initiated to address the few areas of
difference.
I want to thank the dozens of stakeholders, including the
Food and Drug Administration, patient and consumer groups,
industry associations, individuals, companies, and scientific
experts, who have taken the time and effort to give us their
comments and input on the bill. Their assistance has been
invaluable.
I also look forward to working with my colleagues to
advance this important piece of legislation. In the upcoming
year we face an exceptionally full agenda with respect to the
FDA. Besides updating the FDA's authorities--as proposed in S.
3807--we need to reauthorize both the drug and device user fee
programs, as well as the Best Pharmaceuticals for Children and
Pediatric Research Equity Acts. Also, we should move to confirm
the nomination of Dr. Andrew von Eschenbach to be the
Commissioner of Food and Drugs, and hopefully we'll do that
before we leave this time. Dr. von Eschenbach has a strong
record. He is an accomplished scientist, a proven manager, a
man with vision. He's also a cancer survivor and has brought
the perspective and compassion that goes with it to his
government service. He gave up a job he loves directing the
National Cancer Institute to offer his service in what I
believe is a much more challenging and often thankless job of
leading the FDA.
Dr. von Eschenbach has received significant support from
the HELP Committee. I urge my colleagues who are not on the
committee to give Dr. von Eschenbach the chance to effectively
run the FDA with full statutory authority. The FDA needs a
leader with the backing and the mandate that Senate
confirmation provides. This Congress must take up Dr. von
Eschenbach's nomination before we adjourn.
Before I invite Senator Kennedy to make his opening
statement, I want to congratulate him as he prepares to take
the gavel of this committee in the next Congress. I know that
he has served as Chairman of this committee before and wields
the gavel well.
Senator Kennedy. Lightly, lightly.
The Chairman. After the first of the year, he will be my
favorite chairman.
[Laughter.]
Senator Kennedy. But until then----
The Chairman. It's a line I borrowed from him 2 years ago.
Senator Kennedy. There you go. Thank you.
The Chairman. I'm proud that this committee has worked
together to achieve a lot over the last 2 years. We approved 37
bills. Twenty-five of those bills passed the Senate and 15
bills were signed into law. Most of the bills passed with
overwhelming bipartisan support and took up very little time on
the floor. We still have more to do.
This committee has worked together to: strengthen our
pension system, update our mine safety laws, create a national
network of cord-blood stem cell banks, improve our career and
technical education programs, help the chronically ill navigate
our healthcare system and afford health insurance, and allow
doctors and nurses to work together in a protected legal
environment toward reducing medical errors and improving
patient safety.
Now, we have a lot on our plate for the next Congress--No
Child Left Behind, Head Start, WIA, Higher Education, several
pieces of food and drug legislation, and a reasonable solution
for health insurance. If we work together in the same spirit we
did in the last 2 years, I am confident we can get all of this
done and more. So when this Congress comes to a close and the
next one begins, I will be working with Senator Kennedy in
every way possible to see that we can meet the challenges that
are left over from the 109th and stand ready to work with him
on important issues that come before us, just as he has worked
with me.
And I thank you for that and I recognize you for your
opening statement.
Opening Statement of Senator Kennedy
Senator Kennedy. Thank you. Well, thank you very much,
Chairman Enzi, particularly for your kind and generous
comments. You've arranged this extremely important hearing
today with the same kind of consideration and courtesy that
have been the hallmark of your chairmanship, and your
bipartisanship is a major reason why this committee has worked
so effectively over the past years on many, many, many problems
that affect American families. And you've set a very high
standard for reaching out and working with all the members of
the committee to try and find common ground, and that is
certainly a standard which I'll do the best I can to meet. It's
been really a great honor and a pleasure to work with you.
This committee deals with some of the most important issues
and questions that affect ordinary Americans in so many ways.
Today is just one very extremely important aspect of it, but
this committee works in so many different areas. So we have
worked and I hope we will continue to work closely together as
we address the unfinished business of our committee and of the
Congress.
So I thank you for your kind words and congratulate you on
really an extraordinary period of service to this committee and
to the Senate and to Wyoming.
Millions of Americans rely on the drugs that FDA reviews to
protect them from sickness and now the FDA itself urgently
needs treatment. I join my colleague and friend. The agency
needs to have a confirmed leader. We have been nearly 5 out of
6 years with acting directors. We need to make sure that we
have a leader in the FDA, and I join the Chairman in hoping
that the Senate will confirm Dr. von Eschenbach.
Science has too often had to take a back seat at the very
agency which should be setting the standards for objectivity
and integrity. There's growing evidence that the dedicated
professionals at FDA have been pressured to trip the scientific
views to prevailing patient winds. These are symptoms of a
serious illness and we should act without delay to provide the
cure.
The Institute of Medicine has done a valuable service for
the Nation by diagnosing the problem and providing a
prescription for treatment, and it's up to us to see that the
patient takes the right medicine and hopefully has a quick
recovery.
The stakes are high. FDA oversees products accounting for a
quarter of the U.S. economy. Every day it makes decisions that
make the difference between life and death for American
patients.
It's an honor to welcome Sheila Burke, who served the
Senate with such distinction on the staff of former colleague
Bob Dole. Sheila, who is now the Deputy Secretary of the
Smithsonian, found the time to chair the panel on IOM and made
these important recommendations on drug safety. As the IOM
report makes clear, FDA has many needs that Congress must
address, and we join in welcoming Sheila Burke.
The FDA budget is $1.8 billion a year. That may sound like
a lot, but it works out to about $6 a year for every American.
In Washington, DC., you can barely buy a sandwich for $6. Yet
with that amount we expect the FDA to assure the safety of the
food we eat, the drugs we take, the medical devices that save
so many lives. Clearly we need to increase the FDA's budget so
that it can do a better job of guaranteeing drug safety.
When I mention that, I see my friend and colleague from
Utah, Senator Hatch, who's been the former chairman of this
committee and also put the issue of the FDA as a high priority
on his agenda in terms of the safety and making sure that it's
going to have the kind of support here in Congress, along with
my other colleagues Senator Murray and Jack Reed.
Additional authority is needed as well. The Institute of
Medicine's report recommends the FDA have the power to require
post-marketing risk assessment, risk management programs for
new drugs, and require the industry to make the results of drug
safety studies available to the public. The Enhancing Drug
Safety and Innovation Act Chairman Enzi and I introduced
earlier this year addresses these needs and, like the Institute
of Medicine report, our bill emphasizes the need for a life
cycle approach to drug regulation both before and after
approval.
Mr. Chairman, I will include the rest of my statement,
which is an analysis of the bill, which you've done very
capably in your opening statement, in the record. I just wanted
to mention how glad I am to see Senator Murray, who has been
such a strong member of this committee and has been such a
constructive and positive force in ensuring that we're going to
have the best in terms of scientific integrity at the agency,
and my colleague Jack Reed, who was a key figure at the time
that we reauthorized the FDA. He was enormously involved in the
details of this legislation, as he is in so many. So I welcome
other members of our committee here and I thank you.
[The prepared statement of Senator Kennedy follows:]
Prepared Statement of Senator Edward M. Kennedy
Thank you Mr. Chairman. I commend you for calling this hearing on
the role of the Food and Drug Administration in protecting the safety
of the Nation's prescription drugs.
You've arranged today's hearing with the same consideration and
courtesy that have been the hallmark of your chairmanship. Your
bipartisanship is a major reason why the committee has worked so
effectively over the past 2 years on many problems affecting America's
families, and I'll do my best to see that the committee continues to do
business in the same spirit in the next Congress.
Millions of Americans rely on the drugs that the FDA reviews to
protect them from sickness. But now, the FDA itself urgently needs
treatment.
For too long, the agency has been without a confirmed leader.
Science has too often had to take a back seat at the very agency which
should be setting the standard for objectivity and integrity. There is
also growing evidence that the dedicated professionals at the FDA have
been pressured to trim their scientific views to the prevailing
political winds.
These are symptoms of a serious illness, and we should act without
delay to provide the cure.
The Institute of Medicine has done a valuable service for the
Nation by diagnosing the problem, and providing a prescription for
treatment. It's up to us to see that the patient takes the right
medicine, and hopefully has a quick recovery.
The stakes are high. The FDA oversees products accounting for a
quarter of the U.S. economy. Every day, it makes decisions that mean
the difference between life and death for American patients.
It is an honor to welcome, Sheila Burke, who served the Senate with
such distinction on the staff of our former colleague Bob Dole. Sheila
is now Deputy Secretary of the Smithsonian, but she found the time to
chair the panel at the IOM that made these important recommendations on
drug safety. As the IOM report makes clear, FDA has many needs that
Congress must address.
Its budget is $1.8 billion a year. That may sound like a lot, but
it works out to about $6 a year for every American. In Washington, DC,
you can barely buy a sandwich for $6--yet for that amount, we expect
the FDA to assure the safety of the food we eat, the drugs we take, and
the medical devices that save so many lives. Clearly, we need to
increase FDA's budget, so that it can do a better job of guaranteeing
drug safety. But money alone won't meet all the challenges. Additional
authority is needed as well.
The Institute of Medicine's report recommends that FDA have the
power to require postmarketing risk assessment and risk management
programs for new drugs, and to require the industry to make the results
of drugs safety studies available to the public.
The Enhancing Drug Safety and Innovation Act, which Chairman Enzi
and I introduced earlier this year, addresses these needs. Like the
Institute of Medicine report, our bill emphasizes the need for a
``life-cycle'' approach to drug regulation, both before and after
approval.
The bill would require every drug approved by the FDA to have an
enforceable Risk Evaluation and Mitigation Strategy, tailored to fit
the risk profile of each new drug. Where appropriate, the strategy
could include special requirements for labeling, postmarket clinical
studies, and limitations on marketing the drug directly to consumers.
For drugs with the most dangerous side effects, the strategy might
require that only doctors with specialized training be allowed to
prescribe the drug. If a manufacturer fails to implement a precaution
that it has agreed to, the FDA will have new authority to assess civil
monetary penalties to enforce compliance.
By providing a legally enforceable yet flexible way for the FDA to
oversee safety throughout the life cycle of a drug, the bill gives the
agency the authority it now lacks to take effective action to ensure
safety.
The legislation also creates a public-private partnership to
improve the science of drug safety and drug development. It will help
patients and physicians make more informed decisions by requiring the
results of drug trials to be included in a public database. Our bill
also takes stronger steps to avoid financial conflicts of interest by
members of FDA advisory committees.
Again, Mr. Chairman, I commend you for calling this hearing. I look
forward to working with you and our colleagues on both sides of the
aisle to give the FDA the authority it needs to restore public trust in
the safety of prescription drugs. I welcome our witnesses and look
forward to their testimony.
The Chairman. Thank you, and I would mention that anyone on
the committee that has a statement, we'll make it a part of the
record without objection.
I'd like to welcome Ms. Sheila Burke, the Chair of the
Institute of Medicine Committee on the Assessment of U.S. Drug
Safety System and a member of the Institute of Medicine. She is
also the Deputy Secretary and Chief Operating Officer of the
Smithsonian Institution, Vice Chair of the Robert Wood Johnson
Health Policy Fellowships Board, and a member of the Medicare
Payment Advisory Commission.
Ms. Burke began her career as a staff nurse in Berkeley,
California, and as Director of Program and Field Services for
the National Student Nurses Association in New York. She earned
a master's of public administration from Harvard University and
a bachelor of science in nursing from the University of San
Francisco. Ms. Burke will share the Institute of Medicine's
perspective on what Congress can and should do to improve drug
safety while preserving patient access to important
pharmaceutical therapies.
STATEMENT OF SHEILA P. BURKE, CO-CHAIR, COMMITTEE
ON THE ASSESSMENT OF THE U.S. DRUG SAFETY SYSTEM,
INSTITUTE OF MEDICINE
Ms. Burke. Good morning, Mr. Chairman, Senator Kennedy,
members of the committee. I thank you very much for the
opportunity to talk with you this morning.
The Chairman. I don't think the microphone's----
Ms. Burke. On?
The Chairman. Is there a little light on there?
Ms. Burke. It is.
The Chairman. Thank you.
Ms. Burke. I am grateful for the opportunity to talk with
you about the Institute of Medicine's report. The committee was
convened in 2005 at the request of the Food and Drug
Administration. In addition, we were supported by the Centers
for Medicare and Medicaid Services, the Agency for Health Care
Research and Quality, the National Institutes of Health, and
the Department of Veterans Affairs.
One of the major areas of debate in the world of drug
regulation is how one can monitor the safety profile of drugs
once they are on the market. This, in fact, was our focus. As a
result, while the committee considered a wide array of issues,
there are several important topics that either fell outside of
our charge or we were unable to consider.
For example, we did not undertake a systematic assessment
of concerns related to the specific drugs that have captured
the public's interest in recent years. Our report focuses on
the post-
approval process and period and therefore does not include a
detailed examination of the pre-approval process, including the
conduct of clinical trials.
The committee's attention was solely on prescription drugs
and the drug safety system, in particular the functioning of
the FDA's Center for Drug Evaluation and Research, or CDER,
which is responsible for drug review, approval, and regulation.
The report puts forth the vision of a transformed drug safety
system that has at its core a life cycle approach to drug risk
and benefit. Life cycle describes the level of attention to a
drug's safety and efficacy that does not taper off after the
time of approval, but is sustained from discovery and
development to the end of useful product life. This is not a
new concept, but it is one that we believe has been implemented
at best in a limited and a fragmented manner.
The report contains 25 recommendations in 5 topic areas:
CDER's organizational culture, science, scientific expertise,
regulation, communication, and resources. There are 11
recommendations that may be of particular interest to the
committee that are, in fact, very similar to provisions that
are contained in S. 3807, the bill introduced by the Chairman
and Mr. Kennedy. The key areas covered by these recommendations
include regulatory authority, agency leadership, resources, and
credible science.
First, the FDA's regulatory authorities are derived from a
statute that has been amended numerous times, yet requires in
our view strengthening and clarification to allow the agency
the flexibility to regulate increasingly complex drugs. The
committee was cognizant of the fact that the outcomes of
regulation are not simply paper documents, but, in fact, the
health of living, breathing patients. Delaying approval until
absolute complete certainty is reached or withdrawing a drug
once safety problems arise are often not realistic options. Yet
they reflect the largely all or nothing nature of FDA
regulatory authorities.
Our committee recommended that FDA be given a tool kit of
regulatory options that it can apply as appropriate and
necessary at any time in the life cycle of a drug and clarified
authority to enforce sponsor compliance with restrictions or
limitations on marketing imposed at or after the time of
approval.
Second, the committee found that, while CDER staff work
with great dedication and professionalism, the center's
organizational culture is in some ways and at some times
dysfunctional. The report identified several factors that seem
to shape organizational culture at CDER and offered solutions
to strengthening collaborations, improving stability and the
support of leadership's ability to affect organizational
change.
We believe that the turnover and the instability in the
commissioner's office leave the agency without effective
leadership, and without stable leadership strongly and visibly
committed to drug safety all other efforts to improve the
effectiveness and the efforts to improve the agency or its
position to effectively deal with safety for the truth and for
the future will be seriously, if not fatally, compromised. To
this end, the committee, among other things, has recommended
that the commissioner be appointed for a 6-year fixed term.
Third, the commitment of public servants, the concern of
Congress, the advocacy of consumer organizations, among others,
is not enough to transform the drug safety system. A
substantial and sustained financial investment is needed. An
agency whose crucial mission it is to protect and advance the
public's health should not have to go begging for resources to
do its job.
We acknowledge that the user fee program in place has had
many positive effects on the drug safety and drug approval
process. However, we prefer that additional funding required to
implement the recommendations in the report come entirely from
appropriations. If securing this additional funding entirely
from appropriations proves impossible, the committee urges that
restrictions on the use of PDUFA funds be curtailed.
Fourth, the infusion of additional resources will also
support the FDA's need for expertise in science and data.
Research and the data that it produces is in many ways the
lifeblood of the drug safety system. The committee believes
that CDER needs to substantially increase the amount and
quality of the data that accrue after a drug is on the market
and to ensure systematic reviews of what has been learned about
a truly novel drug after its launch and its use in the real
world.
We recognize that it is not enough to have strong science
backing up regulatory decisions about safety. Safety science
has to be credible. The committee has made several
recommendations intended to expand expertise and research on
drug safety at CDER. We have recommended measures to increase
the credibility of the committee process as well, to increase
opportunities for appropriate review of drug safety issues by
advisory committees, provide greater transparency for patients
and for providers of the information accumulated about a drug.
Our committee is grateful to have had the opportunity to be
of assistance to the FDA and hopes that the agency and the
Congress find that the report is useful in moving ahead to
strengthen drug safety. Again my thanks for the opportunity to
be with you today and I'm more than happy to answer any
questions.
[The prepared statement of Ms. Burke follows:]
Prepared Statement of Sheila P. Burke
Good morning, Mr. Chairman and members of the committee. Thank you
for the opportunity to come speak to you this morning. My name is
Sheila Burke. I am Chair of the Institute of Medicine (IOM) Committee
on the Assessment of the U.S. Drug Safety System.
The Institute of Medicine of the National Academies is an
independent, nongovernmental, nonprofit organization operating under
the 1863 congressional charter to the National Academy of Sciences. The
Institute of Medicine has provided advice to the Nation on matters of
health and medicine for over 30 years. Early in 2005, the Food and Drug
Administration (FDA) asked the Institute of Medicine to convene a
committee of experts to conduct an independent assessment of the
current system for evaluating and ensuring drug safety postmarketing
and make recommendations to improve risk assessment, surveillance, and
the safe use of drugs. In addition to FDA, the study was funded by the
Centers for Medicare and Medicaid Services, the Agency for Healthcare
Research and Quality, the National Institutes of Health, and the U.S.
Department of Veterans' Affairs. The Committee on the Assessment of the
U.S. Drug Safety System met for the first time in June 2005. The
committee's areas of expertise include public policy, statistics,
health informatics, pharmacy, clinical medicine, health plan
management, pharmacoepidemiology, economics, drug regulation, consumer
concerns, law and ethics, and academic research. The committee met six
times, and held several information gathering sessions that were open
to the public and included presentations from industry representatives
and a variety of patient, consumer, and professional organizations.
Some committee members also made two site visits to FDA, and engaged in
confidential conversations with more than 30 former and current staff
and leaders from FDA and especially its Center for Drug Evaluation and
Research (CDER). The committee's report was released September 22,
2006.
First, let me speak briefly about what the report does and does not
cover. The committee considered a wide array of issues, but there are
several important topics that either fell outside the charge to the
committee, or that the committee was unable to consider. For example,
the committee did not undertake a systematic assessment of
postmarketing safety concerns related to specific drugs that have
captured the public's interest in recent years, such as the COX-2
inhibitors or the selective serotonin reuptake inhibitors. The report
focuses on the postapproval period and therefore does not include a
detailed examination of the preapproval process. The report also does
not address over-the-counter drugs, or generics, nor does it treat at
length the complex issues related to the conduct of clinical trials.
The committee's focus was solely on prescription drugs and the drug
safety system, in particular the functioning of FDA's Center for Drug
Evaluation and Research, which is responsible for drug review,
approval, and regulation.
The report recognized at the outset that it is impossible to think
about safety independent of efficacy, and that the two must be
considered together throughout the lifecycle of a drug. A drug's
lifecycle begins at drug discovery and concludes at the end of useful
product life. Drugs are approved after risk-benefit determinations made
by FDA, but those determinations are made on the basis of clinical
trials with carefully selected participants and under controlled
conditions. The real-life use of drugs is often quite different--a drug
tested in a few hundred or thousand people is prescribed and used by
millions often for longer periods and in conjunction with other drugs
or supplements. That is why approval does not signify the end of
uncertainty about a drug, and continued monitoring is necessary after
approval. Most stakeholders in the drug safety system are aware of the
need for continued attention to a drug's risk-benefit profile during
the drug's lifecycle. However, the committee found an imbalance in the
regulatory attention and resources available before and after a drug's
approval. Staff and resources devoted to preapproval functions in CDER
are substantially greater than those available for postapproval
functions. The new drug review process involves sophisticated clinical
trial design and execution; after approval, few high-quality studies
are designed, conducted, and completed, and in general, the data
available is quite limited. Before approval, regulatory authority is
well-defined and robust; once a drug is marketed, FDA's ability to
regulate and enforce becomes greatly diminished. Many of the
committee's recommendations are intended to bring some of the strengths
of the preapproval process to the postapproval process, to ensure
ongoing attention to a drug's performance.
The committee made 25 recommendations in 5 topic areas: CDER
organizational culture, science and scientific expertise, regulation,
communication, and resources. A complete copy of the report is
submitted for the record. Of the 25 recommendations, 11 are uniquely
within Congressional purview or likely to be of interest to Congress.
These include recommendations pertinent to expanding funding for the
agency's mission, strengthening regulatory authority, stabilizing
agency leadership, ensuring the credibility of regulatory science, and
establishing a new advisory committee. More detailed discussion of key
recommendations follows.
Research and the data it produces is in many ways the lifeblood of
the drug safety system. The committee believes that CDER needs
substantially increased resources to conduct and access better
postmarketing safety research. The committee made a number of
recommendations to increase the amount and quality of data that accrue
after a drug is on the market. The committee recognized that it is not
enough to have strong science backing up regulatory decisions about
safety--safety science has to be credible. The committee made several
recommendations intended to expand the expertise and research on drug
safety at CDER. In addition, the committee recommended increased
opportunities for appropriate review of drug safety issues by advisory
committees, and transparency of the information accumulated about a
drug (for example, the posting of structured field summaries and
results of all efficacy and safety studies on a government Website, and
the posting of all NDA and sNDA packages on the FDA Website). Other
recommendations include: establishing a public-private partnership to
prioritize, plan, and organize funding for confirmatory drug safety,
efficacy, and effectiveness studies; demonstrating a commitment to
research by appointing a Chief Scientist to oversee intramural and
extramural research and by requesting and applying the necessary
funding to support intramural research; and taking specific steps to
increase the credibility of the advisory committee process.
FDA's regulatory authorities are derived from a statute that has
been amended numerous times, yet requires some strengthening and
clarification to allow the agency the flexibility to regulate
increasingly complex drugs. In its discussion of FDA's ability to
regulate, the committee was cognizant of the fact that the outcomes of
regulation are not paper documents but the health of living, breathing
patients. Delaying approval until complete certainty is reached, or
withdrawing a drug once safety problems arise are often not realistic
options, yet they reflect the largely all-or-nothing nature of FDA
regulatory authorities. The committee recommended that FDA be given a
tool kit of regulatory options it can apply as appropriate and
necessary at any time in the lifecycle of a drug, and clarified
authority to enforce sponsor compliance with restrictions or
limitations on marketing imposed at or after the time of approval. The
committee also recommended that CDER establish a milestone moment at 5
years after the approval of a new molecular entity (NME) (roughly 20-25
are approved yearly) to review all accumulated safety and efficacy data
related to that NME. This will ensure that there is a systematic look
back at everything that has been learned about a truly novel drug after
its launch and use in the ``real world.'' In another recommendation,
the committee called for designating a special symbol to mark all new
drugs, with the function of informing and educating the public that
those products are placed under greater regulatory scrutiny and perhaps
subject to stronger regulatory action (such as a moratorium on direct-
to-consumer advertising during the period of time that the special
symbol is in effect).
Anyone who has followed drug safety issues over the last several
years has surely noticed that a theme that often surfaces is some type
of management problem in CDER. Information has emerged--both in the
media and in government reports (e.g., from the DHHS Office of the
Inspector General, and the Government Accountability Office)--about
scientific disagreement poorly handled, a lack of collaboration among
divisions, an appearance of interdisciplinary tension, a perception of
inappropriate management expectations, and so on. On the basis of that
information and discussions with present and former FDA staff and
leaders, the committee has found that while CDER's staff work with
great dedication and professionalism, the Center's organizational
culture is, in some ways and at some times, dysfunctional. The report
identified several factors that seem to shape organizational culture in
CDER, and offered solutions to strengthening collaboration, improving
stability and support of leadership's ability to effect organizational
change, and addressing some of the challenges presented by a major
force in FDA's external environment--the Prescription Drug User Fee
Act. I'd like to draw your attention to two recommendations from the
chapter on culture. The committee recommended that postmarketing safety
staff have a formal role before approval and specific authority after
approval. Although postmarketing staff, and specifically the staff of
the Office of Drug Safety, now the Office of Surveillance and
Epidemiology, are invited to some preapproval meetings, this does not
occur consistently, it sometimes does not take place early enough in
the preapproval process. Office of Surveillance and Epidemiology staff
do not have a formal role before approval or authority after approval.
This recommendation in the context of others in this report reflects
the committee's view that keeping postmarketing safety activities
closely linked with the drug approval process is crucial.
The committee also recommended a fixed-term for the FDA
commissioner to stabilize the agency and promote a better integration
of safety into the work of CDER. In the last 30 years, FDA has had
eight commissioners and seven acting commissioners (including the
current acting commissioner) or, when the post was vacant, an acting
principal deputy commissioner. The eight commissioners have served an
average of 2.5 years with a range of 2 months to 6.3 years. The
committee believes that turnover and instability in the commissioner's
office leave the agency without effective leadership or the potential
to emphasize safety as having high priority in the work of the agency.
Without stable leadership strongly and visibly committed to drug
safety, all other efforts to improve the effectiveness of the agency or
position it effectively for the future will be seriously, if not
fatally, compromised.
In the area of communication, the committee referred to and
endorsed the sentiment behind recommendations made in the recent report
of the Committee on Preventing Medication Errors, released July 2006.
(The summary of that report is found in Appendix E of the Future of
Drug Safety report.) The committee also recommended a new mechanism--an
advisory committee with the requisite expertise and representation--for
improving FDA's communication to and with patients and the general
public.
The commitment of public servants, the concern of Congress, the
advocacy of consumer organizations, the interest of industry, among
others, is not enough to transform the drug safety system in the ways
outlined by the committee's suite of recommendations. A substantial and
sustained financial investment is needed. The suite of recommendations
put forward in this report--to improve the culture in CDER, attract and
retain highly qualified staff, improve technological capacity, obtain
and benefit from access to data and innovative scientific partnerships
and so on--is dependent on adequate resources. An agency whose crucial
mission is to protect and advance the public's health should not have
to go begging for resources to do its job. The committee has
acknowledged that the user fee program has had many positive effects on
drug approval. However, the committee gave several reasons why it
prefers that the additional funding required to implement the
recommendations in the report for an improved drug safety system come
entirely from appropriations. CDER's dependence on PDUFA funding with
its associated restrictions may hurt FDA's credibility. If securing
this additional funding entirely from appropriations proves impossible,
the committee urges that restrictions on the use of PDUFA funds be
curtailed.
The committee is grateful to have had the opportunity to be of
assistance to FDA, and hopes that the agency and Congress find the
report useful in moving ahead to strengthen drug safety.
Thank you for the opportunity to testify. I would be happy to
address any questions the committee might have.
The Chairman. Thank you very much for chairing this very
important committee and putting out this extremely helpful
report. I do have, as many may have, some very detailed
questions regarding the report and I would submit some of those
in writing. We definitely want to know what we've left out in
the bill, and there are other people that have proposals and
we'll have some evaluation of that, too.
But one of the big items is the benefit versus risk on
prescription drugs, and I believe that they have to be
considered together, not separately. Did the panel consider the
idea of a separate office of drug safety, and if so what did
the members of the panel think of that idea?
Ms. Burke. Thank you, Mr. Chairman. We did, in fact,
discuss that question and do not believe that breaking apart
the agency and setting up a separate freestanding safety unit
is in the interests of the kind of changes that we'd like to
see go forward. We believe, in fact, it is inconsistent with
the life cycle approach to drug safety and believe that for the
regulatory staff to work more productively together, both pre-
and post-marketing, that they are best kept together and have
made a number of recommendations that would involve the post-
marketing staff much earlier in the process, so, in fact, there
is this attention to life cycle and they do develop the kind of
collaboration we think is critical.
The Chairman. The report talks about life cycle of a
product and how knowledge changes over time. Could you
elaborate a little bit more on life cycle?
Ms. Burke. Literally, Mr. Chairman, it is our view that the
life cycle is from the point of the initial research until the
end of a product life cycle. That is, its use in the market is
really the timeframe in which we ought to really have in place
a regulatory system that is adept at dealing with all aspects
of that. That is in the gathering of the information on the
pre-marketing and the review of that information and a linkage
with the post-marketing tracking of data and analysis, and
continue to be informed as new information becomes available.
One of the challenges I think that we face is in the course
of clinical trials and the focus of those tends to be on a very
narrow population, and one of the realities that we face in
today's world is that once it goes into the market we are now
in an instance where, in fact, there are patients perhaps that
have different comorbidities, that may, in fact, be on
different medications, that present a different picture than
perhaps was looked at in the narrow range of a clinical trial,
and that the gathering of that information and the continued
information review and analysis is important to make sure that
we fully are aware throughout that period of time of what takes
place.
The Chairman. Thank you.
You also mentioned the cultural and administrative issues
at the FDA and I appreciate that. Do you think it's possible
for legislation to change an organization's culture?
Ms. Burke. No, sir.
The Chairman. Would the pending legislative proposals on
drug safety do so?
Ms. Burke. You raise a very important question. In fact,
there is nothing that we can do legislatively or, more
appropriately, you could do legislatively that would, in fact,
force a change in the culture. There are recommendations
contained in the report that relate to essentially integrating
the staffs differently, suggesting that, in fact, there be
folks brought in from the outside to assist them and look at
how one implements cultural change within the agency. We
believe that there are in the normal course the kinds of
relationships and challenges that occur in any environment
where there are professionals that have different views,
whether you have the folks that are managing the clinical
trials who may approach it differently than the
epidemiologists, for example.
But we leave the leadership, the stability of the
leadership; the integration of those teams, the introduction of
the safety decisionmaking earlier in the process that forces an
integration, the placement of safety staff on that team, we
hope, in fact, will begin to address some of those issues. But
there is no question that it has to be done within the agency
and it has to come from the top, which is why we think the
stability and the leadership is so critical.
The Chairman. Thank you, and I really appreciate that the
chairman of this very important committee is so able to speak
in layman's terms so that even I can understand.
It's been very helpful, and I know that you have a plane to
catch at 11 o'clock, so I'll relinquish the rest of my time and
turn to Senator Kennedy.
Senator Kennedy. Well, thank you and thank you, Sheila
Burke, for a wide swath of service to the public interest.
We're glad to have you here this morning.
Let me ask you, if we don't implement either the
recommendations of IOM or some aspect of the Enzi legislation,
what could you tell the public? I mean, how important is it
that we do something, both in terms of innovation, and in terms
of safety. How urgent is it? What's your sense and the sense of
your committee, about the importance of moving this legislation
forward? As you know from your own experience, we're going to
be encumbered with a lot of different choices here in the
Congress in prioritizing, and I'm just interested, based upon
your own understanding of this institution and a very detailed
study, how important is it in terms of the safety and
innovation in a period I like to call the life science century?
How important is it that we pass legislation, either what
you've recommended or what we have recommended?
Ms. Burke. I think, Senator Kennedy, it is enormously
important, and I think you have--I mean, often you have
circumstances where the stars align, where there are
opportunities that arise. Certainly in the course of the review
of PDUFA you have an opportunity. I think the timing is
critical. I think passage of legislation is critical. I think
the absence of that over the longterm would leave the agency
starved for resources, I think with unclear authority in terms
of being able to deal with the industry and to effect the kinds
of changes that we believe are necessary.
We are an increasingly complex world with increasingly
complex drugs dealing with increasingly complex problems. Drugs
are now used far more consistently and prevalently than they
ever have been in the course of caring for patients. So I think
if there were ever a time when it is critical to address these
issues, it is now.
Senator Kennedy. I think just as you were mentioning, this
is for me the life science century, with all of the
possibilities that are out there. The difference of getting
drugs on stream earlier can offer incredible opportunities for
people and yet we have, obviously, as we've seen in the recent
times, serious kinds of safety issues and we have to bring the
agency up to speed in terms of being able to do both.
One aspect of it is information technology. Using
information technology, we can advance and bring on stream
these newer prescription drugs and then monitor them more
completely and get the telltale signals or potential dangers of
it.
Isn't this an important area for us to give some focus and
attention if we're interested in getting drugs on earlier and
getting a better review of safety?
Ms. Burke. You are absolutely correct, both in the nature
of investment in the technology as well as the training of the
staff in order to be able to use the information. The AIR
system is a good example, where you are producing an enormous
amount of information, in excess of 400,000 reports, but the
ability to mine that information, the ability, for example, to
partner with Medicare, the new information that will be
produced in the course of the Part D benefit, we ought to be
able to utilize that and FDA ought to have access to that and
be able to utilize it to assist them in tracking what's
occurring.
So investments both in human resources as well as
technology I think are a very wise investment.
Senator Kennedy. Finally, to underscore the importance of
having administrative leadership out there in the FDA, if you
could just underline that point. And finally, the safety issue
is obviously front and center for many members of this
committee, and other committees. We have a more elaborate
description in your report about the administrative steps that
can be taken, that you think will enhance drug safety in an
effective way. If you could comment on both of those elements
I'd appreciate it.
Ms. Burke. I think the report does contain a number of
recommendations both with respect to administrative changes,
the integration of the staff, the placement of the safety staff
earlier in the process, as well as the commitment on the part
of the leadership at the agency to essentially instill safety
as a critical component. Clearly the stability of the
leadership of the agency is critical to that. The investment in
human resources and technology resources allowing the staff to
essentially do their jobs. They are a dedicated group of people
who need the resources to do so.
There is currently an imbalance in the pre-approval and
post-
approval process in terms of resources. Clearly a great
emphasis has been placed on pre-approval for good reasons in
terms of the speed of drugs to the market. A similar emphasis
needs to be placed on post-approval in terms of resources and I
think that will help to address some of these issues.
Senator Kennedy. Thank you very much.
Thank you, Mr. Chairman.
The Chairman. Thank you.
Mr. Hatch.
Opening Statement of Senator Hatch
Senator Hatch. Well, thank you, Mr. Chairman.
Welcome to the committee, Sheila.
Ms. Burke. Thank you.
Senator Hatch. We're glad to see you again.
I'm interested in your assessment of the next steps. I
think the report is very interesting, but one of the questions
I have is: do we really need legislation or can the
recommendations in the report be implemented administratively?
Ms. Burke. Mr. Hatch, we believe very firmly that there are
areas that do, in fact, require legislation. In addition to
those dealing with resources, that is obviously the
appropriations process----
Senator Hatch. Well, that's obvious. But I'm talking
about----
Ms. Burke [continuing]. Clearly you need additional
resources. But in terms of legislation otherwise, we clearly
believe that the agency needs far greater clarity in terms of
its authority, with respect to both the pre-approval and post-
approval process, the ability essentially to do more than
simply negotiate in good will with the agency--between the
agency and the drug industry.
We believe the agency needs to have the authority to
require that certain things occur, the ability for example to
call unilaterally for changes in labels, the ability to
essentially provide for followup to the kinds of studies.
Intervening sanctions, for example, to encourage compliance we
think need clear, clarified statutory authority on the part of
the agency.
Senator Hatch. It still looks to me like a number of your
suggestions can be implemented administratively.
Ms. Burke. Yes, sir, many can, in fact, be implemented
absent legislation. Some will, in fact, require statutory
change.
Senator Hatch. Yes, I agree with you on that.
Could you please expand on your comments about PDUFA?
Because you indicated--let's see; I've got your statement right
here--that you felt like CDER's dependence on PDUFA funding
with its associated restrictions may hurt FDA's credibility.
Then you say: ``If securing this additional funding entirely
from appropriations proves impossible, the committee urges that
restrictions on the use of PDUFA funds be curtailed.''
Could you expand on that?
Ms. Burke. Yes, sir. Our point in making that comment is
that currently there are limitations in terms of the use of
PDUFA funding. The bulk of the funding is clearly targeted
towards the approval process and that is the time prior to
marketing in terms of the staffing and the assets necessary for
that process. It has made an enormous difference and a very
positive one in speeding drugs to the market.
There have been restrictions on whether or not those funds
can be used, for example, post-approval in terms of the
additional safety staff, in terms of both the number of staff
as well as their capacity, for example, to do research as well
as contract with the drug companies themselves, but for the
agency itself to do some of this analysis.
So again, our view is that, with additional funds
necessary, our preference would be the appropriations process;
should, in fact, that not be possible, if PDUFA funds, in fact,
are the only source of funding that is available, that the
limitations currently in place that limit largely its emphasis
on the pre-approval process, be broadened to allow for more use
in the post-approval safety process as well.
Senator Hatch. I notice that some of the folks in the
House, when they resume their leadership after the first of the
year, have indicated that they would like to do a Hatch-Waxman
or Waxman-Hatch approach to bio. Could you tell us what the IOM
recommendations are there?
Ms. Burke. We did not address that, sir.
Senator Hatch. I didn't think you did, but do you think we
should weigh in and get IOM to address that?
Ms. Burke. Senator, I frankly am not--I couldn't opine
based on what the committee has done.
Senator Hatch. Well, it's a big problem because, of course,
we had a time bringing about the Hatch-Waxman bill----
Ms. Burke. Yes, sir.
Senator Hatch [continuing]. Because of the conflicts
between the generics and the brand companies. And there's no
question one of the big complaints is that the bio work is so
expensive that it would be well if we could find some way of
bringing some of those therapies into generic form. But then
the next question is how do you do that since it's so difficult
to duplicate large molecule individual therapy approaches.
I would like to have the IOM's viewpoint on that and how--
Congressman Henry Waxman's talking about, using terms like
``comparable'' or ``like.'' That is not as specific as the
original Hatch-Waxman, which had an easier time being specific.
These are areas that are really concerning me because I don't
think they should be political areas. We ought to get these
down so that they work well in the interests of the whole
pharmaceutical industry, whether generic or brand name or
whatever, in the interest of consumers, but also in the
interest of propelling this type of really outstanding research
forward.
So I would encourage you to get the folks there to spend a
little time on this, because we could really screw this up.
We're good at that. And I don't want to----
Ms. Burke. I won't comment.
Senator Hatch. You're not going to comment? Here I give you
a perfect opportunity and you won't do it.
Well, to make a long story short, I'd like to have some
advice on that.
Ms. Burke. All right, sir.
Senator Hatch. I think probably our chairmen would like to
have advice. Certainly Congressman Waxman and Congressman
Dingell would like advice. It's an area we just have to work on
in the next Congress and hopefully we can come up with
something that will function as well as the Hatch-Waxman bill
did or has. It's still functioning well and saving over $10
billion a year in pharmaceutical costs. But we could use your
help on it.
Ms. Burke. All right, sir. Thank you.
Senator Hatch. Thank you.
Thanks, Mr. Chairman.
The Chairman. Thank you.
Senator Murray.
Opening Statement of Senator Murray
Senator Murray. Thank you very much, Mr. Chairman. I really
appreciate you and Senator Kennedy working together on this.
Ms. Burke, it's good to see you again and thank you for the
incredible work your committee's done. I really appreciate the
opportunity to have this hearing. I hope we have more of them
as we really try and do this right in the coming Congress,
because I think we have a real opportunity to restore some of
the confidence the public needs to have in the health and
safety mission of the FDA and a real chance to give the
scientists at the FDA the tools and the authority they need to
ensure greater safety for all Americans. I hope we really use
this as an opportunity to restore the FDA to the gold standard
of safety and efficacy that we all know is so important.
My colleagues and I have been very concerned about the
political ideology that has undermined sound science at the
FDA. I think we need to make sure that we address that and it
is not a concern in the future. There are several other areas
I'm concerned about. One of them is the critical balance
between post-market safety and ensuring timely access to safe
and effective drugs and devices. We have a system that relies
heavily on user fees to ensure timely review process of our
drug applications and I'm concerned the FDA's financial
dependence on those fees may create a situation where user fees
are having undue influence on approval decisions, and I want to
make sure that user fees are providing timely reviews and not
automatic approvals. It's a difficult balance, but I hope that
we explore that as we move forward.
But let me take the short time--I know you need to leave--
to just ask you a question. You touched on this briefly with
Senator Hatch, but this committee held 2 days of hearings
talking about drug safety in response to a number of the high
profile cases involving Vioxx, and it was very troubling to
hear that FDA spent almost 18 months negotiating with Merck for
label changes and additional safety warnings. It's my
understanding that FDA was prompted to propose those additional
safety regulations because of a growing body of evidence. So a
number of people were using those drugs while FDA was
negotiating for 18 months and impeded the ability to get the
information out there.
You have talked about this in your proposal of how we make
sure that FDA has the authority to negotiate but still the
companies have an ability to respond to that in a timely
fashion. Can you talk about how you think we need to address
that?
Ms. Burke. Thank you, Senator. In fact, one of the
provisions we believe does need clarity and does need statutory
change is, in fact, to make it clear that the FDA does have the
ability to act unilaterally. Clearly our goal here is not to
prevent nor to discourage a relationship or a discussion
between the industry and the FDA. But in cases where, in fact,
evidence has arisen and time is of the essence, we believe, in
fact, the FDA ought to be given the authority not simply to
negotiate and depend on the good will of that relationship, but
rather to intervene. So the report specifically calls for that
authority to be given to the FDA.
Senator Murray. Thank you, and I really appreciate your
attention to that as well. I think that's important.
The other question I wanted to ask you quickly, both the
IOM and the Enzi-Kennedy bill place restrictions on direct-to-
consumer advertising for new drugs and I think that is
something we are all deeply concerned about addressing, and I
agree with that approach. But I do know that sometimes getting
information to consumers is just as important. If a parent
hears about a new vaccine to protect their daughter against
cervical cancer because of information that they heard, that
can save lives, too.
So talk to me about how the IOM is looking at how we
address that balance between not creating just a market
situation, but we also assure that people get the information
that is out there they may not hear otherwise?
Ms. Burke. The point you raise is an extraordinarily
important one. One of the questions of course is the balance of
that information. Our concern obviously with the advertising in
that period of time when a drug has just come onto the market
is speeding up the use of the drug before we fully appreciate
the risks that the drug might, in fact, present, that may well
not have been fully understand in the pre-approval process.
Having said that, we also think it is incredibly important
to provide a much better process for informing the consumer,
and, in fact, there are a number of recommendations related to
establishing a group to essentially assist the FDA in looking
at exactly that question: What is the method by which you best
communicate both with consumers as well as providers? The
relationship between the provider, the physician who cares for
the patient, and the patient is an enormously important one.
That ought to be the source of the information that the
patients seek out, rather than simply sitting at a Super Bowl
and watching ads come up on TV.
So it is really both of those values that we're trying to
balance. That is, informing the consumer, but in a way that is
useful, that doesn't encourage use before perhaps it's best
known what will happen. And how we deliver the information--
some of the materials to date tend to be very complex, tend to
be very lengthy, tend not to be very user friendly. We think a
great deal of attention needs to be given to incorporating
consumers into that review process and establishing a committee
that essentially really pulls together the best information,
frankly, from Madison Avenue and others about how you interact
and how you inform.
So certainly, in no way do we intend for there not to be
information, but the question is how is it delivered, by whom,
and for what purpose. That we think has to be balanced and
that's why we've suggested the creation of this committee and
involving consumers in that process.
Senator Murray. Thank you very much. I really appreciate
the opportunity to look at this.
I do have several more questions. I'll submit them for the
record because of the timing, but thank you.
The Chairman. Senator Reed.
Opening Statement of Senator Reed
Senator Reed. Well, thank you very much, Mr. Chairman.
Welcome, Sheila Burke, and thank you, not only for your
great public service, but for your service to the Kennedy
School.
Ms. Burke. Thank you, sir.
Senator Reed. Good to see you again.
I have just two questions because I know your time is
curtailed this morning. One of the recommendations in the IOM
report was the introduction of specific safety-related
performance goals as a means to restore the appropriate balance
between the FDA's competing goals, speeding access as well as
safety of the product. What kinds of safety and performance
standards did you envision would be necessary to do this?
Ms. Burke. Thank you, Senator Reed. One of the things that
concerned the committee is, in fact, currently under the PDUFA
structure there are very clearly established goals that are in
place with respect to timing, that are, in fact, tracked and
used to assist both the agency as well as the industry in
understanding whether or not the agreements are being kept.
There are no such similar requirements with respect to safety
either in the course of the advisory committee process, the
frequency with which they're used, when they're called
together, the kind of followup in terms of safety information
that's being gathered, the reports that have been required or
requested by the agency prior to approval, then what occurs
post-approval.
Our thought is that there ought to be a discussion and
introduction of safety-related, whether it is about the
advisory committee process, whether it is about the followup in
terms of studies, that also ought to be tracked so that the
Congress as well as the agency can fully understand whether, in
fact, those requirements are being kept. So there really is--
there are no specifics in terms of we've not listed specific
goals, but rather suggested that conversation needs to occur.
But those are the kinds of things that we're thinking about.
Senator Reed. So it's more procedural than substantive
recommendation?
Ms. Burke. It is exactly that, yes, sir.
Senator Reed. Let me follow on Senator Murray's questioning
about advertising. I know the report recommends direct-to-
consumer advertising on products be reviewed at least. A lot of
the advertising, a lot of the promotion of these products, is
done by representatives of the companies to physicians. Are you
thinking about that as a way or an issue that you have to deal
with?
Ms. Burke. Senator, we only focused on the direct-to-
consumer advertising. However, having said that, clearly there
is also this issue of the information given to providers as
well. One of the things we think needs great attention by the
agency is the nature of the material that is given both to
physicians as well as to consumers--its appearance, its
content, its presentation, whether, in fact, it is easily
understood, the frequency with which it is changed and updated,
how one delivers it. So really both of those issues, but the
specific moratorium issue relates specifically to direct-to-
consumer.
Senator Reed. With respect to the later issue, that is
something, obviously, the agency can do. Are they interested
and engaged in that process? Is that something that we have to
pay attention to, the company-to-physician relationship?
Ms. Burke. I can't speak for the agency. Certainly it was
of interest to the committee, because again we believed so
firmly that the physician ought to be the source of information
in many instances and the first contact for the patient, as to
how one delivers that information, the timing by which it is
delivered, the nature of the information. So while it is not
something we spent a great deal of time on, it is certainly
something that clearly the agency ought to be concerned about.
Senator Reed. Thank you very much.
Ms. Burke. You're welcome, sir.
The Chairman. Senator Isakson.
Opening Statement of Senator Isakson
Senator Isakson. Ms. Burke, I apologize. I missed your
testimony and I wasn't going to ask a question, but Senator
Reed piqued my interest when he talked about the advertising. I
thought I heard him say you made a recommendation on the
direct-to-consumer advertising; is that correct?
Ms. Burke. Yes, sir, we do.
Senator Isakson. What is that recommendation?
Ms. Burke. It relates specifically to new drugs coming on
the market, that the FDA ought to have the authority to
essentially curtail direct-to-consumer advertising during the
startup period when the market is just new in terms of the
drugs, that first 2 years or less, depending on what the agency
decides makes sense. It will obviously relate to the risk
issues with respect to the drug, to what extent they expect to
have new information as a result of its broader use in the
community.
So it's specifically to new drugs. It is specifically
within that timeframe in which they are first introduced into
the market.
Senator Isakson. In the case of mature--I don't know if
``mature'' is the right word, but drugs that have been on the
market-
place----
Ms. Burke. Yes, sir.
Senator Isakson [continuing]. For some time, more than 2
years, did you find any problems with direct-to-consumer
advertising?
Ms. Burke. We didn't examine that question, sir. Our focus
was really on that new period when, in fact, we don't really
yet have information about its use in a broader community.
Senator Isakson. Thank you very much.
Ms. Burke. You're welcome.
The Chairman. Senator Clinton.
Opening Statement of Senator Clinton
Senator Clinton. Thank you very much, Mr. Chairman, and
it's wonderful to be here, and especially to see Sheila Burke.
Welcome back to the Senate.
Ms. Burke. Thank you.
Senator Clinton. I want to thank you for really embarking
upon this important effort. You know, from my perspective there
couldn't be anything more critical that we turn our attention
to. I was able to get briefed on some of the questions and
comments that were made before I arrived.
I want to ask the witness about something that I'm very
concerned about. We're talking about post-approval, but I
believe strongly in comparative effectiveness studies. I was
able to get that through an amendment into the Medicare
Modernization Act. One of the first studies to be carried out
under that provision was a systematic review of the COX-2
drugs, and the results of the study, which were released in
September, found no difference in the effectiveness of COX-2
painkillers compared with over-the-counter pain relieving
drugs.
So I believe strongly that as we're looking at how to
modernize the FDA, how to provide it additional resources,
additional statutory authority where appropriate, that we
really look at these comparative effectiveness studies, because
they complement the drug approval work of the FDA. As we know,
the agency's approval process focuses largely on ensuring that
the drugs that come to market are safe for consumers. There is
nothing more important than that, safe and efficacious.
But newer drugs are not always better drugs and they may
not be the clinically appropriate choice for all patients with
a given condition. Comparative effectiveness studies allow us
to determine the benefits of a range of treatments for certain
conditions and to make sure that providers and patients are
making treatment choices that, frankly, are not unduly
influenced by direct-to-consumer advertising or other marketing
efforts.
So I would like to see us use the so far quite promising
results of the comparative effectiveness studies through the
Medicare Modernization Act amendment that I introduced and was
approved, and I would like to ask our witness how she sees
comparative effectiveness fitting into the pre-approval, post-
approval, almost spectrum of concerns that we should be
constantly addressing as we move forward.
Ms. Burke. Thank you, Senator. We, in fact, didn't as a
committee look specifically at that question. Having said that,
there is clear attention in our recommendations to the value in
the FDA both partnering with the private sector as well as
seeking partnerships with the VA, with Medicare, with other
Federal agencies that essentially have the ability to either
sort out information, provide information, support studies
either done with partnerships with either the industry or
individually having the FDA seek out these kinds of studies to
inform them farther along in the process.
Our particular attention, too, was that period largely just
post-approval. Having said that, we know that the life cycle
would produce lots of new information. The introduction of sort
of new treatments, new opportunities, will inform us about
drugs on the market as well as those coming on the market.
Again, we believe the agency ought to have the resources to be
able to test those questions, either again through partnerships
in the private sector or individually with the companies or
individually through the agency having the resources to conduct
its own studies or call for those studies.
So clearly the life cycle, the point of that is, in fact,
to inform us throughout that period of time where new
information could well become available.
Senator Clinton. Well, Mr. Chairman, I hope that as we move
forward under your leadership and Chairman-to-be Kennedy's
leadership that that will be part of our consideration. I would
underscore the point that has been made by a number of my
colleagues. You know, the FDA truly is the gold standard of
drug approval for the entire world, and we've got to get back
to absolute scientific impeccably independent judgments, so
that no one can second-guess them. Scientists may be wrong. We
all know that. Research may not be complete or it may be in
some way inadequate for the purposes for which it was intended.
But we shouldn't be engaged in any political debates about
whether other agendas, ideological or other agendas, are
driving the decisions made at the FDA.
Whatever we can do to guarantee the independence and the
open scientific discourse that is needed as part of drug
approval and review I am certainly going to support strongly,
and I want to echo Senator Hatch's concern that we begin to
look carefully at biologics, because this is an area of
extraordinary complexity and we just don't have the range of
infrastructure, intellectual capital, yet in the government to
be a partner with the drug companies as they move forward.
The Chairman. I want to thank you for your time today in
testifying, and your outstanding answers. Of course, we will be
relying on you to give answers to any written questions that
will be submitted. We'll keep the record open for 10 days.
But beyond that, we hope that you'll continue to work with
us as we work through this very complicated piece of
legislation to make sure that you and the members of your
committee's ideas are properly represented as we do it.
So thank you very much----
Ms. Burke. Thank you, Mr. Chairman.
The Chairman [continuing]. And we're getting you out before
your plane deadline.
Ms. Burke. You are. Thank you, sir.
The Chairman. Thank you very much.
As the next witnesses take their place at the table, I'll
introduce the witnesses all at once and then they can give
their statements and then we'll move to questions.
Ms. Diane Thompson is Vice President of Public Policy and
Communications for the Elizabeth Glaser Pediatric AIDS
Foundation, the worldwide leader in the fight against pediatric
AIDS. Diane is a public policy manager with over 20 years
experience in government and nonprofit organizations. She holds
a bachelor's degree from Vassar College and a law degree from
George Washington University's National Law Center.
The foundation is a founding member of the Alliance for
Drug Safety and Access, which is comprised of 11 patient and
provider organizations. ADSA members advocate on behalf of over
31 million patients, including those suffering from HIV-AIDS,
spinal cord injuries, paralysis, multiple sclerosis, and over
6,000 known rare diseases.
She will share patient views on whether the IOM proposal
and pending legislation would contribute to improving drug
safety while preserving patient access to innovative
pharmaceuticals.
Dr. Steven Nissen is the--did I get that right?
Dr. Nissen. You got it right.
The Chairman [continuing]. Chairman of the Department of
Cardiovascular Medicine at the Cleveland Clinic and President
of the American College of Cardiology. From 2000 to 2005 he
served on the FDA Cardio-Renal Advisory Panel, chairing this
committee during the final year of his term. Dr. Nissen is
actively involved in drug development and has served as
principal investigator for several clinical trials designed to
explore drug efficacy. He has also been an active proponent for
improved drug safety.
Dr. Nissen is speaking on his own behalf today and not for
any of the institutions he's affiliated with. He will discuss
pending legislative proposals from his perspective as a
physician who both treats patients and conducts large clinical
trials to evaluate pharmaceutical benefits and risks.
Dr. Adrian Thomas is Vice President of Benefit-Risk
Management at Johnson & Johnson Pharmaceuticals Group. Dr.
Thomas is a visiting professor at Temple University and a
research-trained clinical pharmacologist and vascular
specialist. Dr. Thomas is an internationally recognized expert
in drug safety and has 12 years experience in the
pharmaceutical industry. His research experience includes
clinical trials design and methodology, public health and
preventive medicine.
Dr. Thomas has held academic and research appointments in
epidemiology and preventive medicine at Monash University,
Australia. Dr. Thomas will discuss current requirements for
pre- and post-market safety evaluation by industry, as well as
what Johnson & Johnson is doing beyond those requirements and
how the IOM proposals and pending legislation would impact both
drug safety and drug innovation.
Mr. Jim Guest is President and Chief Executive Officer of
Consumers Union. Mr. Guest became President of Consumers Union
in February 2001 after a long career in public service and the
consumer interest, including 21 years as chair of Consumers
Union's board of directors. Consumers Union is an independent
nonprofit organization whose mission is to work for a fair,
just and safe marketplace for all consumers. Consumers Union
publishes Consumer Reports and consumerreports.org.
Mr. Guest's public service career has spanned more than 3
decades. He will share his perspective as President of a
leading consumer organization on the challenge of ensuring drug
safety without compromising patient access to important
pharmaceutical advances.
Mr. Greg Simon joined as President of FasterCures in July
2003. FasterCures is an action tank committed to saving lives
by saving time. The nonprofit, nonpartisan organization
examines the medical research and development process to
discover and promote ways to accelerate the discovery,
development, and deployment of new medical treatment for
today's deadly diseases.
Prior to joining FasterCures, Mr. Simon was a principal of
Infotech Strategies, a Washington, DC., consuming firm, with
special expertise in health technology, biotech, education
technology, and communication technology. Earlier he was the
CEO of Simon Strategies-Mindbeam, a consulting firm
specializing in biotech-
nology, healthcare technology, and information technology,
among other issues.
Mr. Simon received his bachelor's degree from the
University of Arkansas and his law degree from the University
of Washington School of Law. He will share a somewhat different
patient perspective on whether the IOM proposals and pending
legislation would contribute to improving drug safety while
preserving patient access to innovative pharmaceuticals.
Ms. Thompson, you may begin.
STATEMENTS OF DIANE E. THOMPSON, VICE PRESIDENT, PUBLIC POLICY
AND COMMUNICATIONS, ELIZABETH GLASER PEDIATRIC AIDS FOUNDATION;
STEVEN E. NISSEN, M.D., CHAIRMAN, DEPARTMENT OF CARDIOVASCULAR
MEDICINE, CLEVELAND CLINIC FOUNDATION; ADRIAN THOMAS, M.D.,
VICE PRESIDENT, BENEFIT-RISK MANAGEMENT, JOHNSON & JOHNSON
PHARMACEUTICAL GROUP; JIM GUEST, PRESIDENT AND CHIEF EXECUTIVE
OFFICER, CONSUMERS UNION; AND GREG SIMON, PRESIDENT,
FASTERCURES
Ms. Thompson. Mr. Chairman, members of the committee, thank
you very much for the opportunity to participate in today's
hearing. I am Diane Thompson, Vice President for Public Policy
and Communications at the Elizabeth Glaser Pediatric AIDS
Foundation. I am testifying today on behalf of the Alliance for
Drug Safety and Access, a coalition of 11 patient and provider
organizations whose members advocate on behalf of over 30
million patients suffering from serious life-threatening
illnesses and diseases, and also represent over 100,000
providers of care to children and individuals with mental
illnesses.
As a representative of the Elizabeth Glaser Pediatric AIDS
Foundation, I am proud to offer the perspective of an
organization that has been focused on speeding patient access
to safe medicine since its inception in 1988. The foundation's
creation was sparked by Elizabeth Glaser's outrage over the
lack of safe and effective options for treating her two HIV-
infected children. Although Elizabeth's efforts were too late
to save her daughter Ariel, who died from AIDS at the age of 7,
her legacy includes her son Jake, now 22 years old, and the
thousands of HIV-infected children around the world who now
have the chance to grow up healthy thanks to the search for
life-saving pediatric medicines that Elizabeth Glaser and the
foundation have championed.
I would like to thank the committee for your leadership on
this issue, for moving beyond the headlines to take on the
difficult task of crafting bipartisan legislation to truly
reform our Nation's drug safety system. We appreciate your
efforts that you and your staff have made to work with patient
advocates and your willingness to adopt so many of the
recommendations of our coalition. We know you share our goal of
ensuring that patients continue to have timely access to new
therapies while strengthening and improving the drug safety
system.
Simply put, we do not accept that patients should have to
choose between safety and speedy access to new medications. The
history of our foundation, of the broader HIV-AIDS community,
and that of many of our coalition is the story of the power of
patients' contributions to regulatory and scientific
decisionmaking. One mom's determination to fight for her
children's survival helped transform drug development for
children in this country.
Given that no one stands to lose more than patients in drug
safety decisions, we urge you to ensure that patient voices
have an important place in the development of risk safety plans
and particularly in the resolution of risk management disputes
as provided for in the legislation.
We are pleased to see that both S. 3807 and the IOM report
propose a fundamental paradigm shift in this country's approach
to drug safety. There is agreement that attention to safety
must be integrated throughout the life cycle of every drug and
that continuous assessment of benefit and risk is every bit as
important once a product is on the market and in the hands of
patients as it is during the drug review phase.
Changing the paradigm will require leadership,
determination, clarity, and resources. In addition to the
important changes already included in S. 3807, we agree with
the IOM's recommendation that FDA's safety staff must have a
greater formal role in drug review and in development of risk
management plans. We also strongly agree that safety-related
performance goals must be added to PDUFA.
We applaud the focus of the legislation and the IOM report
on strengthening FDA's ability to enforce requirements for
continuing safety monitoring, on the importance of public
dissemination of clinical trials data, and on the need for
sufficient resources for the FDA to implement its new
responsibilities. We need to make certain that we close the
gaps that exist in each of those areas.
As the IOM report notes, a recent study found that 21
percent of prescriptions are written for off-label uses. Any
effort to reform the drug safety system that fails to address
one-fifth of the use of drugs in real world settings would
create a significant safety gap, a safety gap particularly
important to children because still far too few drugs are
tested in children. The FDA's authority to require post-market
safety studies must clearly extend to both on-label and off-
label uses if we are to close that gap.
FDA needs enforcement mechanisms, including civil money
penalties, that are substantial enough to be effective. By
providing FDA the flexibility to impose fines for
noncompliance, we can avoid the worst possible outcome for
everyone, that FDA would have to resort to pulling a drug from
the market that still holds some benefit for some group of
patients because it has no other effective recourse.
In terms of clinical trials, we endorse the IOM
recommendation that a mandatory clinical trials database
incorporate phase two trials. In our view, however, that
database should also include trials completed prior to
enactment of this legislation and those for medical devices.
From the point of view of a patient it is irrelevant whether a
new therapy comes in the form of a drug or a device. The
results of all such studies should be made publicly acceptable.
For FDA to succeed in implementing these reforms, it must
have resources paired with its new responsibilities. A drug
safety system that incorporates these core elements ultimately
will benefit all stakeholders and we believe the changes
outlined above, if adopted and resourced, will serve both
timely review and safety.
Mr. Chairman, members of the committee, this committee has
before it a historic opportunity to finally match our Nation's
success in speeding new therapies to patients with a system
that can better ensure the safety of those products once on the
market. We very much appreciate your interest in the patient's
perspective on these critical issues and we look forward to
continuing to work with you over the next year to accomplish
these goals. Thank you.
[The prepared statement of Ms. Thompson follows:]
Prepared Statement of Diane E. Thompson
Mr. Chairman, Senator Kennedy, and members of the committee, thank
you for the opportunity to participate in today's hearing. I am Diane
Thompson, Vice President for Public Policy and Communications at the
Elizabeth Glaser Pediatric AIDS Foundation. Today, I will be testifying
on behalf of the Alliance for Drug Safety and Access (ADSA), a
coalition of 11 patient and provider organizations. Collectively,
members of ADSA advocate on behalf of over 30 million patients,
including those suffering from HIV/AIDS, Parkinson's disease, spinal
cord injuries, paralysis, multiple sclerosis, leukodystrophies,
Tourette Syndrome, and over 6,000 known rare diseases. In addition, our
members represent over 100,000 providers of care to children and
individuals with mental illnesses.
As a representative of the Elizabeth Glaser Pediatric AIDS
Foundation, I am also proud to offer the perspective of an organization
that has been focused on speeding patient access to safe medicines
since its inception in 1988. This issue is at the heart of our
mission--the Foundation's creation was sparked by Elizabeth Glaser's
outrage over the lack of safe and effective options for treating her
two HIV-infected children. Although Elizabeth's efforts were too late
to save her daughter, Ariel, who died from AIDS at the age of 7, her
legacy includes her son Jake, now 22 years old, and the thousands of
HIV-infected children around the world who now have the chance to grow
up healthy and even start families of their own, thanks to the search
for lifesaving pediatric medicines that Elizabeth Glaser and the
Foundation championed.
First, let me begin by thanking the Chairman, Senator Kennedy,
Senator Dodd and other members of the committee for your leadership on
this issue, for moving beyond the headlines to take on the difficult
task of crafting bipartisan legislation to truly reform our Nation's
drug safety system. We certainly appreciate the magnitude of the task
and the historic nature of this undertaking.
We also appreciate the efforts you and your staff have made to
incorporate the recommendations of our coalition. We know that you
share our interest in both continuing the timely access of patients to
new therapies and strengthening oversight of drugs already on the
market. And, we believe that with sufficient resources both goals are
achievable. Simply put, we do not accept that patients should have to
choose between safety and speedy access to new medications.
Patients with serious illnesses understand that bringing drugs to
market in a timely way means that not every risk can be identified in
advance. However, what they also demand is sufficient information for
them and their providers to continue to assess risks and benefits--
which often means further testing of the drug after approval. Yet, as
the report by the Institute of Medicine (IOM) so clearly illustrates,
the Food and Drug Administration (FDA) has virtually no authority to
compel drug manufacturers to continue to study the safety of products
after they have been approved, to force changes to drug labels if
dangerous side effects are uncovered, or to require that the results of
critical studies be shared with patients and providers. In addition, at
current funding levels, FDA lacks the resources to successfully
accomplish many activities it is authorized to undertake, including
effective collection and analysis of postmarket safety data.
Giving FDA these authorities and flexible tools to enforce them, as
legislation pending before the committee would do, ultimately benefits
both patients and drug manufacturers. Allowing FDA to require
additional testing of drugs when there are clear signals of safety
problems could actually allow the FDA to approve drugs more quickly,
knowing it will have the ability to act if there are new safety
concerns once the drug is in the hands of patients. Also, by giving FDA
the flexibility to impose fines for noncompliance, we can avoid the
worst possible outcome for everyone: pulling a drug from the market
that still holds some benefit for some group of patients.
We were pleased to see that S. 3807 essentially contains these
critical elements. Perhaps most importantly, it frames them in a
context of a risk-based approach. That model, rather than a one-size-
fits-all approach to patient safety, will be key to the appropriate
balancing of drug risks and benefits that is so critical to patients
with life-threatening illnesses. Similarly, we welcome the IOM's vision
of applying a ``life-cycle'' paradigm to drug risks and benefits, with
its emphasis on the continuing pursuit of knowledge about a drug's
safety profile and timely communication of that information to patients
and providers. As recommended by the IOM, we hope that this will
include the significant improvements to FDA's capacity to collect and
analyze safety data through passive and active surveillance systems, as
well as through prospective studies.
We are concerned however, that S. 3807 lacks sufficient mechanisms
to elicit much needed patient and provider input. Some of the most
critical patient safety decisions under the new structures proposed in
the legislation will be those that relate to the development of risk
evaluation and management strategies (REMS) plans. Yet, the bill
currently assigns the responsibility for developing those plans and
resolving related disputes solely to FDA and to an internal board
composed entirely of Federal employees, with no opportunity for input
from outside experts, patients, or providers.
The history of our Foundation and of the broader HIV/AIDS community
is the story of the power of patients' contributions to scientific
decisionmaking. Although they began as three mothers around a kitchen
table with no formal training in science and medicine, Elizabeth Glaser
and the other founders of the Foundation ultimately changed the
accepted thinking of both the National Institutes of Health and FDA
about the risks of not studying AIDS drugs in children--a success story
that is repeated throughout the histories of patient organizations.
Given that no one stands to benefit or lose more than patients in
drug safety decisions, we ask that you consider a greater role for
patients in the development of REMS plans and resolution of REMS
disputes. Specifically, we recommend that an existing or new advisory
committee be utilized rather than the Drug Safety Oversight Board. Such
a committee could draw on more diverse expertise, including the voices
of patients and providers, and could make its deliberations public,
which would be an important step in improving public trust in the
process.
To further improve the depth and breadth of input into drug safety
decisionmaking, we ask the committee to adopt the recommendation of the
IOM that the Office of Surveillance and Epidemiology (OSE) be given a
greater role in drug review and the development of safety plans. The
lack of communication and cooperation between that office and the
Office of New Drugs, highlighted in both the IOM report and a March
2006 report by the Government Accountability Office, is deeply
troubling. At minimum, we urge the committee to formally assign OSE
staff a role in the review of new drug applications and postapproval
regulatory actions, as the IOM recommends.
We also urge the committee to clarify that the authority of FDA to
require studies of postmarket safety concerns is not confined to on-
label uses of the drug. In our efforts to improve the drug safety
system, we need to pay particular attention to not only what happens
inside the FDA, but also what goes on in the real world. As the IOM
report notes, a recent study found that 21 percent of prescriptions
written in 2001 were for off-label uses. Any effort to reform the drug
safety system that fails to address \1/5\ of the use of drugs in real-
world settings would create a significant safety gap.
Children would be placed at particular risk by the failure to
clarify this authority, since as much as \3/4\ of pediatric prescribing
is off-label. Thanks to the efforts of Senators Dodd, Clinton, and
DeWine, there are mechanisms available to both encourage and require
manufacturers to study their products for children. However, there are
gaps in those mechanisms. The existing pediatric study requirement does
not apply to off-label uses. While the existing incentives can be
applied to off-label studies, they are voluntary--and we are seeing
that manufacturers are increasingly opting not to conduct the studies
FDA requests. Unambiguous authority to require such studies when the
off-label use is significant will help ensure that children too can
reap the benefits of an improved drug safety system.
We applaud the significant focus placed by S. 3807 on the public
dissemination of trial results through a clinical trials database. The
establishment of such a database would be a significant step forward in
providing patients and providers with additional information with which
to assess benefits and risks. By linking the registration of new trials
with final outcomes, this database could also help prevent selective
reporting of positive results and further revelations about the
withholding of negative trial results. And, not incidentally, given
that clinical trials could not exist without patients' willingness to
give of their time and health, such a mechanism could help restore
patients' trust in the integrity of the clinical trials process.
However, in our view, a number of additions should be made to the
database established by S. 3807 to ensure that it is as comprehensive
and complete an accounting of trials as possible. We endorse the IOM
recommendation that the database incorporate Phase II trials. We also
believe that to satisfy the objective of providing patients and
researchers with the full body of evidence on a drug or a class of
drugs, there must be an element of retroactivity, perhaps beginning
with trials of already approved products--both for the approved use and
for any uses that were studied but not approved.
Following the recommendations of a previous report by the IOM in
July 2005 on the postmarket safety of pediatric medical devices, we
also ask that device clinical trials be added to the database. From the
point of view of patients it is irrelevant whether a new therapy comes
in the form of a drug or a device; the results of all such studies
should be made publicly accessible. And, finally, while we endorse the
concept of a single, comprehensive, national database that provides
``one-stop-shopping'' for patients and providers, until the concerns
noted previously are remedied, we do not support pre-empting any
efforts by States to also collect this information.
We applaud the inclusion of civil money penalties in S. 3807 as a
critical step in providing FDA with graduated, flexible enforcement
authority. However, we are concerned that the current penalties are too
low to have much impact, particularly for higher sales products, and
ask that they be increased. To ensure compliance with the requirements
of the clinical trials database, we ask that the authority for FDA to
impose fines for other types of violations also be applied to this
section.
Finally, we agree with the IOM recommendation that specific safety-
related performance goals be added when the Prescription Drug User Fee
Act (PDUFA) is reauthorized next year. Clearly the experience from
PDUFA thus far is that deadlines generate attention and focus. Even
with additional funding, if postmarket activities without performance
goals have to compete with pre-market functions with performance goals,
we would be concerned they would remain an afterthought.
Obviously, the drug safety reforms proposed by both S. 3807 and the
IOM create considerable new responsibilities for the FDA. For FDA to
succeed in implementing these reforms, it is essential that new and
expanded safety activities be explicitly paired with increased
resources. We would suggest a combination of an increase in user fees
targeted to drug safety activities and an increase in appropriations.
We also recognize that it may be necessary to prioritize the reforms
that can be implemented in the short- and long-term depending on the
availability of new resources and we look forward to working with the
committee to do so.
Mr. Chairman, the committee has before it an historic opportunity
to finally match our Nation's success in speeding new therapies to
patients with a system that can better ensure the safety of those
products once on the market. We appreciate your interest in patients'
perspectives on these critical issues and look forward to working with
you over the next year to accomplish these goals. Thank you again for
the opportunity to share our views.
The Chairman. Thank you. I appreciate any summarizations
that any of the presenters do. Your full testimony will be a
part of the record, so if you hit on key points that'll give us
more time for questions.
Dr. Nissen.
Dr. Nissen. Thank you very much. My name is Stephen E.
Nissen, M.D. I am Chairman of the Department of Cardiovascular
Medicine at the Cleveland Clinic and President of the American
College of Cardiology. My testimony does not reflect the views
of either the Cleveland Clinic or the ACC. As an individual who
has frequently served as the point on the end of the spear
during the public debate on drug safety, I appreciate the
opportunity to provide an independent perspective on the
Enhancing Drug Safety and Innovation Act of 2006 introduced by
Chairman Enzi and Ranking Member Kennedy.
We face a crisis in public confidence in the FDA following
an unprecedented series of revelations about drug and device
safety. The American people no longer trust the FDA to protect
their health. Unfortunately, patients are increasingly
suspicious of new therapies and sometimes are reluctant to
accept potentially life-saving medications or devices. Strong
and decisive legislative action is now essential to improve the
safety of drugs and medical devices and restore public
confidence in this critically important regulatory agency.
The initiative now before you represents the best
opportunity in many years to fix these chronic problems. We
need new laws to strengthen the authority of the FDA. Currently
the agency must negotiate with industry to make even simple
changes in drug labels. I served on a 2001 advisory panel that
recommended a warning label for Vioxx, but it took 14 months
before the FDA could secure agreement from the company to
accept a weakly written warning. Companies routinely make
commitments to perform phase four studies, but never actually
launch the promised clinical trials, and the agency is
powerless to act.
When drug studies reveal toxicity or efficacy, the agency
is not permitted to release the results and the findings are
often not published, thereby denying patients and physicians
access to vitally important safety information. The problem of
negative publication bias, the practice of suppressing and
never publishing unfavorable studies, has a catastrophic effect
on the drug development system. When drugs show serious
toxicity in patients, the results are rarely published.
Accordingly, other companies subsequently expose patients to
closely related drugs without knowing that their competitor's
study of a similar agent showed significant harm.
I am aware of a class of drugs where more than a dozen
compounds showed serious toxicity, resulting in termination of
development, but without a single publication of results. In my
view, when a patient volunteers to participate in a drug or
device study there is an implicit moral obligation that
patients' participations will benefit medical science. When
studies are not published, we learn nothing from the experiment
and make the same mistakes over and over again.
The post-marketing surveillance system for drugs and
devices functions poorly. Adverse event reporting is voluntary
and studies show that only 1 to 10 percent of serious adverse
events are ever reported to the agency. Accordingly, the actual
incidence of serious or life-threatening complications cannot
be calculated accurately.
The current legislation proposed by Senators Enzi and
Kennedy addresses many of these problems in a thoughtful
fashion. The bill's authors have sought to simultaneously
facilitate development of innovative therapies while
aggressively protecting public safety. The proposed risk
evaluation and mitigation strategy is a step toward a more
robust post-marketing surveillance system. The system for
dispute resolution is fair to the industry but makes certain
that safety concerns are promptly addressed. The requirement to
register clinical trials is essential and the establishment of
a mandatory clinical trials results registry will guarantee
that society reaps the benefits of knowledge whenever a study
is conducted in human subjects. Finally, the improvements in
the advisory committee process will help to ensure FDA
consultants are less likely to be influenced by financial
conflicts of interest.
Although this bill is a major step forward, I would like to
see further legislative actions. The agency should be better
funded. Virtually every American takes one or more medications,
so drug safety affects every one of us. However, the annual
expenditure for drug regulation approximates only about $500
million and is largely supported by user fees, creating a
conflict in loyalty for FDA employees. We cannot expect
outstanding performance from an agency operating on a poverty
budget.
For high-risk drugs, another approach to drug approval
should be considered: provisional approval, a limited term
approval that would automatically expire unless certain
criteria for efficacy and safety are met.
I believe that direct-to-consumer advertising requires
legislative action. The standard for acceptable DTC advertising
should require demonstration of a compelling public health
benefit for this type of communication. Drugs with an addiction
potential, such as sleeping medication, should be specifically
prohibited from consumer advertising.
Finally, there is an important drug safety problem not
addressed in this bill--the nutraceutical industry. I recognize
that the HELP Committee has made progress by unanimously
approving legislation requiring serious adverse event reporting
for diet supplements. However, more needs to be done. These
products are often worthless and occasionally harmful. It must
be recognized that some patients take dietary supplements
instead of effective medications, with negative implications
for their health.
The current bill is an important step toward improving the
safety of drugs and devices and restoring public confidence in
the FDA. I strongly support its passage and commend the
Senators for their bipartisan leadership. Let me add, if there
was ever a bipartisan issue protecting the health and safety of
the 300 million Americans who take drugs, this is a bipartisan
issue and I really strongly support your efforts.
Thank you.
The Chairman. Thank you.
Dr. Thomas.
Dr. Thomas. Thank you. Mr. Chairman and members of the
committee: I'm pleased to be here today on behalf of Johnson &
Johnson to discuss the important topics of drug safety and
innovation. I am Dr. Adrian Thomas. I serve as Vice President
of Benefit-Risk Management, which is drug safety for the J&J
pharmaceutical companies.
J&J and this committee share a common goal of ensuring that
doctors prescribe and patients use healthcare products safely.
We commend you for the deliberative approach you've taken in
crafting your bipartisan legislation, S. 3807, and we thank you
for the opportunity to speak here today. J&J believes that
patient needs are best served when benefits and risks are
considered together in the context of how our medicine is
actually being used. We know, for example, that patients and
physicians often consider different levels of risks acceptable
depending upon the disease being treated, the patient
population, an individual's health status, and the availability
of alternative therapies. The full benefits and risks of any
medicine often emerge, however, over a significant period of
time after approval. Rare risks will only appear after a
medicine has been used in many thousands of patients. Thus any
legislative solution should balance established benefits for
populations against potential risks for individuals.
As important as this bill is, it is no substitute for
enhanced tools for monitoring patient safety or adequate
appropriations to ensure a strong and science-based FDA.
I'll now provide some highlights of our analysis of S.
3807. With respect to the risk evaluation and mitigation
strategies, recent concerns have rightly attracted attention on
improving drug safety. Whilst we agree that safety issues must
receive the attention they deserve, we cannot consider risks in
isolation from product benefits or we risk denying patients
access to valuable therapies.
Anti-cancer drugs are an obvious example of the complex
relationship between risks and benefits. However, more common
drugs such as statins and aspirin similarly provide a clear
benefit, but are nonetheless accompanied by distinct and
manageable risks. In fact, if aspirin were under review today
one could speculate whether or not it would be improved.
This bill integrates risks and benefits through the REMS
mechanism. We support this concept for products where the
potential for risk is greatest, such as new products, novel
mechanisms of action, or products that will be used in
vulnerable populations, particularly the aged and children.
That said, we have a number of concerns that I discussed in my
written testimony. I would like to highlight three.
First, regarding potential requests for industry to conduct
trials, we agree that--we recommend that such requests be
limited to on-label indications under the context of an IND
application.
Second, the committee may want to consider whether options
such as restricted distribution should be authorized in the
bill, as patient access could potentially be affected.
Third, the moratorium on DTC advertising has some problems.
Appropriate DTC advertising can play a valuable role in
education of patients about disease and treatments, although we
acknowledge that there are many issues.
Regarding the dispute resolution process, it's important
that drug safety oversight boards' considerations regarding
product safety be integrated with the appropriate reviewing
division to ensure a holistic view of the product.
I'd like to now comment on clinical trials. We are
generally supportive of the legislation's clinical trial
provisions. We would like to highlight one concern, the chief
of which is the bill's requirement for registration and
disclosure of results from exploratory clinical trials. These
trials are designed to generate hypotheses about medicine, not
confirm findings. As such, these results, either positive or
negative, could be confusing or misleading and need to be
placed in the appropriate scientific context.
With respect to the conflicts of interest, there is a
general need--there's a genuine need for sufficient numbers of
qualified experts for service on FDA committees. This is an
issue of concern for FDA, for industry sponsors, patients, and
providers. Greater transparency of the FDA decisionmaking
process will enhance public confidence and reassure all these
stakeholders. FDA should also be mindful of non-financial
biases, such as institutional affiliation, in the context of
specific advisory committee meetings.
In conclusion, the bill reflects the desire that we all
share, to enhance patient safety and access to new therapy, and
J&J greatly appreciates the opportunity you have provided to
discuss these issues with you today. However, it is important
to note that your efforts to strengthen FDA could be undermined
by increased reliance on user fees to fund FDA activities, as
we've heard today. There is a perception that the agency is
overreliant on user fees in a way that compromises the
integrity of the decisionmaking process. To address this
perception, Congress must increase FDA's appropriated funding
to enable the agency to fulfill its mission and restore public
confidence in its independence. Although we appreciate this
committee is not responsible for appropriations for FDA, your
status as the authorizing committee for FDA allows you to
exercise considerable influence on your colleagues in the
Senate.
On behalf of Johnson & Johnson, we look forward to working
with you and your colleagues to address these important issues
of patient safety and information. I want to thank you for the
opportunity to speak with you today. I'm happy to answer any
questions you may have.
[The prepared statement of Dr. Thomas follows:]
Prepared Statement of Adrian Thomas, M.D.
Mr. Chairman, Ranking Member and members of the committee, I am
pleased to be here today on behalf of Johnson & Johnson to discuss the
important topics of drug safety and innovation. I am Dr. Adrian Thomas,
and I serve as Vice-President for Benefit-Risk Management for the
pharmaceutical companies of Johnson & Johnson.
Let me start by saying that Johnson & Johnson and the Senate
Health, Education, Labor, and Pensions Committee share a common goal of
ensuring that doctors prescribe and patients use healthcare products
safely. We commend you for the deliberative approach you have taken in
crafting your bipartisan legislation, S. 3807, and we thank you for the
opportunity to speak here today.
I will begin by setting forth the broad perspectives of my company
on the topics of drug safety and innovation. Then I will provide some
background on how companies such as Johnson & Johnson assess the safety
of our products over their life cycles. Finally, I will comment on key
provisions of S. 3807, Enhancing Drug Safety and Innovation Act of
2006, as well as recommendations of the Institute of Medicine's (IOM)
Committee on the Assessment of the U.S. Drug Safety System regarding
proposed changes to aspects of the system whereby the Food and Drug
Administration (FDA) regulates medicines.
PERSPECTIVES
Since before Hippocrates first cautioned that physicians should
``help, or at least, do no harm,'' treating disease has always involved
balancing a therapy's benefits with its potential risks. At Johnson &
Johnson, we believe that patient needs are best served when benefits
and potential risks are assessed together, in an integrated, holistic
way, and within the context of how a medicine is actually being used.
We know, for example, that patients and physicians often consider
different levels of risk acceptable, depending upon the disease being
treated, the population being served, a patient's health status, the
availability of alternative therapies, and other variables.
It is also important to note that as society addresses issues of
drug safety, the full benefits and risks of any medicine often emerge
over a significant period of time after approval. Many risks are
exceedingly rare and may only emerge after a medicine has been used in
many thousands of patients. So as Congress develops new legislative
approaches, it should also continue to make it possible for patients to
access a broad range of existing, and new, therapeutic options. This
requires balancing protections for broad populations with access for
appropriate patients.
I would like to make a few other broad comments: We support the use
of Risk Evaluation and Mitigation Strategies proposed in S. 3807 to
enhance safety, where these strategies are most needed. We believe the
proposed Reagan-Udall Institute could be a valuable impetus to spur
scientific innovation if consistent and adequate appropriations are
provided. We support the provisions of S. 3807 and the IOM report
regarding the registration and disclosure of results of confirmatory
clinical trials. We support efforts to manage conflicts of interest in
FDA Advisory Committees and to enhance transparency while retaining
FDA's access to expertise. Finally, we believe that Congress should
adequately fund the Food and Drug Administration in the interest of all
Americans.
COMPANY SAFETY AND SURVEILLANCE ACTIVITIES
As I mentioned earlier, I serve as Vice-President for Benefit-Risk
Management for Johnson & Johnson's pharmaceutical companies. In that
capacity, my department and I work with the pharmaceutical research and
development units and with the medical affairs organizations in our
commercial operating companies to ensure that we appropriately consider
safety, together with efficacy and outcomes data, throughout the life
cycle of our products.
Like other pharmaceutical manufacturers, we evaluate the benefit-
risk profiles of our products continuously, since important additional
information is gained after approval of a medicine during real world
use. At the time of submission, our knowledge of the risks and benefits
of products, though quite detailed, is based typically on experience of
the medicine in thousands of patients in a controlled clinical setting,
whereas in the postmarketing life of the product additional data is
gathered from many times more patients in settings that are less
controlled. For example, in a study with 3,000 patients, one can
identify adverse reactions that occur at a rate of 1 in 100 patients,
but it is not possible in such a study to reliably identify an adverse
reaction that occurs in fewer than 1 in 1,000 patients.
Monitoring the safety profile of products postapproval requires
effective pharma-
covigilance and postmarketing surveillance. Like others in our
industry, we collect, assess, and evaluate safety reports from
consumers, physicians, healthcare providers, regulatory agencies,
clinical investigators, the literature and other sources globally. This
requires numerous technical tools and substantial medical expertise,
underpinned by a variety of specific processes to ensure diligence.
Not all products have the same level of risk. The degree of
scrutiny for a given product depends on a number of variables, such as
the stage of the product in its life cycle, known safety issues
associated with the product or class, or specific requests from
regulatory agencies. All products, however, are regularly reassessed as
new knowledge routinely emerges about medical interventions; and
science is not static. Companies such as ours continually invest in new
technologies and methodologies to conduct pharmacovigilance and risk
management. In the postapproval environment, we rely primarily on
safety information from postmarketing reports, but we also conduct
additional research, including epidemiologic studies and targeted
trials, to evaluate potential safety concerns. In instances of serious
unexpected safety issues, this integrated approach has proven to be
successful in assuring patient safety while maintaining access for
patients with significant medical needs.
Risk management cannot be undertaken in isolation by a
pharmaceutical company, but requires interaction and cooperation
between regulatory agencies and the company, as well as communication
of benefit-risk information in a timely and transparent manner to
healthcare professionals and ultimately to patients. The interaction
between the company and regulatory agencies is a critical partnership
from the time of early drug development throughout its marketed life,
with the ultimate goal of providing and maintaining patient access to
beneficial therapies. In this regard, it will be important for the
committee to hear from FDA when its Study Groups report back early next
year on any additional steps the agency may take to ensure the safe use
of medicines.
ANALYSIS OF S. 3807
Title I--Risk Evaluation and Mitigation Strategies
Reports of unanticipated adverse effects associated with medicines
taken by, in some cases, millions of Americans have undermined public
confidence in the ability of the FDA to ensure the safe use of
medicines. In that regard, today's hearing represents a step forward in
defining specific activities that could make a real difference in
safety margins, without unduly burdening the efficiency or speed of the
FDA approval process. Access to novel treatments is of particular
concern for patients suffering from serious or life-threatening
diseases--especially in cases where previous therapies have failed.
Safety issues have attracted much attention, both in the Congress
and among academicians. Some of the proposals (legislative and
otherwise) have sought to elevate the profile of safety considerations
by creating separate safety offices within FDA that would have equal or
superior authority over drug approvals to that of the reviewing office,
without having line of sight to the data on efficacy. This effective
veto power over approval of new medicines fails to appropriately take
into account the importance of benefit or efficacy considerations in
achieving a balanced understanding about a medicine.
For example, many traditional cancer drugs are associated with
substantial toxicities, but those toxicities are inseparable from the
effectiveness of the drugs. Oncologists who administer those drugs are
well aware of the toxicities and are capable of managing them for the
benefit of their patients with cancer. Cancer patients also understand
that the benefits of chemotherapy come with risks and those who elect
to take these therapies accept the risks that are inherent in these
drugs. If safety considerations had been permitted to trump drug
efficacy or benefit, many of these life-extending drugs might never
have been approved and might never have been available to cancer
patients.
While anti-cancer drugs offer an obvious example of the complex
relationship between risks and benefits, there are many other examples.
Medicines known as TNF-inhibitors provide substantial relief to
patients with rheumatoid arthritis, not only alleviating pain but
actually affecting the progression of the disease. The drugs'
mechanism, however, can interfere with normal immune system
functioning, and use of TNF inhibitors requires careful management.
Other more common drugs, ranging from statins to aspirin, similarly
provide clear benefit but are nonetheless accompanied by distinct,
though manageable, risks.
Your legislation, S. 3807, appropriately gives equal consideration
to the inseparable elements of safety and benefits. It accomplishes
this primarily through a mechanism called a Risk Evaluation and
Mitigation Strategy, or REMS. At the core of REMS is a
pharmacovigilance statement that creates a plan for managing the risks
associated with a particular drug. The pharmacovigilance statement is
based on an assessment of key variables, including estimated size of
the treatment population, the seriousness of the disease or condition
being treated, duration of treatment, availability of a comparable drug
or other therapy, and the seriousness and incidence of the risk in the
treatment population.
We support the concept of REMS for products where the potential for
risks is greatest, such as new product classes, products with new
mechanisms of action, or products that will be used in particularly
vulnerable populations, such as the aged or children.
Through the REMS approach, S. 3807 takes into account both the
benefits and risks of potential therapies, as is appropriate, to reach
a balanced regulatory decision. S. 3807 is also commendable in
providing a comprehensive menu of potential remedies that can be
tailored to meet particular risks to be included in a REMS, ranging
from a required medication guide or patient package insert and a
communication plan for healthcare providers, through postapproval
registries and clinical trials, to restrictions on advertising or on
distribution and use.
We agree that these elements of the REMS should reflect the
seriousness of the risks associated with a particular product and
should be considered in a step-wise fashion. Regarding potential
requests for industry to conduct clinical trials, we recommend that
such requests be limited to on-label indications. The committee should
consider whether an additional funding mechanism for off-label studies,
as has been put forth in the context of pediatric drugs, would be
appropriate. In addition, it would be reassuring to industry,
practitioners and patients if it were clear that the most severe of
these approaches--distribution restrictions, for example--would be
limited to situations of very serious risk. Some of the more extreme
elements that could be included in a REMS as set forth in the
legislation, such as restrictions on distribution or direct-to-consumer
advertising, have rarely been used to date and then only with the
acquiescence of the sponsor.
Voluntary restrictions on distribution have occurred in a few
situations in which there was a known serious risk to public health,
with thalidomide being the signal example. A very different situation
is created if the agency is authorized by statute to impose such
restrictions, notwithstanding the negotiation and dispute resolution
process. We recommend that the language of S. 3807 make clear that such
newly authorized remedies should be utilized only in extreme and rare
circumstances. The standard for restrictions on distribution should be
no less than in the current Subpart H regulation on accelerated
approval, 21 CFR 314.520, which permits restrictions ``. . . if FDA
concludes that a drug product shown to be effective can be safely used
only if distribution or use is restricted'' and ``. . . the limitation
imposed will be commensurate with the specific safety concerns
presented by the drug product.'' Certainly, restrictions on
distribution will limit patient access. We believe access to new
therapies should be assured.
Indeed, the committee may want to consider whether some of the
remedies are ever appropriate or in fact have been proven to be useful
in reducing risk. For example, the requirement that a patient must see
a board-certified physician could present a real access problem for a
sick patient who lives many miles from an appropriate doctor. The same
could be said about potential restrictions on pharmacies. We urge the
committee to very carefully weigh issues of patient access as it
further considers this bill.
Another remedy that should be reconsidered is the proposed ability
of FDA, under the legislation, to impose a moratorium on direct-to-
consumer (DTC) advertising for up to 2 years. This restraint on
advertising represents a troubling change. Many members of the
industry, including Johnson & Johnson, have voluntarily agreed to
exercise restraint with respect to DTC advertising, especially during
the period of time after approval. But appropriate DTC advertising
plays a valuable role in educating patients about diseases and
treatments. The value of this education to patients, as well as the
important first amendment issues that arise from banning truthful
speech, even for a period of time, must be carefully considered before
legislating in this area. At a minimum, the standard for imposing DTC
advertising restraints should be much higher than is currently
articulated in the legislation, to ensure appropriate application of
this new authority.
Regarding the dispute resolution process, we have a concern about
the elevation of the Drug Safety Oversight Board, an administrative
creation with no previous statutory authority, to the role of primary
final decisionmaker. As noted earlier, focusing solely on the risks of
a medicine without the context of the medicine's benefits could result
in limited access for patients. Given the enhanced status of the Drug
Safety Oversight Board under this legislation, the committee should
provide clearer definition of its composition and its place in the
governance of FDA. In addition, in connection with dispute resolution,
the Board should receive explicit statutory direction regarding the
appropriate balance of safety and access and should be required, in
resolving disputes, to apply a standard that balances safety concerns
against benefits, particularly in the case of serious or life-
threatening diseases.
S. 3807 provides a valuable platform for discussing how to address
the concerns that have been raised about drug safety, without
jeopardizing medical progress against serious and life-threatening
diseases. We note that many of the recommendations of the Institute of
Medicine (IOM) report on drug safety are consistent with the terms of
the legislation, although they diverge in several significant respects.
It is important to consider whether the IOM recommendation to assign
joint authority for post-approval drug safety reviews to both the
Office of New Drugs (OND) and the Office of Surveillance and
Epidemiology (OSE) creates an unworkable situation with split
accountabilities. We believe such authority should reside with OND,
though with appropriate input from OSE. It is important to note that
while OND reviews both benefit and safety information, OSE sees only
safety data, potentially skewing the OSE's perspective on a particular
medicine.
TITLE II--REAGAN-UDALL INSTITUTE FOR APPLIED BIOMEDICAL RESEARCH
While the drug safety reforms embodied in title I of the
legislation are necessary to restore the confidence of legislators,
regulators and the public in the safety use of marketed products, S.
3807 also makes a significant contribution to product innovation by
operationalizing the FDA vision of a ``critical path'' to discovery.
The industry knows that we lack the predictive tools to make drug
discovery and development more efficient and cost-effective. This is
particularly unfortunate, given the Nation's substantial investment in
biomedical research, through both public and private funding.
Recognizing this shortfall, FDA has fashioned what it terms a Critical
Path Initiative to streamline the drug development and review process.
FDA has met with numerous stakeholders to explore options for
developing its Critical Path Initiative, but lack of resources and
coordination among public and private entities has resulted in
relatively little progress in the development of biomarkers and other
tools that will, in the words of the legislation, ``modernize medical
product development, accelerate innovation, and enhance product
safety.'' The Reagan-Udall Institute for Applied Biomedical Research
could fill an important role in bringing together the best of the
public and private sectors to address this unmet need in a coordinated
manner. The challenges of developing new drugs, biologics, devices and
diagnostics may warrant the creation of a new entity utilizing the
expertise and funding of both public and private entities.
In light of the proposed scope of this new entity's mission and its
potential for advancing the science of drug development and life cycle
management across many disciplines, we question whether it is
appropriate to lodge the Institute within FDA, as currently provided in
S. 3807. Rather it would seem preferable that the Institute be placed
within the Department of Health and Human Services (HHS), reporting
directly to the HHS Secretary with liaison to FDA, the National
Institutes of Health and other relevant agencies within HHS and perhaps
even outside it.
Among the issues of potential concern for industry would be sources
of funding for the work of the Institute. The contribution of Federal
dollars is an important indicator of the Government's commitment to the
process and may make it more likely that industry will choose to
participate financially as well. Funding must be consistent and
sustained for a research-related program of this sort to succeed, and
the Federal contribution must not come from moneys currently allocated
to operations at FDA. Even though this initiative may produce savings
in administrative costs over the very longterm since the drug approval
process may be shortened and simplified, new funds must be made
available during the foreseeable future to avoid shortchanging FDA's
current efforts.
Other issues that may emerge are those that are typical when there
are collaborations among private entities or between private and public
sector players. These include balancing transparency of operations
against the need for confidentiality. Intellectual property issues may
also pose obstacles that need to be addressed before the Institute can
fulfill its mission. Early and frequent consultation with industry on
these and other issues will be essential to the Institute's success.
TITLE III--CLINICAL TRIALS
Johnson & Johnson's pharmaceutical companies have a well-
established policy for registering our clinical trials and publishing
our clinical trial results, both positive and negative. Our policy is
based on our conviction that ``. . . well-informed risk-benefit
assessments about our products rely upon the availability of product
information that is accurate, comprehensive, fair-balanced and
timely.''
Thus, we now publicly register all confirmatory clinical trials of
both marketed and investigational drugs regardless of location. For
studies related to serious and life-threatening diseases, we register
all that include efficacy endpoints, regardless of trial design or
location. Registration is made to the National Library of Medicine's
Website, http://www.clinicaltrials.gov. We believe that both patients
and healthcare providers can benefit from knowledge of clinical trials
that are open for enrollment, and our policy is intended to provide
this information to consumers in a manner that is as clear and easy to
access as possible. In the period from September 2005 to July 2006,
more than 24,000 visitors browsed Johnson & Johnson sponsored studies
on http://www.clinicaltrials.gov. Of these about 250 patients expressed
interest in participating in one of our studies and were subsequently
referred to investigators in their geographic region.
Our policy also addresses disclosure of trial results. For marketed
medicines, we publish the results of all confirmatory clinical studies
regardless of outcome. With respect to all other clinical studies of
marketed medicines, we assess the medical importance of trial results
and publish those results that are material and relevant to the
clinical use of the medicine or to the care and safety of patients.
These trial results appear either in peer-reviewed medical literature
or in the form of a clin-
ical study report synopsis in the ICH-E3 format. At present, our
clinical study results are posted as links from the protocols we have
registered on http://www.clinicaltrials.gov.
Clearly, there is industry support for organized clinical trial
registries to inform patients and providers about the opportunities for
enrollment in relevant clinical trials. Like our colleagues in
industry, we also recognize the importance of sharing with regulators,
with medical professionals, and with the general public the results of
clinical trials, regardless of outcome.
S. 3807 establishes a comprehensive framework for both trial
registration and reporting of trial results that should provide a clear
roadmap for industry with respect to both activities. If properly
implemented, the trial registry and results database will give industry
clear guidance regarding which trials are covered, when, where, and
what information must be posted, and last the consequences for failure
to comply. Hopefully, the result will be convenient and understandable
web-based destinations where patients and providers, as well as
regulators, can readily access timely information about the
availability of clinical trials and the results of trials, regardless
of outcome.
While we are generally supportive of the legislation's clinical
trial provisions, we are concerned about two matters: the requirement
for registration and disclosure of results coming from exploratory
clinical trials because they are not designed or powered to provide
firm answers to questions regarding the safety and efficacy of
medicines. These trials are designed to generate hypotheses about
medicine--not to confirm findings. As such, these results could be
confusing or misleading to patients and to physicians.
We are also concerned that the requirement to register trials
within 14 days of the first patient enrollment may be an unreasonably
short timeline. We would recommend that the legislation provide for
registration within 21 days of the first patient enrollment in order to
be consistent with the terms of Sec. 113 of the Food and Drug
Administration Modernization Act, with which we and many other
pharmaceutical companies currently comply.
S. 3807 is commendable in its specificity, but its provisions are
not necessarily self-executing, and many questions will undoubtedly
arise in the course of implementation. For this reason, consultation
with industry as well as with patients, providers and other interested
parties, is essential. In that connection, we note that the legislation
contains several references to rulemaking or promulgation of
regulations, as well as a requirement for a Guidance document to
clarify what clinical trials are ``applicable'' for purposes of the
trial registry. We believe that virtually all aspects of the systems
for clinical trial registries and for a trial results database would
benefit from the opportunity for public comment through rulemaking, and
therefore we recommend prior publication in the Federal Register. While
rulemaking might delay somewhat the implementation of these important
policies, the trial registry and trial database are complex
undertakings, and it is more important to get them right than to get
them quickly.
TITLE IV--CONFLICTS OF INTEREST
FDA cannot possibly provide, solely from the ranks of its
employees, the expertise necessary to evaluate the broad array of new
medical interventions being brought to patients today. Therefore,
advisory committees and other panels of outside experts are critical
for the competent review of new drugs, biologics, devices and
diagnostics. S. 3807 makes important changes to FDA's current practices
to enhance the integrity of the advisory process through greater
transparency in initial selection and in management of potential
conflicts of interest for advisory committee members.
Public confidence in the FDA review process requires that members
of advisory committees be as free as possible of financial
entanglements or other possible conflicts such as positions of prestige
or long-time investments in scientific positions or ideas. Such
conflicts could theoretically influence a committee member's judgment.
On the other hand, it is important that advisory committees include
individuals with the highest qualifications and undoubted expertise to
ensure that FDA decisions are guided by the best medical and scientific
advice. Frequently, it is not feasible to exclude those with one or
another type of conflict, as the resulting pool of expertise would be
too small for a meaningful selection process. Thus, it is vital that
restrictions on participation for reasons of conflicts be balanced and
moderate, with sufficient flexibility to address the demand for
expertise from what may be a limited supply of potential advisors.
It is important that S. 3807 seek an appropriate balance by
measuring the magnitude of the potential advisor's financial
involvement or other conflict against the necessity of access to his or
her expertise. The legislation should also set forth a process, with
applicable timelines, for identifying and assessing a range of
potential conflicts, determining the appropriate remedy and
communicating the agency's determination of approval for service,
waiver, limited waiver or recusal. Greater transparency of the FDA
decisionmaking process will enhance public confidence and reassure all
stakeholders.
Unavailability of sufficient numbers of qualified experts to serve
on advisory committees, however, could pose a serious obstacle to the
efficiency as well as the competency of product review at FDA. It is
therefore critical that conflict of interest provisions be applied in a
fair and balanced manner so as not to unduly limit participation. While
it is important that FDA have the tools to improve the current system
for managing potential conflicts, attention must also be given to
recruiting more qualified potential members of advisory committees. We
support creation of a mechanism for nominating qualified academics and
practitioners for potential advisory committee service and the
publication of Guidance in the Federal Register establishing this
mechanism. The need for sufficient numbers of qualified experts for
service on FDA committees is an issue of concern for FDA, industry
sponsors, patients and providers.
ANALYSIS OF IOM DRUG SAFETY REPORT
While we agree with many aspects of the IOM report, we disagree
with the recommendation to incorporate specific safety-related
performance goals in the standards for the 2007 version of the
Prescription Drug User Fee Act (PDUFA). We accept that user fees may be
applied to safety-related activities at FDA, but we question whether it
would be appropriate to create new and untested safety-related
performance goals as a measure of agency compliance with its user fee
obligations.
As we discuss below, we are concerned that imbalances in financing
of FDA activities, with increasing reliance on sponsor user fees as the
core of agency funding accompanied by additional mandates for agency
activities, are already a serious problem, which would only be
exacerbated by this IOM proposal. Related to this, it is important to
note that safety issues may also emerge in older products that are no
longer marketed by research pharmaceutical companies. Additionally, we
feel that the committee needs to consider what specific funding
mechanism will be implemented for safety activities associated with the
products of generic manufacturers.
CONCLUSION
S. 3807 reflects a desire that we all share, to enhance drug safety
and access to new therapies, and Johnson & Johnson greatly appreciates
the opportunity you have provided to discuss these issues with you
today. An important consideration for the committee is the potential
undermining of its efforts to strengthen FDA by increased reliance on
user fees to fund FDA activities. User fees currently account for more
than 50 percent of the agency's operating budget. At the same time,
Congress and the Administration continue to burden FDA with additional
unfunded responsibilities. We do not believe that FDA dependence on
user fees creates institutional conflicts of interest. FDA's integrity
is intact despite its receipt of user fees. Nevertheless, there is a
perception, fostered by critics of FDA and of industry, that the agency
is overly reliant on user fees in a way that compromises the integrity
of its decisionmaking processes.
To address this inaccurate perception, Congress must increase FDA's
appropriated funding, to restore balance to the agency's financing and
to ensure public confidence in its independence. Although we appreciate
that this committee is not responsible for appropriations for FDA, your
status as the authorizing committee for FDA allows you to exercise
considerable influence on your colleagues in the Senate.
On behalf of my colleagues at Johnson & Johnson, we look forward to
working with you and your congressional colleagues to address this
funding issue and to collaborate throughout the 110th Congress to
refine the terms of this very important legislation on drug safety and
innovation.
Thank you once again for the opportunity to speak with you today.
The Chairman. Thank you.
Mr. Guest.
Mr. Guest. Mr. Chairman and members of the committee, I am
Jim Guest, the President of Consumers Union, publisher of
Consumer Reports, and I appreciate the opportunity to testify.
For 70 years Consumers Union has provided consumers with
independent unbiased information on vital public health issues.
In the wake of the Vioxx and Paxil disasters, for example,
where tens of thousands of Americans needlessly suffered, we
have educated our more than 7 million subscribers, our more
than 20 million readers, our many thousands, hundreds of
thousands of citizen activists, on the need for stronger drug
safety laws, and there is strong, compelling support for
improvements in the FDA.
We applaud you, Mr. Chairman and Senator Kennedy, on S.
3807, which is a good first step towards meeting this need. It
would bring greater balance to the process, save lives, help
restore public trust in our Nation's drug safety system.
Further, it does not impede another shared goal, which is rapid
approval of safe, effective medications, particularly life-
saving drugs.
In the interest of protecting consumer safety, we further
urge that you strengthen the bill in several key areas. We
endorse the bill's clinical trials registry requirements for
phase two through phase four trials and indeed we support and
recommend even stronger provisions in S. 470. Publication of
trials--however, should be within 1 year, not 2--would be our
recommendation, and we urge that you require speedy publication
of any other studies that indicate safety concerns. Too many
Americans have died because pharmaceutical companies have
suppressed clinical trials and other studies with crucial
safety information.
We urge modifying the bill's GAO study requirements. It
should be a given that all phase two trial results be public.
That doesn't need a study. Rather, we urge a requirement that
the GAO consider what useful phase one trial data might also be
important to be made public, and we hope the registries, as you
heard earlier, will be gradually expanded to include trials
completed before the date of enactment.
The bill makes clear that once a drug is approved emphasis
on safety does not end. We support the REMS provisions and urge
that they be strengthened further, recognizing that the average
drug adverse event does not show up until nearly 7 years after
approval. To ensure that these risks are identified once a drug
has been used by millions of people over time, we suggest the
bill should approve--should provide for review on a 5-year
basis and perhaps again on a 10- or 15-year basis as well.
In addition, advertising new drugs should be subject to
limits for 3 years, not 2 as is in the bill. The FDA should
require safety studies of those drugs most widely used off-
label and civil monetary penalties should be strengthened,
especially for repeat offenders.
Another area of great concern are the various reports about
the severe morale and cultural problems at the FDA. These can
be difficult to address, but we believe that legislation indeed
can help set a higher ethical standard by requiring that all or
at a minimum 90 percent of advisory committee members be free
of conflict of interest.
Establish a climate of open and honest scientific debate
and discussion at the FDA by institutionalizing a system of
transparency, with staff dissenting or additional views on all
new drug applications being public, along with whistleblower
protections such as are contained in H.R. 5922.
Ensure more resources to the agency so it can do its job.
One option would be to free the FDA from the detailed
restrictions on how user fees are spent. Another option would
be to increase user fees to deal with the huge backlog of
safety issues. The appropriations process you have heard is
ideal, but it's important one way or another that the FDA be
sufficiently funded.
S. 3807 allows user fees to be used for post-market safety
approval. We suggest it also set standards for the performance
and safety of the computer modernization goals.
Finally, Consumers Union hopes that S. 3807 will be
expanded to include reforming the laws on generic and
biogeneric drugs and provide resources for the timely approval
of safe, low-cost generics. Far too many families have suffered
because the drug safety system is broken. Many victims and
survivors are working tirelessly for reform so others won't
have to endure their heartbreak.
I just want to note that two such extraordinary people are
in the room today, Mr. Chairman, for this occasion: Eric Swann,
whose brother-in-law Woody Witzak was casually prescribed an
anti-
depressant for insomnia and 5 weeks later killed himself; and
Matthew Downing, whose daughter Candace was put on Zoloft
because she was anxious taking tests at school and 10 months
later she took her own life at the age of 21. Neither Eric nor
Matthew knew about clinical trial results because they had been
suppressed, that indicated increased risk of suicide for these
types of anti-depressants.
For their sake, Mr. Chairman and members of the committee,
and for others, thank you for the important work you're doing
and thank you for your consideration of our recommendations.
Again, we appreciate the chance to testify.
[The prepared statement of Mr. Guest follows:]
Prepared Statement of Jim Guest
Mr. Chairman and members of the committee, thank you for inviting
Consumers Union, the nonprofit publisher of Consumer Reports, to
testify. I request that our full statement appear in the Record.
For 70 years Consumers Union has provided consumers with
independent, unbiased information on vital public health issues. In the
wake of the Vioxx and Paxil disasters, for example, where tens of
thousands of Americans needlessly suffered, we've educated our more
than 7 million subscribers, our more than 20 million readers, many
hundreds of thousands of our citizen activists, on the need for
stronger State and Federal drug safety laws. They seek action.
We applaud you, Mr. Chairman and Senator Kennedy, on S. 3807, a
good first step toward meeting this need. It would bring greater
balance to the process, save countless lives, and help restore public
trust in our Nation's drug safety system. Further, it does not impede
another shared goal--rapid approval of safe, effective medications,
particularly life-saving drugs.
We believe the committee would miss a great opportunity for
protecting consumer safety, however, if you don't strengthen the bill
in several key areas:
assuring quicker publication of the results of more
clinical drug trials;
enhancing the FDA's power to protect public health;
restoring the science-based culture and morale of the FDA;
garnering more resources, especially for postapproval
safety and information technology; and
reforming the generic and biogeneric laws to bring lower-
cost medicines to patients.
We will elaborate on each of these issues below, noting how the
proposed bill addresses them, what the Institute of Medicine (IOM) and
other research groups have concluded, and where Consumers Union
recommends strengthening the bill.
1. DISCLOSURE OF CLINICAL TRIALS
Background
There are several major issues in the clinical trial area: the
registration and disclosure of trials and studies, and the scientific
integrity and reasonable patient safety of those trials.
Registration and Disclosure: The registration and public disclosure
of clinical trials and other studies is key to determining the safety
of drugs. Transparency of study results is necessary to understand the
true safety and efficacy of drugs, to identify further research efforts
and to ensure appropriate safety warnings. Too often, pharmaceutical
companies distort, manipulate and conceal results from clinical studies
in order to guarantee the approval of their drug. Today, there is an
enormous bias toward reporting favorable results and the hiding or
minimizing of lackluster and negative results. As one analyst has
written:
``Another problem with the existing system is that
nonpublication of negative trials and nonreporting of negative
outcomes, coupled with redundant publication of positive
findings, has led to systematic publication bias, which can
undermine the reliability of medical evidence.'' \1\
Two such examples are Vioxx and Paxil. Vioxx was removed from the
market in 2004 after clinical trials revealed an increased risk of
heart attack and stroke for those taking the drug.\2\ According to
testimony from Dr. Sandra Kweder, deputy director of the FDA's Office
of New Drugs (OND), these trial results were not made available to the
FDA prior to Merck's voluntary withdrawal of the drug.\3\ Similarly,
GlaxoSmithKline, maker of Paxil, concealed results from clinical trials
linking the drug to an increased risk in suicidality among adolescents,
as proven by New York Attorney General Eliot Spitzer's successful
complaint against GlaxoSmithKline.\4\ These trials also revealed that
the drug was actually less effective than placebos among
adolescents.\5\
These abuses have not ceased. As recently as September 29, 2006,
the FDA released a Public Health Advisory that Bayer, maker of
Trasylol, failed to inform the FDA Advisory Committee (which had
convened 8 days earlier on September 21, 2006 to discuss Trasylol) of a
new study that revealed an increased risk of death, serious kidney
damage, congestive heart failure and stroke.\6\ The FDA began
conducting a review of Trasylol in January, 2006, after two published
research articles reported serious risks associated with use of the
drug.\7\ \8\ Such research misconduct has contributed to injuries and
deaths by consumers who use these potentially dangerous drugs, and USA
Today reports that the pharmaceutical industry faced more product
liability lawsuits than any other industry last year.\9\
Abuses in the registration and reporting of clinical trial and
study results highlight the need for increased transparency. Such
transparency would enable the scientific community to better assess the
true safety and efficacy of drugs. The World Health Organization (WHO)
has taken steps to standardize trial registration and reporting through
the International Clinical Trial Registry Platform (ICTRP), identifying
a 20-item minimal dataset for all clinical trials, which includes
target sample size and primary and secondary outcomes.\10\ Many medical
journals have formally supported these steps taken by the WHO and will
now consider the publication of the results of a clinical trial only if
it has been registered before the enrollment of the first patient.\11\
The Journal of the American Medical Association is responding even more
aggressively to ensure accuracy in data analysis by requiring all
submissions of clinical trial results funded by industry to hire an
independent statistician to analyze the data.\12\ A coalition of over
100 healthcare stakeholders have signed the Ottawa Statement, making a
moral case for full disclosure:
``When members of the public agree to participate in trials,
it is on the understanding that they are contributing to the
global body of health-related knowledge. It is thus unethical
to conduct human research without ensuring that valid
descriptions of the study and its findings are publicly
available.'' \13\
Lack of oversight and reasonable patient safety in clinical trials:
The need for registration of clinical trials (at all phases) became
even clearer after this spring's Phase 1 TGN1412 trial in which 6
healthy UK volunteers suffered catastrophic multiorgan failure after
taking the drug. Many argue that these events could have been avoided
had trial information been available for public review.\14\ Although
pharmaceutical companies argue that disclosing such sensitive
information would allow competitors to conduct similar trials of their
own, the WHO and many others in the field find that these concerns are
not sufficient to delay disclosure.\15\ Given the extraordinarily
aggressive patenting of all aspects of a new drug, we do not believe
that these public registrations will cause proprietary commercial
losses. Disclosure of the TGN1412 trial would have allowed experts to
determine if the trial was generally appropriate and if the procedures
that were followed were sound.\16\
The research community must take more responsibility in protecting
human volunteers, yet recent reports indicate that the FDA is about to
loosen regulations in this area. Senator Charles Grassley, in a letter
to the HHS Office of Inspector General (OIG), asserts that clinical
trial subjects are not always adequately warned of potential risks, and
are sometimes endangered and harmed as a direct result of participating
in such trials.\17\ Bloomberg News investigative reporting has found
that safety oversight of clinical trials is often left in the hand of
pharmaceutical companies and their contractors and that the quality of
these experiments is often suspect and certainly dangerous to the
participants.\18\ The consequences are clear: the Center for Drug
Evaluation and Research (CDER) recommended official action against 6
percent of the 319 clinical investigators it inspected in 2006 for
noncompliance of regulations.\19\ CDER requested voluntary corrections
for an additional 42 percent of clinical investigators whose deviations
from the regulations were considered to be ``minor.'' Senator Grassley
asserts that a fundamental concern regarding the participation of human
subjects is the ``lack of protections and respect for research
participants who place their health and their lives in the hands of
clinical investigators and the entities that are expected to monitor
and oversee the studies.'' \20\
In addition to the lack of safety for individuals enrolled in some
trials, there is the safety problem created by fraud in the
falsification of data used to justify a drug's approval. In the recent
case of Ketek, the FDA found multiple instances of fraud in the
company's clinical trial of about 24,000 patients, some cases of which
the maker Sanofi already knew about yet failed to notify the
agency.\21\
In light of the various abuses that may potentially occur while
conducting clinical trials, the FDA must do more to ensure scientific
integrity and patient safety in clinical trials. We comment on this
problem further in the ``Additional FDA Resources Needed'' section.
Discussion of Solutions in S. 3807 and Further Recommendations
S. 3807 addresses the issues regarding transparency in research by
establishing (1) a Clinical Trial Registry Database and (2) a Clinical
Trial Results Database, both of which would be made public. These
databases conform to the WHO ICTRP described in the previous section.
If they are seeking journal publication, sponsors may take up to 2
years after they determine the trial is ended to report Phase 3 and
Phase 4 trials to the public.
Consumers Union strongly supports the establishment of the Clinical
Trial Registry Database and the Clinical Trial Results Database, but
recommends that sponsors be required to report results, including the
results of Phase 2 trials, within one (1) year, and that results from
trials of drugs revealing safety concerns be reported publicly as soon
as trials are completed. This recommendation follows that of the
Institute of Medicine (IOM), which requests that trials be registered
``in a timely manner.'' \22\ Given the history of manipulation and
concealment of results by pharmaceutical companies, a stricter deadline
than 2 years for reporting results seems appropriate.
While the proposed legislation requires the registration of the
results of Phase 3 and 4 trials, it does not require the registration
of the results of Phase 2 trials unless the Government Accountability
Office (GAO) specifically recommends registration, which would then be
implemented through a further rulemaking process. The Institute of
Medicine report recommends that, at a minimum, all Phase 2-4 trials be
registered, including a posting of a ``structured field summary of the
efficacy and safety results of the studies.\23\ Furthermore, trial
registration will do nothing to diminish publication bias and
misreporting if only trials that have been completed and reveal
favorable results are reported and published.\24\ In order to really
address the problem of selective reporting--which is clearly an issue
given recent history--all clinical trials should be registered.
In addition, some argue that even Phase 1 trials can gather data on
efficacy in addition to safety, and therefore should also be subject to
registration.\25\ The data found in a Phase 1 trial can contribute to
meta-analyses of adverse events and is used by successful safety
projects such as RADAR.\26\ Finally, there is a strong moral argument
for such registration: fellow human beings have volunteered to serve
basically as guinea pigs to test the basics of a new drug idea. If
there is any adverse side effect from such tests, it seems immoral not
to report such results and not to warn other companies who may stumble
down the same research pathway. There may be little merit in the
concern that a company will lose ``proprietary'' data. A company's
proprietary and commercial interests are undoubtedly protected by the
aggressive patenting that occurs in the drug industry. The safety of
human test subjects should come first.
Consumers Union supports the public disclosure of as much
scientific data as possible. S. 3807 should be amended to change the
GAO study of whether Phase 2 trial results should be disclosed. We
believe that Phase 2 disclosure should be a given. Instead, the GAO
study should concentrate on whether all or some of Phase 1 trials
should be disclosed at the point when a final decision is made on the
drug subject to the trial (i.e., it is approved, or withdrawn).
Consumers Union also urges that the legislation extend the registry
to gradually include all studies completed since at least 1996, and
hopefully earlier. For example, each year over the next 5 years, 2
years of pre-enactment of S. 3807 trial results could be publicly
posted. It would be a great service to the world's scientific community
to have in one place an expanded, Internet available library of these
past trials.
In order to address the potential of trial abuses and
falsifications, the proposed bill calls for the FDA to ``sample''
clinical trials to ensure that the descriptions of results are
``nonpromotional, and are not false or misleading in any particular . .
. '' In light of past abuses, Consumers Union recommends that
pharmaceutical companies that neglect to provide relevant results or
falsify results should be subject to FDA Civil Monetary Penalties
(CMPs). In the ``Additional FDA Resources Needed'' section, we urge
that a higher percentage of trial and study papers be audited for
scientific integrity and honesty.
Finally, S. 3807 pre-empts State laws that require clinical trial
registration. Because of lack of action at the Federal level, Consumers
Union has been a driving force behind these State debates and laws. We
accept the idea of pre-emption, but only if there is a strong Federal
law. If the type of changes we recommend above are not included, we
oppose State pre-emption. The States should be able to do more to
protect the safety of their citizens.
2. FDA POWER TO ENSURE SAFETY
The IOM report highlights the fact that PDUFA has done a great deal
to ensure speed in the drug approval process--perhaps at the neglect of
safety. The report notes that although the PDUFA laws have established
performance goals relating to review speed, there are no performance
goals relating to safety.\27\ Thus the FDA assigns priority to specific
drug approval performance goals, and in turn (as the recent history of
withdrawals suggests), lacks resources to act aggressively on safety
issues which have no such performance goals.
S. 3807 provides exciting new powers, resources, and enforcement
tools for the FDA to improve post-market approval safety. But in light
of recent history, we urge even stronger actions. The following five
(5) subsections offer recommendations on how to give the FDA clearer
additional authority to ensure safety without in any way slowing the
approval of life-saving medicines:
A. Effective use of adverse event reports
B. Postapproval management
C. Direct-To-Consumer (DTC) advertising
D. Off-label use
E. Enforcement
A. Effective use of Adverse Event Reports
Background
An estimated 700,000 people required emergency department attention
due to Adverse Drug Reactions (ADRs) in 2004 and 2005.\28\ ADRs are
responsible for as many as 100,000 deaths annually.\29\ Although these
numbers indicate that ADRs are an enormous problem, no effective
mechanisms for reporting and analyzing potentially serious ADRs exist
today.\30\ Spontaneous reporting systems such as MEDWATCH, while
sometimes useful, are incapable of reliably or quickly detecting many
long-range ADRs.\31\
Discussion of Solutions in S. 3807 and Further Recommendations
S. 3807 establishes a key principle: that drug safety issues do not
stop with the approval of the drug. Instead a drug must be looked at
over its ``life cycle''--drugs need to be monitored and studied over
many years. The bill establishes a system of Risk Evaluation and
Mitigation Strategies (REMS). In addition, in title II it creates the
Reagan-Udall Institute, in consultation with the National Institutes of
Health (NIH) and other research programs, to explore ways to improve
adverse event reporting and analysis and improve the science of drug
development and safety.
The IOM report specifically calls for an improved Adverse Event
Reporting System (AERS), and asks that the Center for Drug Evaluation
and Research (CDER) conduct a scientific review of AERS to identify and
implement improvements, and, ``systematically implement statistical-
surveillance methods on a regular and routine basis for the automated
generation of new safety signals.'' \32\ While spontaneous reporting
methods, such as MEDWATCH, may contribute to AERS, these methods are
not the only tool to track and evaluate ADRs. Consumers Union
recommends the incorporation of a temporary demo whereby the FDA
devotes resources (including user fees) to support NIH funding of a
program like the Research on Adverse Drug Events and Reports (RADAR)
project in which medical scientists proactively search ADRs for
patterns.\33\ The RADAR project is funded entirely by peer-reviewed
grants from the NIH, the Veterans Administration (VA), and the American
Cancer Society (ACS). Summary safety information from the project is
synthesized into reports for medical journals, revised package inserts,
and ``Dear Doctor'' letters. The information is presented to
physicians, the FDA and relevant sponsors. The RADAR project may
provide important answers as to how more ADRs can be reported and
evaluated in a meaningful way.
Today, it is estimated that only 1 to 10 percent of all adverse
events are reported. But with the coming age of health information
technology and personal health records (PHRs) where patients can be
electronically warned of dangers and asked to report reactions to new
drugs, we will soon have access to a huge amount of new data. The FDA
is to be commended for contracting with a number of large patient
encounter databases. The use of these large databases can eventually
permit the FDA to detect patterns of ADRs that are invisible when only
smaller populations are examined. But it is not yet clear when and how
they will be able to use the extraordinarily rich data that will be
available from Medicare Parts A, B and D. We urge the committee to lay
the groundwork in S. 3807 for FDA to use the Medicare databases and PHR
systems to establish a truly effective AERS that will be able to detect
many more kinds of drug interactions. Further, such a system will help
us compare drug effectiveness to determine which medicines and courses
of treatment are most effective in fighting life's diseases. Of course,
using large databases to aggressively search out adverse drug events
will take significant new resources (which we discuss below).
B. Postapproval Management
Background
As noted in the previous subsection, ADRs pose serious safety
concerns. According to a study by the General Accounting Office (GAO),
over 50 percent of all approved drugs had serious postapproval
risks.\34\ These ADRs are often detected years after the drug has been
on the market. One study indicates that only 50 percent of ADRs are
discovered within 7 years after approval.\35\ This delay in detecting
drugs with serious risks is apparent in the withdrawal process as well;
one report documents the median time on the market, before a drug is
withdrawn, to be 5.4 years.\36\
These figures highlight the importance of postmarketing
surveillance, but in the current system the FDA focuses almost
exclusively on pre-approval indicators. This strategy has proven to be
inadequate and dangerous. Although pre-approval trials may assess
efficacy, they cannot assess safety due to the fact that they are
conducted in small, selected populations (often disproportionately
males who are younger and healthier than the population which will
actually use the drug) for very limited periods of time. In general,
Phase 1 trials are conducted on several dozen healthy humans to
determine safe dosages and generally evaluate safety. Phase 2 trials
are conducted on a slightly larger population--perhaps several hundred
people--to test effectiveness and further evaluate safety. Phase 3
trials are conducted on large populations of several thousand to
confirm effectiveness, monitor side effects, and gather additional
information that will allow the drug to be used safely. An abbreviated
trial may be conducted for as little as 6 months. Finally, Phase 4
trials are conducted after a drug has been marketed to evaluate long-
term safety. FDA regulations allow for the approval of a drug with
evidence from a single clinical trial.\37\ Clearly, clinical trials are
simply incapable of portraying an accurate picture of how a drug will
behave in the general population or the older patient population over
many years. Thus, the need for reviewing drugs once they are on the
market is essential.\38\ \39\
Although the FDA has the authority to recommend Phase 4
postapproval studies, sponsors of drugs often fail to complete such
studies. For example, Sanofi-Aventis failed to complete a postapproval
study on the arthritis drug, Arava, after the FDA questioned its long-
term safety at the time of its approval in 1998.\40\ Arava has been on
the market for 8 years and fatal liver complications have been reported
in those using the drug.\41\ Bloomberg News reports that 860
postapproval studies requested by the FDA have yet to be completed, 260
of which are on drugs that were approved at least 5 years ago.\42\ It
appears that many of these trials have not even been started and the
commitments given to the FDA are often ignored.
Not only is there a problem with getting companies to fulfill their
post-market study commitments, but lack of FDA resources has led to
poor enforcement of this program. In June 2006 the HHS Inspector
General reported that:
FDA cannot readily identify whether or how timely post-
marketing study commitments are progressing toward completion.
About one-third of ASRs [Annual Status Reports on these
studies] were missing or incomplete, . . . ASRs contain
information of limited utility . . . FDA lacks an effective
management information system for monitoring post-marketing
study commitments. . . . Monitoring post-marketing study
commitments is not a top priority at FDA. . . . Our analysis
showed that FDA validated only 30 percent of ASRs submitted in
fiscal year 2004. . . .
The OIG called on FDA to instruct companies to provide
``additional, meaningful information in their ASRs, improve the
management information system for monitoring post-marketing study
commitments so that it provides timely, accurate, and useful
information, and ensure that post-marketing study commitments are being
monitored and that ASRs are being validated.'' \43\
Discussion of Solutions in S. 3807 and Further Recommendations
This year's GAO report on the FDA comments on the agency's
inability to ensure the completion of postapproval studies, asserting
that ``FDA needs greater authority to require such studies.'' \44\ The
report goes on to further document cases where the FDA has been unable
to negotiate with sponsors to ensure that postapproval studies are
conducted. Since sponsors voluntarily agree to conduct such studies,
the FDA has no authority to ensure their completion.
As part of REMS, S. 3807 gives the FDA authority to require safety
trials and tools to enforce the requirement. Consumers Union strongly
supports this provision: it is one of the most important in the bill.
In addition, required REMS call for 3 years of review, and
additional review may be required ``at a frequency determined by the
Secretary for subsequent years.'' The IOM repeatedly highlights the
need to perform postmarketing surveillance throughout the entire life
cycle of a drug. In particular, the IOM recommends that the evaluation
of a new drug's total safety profile occur after 5 years. Consumers
Union strongly supports the IOM's recommendation and asks that the
review time cycle for a drug be increased from S. 3807's 3 years to 5
years. This review should be institutionalized, and not left to the
total discretion of the Commissioner. Given the history of ADRs and
drug withdrawals that occur many years after a drug is first on the
market, this kind of extended postmarketing surveillance is necessary.
Because of the history of problems detected many years and even decades
after a drug's approval, we also support the institutionalization of
another focused review of the literature, ADERs, etc., at some later
interval, perhaps at the 10th or 15th year a drug has been on the
market.
With respect to industry conducted post-approval safety studies,
HHS OIG recommended that the FDA instruct sponsors to provide
``additional, meaningful information'' in their annual status reports
in order to determine how timely post-marketing study commitments are
progressing toward completion.\45\ According to the OIG, the FDA
disagreed with this recommendation, stating that the implementation of
such a recommendation would require additional regulations. The OIG
concludes that the FDA cannot identify the progress of post-marketing
study commitments, and that regulatory changes may need to be enacted
in order to address these issues. Consumers Union supports the OIG's
recommendation that sponsors include progress reports on post-approval
safety issues in their annual status reports. S. 3807's annual REMS
review process is a major step in this direction.
C. Direct-To-Consumer (DTC) Advertising
Background
Although full safety risks are often unknown for years after
approval, pharmaceutical companies invest a great deal of money in the
immediate promotion of approved drugs, including billions of dollars in
Direct-To-Consumer (DTC) advertising. We have seen, too many times, the
devastating effects of such DTC advertising. At least one study has
commented on how DTC advertising contributed to the overuse and misuse
of Vioxx by both consumers and physicians, which led to an unnecessary
increase in the number of people at risk of heart attack and
stroke.\46\ In addition to the safety concerns, DTC advertising of
Vioxx increased costs to consumers and health plans alike, which were
paying significantly more for a new drug that added little or no
benefit.\47\
Some defend the use of DTC advertising, asserting that it promotes
patient-physician dialogue and increases awareness of diseases and
treatments. One study shows, however, that these ads are rarely
educational; while many advertisements gave the name of the drug and
the condition being treated, very few provide any additional health
information on alternative treatment of the condition.\48\ The study
reports that out of a possible 11 educational codes (specific
educational points), the average number of codes present in
advertisements was 3.2. Despite the lack of truly educational
information in DTC advertising, consumers tend to believe the
pharmaceutical industry's message that only the safest and most
effective drugs appear in advertisements.\49\ This is particularly
dangerous given the fact that the goal of this advertising is to sell a
costly product that can potentially have serious safety risks.
Consumers Union believes that if we need to increase awareness or
dialogue about certain medical problems, the industry could contribute
to scientifically-based Public Service Announcements approved or
managed by an impartial, expert group, such as the FDA, CDC, or
NIH.\50\
Discussion of Solutions in S. 3807 and Further Recommendations
As a part of REMS, the proposed bill gives the FDA authority to
require the pre-clearance of advertisement to ensure disclosure of a
serious risk listed in the labeling of the drug. In light of the
promotional nature of DTC advertising and the long history of abuses in
DTC advertising, and given that such advertising strongly influences
consumers, Consumers Union recommends a requirement that ALL
advertisements be pre-cleared by the FDA for accuracy and honesty,
including the growing use of ads in the Internet and other
nontraditional sites.
In addition, the FDA may impose a 2-year moratorium on DTC
advertising for drugs showing more serious safety concerns. Given the
amount of influence this type of advertising has on consumers, and
given the potential serious ADRs that may occur years after approval,
Consumers Union recommends a moratorium on DTC advertising of 3 or more
years for all new drugs. The history of ADRs and withdrawals shows that
drugs cannot be assumed safe after just 2 years. Adding a possible
third year to the moratorium authorities in S. 3807 would be prudent
and constitutional.\51\
D. Off-Label Use
Background
The FDA currently approves drugs for specific indications based on
scientific evidence and clinical trials. Off-label uses of these drugs
(in which physicians prescribe medicines for indications other than the
ones for which a drug is approved) lack the same kind of scientific
scrutiny. In an analysis of 160 commonly prescribed drugs from 2001,
off-label uses accounted for 21 percent of overall use, and most uses
had little or no scientific support for such use.\52\ In some classes
of drugs, off-label use accounts for up to 75 percent of
prescriptions.\53\
Often, drug companies inappropriately and illegally influence
doctors to prescribe medications for off-label uses. In the case of
gabapentin, pharmaceutical company Parke-Davis used teleconferences,
consultant meetings, selective research, as well as other tactics to
encourage doctors to use the drug for off-label uses.\54\
Despite the high occurrence of off-label uses, the scientific
efficacy of such drugs for unapproved indications is not
established.\55\ \56\ Many off-label uses are often helpful and
probably have little adverse consequences, but since off-label uses are
not subject to FDA approval, it is difficult to determine what
scientific evidence exists to prove clinical effectiveness. Off-label
use of prescription drugs also generally raises concerns regarding
potential risks to patients as well as issues about the reimbursement
and coverage of these drugs.\57\ Adverse drug events may also occur
more commonly in off-label settings than in on-label settings, since
clinical trial information is often unavailable.\58\ The Wall Street
Journal recently reported on the off-label use of Actiq, a potent
narcotic that is indicated for use in cancer patients who experience
intense pain.\59\ According to the article, Actiq is 80 times as potent
as morphine and is in a group of drugs that has the highest risk of
fatal overdose. In fact, 47 deaths due to overdose were associated with
the use of Actiq. Despite the safety risks, data suggest that 80
percent of patients use the drug not for cancer pain, but for off-label
uses such as headache and back pain.
Discussion of Solutions in S. 3807 and Further Recommendations
S. 3807 is silent on the issue of off-label use. Given the
potential for off-label uses to create serious safety problems,
Consumers Union recommends that the FDA develop a program to
scientifically study drugs widely used in off-label settings. We are
not advocating a ban on such use. We are simply asking that some
scientific study be brought to this area, so that the labels on these
drugs may be expanded and improved in the cases where the scientific
evidence is supportive.
E. Enforcement
Background
As described above, the FDA has limited authority to effectively
enforce postapproval safety. As this year's GAO report highlights, the
``FDA has little leverage to ensure that these [commitments for post-
approval safety studies are carried out . . . by imposing
administrative penalties.'' \60\ The IOM also reports that lack of
clear regulatory authority is a serious problem at the FDA.
In addition to the lack of clear authority in some areas, there is
the issue of failing to use existing authorities. Rep. Henry Waxman has
reported that the level of enforcement actions has been declining and
the recommendations of FDA field staff for corrective actions are often
disregarded:
``Internal agency documents show that in at least 138 cases
over the last 5 years involving drugs and biological products,
FDA failed to take enforcement actions despite receiving
recommendations from agency field inspectors describing
violations of FDA requirements.''
The House Government Reform Committee report noted a 50-percent
decline in warning letters in recent years.\61\
Discussion of Solutions in S. 3807 and Further Recommendations
In addition to existing authorities (some of which like drug
withdrawals or seizures are so serious and disruptive they are not
creditable and almost never used), the bill allows the FDA to issue
Civil Monetary Penalties (CMPs) of between $15,000 to $250,000. CMPs
may not add up to more than $1,000,000 for all violations ``in a single
proceeding.'' While this CMP authority is a major improvement, given
the large profits that pharmaceutical companies can enjoy every day a
drug is on the market, Consumers Union recommends that CMP authority be
increased to more than $1,000,000, especially when companies are
repeated offenders.
S. 3807 also gives the FDA more authority to order changes in drug
labels and to control the dispensing of drugs so to ensure that
particularly vulnerable populations (such as pregnant women) are better
protected from unnecessarily dangerous forms of treatment. Consumers
Union strongly endorses these labeling and dispensing provisions in S.
3807. As the Office of New Drugs Director Dr. John Jenkins said,
``There's no doubt that there are situations where we
internally feel frustrated that the discussions about label
changes are taking longer than we would like. Remember that
labeling is the primary way we have to communicate to
practitioners and health providers about the safety and
effectiveness of the drug. So everything keys off the
labeling.'' \62\
The language in S. 3807 should prevent a recurrence of the 22
months of FDA-Merck ``negotiating'' on the Vioxx label while millions
of patients continued to take an unnecessarily dangerous drug.
3. RESOURCES AT THE FDA
Background
The FDA needs more resources if it is to truly be the world's Gold
Standard in prescription drug approval and safety.
We agree with the IOM report that the FDA suffers from serious
resource limitations. The IOM notes that although user fees have
greatly increased the resources for new drug review, FDA's other
functions--such as post-approval drug safety monitoring--are seriously
under funded. As the IOM notes, PDUFA not only sets performance goals,
but also tightly restricts CDER's use of its funds: ``each round of
PDUFA negotiations has led to more demands on CDER and continued
restrictions on CDER's flexibility.'' \63\
The lack of resources for safety is appalling. The public would be
truly shocked if they realized how huge the FDA's jurisdiction is and
how little the agency can really manage to do with its limited budget.
Unfortunately, the public is periodically reminded of those limitations
by outbursts of fatalities--such as the recent E. coli spinach deaths.
According to the 2006 GAO report on post-market drug safety, the
FDA has currently allocated $1.1 million per year for its contracts
with researchers outside of FDA to conduct postapproval studies. Yet
the GAO also reports that just one clinical trial designed to study
long-term drug safety could cost between $3 million and $7 million.\64\
The IOM report also highlights the need for increased resources to
support new staff devoted to post-market safety work. PDUFA funding has
supported the surge of new drug review staff, whereas ODS has not
experienced such a dramatic increase in staff: between 1996 and 2004,
new drug review staff increased by 125 percent (from 600 to 1320) but
ODS staff increased by only 75 percent (from 52 to 90).\65\ While the
drug companies flood the airwaves and Internet with ads, the FDA is
only able to review about 24 percent of these for accuracy.\66\ And
while generic drugs can save consumers billions of dollars, this fall
there is a backlog of 394 generic drugs awaiting approval because of
FDA bottlenecks.\67\
The IOM highlights the need for resources to support Information
Technology (IT) at the FDA, and concluded that CDER's IT systems are
antiquated. Consumers Union staff has been told that half the FDA's
computer systems are so old that they will no longer be served by
vendors after this year. It is worth quoting at length Dr. Scott
Gottlieb, writing before his appointment to the FDA:
``Although it is impossible to calculate exactly how much the
agency's review programs spend on IT-related infrastructure
(because it is embedded in many different programs), consider
that total spending on IT-related activities at the FDA was cut
$29.1 million in 2004 from what the agency had requested so
that the FDA could find savings to stay inside its
congressional budget allocation. That exceeds the entire $23.8
million budget of the FDA's Office of Drug Safety for 2004.''
``All of this leaves little doubt that even the most basic IT
improvements have been slow in coming, hobbled by a lack of
budget and vision. As a result, information is made available
to the FDA slowly and takes even longer to analyze by the FDA's
trained personnel. Subtle side effects--especially medical
problems that occur naturally in a large population or as a
consequence of the condition that a drug aims to treat (the
side effects at issue with Vioxx and the SSRIs met these
criteria) could be easily dismissed as normal or ``background''
events as a result of inadequate sample sizes and the inability
to easily aggregate and analyze population-based data on actual
drug use.'' \68\
Yet IT resources are essential for making post-market surveillance
work, improving AERS, and--in the long run--making comparative
effectiveness analyses that will save the Nation tens of billions of
dollars by identifying what courses of treatment work and don't work.
In addition to modern systems, the FDA needs the resources to develop
electronic data submission formats; today, all too many applications
are submitted as expensive-to-process reams of paper, because the FDA
says it doesn't have the resources to develop regulations for
electronic submission formats.
Discussion of Solutions in S. 3807 and Further Recommendations
S. 3807 allows PDUFA user fees to be available for REMS work to
improve postapproval safety. Many are concerned, however, that the FDA
is too closely tied with the industries it regulates. User fees may
contribute to the pharmaceutical industry's ``capture'' of the FDA.\69\
The IOM recommends that Congress approve a substantial increase in both
funds and personnel for FDA safety activities in order to counteract
PDUFA's restrictions on how the FDA can use its funds. The IOM
discusses the ideal option of general Treasury revenues to adequately
fund the FDA. Importantly, however, the IOM notes that if user fees are
required, Congress should greatly reduce current restrictions on how
the FDA can use those funds.
Consumers Union strongly supports the IOM's recommendations for
more resources with no ``strings attached.'' This could be achieved, as
Rep. Maurice Hinchey's bill (H.R. 2090) does, by depositing user fees
into the Treasury, then entitling the FDA to an amount of money from
the Treasury equal to the amount currently raised by user fees, but
freeing the agency from detailed restrictions on how such moneys are
spent. As noted in section 5 below, freeing the FDA from dependence on
the industry is probably the single major thing we can do to improve
the morale and culture within the FDA on behalf of consumers.
Another option would be to increase user fees to deal with a huge
backlog of safety issues. Consumers Union echoes the IOM's words that
regardless of the funding source, ``the functioning of a drug safety
system that assesses a drug's risks and benefits throughout its
lifecycle is too important a public health need to continue to be under
funded.'' \70\
If a user fee system is continued, we urge that S. 3807's section
104 be strengthened to spell out adequate levels of resources and
performance goals for safety. Just as the industry has goals for rapid
drug approvals, consumers and patients should have goals for rapid
resolution of safety concerns.
Attachment #1 is a list of the kind of safety goals that should be
funded, ideally by the general Treasury, but if the user fee program is
continued, then by user fees. This list is illustrative. Of course,
your committee would need to provide details on the exact performance
levels and the realistic rate of increase in safety quality after
consultation with the FDA, OMB, and after studying the President's
fiscal year 2008 budget and the FDA's actual safety budget deficiencies
in the middle of fiscal year 2007.
While all these safety standards are important, we particularly
appreciate S. 3807's study of the FDA's IT needs. But another IT study,
without funding, is meaningless. We urge you to give a priority to
funding these crucial IT building blocks.
4. ADVISORY COMMITTEES (ACS) AT THE FDA
Background
Advisory committee meetings are a very important resource for the
FDA. Such meetings are public and provide an opportunity for the
agency's scientific experts, consumer advocates, and industry
representatives to contribute to the regulatory process. Recently,
however, there have been serious concerns about the process.
Although AC meetings provide a valuable contribution to the FDA's
efforts to regulate drugs, the frequency with which they convene has
been declining. The OIG reported that the number of AC meetings
decreased from 40 in 1998 to 23 in 2001.\71\ The OIG also reported that
FDA managers believed that they had little time to hold these meetings.
In addition, only 21 percent (5/24) of approved New Molecular Entities
(NMEs) were preceded by an advisory committee meeting. NMEs are drugs
that contain an active ingredient that has never before been approved,
and may be more likely to carry safety risks.\72\
In addition to the recent reduction of meetings, important
information regarding drug safety is sometimes purposefully excluded.
For example, a senior epidemiologist at the FDA, Dr. Andrew Mosholder's
concerns that Paxil increased suicidal behavior in children were
dismissed by higher FDA authorities.\73\ Dr. Mosholder was not allowed
to present his analysis at the February 2004 joint meeting of the
Psychopharmacologic Drugs Advisory and the Pediatric Subcommittee of
the Anti-Infective Drugs Advisory Committee because it was believed to
be too preliminary.\74\ In later interviews with the GAO, the Directors
of CDER and the Office of New Drugs (OND) said that in retrospect they
felt it was a mistake for the FDA to have restricted Dr. Mosholder from
presenting his safety information.\75\
The GAO report on post-market drug safety notes that the role of
the Office of Drug Safety (ODS) in AC meetings is unclear. The report
cites another case (in addition to the one above) in which ODS staff
was not allowed to present their analysis: the OND did not allow the
ODS to present their review of Arava at the Arthritis Advisory
committee meeting in March 2003 because the OND division believed that
ODS's review lacked scientific merit. ODS found the use of Arava to be
associated with acute liver failure. GAO reports that after the
meeting, ODS epidemiologists and safety evaluators requested
clarification of ODS's role in advisory committee hearings, but that
there was no written response to this request.
Although certain FDA experts have been refused permission to
testify at AC meetings, many outside scientific experts are free to
participate in such meetings despite having outstanding conflicts of
interest. For example, at the February 2005 joint meeting of the
Arthritis Advisory Committee and the Drug Safety and Risk Management
Advisory Committee to discuss the safety of cyclooxygenase-2 (COX-2)
inhibitors, 10 of the 32 voting panel members had financial
associations with the manufacturers of these drugs (such as consulting
fees or research support).\76\ All 10 members were issued general
waivers that allowed them to participate in the meeting. Twenty-eight
out of the thirty votes cast by these 10 members favored marketing of
Bextra, Celebrex and Vioxx, whereas only 37 out of the 66 votes cast by
the remaining 22 members favored marketing of these drugs.\77\ If the
10 panel members with conflicts of interest had not participated in the
meeting, the committee would have voted to remove Bextra from the
market, and to keep Vioxx from returning to the market (Merck
voluntarily withdrew Vioxx from the market in 2004). Instead, due to
the inclusion of the votes from the 10 conflicted panel members, the
committee voted to keep these drugs on the market. The FDA consequently
announced that it had asked Pfizer to voluntarily withdraw Bextra from
the market, which it did in April 2005, 2 months after the advisory
committee meeting.
Discussion of Solutions in S. 3807 and Further Recommendations
Frequency of Meetings: Title IV of S. 3807 recommends a series of
clarifying efforts to reduce or disclose conflicts of interest. The IOM
recommends that FDA advisory committees review all NMEs either prior to
approval or soon after approval. The IOM notes that although it might
be impossible to convene AC meetings for all NMEs prior to approval,
the FDA should have the authority to require such meetings after
approval. Since advisory committees provide valuable scientific
expertise, it is important that the FDA capitalize on such a resource.
Consumers Union supports the IOM's recommendation that all NMEs be
reviewed by FDA advisory committees and be part of the REMS process.
ODS involvement in ACs: In addition to encouraging participation of
outside scientific experts through AC meetings, it is important that
FDA's own scientific experts also be heard. ODS staff has recommended
that as a matter of policy, they present post-market safety data at
these meetings.\78\ Consumers Union recommends that ODS always have the
right to testify before ACs. If ODS chooses not to testify, Consumers
Union strongly recommends that ACs be granted the authority to request
such testimony or a statement from ODS that they have no safety
concerns to raise.
The IOM highlights the fact that the FDA must undergo cultural
changes if postapproval safety is to be improved. Consumers Union
encourages language in S. 3807 that would speak to this issue and
assure the right of FDA scientists to dissent or provide ``additional
views'' to the majority view. The right to dissent must be especially
acknowledged at AC meetings.
Also, a recent report by the National Resource Center for Women and
Families \79\ shows that while ACs often raise safety questions, they
very seldom reject a drug. There appears to be a clear bias toward
approval and a suppression of safety concerns (which is another reason
to seek more conflict-free experts). The study also shows that even
when an AC rejects a drug, the FDA frequently ignores the
recommendation. We believe that if the FDA overrules an AC
recommendation, it should provide a detailed public statement of why it
disagrees and why it believes the science supports the FDA's disregard
of the expert outside panel.
Ending Conflict of Interest: AC meetings must be conducted in such
a way that scientific integrity is promoted. Recent history suggests
that committee members are given voting rights despite significant
financial associations with the pharmaceutical companies affected by
the committee's review. The New England Journal of Medicine reports
that, according to Dr. J. J. Wood, the chair of the joint meeting that
reviewed the COX-2 inhibitors, the FDA made a ``judgment error'' when
it decided to issue a general waiver and not to disclose specific
information regarding the conflicts of interests of committee
members.\80\ The IOM recommends that a ``substantial majority'' (and
suggests 60 percent) of the members of each advisory committee be
``free of significant financial involvement'' with the pharmaceutical
companies that would be affected by the committee's review. In
addition, the IOM recommends that the FDA issue waivers to committee
members ``very sparingly.''
Consumers Unions recommends that no advisory committee meeting be
convened unless a substantial majority of the committee is free of
significant financial involvement. We think it is important for
restoring public confidence in the agency and creating a culture of the
highest public service that no less than 90 percent, and ideally 100
percent, of advisory committee members be free of conflict.
The public has lost confidence in the FDA. The Wall Street Journal
reported on a May 24, 2006 WSJ Online/Harris Interactive poll that 58
percent of the public feels the FDA does a fair or poor job on ensuring
the safety and efficacy of new drugs, and 80 percent said they are
somewhat or very concerned about the agency's ability to make
``independent'' decisions. Clearly, this is a time to bend over
backwards to ensure integrity and public interest in all aspects of the
FDA, including the integrity of its Advisory Committees.
It is argued that the best experts in a field are those who have
been working with drug companies on the research and development of
specific drugs and that it would be impossible to staff conflict-of-
interest-free committees with qualified experts. We argue that when one
looks at the recent FDA's reports to the Congress on advisory
committees, it is clear there is no one person at the FDA charged with
coordinating the recruitment of advisors to all the various FDA
Centers. We urge the Congress to support a major outreach effort by the
FDA to find nonconflicted advisory committee members. Until one
actively recruits, how can one know that AC's that would inspire public
confidence cannot be created?
5. IMPROVING CULTURE AND MORALE AT FDA
Background
Some of the conflict of interest problems that plague FDA's
advisory committees appear to affect other aspects of life at the FDA
as well. The fact that many career FDA scientific staff members believe
their voices are silenced speaks of larger, extremely serious troubles
relating to culture and morale at the agency.
In August 2006, the Union of Concerned Scientists (UCS) and Public
Employees for Environmental Responsibility (PPER) released their survey
of FDA staff. The findings echoed those reported by the Office of
Inspector General (OIG) in 2003.\81\ For example, in response to the
question: ``Have you ever been pressured to approve or recommend
approval for an NDA despite reservations about the safety, efficacy, or
quality of the drug?'' Forty-one respondents out of 217 Center for Drug
Evaluation and Research (CDER) staff (nearly 19 percent) answered
``yes.'' \82\ These types of responses raise concerns regarding the
extent to which these experts are capable of practicing their right to
dissent on issues of drug safety.
These poll findings support the IOM report's finding that the
organizational culture at the FDA is partially responsible for the
marginalization of dissenting voices.\83\ The IOM says that the
polarization between the pre-marketing and post-marketing review staff
contributes to a negative culture at the FDA. This polarization is
evidenced in advisory committee meetings as described in the previous
section, where the OND has prohibited the ODS from presenting pertinent
safety information. In addition, the resource gap resulting from the
introduction of user fees has further divided the two offices and
increased tension.\84\ The IOM notes that ODS staff have been
considered marginal players compared with OND staff, and that the ODS
is perceived to have a lower status compared to the OND. According to
the IOM, various concerns relating to culture at the FDA have resulted
in a ``persisting problem with retention, turnover, and morale in
CDER.'' \85\ Key relevant staff members are sometimes excluded from
discussion and decisionmaking about the agency and the work they
perform daily.
Discussion of Solutions in S. 3807 and Further Recommendations
In order to address the culture and morale challenges facing the
FDA, it is imperative that the agency establish a climate of open
scientific debate. Consumers Union recommends institutionalizing a
system of public staff dissent and additional views on all new drug
applications, accompanied by ``whistleblower'' type staff protections.
Representative Ed Markey (D-MA) has a bill (H.R. 5922) with
whistleblower language.
Just as Congress or the Courts have institutionalized a system
where Members can and are expected to offer additional or dissenting
views, we believe a similar, institutionalized system within the FDA
would improve culture and morale, and contribute to a healthier
scientific debate. Some say that this kind of dissent would confuse the
public, make practitioners uncertain about whether a drug was good or
not, and make people too cautious to use new, important new drugs. We
believe that consumer empowerment is good, and that by making it clear
where the scientific questions and uncertainty are, it will help
researchers around the world concentrate on answering those questions
as quickly as possible. The public would understand that while a
majority of the FDA found a drug to be effective and safe, dangers were
not swept under the rug as part of some pro-drug company conspiracy.
The public will support dissent and debate--suppression of dissent will
destroy confidence in the system.
6. SPEEDING APPROVAL OF GENERICS AND BIOGENERICS
Background
Healthcare costs continue to surge at double or triple the rate of
general inflation, in part due to the high cost and rate of inflation
of brand-name prescription drugs. Generic and biogeneric drugs, can
dampen health inflation by providing equally safe and effective
medicine at a far lower price--often prices only 70 percent or less of
the brand name drug. Generics and biogenerics save consumers billions
of dollars. For example, according to one study by the Pharmaceutical
Care Management Association (PCMA), generic drugs could save consumers
over $23 billion over the next 5 years if optimal use is made of the 14
generic drugs scheduled to enter the market during this time.\86\ These
savings could also significantly help reduce Medicare and Medicaid
costs, since many of these 14 generic drugs are commonly used by senior
citizens.
Despite the enormous savings available from generics, the FDA has
been unable to ensure that these drugs are approved for the market in a
timely manner. In a memo to Consumers Union this autumn, the FDA
reported that an unduplicated count of pending generic applications
showed a backlog of 394 drugs pending more than 180 days--drugs which
could help lower costs to consumers if they were approved. An article
in the Washington Post \87\ explains that part of the problem is the
lack of staff to review these applications: the Office of Generic Drugs
only has 200 employees. This is in stark contrast with the OND, which
has more than 2,500 employees to review about 150 (admittedly more
complex) applications.
There is no clear law providing for the development of generic
versions of more complex molecular biologic medicines. These new
products are the most expensive medicines on the market--some costing
as much as $100,000 to $250,000 for a course of treatment. Some
criticize the notion that biogenerics could bring cost-
saving benefits, saying that these drugs are far more complex than
other drugs because they are made from living organisms, and therefore
cannot be copied as easily, as inexpensively, or as safely as other
drugs.\88\ Nevertheless, the European Medicines Agency is creating a
framework for biogenerics to be approved.\89\ Consumers Union joins
most other observers in believing that biogenerics could provide some
savings and can be provided safely, thus helping some of our most
severely ill patients.\90\ The law should be clarified to allow us to
do what the Europeans are doing: bringing some relief to consumers.
In addition to backlogs in the approval of generics and legal
uncertainty and stalemate on the issue of biogenerics, there are a
series of legal loopholes in the law that have allowed drug companies,
often in collusion with generic companies themselves, to block the
entry of lower-cost generics--sometimes for years. These loopholes
range from abuse of the pediatric exclusivity provision to payment
arrangements to keep a generic from entering the market. In recent
years, the use of phony citizens petitions has cost consumers millions
of dollars by delaying the entry of generics. According to the FDA,
only 3 of 42 petitions answered between 2001 and 2005 raised issues
that merited changes in the agency's policies about a drug. For
example, Flonase, a commonly used prescription allergy medication, went
off patent in May 2004. But GlaxoSmithKline stretched its monopoly
window by almost 2 years with petitions and a legal challenge to the
use of generics.\91\
Discussion of Solutions in S. 3807 and Further Recommendations
The current legislation is silent on issues surrounding generics
and biogenerics.
Consumers Union urges that a major new title be added to S. 3807 to
correct the full range of generic and biogeneric problems, or that the
committee address these issues in separate legislation early in 2007.
Specifically, Consumers Union asks that language be added to S.
3807 to:
increase funds and staff at the Office of Generic Drugs,
and to set goals to ensure that application backlogs do not occur.
Given the significant savings that are associated with the marketing of
generic drugs, this language will help moderate rising healthcare
costs; and
establish a path for the approval of biogenerics. We
strongly endorse H.R. 6257, a bill by Rep. Henry Waxman and others,
that provides legal direction to the FDA to approve biogenerics.
Consumers Union hopes that Congress, learning from the European Union
experience, will soon create a framework for biogenerics to enter the
market.
We hope that the committee will hold hearings on the abuse of the
citizen petition and patent and exclusivity laws to keep generics from
the market. Senators Kohl and Leahy (S. 3981) and Stabenow and Lott (S.
2300) and Rep. Waxman and others (H.R. 6022) have bills to close these
loopholes that are worth exploring in hearings and adopting as part of
FDA reform legislation or as stand-alone proposals.
7. IMPROVING SCIENCE AT THE FDA: THE REAGAN-UDALL INSTITUTE
Background
The FDA's ability to make sound decisions and to regulate the
pharmaceutical industry depends on the quality of scientific data that
it receives. Recently, many experts have raised concerns regarding the
quality of reports submitted to the FDA and the quality of the science
used at the FDA. In particular, questions have been raised about
noninferiority trials and the use of surrogate endpoints.
Often, drug company sponsors conducting clinical trials use
``surrogate endpoints'' rather than final outcomes. These endpoints are
relatively easily and quickly obtainable physical markers that are used
to reflect what is believed to be a clinically meaningful outcome.
Clinically meaningful outcomes are often difficult and costly to obtain
directly because they often require very large and long clinical
trials. Although the use of surrogate endpoints is sometimes
appropriate, this methodology is often abused and clinical trials which
use surrogate endpoints often exaggerate the benefits. One recent
article in Health Affairs reports that this methodology resulted in the
overestimation of the benefits of Natrecor, a drug used to treat acute
exacerbations of congestive heart failure.\92\ The authors of the
article note that
higher rates of kidney impairment and mortality are found in those
using the drug.
The use of the noninferiority design has also created a great deal
of controversy. Non-inferiority trials are intended to show that the
effect of a new treatment is not worse than that of a currently
marketed treatment. But as FDA experts have pointed out, it is possible
over time that the use of noninferiority trials could lead to the
approval of drugs that are actually less effective and/or harmful
compared to a placebo. A number of Members of Congress have requested
that the GAO investigate the FDA's acceptance of noninferiority
studies, and Rep. Markey's bill, H.R. 5922, calls for reports on the
use of this method of approving drugs.\93\ This congressional concern
has been heightened by the FDA's approval of Ketek, which was based on
noninferiority trials. Ketek, which is indicated for pneumonia, throat
and sinus infections, and chronic bronchitis, has caused serious liver
toxicity in some patients.\94\
Discussion of Solutions in S. 3807 and Further Recommendations
S. 3807 proposes the establishment of the Reagan-Udall Institute to
``modernize medical product development, accelerate innovation, and
enhance product safety by initiating, sponsoring, and organizing
collaborative and multidisciplinary research.'' The Institute appears
to be part of the Critical Path Initiative to increase the level of
FDA's scientific research and to find faster, cheaper, and more
effective ways to develop drugs. It appears that the Institute's
responsibilities are in line with some of the science recommendations
of the IOM's report.
We strongly support increased high quality scientific work at the
FDA, and research on how to solve problems like those that can occur
with surrogate endpoints, noninferiority, and determining the
comparative effectiveness of drugs and classes of drugs. Nevertheless,
we hope the committee will hold further hearings on the idea of this
Institute. It is not clear why these functions could not be placed
within the FDA directly, rather than conducted through a quasi-private
institute. It is important that any actions in this area are not just
another industry-dominated effort to speed the development of drugs
without adequate regard to their safety. \95\ We commend you for
including many references to drug safety in the Reagan-Udall Institute
language. But the governing board of the Institute is tilted toward
industry and lacks the guarantee of governance by nonconflicted public,
consumer board members. The language calls for the acceptance of funds
from private entities, which raises the same independence issues as we
have seen in PDUFA fees. To repeat, we hope you will spend more time on
this issue and refine some of the language to ensure that whatever is
done serves the public in a balanced way.
We note that one way to improve science at the FDA is to reduce the
level of staff turnover of experienced, trained personnel, which is
higher at the FDA than many other Federal science agencies. Improving
the FDA's culture and morale, as discussed earlier, and allowing FDA
scientists more freedom to publish academically (as provided in Rep.
Markey's bill H.R. 5922) are all keys to creating a better scientific
climate.
CONCLUSION
Finally, I would be remiss not to acknowledge the countless
families who have suffered because of our broken drug safety system.
They are the reason we are here today. And many of them have worked
tirelessly on this issue so others won't have to endure their
heartbreak.
Two of these fine people are here today--Eric Swann, whose brother-
in-law, Woody Witzak was casually prescribed an antidepressant for
insomnia, and 5 weeks later killed himself. And Mathy Downing, whose
daughter, Candace, was put on Zoloft because she was anxious taking
tests at school. Ten months later, she took her own life at the age of
12. Neither Eric nor Mathy knew about clinical trial results that
indicated increased risk of suicide from these types of
antidepressants.
Senators, I deeply appreciate your time, and I thank you for your
consideration of these ideas--and for the good work you have begun.
Endnotes
1. ``Publishing Clinical Trial Results: The Future Beckons,'' by
Elizabeth Wager, www.plosclinicaltrials.org, Oct., 2006 e31.
2. Curfman, et al. Expression of Concern: Bombardier et al.,
``Comparison of Upper Gastrointestinal Toxicity of Rofecoxib and
Naproxen in Patients with Rheumatoid Arthritis,'' N Engl J Med.
2000;343:1520-8. New England Journal of Medicine. 2005; 353: 2813-2814.
3. U.S. Congress. Senate. Committee on Finance. Hearing on ``FDA,
Merck and Vioxx: Putting Patient Safety First?'' Testimony of Sandra
Kweder, M.D. (November 18, 2004).
4. People of the State of New York v. GlaxoSmithKline and
SmithKline Beecham Corporation.
5. Ibid.
6. FDA Public Health Advisory: Aprotinin Injection (marketed as
Trasylol). (September 29, 2006).
7. FDA Public Health Advisory: Aprotinin Injection (marketed as
Trasylol). (February 8, 2006).
8. Mangano DT, Tudor IC, and Dietzel C. The Risk Associated With
Aprotinin in Cardiac Surgery. N Engl J Med. 2006; 354:353-365.
9. Schmit, Julie. ``More Drugs Get Slapped With Lawsuits.'' USA
Today. August 23, 2006.
10. World Health Organization. World Health Organization
International Clinical Trials Registry Platform: Unique ID Assignment.
Geneva: World Health Organization; 2005.
11. DeAngelis CD, Drazen JM, Frizelle FA, Haug C, Hoey J, et al.
Clinical Trial Registration: A statement from the International
Committee of Medical Journal Editors. JAMA. 2004; 292: 1363-1364.
12. Fontanarosa PB, Flanagin A, DeAngelis CD. Reporting Conflicts
of Interest, Financial Aspects of Research, and Role of Sponsors in
Funded Studies. JAMA. 2005; 294: 110-111.
13. Ottawa Statement on Trial Registration, http://
ottawagroup.ohri.ca/statement.html.
14. Kenter MJH and Cohen AF. Establishing Risk of Human
Experimentation With Drugs: Lessons from TGN1412. The Lancet. 2006;
368: 1387-1391.
15. Establishing Transparency to Restore Trust in Clinical Trials.
The Lancet Neurology. 2006; 5: 551.
16. Goodyear M. Learning From the TGN1412 Trial. BMJ. 2006; 332:
677-678.
17. Grassley, Charles. Letter to the Department of Health and Human
Services Office of Inspector General. November 8, 2005.
18. Evans, David. ``Human Guinea Pigs Pay for Lax FDA Rules.''
Bloomberg News. November 6, 2005.
19. Gidron, Martin. ``Six Percent of Clinical Investigators
Violated Regulations, FDA Says.'' Washington Drug Letter. October 2,
2006.
20. Grassley, Charles. Letter to the Department of Health and Human
Services Office of Inspector General. November 8, 2005.
21. ``Designer Labeling,'' by Ramsey Baghdadi, The RPM Report,
November, 2006. It is equally disturbing that the FDA did not disclose
this known fraud to the Advisory Committee members who met to review
Ketek.
22. IOM, 2006.
23. Ibid.
24. Ibid.
25. Rennie D. Trial Registration; A Great Idea Switches From
Ignored to Irresistible. JAMA. 2004; 292: 1359-62.
26. Bennett, C.L., et al., The Research on Adverse Drug Events and
Reports (RADAR) Project, JAMA, May 4, 2005, Vol. 293, No. 17.
27. Institute of Medicine (IOM), 2006.
28. Budnitz DS, et al. National Surveillance of Emergency
Department Visits for Outpatient Adverse Drug Events. JAMA. 2006; 296:
1858-1866.
29. Lazarou J, Pomeranz BH, Corey PN. Incidence of Adverse Drug
Reactions in Hospitalized Patients: A Meta-analysis of Prospective
Studies. JAMA. 1998; 279: 1200-1204.
30. Bennet CL, et al. The Research on Adverse Drug Events and
Reports (RADAR) Project. JAMA. 2005; 293: 2131-2139.
31. Brewer T, Colditz GA. Postmarketing Surveillance and Adverse
Drug Reactions: Current Perspectives and Future Needs. JAMA. 1999; 281:
824-829.
32. IOM, 2006.
33. Bennet CL, et al, 2005.
34. U.S. General Accounting Office. FDA Drug Review: Postapproval
Risks, 1976-1985. Washington, DC.: U.S. General Accounting Office;
April 26, 1990. GAO/PEMD 90-15.
35. Lasser, KE et al. Timing of New Black Box Warnings and
Withdrawals for Prescription Medications. JAMA. 2002; 287: 2215-2220.
36. Man, F et al. Evaluation of the Characteristics of Safety
Withdrawal of Prescription Drugs From Worldwide Pharmaceutical
Markets--1960-1999. Drug Information Journal. 2001.
37. 505(d) Federal Food Drug and Cosmetic Act.
38. IOM, 2006.
39. Furberg, CD et al. The FDA and Drug Safety: A Proposal for
Sweeping Changes. Arch Intern Med. 2006; 169: 1938-1942.
40. Blum, Justin. ``Sanofi, Drugmakers Fail on Promise to Study
Medicines' Effect.'' Bloomberg: June 9, 2006.
41. U.S. Government Accountability Office. FDA Postmarket Drug
Safety. Washington, DC.: U.S. Government Accountability Office; March,
2006. GAO-06-402.
42. Blum, 2006.
43. ``FDA's Monitoring of Postmarketing Study Commitments,'' HHS
OEI-01-00390, June, 2006.
44. GAO-06-402.
45. Office of Inspector General. FDA's Monitoring of Postmarketing
Study Commitments. June, 2006.
46. Dai C, Stafford RS, Caleb GC. National Trends in
Cyclooxygenase-2 Inhibitor Use Since Market Release: Nonselective
Diffusion of a Selectively Cost-effective Innovation. Arch Intern Med.
2005; 165: 171-177.
47. Ibid.
48. Bell RA, Wilkes MS, Kravitz RL. The Educational Value of
Consumer-targeted Prescription Drug Print Advertising. J Fam Pract
2000; 49: 1092-1098.
49. Bell RA, Kravitz RL, Wilkes MS. Direct-to-consumer Prescription
Drug Advertising and the Public. J Gen Intern Med 1999; 14: 651-657.
50. Wolfe, SM. Direct-to-Consumer Advertising--Education or Emotion
Promotion? N Engl J Med. 2002; 346: 1424.
51. ``The Court has developed a four-pronged test to measure the
validity of restraints upon commercial expression. Under the first
prong of the test as originally formulated, certain commercial speech
is not entitled to protection; the informational function of
advertising is the first amendment concern and if it does not
accurately inform the public about lawful activity, it can be
suppressed. Second, if the speech is protected, the interest of the
government in regulating and limiting it must be assessed. The State
must assert a substantial interest to be achieved by restrictions on
commercial speech. Third, the restriction cannot be sustained if it
provides only ineffective or remote support for the asserted purpose.
Instead, the regulation must `directly advance' the governmental
interest. The Court resolves this issue with reference to aggregate
effects, and does not limit its consideration to effects on the
challenging litigant. Fourth, if the governmental interest could be
served as well by a more limited restriction on commercial speech, the
excessive restriction cannot survive. The Court has rejected the idea
that a `least restrictive means' test is required. Instead, what is now
required is a `reasonable fit' between means and ends, with the means
`narrowly tailored to achieve the desired objective.' '' Central Hudson
Gas & Electric Co. v. Public Service Comm'n, 447 U.S. 557 (1980). Quote
from http://caselaw.lp.findlaw.com/data/constitution/amendment01/
17.html.
52. Radley, et al. Off-label Prescribing Among Office-Based
Physicians. Archives of Internal Medicine. 2006; 166: 1021-1026.
53. Young, Alison and Adams, Chris. ``Off-label Drugs Take Their
Toll,'' Knight Ridder Newspapers, November 2, 2003.
54. Steinman MA, Bero LA, Chren M, Landefeld CS. Narrative review:
The Promotion of Gabapentin: An Analysis of Internal Industry
Documents. Annals of Internal Medicine. 2006; 145: 284-93.
55. Radley, et al., 2006.
56. Henney, JE. Safeguarding Patient Welfare: Who's in Charge?
Annals of Internal Medicine. 2006; 145: 305-307.
57. Nightingale, SL. Off-label Use of Prescription Drugs. American
Family Physician. 2003; 68: 425-427.
58. Bennet CL., et al., 2005.
59. Carreyrou, John. ``Narcotic Lollipop'' Becomes Big Seller
Despite FDA Curbs. Wall Street Journal. November 3, 2006.
60. GAO, 2006.
61. FDA Week, November 10, 2006, ``Waxman May Investigate FDA on a
Broad Range of Issues.''
62. ``Designer Labeling,'' by Ramsey Baghdadi, The RPM Report,
November 2006.
63. IOM, 2006.
64. GAO-06-402.
65. FDA. Center for Drug Evaluation and Research-Activities and
Level of Effort Devoted to Drug Safety. 2005.
66. FDA, ``White Paper: Prescription Drug User Fee Act (PDUFA),''
p. 34. As the FDA says, ``In 2004, [FDA] reviewed 142 proposed
broadcast ads, with the 4 full-time staff available to perform these
reviews. Although FDA review of all materials would ensure alignment
with the approved labeling and a fair balance of information on
benefits and risks, current FDA resourcing for this work would probably
result in delayed reviews if all companies were to submit their ads.
Such delays would likely affect companies' ability to meet their
marketing timelines, and discourage them from submitting the materials
for prior FDA review.''
67. FDA e-mail memo to Consumers Union.
68. Gottlieb, in ``Opening Pandora's Pillbox: Using Modern
Information Tools to Improve Drug Safety,'' Health Affairs, July/August
2005, p. 938ff.
69. IOM, 2006.
70. IOM, 2006.
71. Department of Health and Human Services. Office of Inspector
General, Report No. OEI-01-01-00590, FDA's Review Process for New Drug
Applications: A Management Review 42 (2003).
72. IOM, 2006.
73. Ibid.
74. GAO-06-402.
75. Ibid. The exclusion of information at advisory committee
meetings has been documented with devices as well: the European
experience with anti-wrinkle device ArteColl was not part of the
discussion at the February 2003 Medical Devices Advisory Committee for
ArteFill (same product under a different brand name), despite the fact
that the device caused serious disfigurations years after implantation.
(Rundle, Rhonda. ``Antiwrinkle Shots Spark Debate.'' The Wall Street
Journal D3, October 31, 2006.)
76. Center for Science in the Public Interest. Conflicts of
interest on COX-2 panel. February 25, 2005. (Accessed October 30, 2006,
at http://cspinet.org/new/200502251_print.html.)
77. Harris G, Berenson A. 10 Voters on panel backing pain pills had
industry ties. New York Times. February 25, 2005.
78. GAO-06-402.
79. NRCWF, ``FDA Advisory Committee: Does Approval Mean Safety?''
August 28, 2006.
80. Steinbrook, R. Financial Conflicts of Interest and the Food and
Drug Administration's Advisory Committees. N Engl J of Med. 2005; 353:
116-118.
81. Union of Concerned Scientists (UCS) and Public Employees for
Environmental Responsibility (PEER). UCS 2006 Food and Drug
Administration Survey Compared to the 2002 Health and Human Services
Inspector General Survey.
82. Ibid.
83. IOM, 2006.
84. Ibid.
85. Ibid.
86. Pharmaceutical Care Management Association (PCMA). ``Potential
Savings to Medicare from New Generic Drugs Becoming Available.''
Accessed November 7, 2006 available at: http://www.pcmanet.org/
newsroom/2006/Pr_4_06/Medicare%
20Savings%20from%20Generics.pdf.
87. Kaufman, Marc. ``Generic Drugs Hit Backlog at FDA--No New Plans
to Expand Review Capabilities,'' The Washington Post, February 4, 2006.
88. Pharmaceutical Business Review. ``Biogenerics: the battle is
only just beginning,'' January 18, 2006.
89. Ibid.
90. Tsao, Amy. ``Seeking a Prescription for Biogenerics.'' Business
Week. October 24, 2003.
91. Consumer Reports, November, 2006, p. 58.
92. Kesselheim AS, Fischer MA, and Avorn J. The Rise and Fall of
Natrecor for Congestive Heart Failure: Implications for Drug Policy.
Health Affairs. 2006; 25: 1095-1102.
93. Letter to the GAO. 09-06-06 Letter to GAO.pdf.
94. Letter to the GAO, 2006.
95. There is certainly no evidence that approval times are a
problem. The United States leads the world in the first introduction of
new drugs. In 2006, standard reviews are averaging 12.7 months, half
the 25.4 months it took to review applications in 2005. Priority review
times in 2006 average 9.4 months, down 16 percent from 2005 and 33
percent from 2004. ``Designer Labeling,'' by Ramsey Baghdadi, The RPM
Report, November, 2006.
______
Attachment #1
PROPOSAL FOR SAFETY RESOURCES AMENDMENT
Idea for amendment to S. 3807 to ensure adequate resources for
needed FDA safety improvements and to set performance goals for the use
of such resources. The percentage increases are just illustrative: the
exact increases would have to be determined in consultation with the
FDA and in light of the fiscal year 2007 appropriations and the
President's budget proposals for fiscal year 2008.
On page 34, line 19, insert the following before the quotation
mark:
``Such estimate shall provide enough increased revenue to achieve
the following safety improvement goals on a phased-in basis between the
date of enactment and the end of fiscal year 2012:
(A) ensure the pre-clearance of all electronic media (including
Internet) advertisements and informationals\1\;
---------------------------------------------------------------------------
\1\ It would be good to define ``advertisements'' so as to pick up
the many forms of promotions used to promote drugs and frequently to
promote off-label use.
---------------------------------------------------------------------------
(B) increase by 100 percent (that is, double) the percent of
clinical trial data and investigational review board applications
audited to ensure the ethical treatment of enrollees, and the
experiments integrity and compliance with good scientific practice\2\;
---------------------------------------------------------------------------
\2\ It is reported that the FDA is revising regulations allowing
drugs used in a Phase 1 trial to be exempt from quality control
manufacturing requirements. If this is accurate, there should be some
system of sampling a certain percentage of these drugs for purity and
safety. See Triangle Business Journal, Nov. 3, 2006, ``Triangle
scientists reticent about FDA shift.''
---------------------------------------------------------------------------
(C) ensure the electronic filing of all applications, amendments,
petitions, adverse event reports, and other data required by FDCA laws
relating to drugs;
(D) investigate all serious adverse event reports within 15 days,
and conduct at least XX investigations per year into patterns or
clusters of adverse event reports to determine if REMS action should be
taken;
(E) increase by 100 percent the inspection of manufacturing
(including compounding) facilities for compliance with FDCA laws;
(F) through active outreach and recruitment, develop and maintain a
list of potential advisory committee specific experts who have no
conflicts of interest and who have indicated a willingness to be
appointed to future relevant advisory committee vacancies, and such
advisory committee specific list shall equal 50 percent of the number
of individuals serving on each such advisory committee;
(G) between the completion of the strategic plan for information
technology provided for by subsection (c) of this section and the year
2012, collect and apply the resources described by subparagraph (4) of
such subsection (c) to the implementation of the strategic plan;
(H) in addition to the clinical trial registry and results
databases established by title III of this act for drug applications
received after the enactment of this act, develop over a phased-in 4-
year period ending in 2012 a similar registry of clinical trials and
clinical trial results for those trials initiated or completed after
1997 and before the effective date of this act.
(I) take action, which may include the levying and collection of
civil monetary penalties provided under section 502(f)(3) (as added by
this Act) against at least 50 percent of the applicants who have failed
to complete follow-up safety studies or trials as provided under
section 505(o)(4)(D) and (E) (as added by this Act).
The Chairman. Thank you.
Mr. Simon.
Mr. Simon. Thank you, Mr. Chairman. It's an honor to be at
this hearing today and to serve on this panel with these
distinguished witnesses. FasterCures is dedicated to saving
lives by saving time in the way we research and discover new
cures for diseases. We are independent and nonpartisan. We do
not take funds from pharmaceutical companies, biotech
companies, or medical device companies. We have one mission and
that is to save patients' lives as quickly as possible, and we
approach every problem from the patient's point of view.
This committee is asking a very important question, not
just about the details of how the FDA should run, but how do we
create an FDA for the 21st century? In the 20th century we saw
the greatest extension of life expectancy in the history of
humankind, 50 percent in the United States and a doubling of
life expectancy globally. In the 21st century it is our
challenge to make sure that those extra lives and extra years
are quality years, free from debilitating pain and disease.
That raises the central question at this moment in our
history as a Nation concerned about our people's safety and
wellbeing: Do we believe that we can cure any of the diseases
in this generation that are taking the lives of our friends and
loved ones long before they otherwise would die? If you believe
that we can do that and that we must do that, then creating an
effective FDA for the 21st century is of the greatest
importance.
But there is no defending the fact that the FDA budget for
providing 300 million people and the global population
confidence in the food supply and the medicine supply is the
same in real dollars as it was in 1996. The superintendent of
the Montgomery County School Board has a budget equal to the
commissioner of the FDA. Now, that's great for Montgomery
County's children. It doesn't speak well of our commitment as a
Nation to food and drug safety.
Many of the recommendations contained in the IOM report and
the Enzi-Kennedy bill would go a long way toward building the
proper FDA for the 21st century. FasterCures believes that the
FDA needs to be able to assess a drug's impact post-approval,
and to do that it needs stronger authority to regulate the way
drugs enter the market, and to do that we have to have
increased appropriations, not user fees that are restricted
from being applied to post-market approval surveillance. To do
any of this, we need strong leadership, and we support the
confirmation of Dr. Andy von Eschenbach to be the commissioner
of the FDA.
And the FDA, if it is trying to communicate risks to the
public, has never hit the mark. We need to engage the patient
community to help the FDA learn how to communicate risks and
benefits to the patients. People with terminal diseases or
debilitating diseases have a very different viewpoint about
risks and benefits than those of us who are well. If the post-
approval system is neglected, then the pre-approval system
becomes too cautious because approval is the whole ballgame.
That is why we support a strong approval system after a drug is
marketed, so that we can move more expeditiously and quickly to
get drugs to the market knowing that we're taking the life
cycle approach, as was suggested by Sheila Burke.
Every one of us is touched every day by the FDA. Its
mission in my opinion is the best example of the core function
of government to protect the health and safety of people who
could not do what the FDA does for themselves. We need to
empower the FDA to do that for us and we need to show our
commitment to the FDA by valuing its work at the same level
that we value our health and the health of our families and our
neighbors.
Thank you for having this hearing today.
[The prepared statement of Mr. Simon follows:]
Prepared Statement of Greg Simon
I. INTRODUCTION
I want to thank the committee for the opportunity to present
testimony today. My name is Greg Simon, and I am the President of
FasterCures/The Center for Accelerating Medical Solutions, based in
Washington, DC.\1\
---------------------------------------------------------------------------
\1\ Before joining FasterCures, I served as the Chief Domestic
Policy Advisor to Vice President Al Gore from 1993 to 1997,
specifically on economic, science and technology issues. In that role,
I oversaw a number of initiatives, including the programs of the
National Institutes of Health, the National Cancer Institute, the Food
and Drug Administration (FDA), the Human Genome Project, and the
development of the regulatory framework for biotechnology products.
From 1991-1993, I served as Legislative Director for then-Senator Al
Gore. From 1985 to 1991, I was Staff Director of the Investigations and
Oversight Subcommittee of the House of Representatives Committee on
Science, Space and Technology.
---------------------------------------------------------------------------
FasterCures is dedicated to saving lives by saving time in the
discovery and development of new therapies for the treatment of deadly
and debilitating diseases both in the United States and around the
globe. The organization was founded in 2003 under the auspices of the
Milken Institute to catalyze systemic change in cure research and to
make the complex machinery that drives breakthroughs in medicine work
for all of us faster and more efficiently. During our relatively brief
history, FasterCures has worked with a broad range of individuals and
organizations to eliminate barriers to efficiency and effectiveness in
our systems of disease prevention, treatment, research and development.
FasterCures is independent and nonpartisan. We do not accept
funding from companies that develop pharmaceuticals, biotechnology
drugs, or therapeutic medical devices. Our primary mission is to
improve the lives of patients by improving the research environment,
research resources, and research organizations.
I am honored to appear before this committee, which has a long
history of spearheading efforts to protect and promote the health of
the public by improving our Nation's process of drug discovery and
evaluation. I want to commend Chairman Enzi, Senator Kennedy, and other
members on this committee who have introduced and supported bipartisan
legislation to strengthen the FDA's oversight of drug safety. I commend
you for focusing this hearing on the broader issue of how to ensure
that the FDA is truly prepared to meet the challenges and reap the
benefits of 21st Century medicine.
Earlier this year, FasterCures provided detailed comments to
Chairman Enzi and Senator Kennedy regarding the specific provisions of
the ``Enhancing Drug Safety and Innovation Act of 2006.'' I will touch
on some of the major points covered in those comments that we believe
deserve continued focus. However, I primarily want to discuss today the
broader principles that FasterCures believes should guide any effort to
strengthen the FDA so that the agency can continue to play a vital role
in advancing 21st Century cures.
These principles are as follows:
1. The FDA needs to be able to assess a drug's impact postapproval,
weigh both benefits and risks and take appropriate action to protect
the public;
2. To do that the FDA needs much stronger authority to regulate and
enforce how an approved drug enters the market, how it is advertised,
what claims are made for it and how labels are updated to reflect
growing knowledge of a product;
3. To do those things the FDA needs increased appropriations from
Congress and should not be forced to rely on industry user fees which
the FDA is largely restricted from using on postapproval activities;
4. To do any of this, the FDA needs a confirmed Commissioner to
provide strong, effective and professional leadership with a long-term
focus and vision; and
5. And for all of this to work, the FDA needs a better
understanding of how to communicate its scientific findings to the
public to make them better informed participants in our healthcare
system.
II. THE FDA AT THE DAWN OF THE 21ST CENTURY
In the past 10 years, we have witnessed dramatic advances in
science that impact the practice of medicine, including the mapping of
the human genome, and advances in computational tools and broadband
communications. Electronic health records and personalized medicine
will likely change the practice of medicine and clinical research in
the coming decade, and offer substantial benefits to monitoring adverse
events.
Yet, while the personalized medicine era is leaping forward into
the 21st Century, the FDA remains tethered to 20th Century technology,
regulations and practices as if the Information Age had never happened.
Worst of all, it remains mired there because we the people, and our
elected government have deprived the FDA of the financial and human
resources it needs to do the job we have asked it to do in the 90 laws
Congress has passed since 1907 setting the FDA's goals and
responsibilities.
There is simply no defending the fact that the FDA budget for
providing 300 million Americans a safe food supply and safe and
effective medical treatments is the same in real dollars as it was in
1996. The Superintendent of Schools for Montgomery County, Maryland has
a budget equal to that of the FDA. This speaks well of Montgomery
County's commitment to education but calls for questions of our
national commitment to food and drug safety and the approval of new
cures for diseases.
Each year, the FDA receives minimal new dollars and yet its costs
increase, missions evolve, the scope of science expands, and inflation
erodes the budget. In addition, innovative, future focused programs of
the FDA such as the Critical Path Initiative that would bring the
agency into the 21st century have not been given full financial
support, and the impact of new technologies such as nanotechnology
cannot be measured and evaluated. The budget is holding the FDA back
and preventing the agency from maximizing the benefits of these
historical advances in science for the American public. The staff of
the FDA are dedicated public servants who are ready to tackle these
problems.
The FDA plays a central role in American medicine. It has an
incredibly challenging role to protect and promote the public's health.
The agency must ensure that products are safe, but also effective. It
must help speed lifesaving drugs to patients, yet ensure that those
same patients have the safest drugs possible. We expect the FDA to be
committed to protecting our health and well-being. But we have not been
committed to giving the agency the tools and resources it needs to meet
our expectations.
So how do the Institute of Medicine (IOM) report The Future of Drug
Safety and the Enzi-Kennedy bill address this gap between where we
would like the agency to be and where it is?
The recommendations contained in the IOM report would go a long way
toward helping the FDA meet the goal of speeding to patients innovative
cures that are both safe and effective. Last month, shortly after the
IOM report was released, FasterCures and the National Health Council
hosted a forum for patients and medical research advocates to consider
and debate the report's findings and recommendations. Sheila Burke, who
chaired the IOM committee, as well as IOM Study Director Kathleen
Stratton, participated in the meeting. The conference was our attempt
to help focus involved members of the patient and research communities
on the implications of the proposed policy changes. We believe the
meeting was an important first step in ensuring that the perspectives
of patients and researchers have a prominent place in any future debate
on drug safety. A brief summary report on that meeting will be
submitted for the hearing record later this week.
We urge the Congress to put the work of the IOM Committee front and
center in its deliberations. As Ms. Burke stated at our meeting on the
report,
``We've revolutionized how we care and manage people with
illness, but the FDA has not been able to keep up with that
complexity. Delaying approval until certainty is reached is not
always a good option. Patients depend on these drugs and yet
there is an all or nothing environment.''
We appreciated the opportunity to provide comments on your proposed
legislation prior to introduction, and we look forward to continuing to
draw on our experience to be a resource to the members of this
committee as you consider any policy that will strengthen the FDA. Some
specific comments are as follows:
On the Risk Evaluation and Mitigation Strategies (REMS)
process, we are concerned that this process has the potential to slow
down product reviews if not constructed correctly and with precision.
We believe scarce FDA resources should be concentrated on activities
that actually mitigate safety risks for designated products rather than
be focused on reviewing risk mitigation plans for all products and
label changes.
We welcome the draft bill's focus on using
www.clinicaltrials.gov to support mandatory reporting of clinical trial
data in a manner that is useful to both medical professionals and
patients.
The Reagan-Udall Institute for Applied Sciences concept
for advancing the Critical Path Institute is an exciting development.
We are pleased that the bill recognizes the importance of Federal
funding and the importance of having representatives of the National
Institutes of Health in this partnership.
Finally, we believe strengthening the FDA Advisory
Committee process is a very important goal, however we do not believe
the bill goes far enough. Extricating all potentially perceived
conflicts of interest will in fact ``dumb down'' these committees
through overly broad definitions of conflict of interest. Conflicts can
never be eliminated from panels of experts, but they can be disclosed
and balanced.
III. FASTERCURES' PRESCRIPTION FOR CHANGE
I want to elaborate on our key principles that FasterCures believes
are essential to strengthening the FDA and ensuring that our Federal
drug approval and oversight processes are fully prepared to harness the
promise of 21st century medical progress.
1. The FDA needs to be able to assess a drug's impact postapproval
and take appropriate action to protect the public. The IOM report cited
the need for a ``lifecycle'' approach to drug oversight. FDA's
regulatory authority should not end with a drug's approval, because
that is just the beginning of what we can learn about a medical
treatment in the marketplace. Rather, we believe that FDA should have a
greater role working with industry, doctors, and others to communicate
what is learned about products once they have been introduced into real
medical practice. As a drug moves from controlled trials in several
hundreds or thousands of people to a potential market of millions, both
its benefits and risks may be magnified. This will require more
resources for the FDA. If the postapproval authority is exercised
properly, we believe it will help speed the approval process because
the agency, policymakers, and the public would have greater confidence
that safety issues that are not apparent during the pre-approval
phase--or that cannot be detected in pre-approval clinical trials--
would be detected and addressed quickly postapproval. This knowledge
should be captured and analyzed in a way that doctors can better
communicate treatment benefits and risks to their patients so more
informed decisions on options can be made.
2. To do proper postmarket surveillance, the FDA needs much
stronger authority to regulate and enforce how an approved drug enters
the market, how it is advertised, what claims are made for it and how
labels are updated to reflect growing knowledge of a product. As the
IOM report recognizes, safety and efficacy are the yin and yang of
every drug and are best weighed together. We need a flexible system of
approval and postapproval that helps consumers, physicians, and
patients more appropriately weigh and respond to those risks and
benefits. We specifically commend to the committee the important role
highlighted by the IOM for nonprofit research organizations and the
patient advocacy community in helping to bridge the gap between FDA and
the public when discussing the benefits and risks of new medicines.
3. To do any of this, the FDA needs a confirmed Commissioner to
provide strong, effective and professional leadership with a long-term
focus and vision. FasterCures supports the confirmation of Dr. Andrew
von Eschenbach to be the Commissioner of the FDA and urges he be
confirmed as soon as possible.
4. And for all of this to work, the FDA needs a better
understanding of how to communicate its work to the public to make them
better informed participants in our healthcare system. Patients and
consumers need timely information to help them make informed decisions.
Toward this end, the FDA should take more aggressive steps to ensure
that labeling information and supplemental safety and efficacy
information are more patient-centered. Moreover, FasterCures supports
proposals found in legislation before this committee and embraced by
the IOM to give the FDA more authority to require sponsors to register
data at a centralized independent Website, www.clinicaltrials.gov. We
believe that posting appropriate information at a single, credible,
widely available source will go a long way toward providing consumers,
patients, providers, scientists and researchers with data they need to
help analyze safety and efficacy information and make more informed
decisions.
5. To do all these things the FDA needs increased appropriations
from Congress and should not be forced to rely on industry user fees
which the FDA is largely restricted from using on postapproval
activities. The FDA needs greater resources to carry out its mission.
Many of the improvements recommended by the IOM and included in several
legislative proposals will simply not be possible without additional
resources. The IOM recommended that Congress approve a substantial
increase in both FDA funding and personnel. FasterCures strongly
believes that any additional funding should come from appropriated
funds, rather than user fees. Because FasterCures believes this is
critical, we are actively participating in two coalitions that are
aggressively advocating for additional funding for the agency: The FDA
Alliance and the Coalition for a Stronger FDA.
IV. CONCLUSION
There is no agency or aspect of our government that touches more
lives everyday than the FDA. Its mission is the highest and best
example of the government's core mission--to protect the health and
safety of the American people. Historically, the FDA has done its work
so well that it represents the gold standard all other countries rely
upon and seek to emulate. There can be no resting on our laurels.
Either we provide the FDA the tools and resources it needs to thrive in
the 21st Century or it will begin to atrophy and our Nations' health
will begin to atrophy with it. Many of the proposals contained in both
the IOM report and the Enzi-Kennedy legislation will help position the
FDA to meet the medical challenges of the 21st Century. But those
proposals will not succeed if we are not committed as a Nation to
valuing the health of our people far greater than is now the case and
to acting accordingly.
Thank you for the opportunity to testify. FasterCures looks forward
to continuing to be a resource to the members of the HELP Committee and
to Congress as you address these important issues.
The Chairman. Thank you very much, and I want to commend
all of you for your ability to stay close to the time that was
allotted. That's extremely helpful. And I've got to say your
testimony, the written as well as what you've just presented,
was outstanding and extremely helpful. I do have a few
questions. Actually, I've got a lot of questions. Some are of a
fairly technical nature. Those I'll submit to you in writing so
that I can get some fairly technical answers that won't put
anybody to sleep, but will aid in the production of good
legislation.
But in the line of some questions, Ms. Thompson, are you
worried that asking the FDA to take on new responsibilities is
going to result in a slowing down of drug approvals?
Ms. Thompson. We're obviously of the position that patients
shouldn't have to choose between speed and safety, and that it
is particularly important that as this committee looks to
asking the FDA to take on new responsibilities or to improve
the way that it performs existing responsibilities that that
request, that mandate, be coupled with resources adequate to do
the job. It can't be an either/or situation.
The Chairman. Thank you.
Dr. Nissen, as a practicing doctor doing these clinical
trials, do you think that the restrictions on distribution and
use interfere with the practice of medicine and prevent doctors
from using their best judgment about how to treat patients?
Dr. Nissen. I'm not sure I understand your question. What
do you mean by ``distribution and use?''
The Chairman. Well, I'll phrase it more broadly than that.
The restrictions that are now being placed on drugs and the
potential under this bill to place some requirements on it, do
you think that will interfere with the practice of medicine and
prevent the doctors from using their best judgment? Do you
think it's open enough that we're not going to be constricting
your practice?
Dr. Nissen. I don't think that from the point of view of
physicians that anything in this bill would restrict our
ability to care for patients. It's important to understand
that, in fact, physicians do retain a great deal of discretion
in what we do and how we do it. But we can only make good
decisions when we have access to all the information, and I
would argue that you really are enhancing the ability of
physicians to make good decisions, because you're providing for
the disclosure of all the information on safety and efficacy
that we need to make good choices, and that's why the increased
transparency that's required in this bill, if anything, will
enhance the ability of physicians to make good decisions.
The Chairman. Thank you.
Dr. Thomas, the legislation that we're proposing gives the
FDA the authority to impose restrictions on drugs. Recently the
iPLEDGE program for the acne drug Accutane has come under fire
because, while it seems to be meeting the goal of reducing
pregnancy exposures, it's also reducing the number of people
who get the drug. We believe that we have taken steps in the
pill to assure that patients get the drugs they need even if
those drugs have restrictions on their use. Your comments?
Dr. Thomas. Thank you, Chairman Enzi. I think the issue of
restriction on distribution or supply is an interesting one and
it's certainly true that there are many situations where the
risk of inadvertent exposure may require agreements about how
products are accessed. I come from a kind of large country with
not many people and I have worked as a flying doctor, and I was
probably one of the only flying vascular surgeons or physicians
around and patients' ability to get from isolated areas, to get
to a specialist was difficult. So I can also foresee that one
unintended outcome of distribution restrictions is, in fact,
restrictions of access by a supplier.
So I think those things need to be carefully thought out.
Without discounting the importance that one needs to place on
the legitimate use of it, unintended consequences may follow.
The Chairman. Thank you.
Mr. Guest, in your testimony you recommended across the
board restrictions on the direct-to-consumer advertising for 3
years as opposed to the 2 years that's in the bill. Banning all
direct-to-consumer advertising is kind of a blunt authority.
The bill that we've introduced tries to get away from that
strict of an approach. Since every drug represents a unique
profile of benefits and risks, would it make sense to give the
FDA some discretion in this area?
Mr. Guest. The bill does give the FDA restriction and
that's okay. We would just say it should be for a longer period
of time, because obviously a lot of the adverse consequences or
events that can occur will occur after a pill is on the market,
when there are then millions, hundreds of thousands and
millions of people. That's the real clinical trial on a drug.
Our concern about direct-to-consumer advertising generally
is that's not a good way for consumers or physicians or medical
providers to be informed. At Consumer Reports our whole history
is that consumers should be given full information, unbiased,
independent, research-based information, about both the
positive qualities and the negative qualities of products or
services, whatever they may be.
The problem with direct-to-consumer advertising is that's a
poor way to give comparative information to consumers so they
can make informed choices. There was a conversation earlier
with Sheila Burke that what's needed is a way for consumers to
have full information about the range of choices that they have
in a fashion that they can understand and not just a particular
hype.
I mean, direct-to-consumer advertising is not a good way to
convey really good information about pharmaceuticals. It's
really--clinical trials should not be a marketing tool. They
should be a tool for consumers to make informed choices and
providers to make informed choices.
The Chairman. Thank you.
My time has expired.
Senator Reed.
Senator Reed. Thank you very much, Mr. Chairman, and thank
you, ladies and gentlemen, for your testimony.
I have just one major question. I think it's a threshold
question for us. I'll start with Mr. Simon. Everyone
understands that the FDA culture has to change and that's a
function of funding, it's a function of other legislation we've
created, PDUFA, the way we collaborate with the industry. But I
presume, and I don't want to have it unstated, that you feel
that the legislation that's being discussed today, both
versions, are important; we have to do something legislatively,
that we just can't rely upon a little more money and some
spontaneous cultural change will happen at FDA. Mr. Simon, do
you want to comment? And you can use this as a broader
springboard to discuss, and I'll go down the line.
Mr. Simon.
Mr. Simon. Thank you. First, Senator, with regard to
resources, there is no amount of leadership or organizational
change that can trump a lack of resources. So you have to have
a balance.
Secondly, the greatest asset of the FDA is its people and
they have too few assets. They need far more people to do this.
We spend as a Nation $100 billion a year researching new drugs
and treatments for diseases as a government, as industry, and
as nonprofits, and then we ask the FDA on a budget of $1
billion on the drug side to review the product of this enormous
pipeline, and then we wonder why they don't do it fast enough
and well enough. So they need more people.
But they also need organizational change. You can't have
people wait until the end to start asking safety questions. You
need people to see all the information through the entire
process. I totally agree with Sheila Burke that we should not
separate these functions. They need to be integrated. And when
you have the money and you have the leadership and you have the
organizational structure, then you need political independence
to be able to take the science where the science goes and be
able to tell the American people, this is where the science is
and now you as the patient with your provider can make a
decision about how to treat your condition.
Senator Reed. Please.
Mr. Guest. Just briefly, I think this legislation, and
hopefully with the changes we recommend, will help restore
trust in the FDA and help the FDA actually earn that trust,
because there's a real skepticism right now among the American
public, are our drugs safe and is this agency that's supposed
to be protecting our safety really doing it in an independent
scientific, unbiased way.
That's why, among other things, we think it's really
important that the other scientists who do the research at the
FDA, that their information also be public, because these
decisions are not all black or all white. There are subtleties
and the public and consumers and members of the medical
community ought to know where there are reservations or
concerns so they can take that into effect when they're making
their decisions.
Senator Reed. Dr. Nissen.
Dr. Nissen. Yes. I must tell you that the staff at the FDA
are demoralized. I know them very well and I've worked with
them 5 years on their advisory panel. Some of the best people
have left the agency. There's a flight going on now. It will
take us years to recover from what's happened already. That
flight has occurred because of underfunding. There is a lot of
concern expressed, not publicly but privately, about the
politicization of the agency. It's very discouraging when you
want to do the right thing and you feel like you're not free to
do so, and I have heard this from staffers at the FDA.
I believe that also, that the entire PDUFA principle has
undermined the FDA. It's created dual loyalty, and we need to
have one loyalty and the loyalty is to the American public.
That's what we've got to get back to. We're not asking for the
Congress to fund this agency with tens of billions of dollars,
just somewhat modest increases, and we could get away from the
user fee principle and we could go to recruiting back into the
agency the kind of quality people that we need to get the job
done.
Senator Reed. Thank you, doctor.
Ms. Thompson, do you have a comment?
Ms. Thompson. Yes. I would certainly like to echo the
comments made about the importance and professionalism of the
FDA and its staff. Clearly the people at that agency are its
most precious resource and in order for them to do the best
that they can they must have effective leadership, they must
have the resources they need to do the job, and there must be a
transparent system that will enable all of us to participate in
rebuilding the sort of support for the FDA that traditionally
has existed.
You know, the ability of a mom and two of her friends
sitting around the table to engage in the drug review process,
as Elizabeth Glaser and her friends in the foundation were able
to do, is enormously important to the public credibility for
this agency. So clearly leadership, resources, and transparency
are key components to re-establishing that credibility.
Senator Reed. Before I call on Dr. Thomas, I think we all
agree with that, but I don't want to assume that people would
be suggesting that we don't need to do this legislation. I
think this legislation's an important part of the ingredients
for that accountability, resources, and structural changes
within the organization, and we have your advice on changes to
that and there's two very good models that have been proposed
by my colleagues. But simply to sit back and maybe put a little
more money into the till is not going to fix the problem.
Ms. Thompson. Well, Senator, if I may.
Senator Reed. Yes, ma'am.
Ms. Thompson. Thank you for that. That's absolutely right.
In resources I would include the tools that the agency needs,
the enforcement tools, informatics infrastructure. There's a
whole range of elements that come under resources, but of
course the ability to keep those key staff as well.
But this legislation and many of the recommendations that
have been made will be key elements to providing--will provide
those key elements in terms of authority, structure, emphasis,
priorities, that will be critical to moving this drug safety
system forward.
Senator Reed. Dr. Thomas, I'd appreciate your comments very
much.
Dr. Thomas. Thank you, Senator Reed. Broadly speaking, this
piece of legislation, this bill, is a very important piece of
work towards enhancing patient safety, and I want to say that
up front. However, I agree with the rest of the panel, you need
to have both the resources and leadership to enable the agency
to meet what is fundamentally a very important and very
significant role within this country, not just this country,
but as someone who works broadly around the world, the U.S. FDA
is today a very respected and strong provider of scientific
leadership in regulatory matters.
So we should not diminish the role they play today. But
without the appropriate leadership, without the appropriate
resources--and industry is not averse to increases in PDUFA
fees. But when the increases lead to industry funding more than
50 percent of the agency's activities, that's a legitimate
matter for public concern. So I think the agency needs all the
things the panel has discussed and we in the industry agree
fully that the first responsibility of the agency and its
accountability is to the American public.
Senator Reed. Thank you very much. Thank you, gentlemen.
Thank you, Ms. Thompson.
Thank you.
The Chairman. Senator Clinton.
Senator Clinton. Thank you, Mr. Chairman.
I want to really thank and compliment this panel. I'm sorry
that I had to step out to tend to some other business, but I am
very grateful to each of you. Dr. Thomas, thank you for your
last comments. I think that that's very helpful. Ms. Thompson,
Elizabeth Glaser was a friend of mine and I'm very pleased that
you're here representing the foundation and that the foundation
continues to play such an important role in public policy. Dr.
Nissen, thank you not only for your testimony but for your
courage. I appreciate you being on the end of the spear, as you
say in your testimony, because we need you there and your
stepping forward and lending your expertise to this debate is
absolutely essential. I also want to thank my friend Greg Simon
for his continuing public service, and this FasterCures
approach is one that I hope we can really see as a tremendous
partner as we move forward in this.
I particularly want to thank Jim Guest for being here. I'm
proud that Consumers Union is based in Yonkers, New York, and I
was delighted to go to their facilities and see all of the
great work that is being done there. Jim, it's terrific that
you're here. I want to also thank the families that you
mentioned in your testimony for joining us today.
As Jim noted, the problems of our drug safety system are
not just abstract questions of studies and trials. Really, the
failure to place concerns about safety above ideological or
economic concerns has had an impact on the lives of Americans.
As we continue to work on drug safety and broader FDA
legislation next year, I think it will be important to give
those impacted, such as the families you reference, a voice in
this debate, because we need to put a human face on it. We
often get caught up in the statistics and the dollars and all
of the complexity of legislative language, but this comes down
to people's lives, to their well-being.
Jim, in your written testimony you talk about the need for
legislation that would establish a path for the approval of
biogeneric drugs. I think we have to look both at what we do
with respect to biologics from pharma as well as biogeneric.
We're not doing a very good job on the former yet. We don't
have a good partnership. I visited a plant in my State that is
one of the great leaders in biologics right in Syracuse, New
York, Bristol-Myers-Squibb, and they have concerns about where
the expertise is going to come from inside the FDA to help them
work on biologics. So we've got to simultaneously work on
biologics and biogenerics and try to understand what we have to
do going forward.
I've introduced along with Senator Schumer and Congressman
Waxman the Access to Life-Saving Medicine Act, a bill that
would improve the FDA's ability to quickly bring safe
biogeneric products to the market. But I just want to say a
word of caution. I don't think we've done a very good job on
biologics yet.
But would you elaborate on the ways in which you think
increasing access to biogenerics could improve access to safe
and appropriate treatments for patients?
Mr. Guest. Well, let me first say I agree with you, it's
both biologics and biogenerics which are really complicated,
and to break through a process for responsible and timely
review on both counts I think is important. I certainly hope
that there'll be hearings and really serious consideration of
your proposals on it. That's a whole new hearing almost and a
whole new set of things to do it.
But I mean, clearly the future of people's health is going
to be significantly affected by biologics and biogenerics.
Again, as an organization that's interested in consumer safety
and consumer opportunity, I think that it's--I think the
emphasis that you're giving it is absolutely well placed and
would hope that the Congress would move forward on that front
as well.
Senator Clinton. I thank you for that, and I think that in
addition to what is clearly a complicated area, there are very
few of us--there are some, but I think there are few of us in
the Congress who really have the background in this complex,
fast-moving area. We need quite a bit of discussion. I would
throw on the table another issue which I am increasingly having
questions about and that's the whole area of nanotechnology and
the creation of these nanodevices and nanoelements. They are
clearly part of the whole biologics effort. We don't really
understand the impact on our health or our environment of them.
We are truly on a new frontier, Mr. Chairman. I hope that
as we go forward we will take the time to educate ourselves
thought-
fully about this range of issues. But the bottom line is we
need, as Dr. Thomas said, to make sure that the FDA remains the
gold standard. We've got to give it the resources, the morale,
and the authority it needs, because we're on the brink of
extraordinary, breathtaking changes and we're not even
particularly well equipped for what's already on the table.
So I thank you, Mr. Chairman, for holding this important
hearing.
The Chairman. Thank you very much.
I want to thank the witnesses for their time that it took
to prepare the testimony, the time to give it, the time to
answer the questions that we've had here. And of course I am
hoping that obligates you to also answer the questions that
we'll provide in writing. Around here there are a lot of things
going on at the same time, so there are a lot of conflicts with
different committees. So members of our committee will have to
educate themselves on what has been said and they'll do that
through staff that's been attending, and we'll undoubtedly have
some questions for you, too. But that will all play a vital
role in us getting it right, which is what we want to do. This
has been a fantastic panel because it's a wide spectrum of
stakeholders and it's been very helpful.
The record will stay open for 10 days and members of the
committee can submit their questions. I would also mention that
I do have a number of comments from other colleagues, some of
whom are not on the committee, and I would ask unanimous
consent that the number of outside groups as well as
colleagues' comments be entered in the record. Without
objection.
Thank you very much. This hearing is adjourned.
[Additional material follows.]
ADDITIONAL MATERIAL
Prepared Statement of the Advanced Medical Technology Association
(ADVAMED)
AdvaMed and its member companies thank the committee for holding
this hearing on improving drug safety and innovation. Although the bill
under review is not specifically intended to affect medical devices,
there are two provisions in the bill pertaining to FDA advisory panels
and critical path which could affect our industry. We respectfully
submit our comments for your review.
AdvaMed member companies produce the medical devices, diagnostic
products and health information systems that are transforming
healthcare through earlier disease detection, less invasive procedures
and more effective treatments. Our members produce nearly 90 percent of
the healthcare technology purchased annually in the United States and
more than 50 percent of the healthcare technology purchased annually
around the world. AdvaMed members range from the largest to the
smallest medical technology innovators and companies.
FDA ADVISORY PANELS
A rational conflict of interest policy for panel members is
critically important to the effective functioning of panels. It is
equally important, however, to ensure that highly capable, expert
physicians and researchers continue to be willing to serve on FDA
advisory panels, and we are concerned that the current bill language
may discourage such experts from participating in the FDA panel
process.
The pool of experts in the device arena is limited due to the fast-
advancing product developments and diverse product areas where only a
handful of national experts may exist within literally thousands of
different product areas. It is important that physicians and
researchers at the top of their fields be able to provide their
expertise, insights and perspective to FDA on emerging technologies to
advance patient care and ensure safe and effective technologies.
Workable conflict of interest rules and/or guidance can strike a
healthy balance between ensuring the participation of knowledgeable
panel members and avoiding bias attributable to self-interest. A more
measured approach to addressing potential conflicts for panel members
should include a broad requirement for the FDA to review its guidance
and rules related to panel member conflicts and to update them to be
more precise and understandable. Any legislation in this area should
avoid impinging on the privacy of persons who are performing a public
service.
AdvaMed is concerned about provisions to standardize how panel
members are evaluated and require FDA to publicly disclose the
financial status of potential panel members over the Internet and via
guidance documents. Under current law, waivers are published on the
Internet and financial and other personal information about panel
members is redacted. The legislation would discourage individuals with
needed expertise from participating in FDA panels by broadly
publicizing the details of determinations about advisory panel members
over the Internet, and by requiring the issuance of guidance that is
aimed at revealing the financial status, including possibly the net
worth of individual panel members. For example, the legislation would
publicly release detailed financial information and ``involvements''--
requirements that will clearly discourage needed panel participation.
AdvaMed recommends changing the legislation to allow the FDA to
individually evaluate each panel member for conflict of interest
status.
We are also concerned about provisions in the legislation to
require the HHS Inspector General (OIG) to ``on an ongoing basis''
conduct reviews ``of the financial interests of a representative sample
of individuals who have served on a[n] [FDA] panel . . . ''. As part of
a semi-annual report, the OIG would also be required to include the
results of the OIG's review of the financial interests of panel
members. These measures would discourage the foremost device experts as
well as experts with no conflicts at all from serving on FDA panels.
CRITICAL PATH
AdvaMed strongly supports the objectives of FDA's Critical Path
Initiative and the intentions of the proposed Reagan-Udall Institute
envisioned in S. 3807, particularly regarding the Institute's potential
role in focusing resources on the unique challenges of medical device
development and evaluation. Our member companies and the academic
research community are pioneering new research methods that can speed
medical product development and more quickly identify and assess
emerging safety issues.
AdvaMed urges the Administration and Congress to allocate new funds
to the FDA device program to ensure that device-related aspects of the
Critical Path Initiative are able to develop fully. The additive nature
of user fee programs should not be violated by diverting these funds to
activities far removed from the product application review function.
AdvaMed also recommends that programs undertaken through both the
Critical Path Initiative and the proposed Reagan-Udall Institute be
implemented to clearly reflect the important differences between drugs
and devices. We recommend the specific inclusion of device expertise in
the leadership structure of both programs at all levels.
The mission of both programs should be adjusted to reflect the
fundamental differences between the medical device development and drug
discovery processes; while new drugs stem from discovered molecules,
new devices are developed through a design and engineering process with
specific, intended functions in mind. AdvaMed and its member companies
are committed to working with FDA and the leadership of the Reagan-
Udall Institute to broaden understanding of the unique nature of
medical device technology development and to working to maximize the
contributions of the medical device community to the Critical Path
Initiative.
CONCLUSION
Again, we thank the committee for holding this hearing today. As
the committee works to create a 21st Century FDA, AdvaMed looks forward
to working with you to create a balanced approach to expert panels at
FDA, increase the attention to devices within the Critical Path
Initiative and Reagan-Udall Institute efforts, and enhance patient
access to lifesaving and life-enhancing medical technologies.
Prepared Statement of the American Society of Health-System
Phamacists (ASHP)
The American Society of Health-System Pharmacists (ASHP)
respectfully submits the following statement for the record to the
Senate Health, Education, Labor, and Pensions (HELP) committee hearing
on ``Building a 21st Century FDA: Proposals to Improve Drug Safety and
Innovation.''
ASHP is the 30,000-member national professional and scientific
association that represents pharmacists who practice in hospitals,
health maintenance organizations, long-term care facilities, and other
components of health systems. For more than 60 years, ASHP has helped
pharmacists who practice in hospitals and health systems improve
medication use and enhance patient outcomes. This includes working with
patients to help them access the medications they need and to use them
safely and effectively.
The Society has long-standing policies that express support for
congressional action to provide the Food and Drug Administration (FDA)
with increased authorities to require post-marketing studies on the
safety of drugs that are in the public interest. ASHP policy has also
supported broader authority for the FDA to require additional labeling
or the withdrawal of certain products on the basis of review of such
studies.
ASHP applauds Chairman Enzi and Senator Kennedy for their efforts
to try and address the difficult challenge of establishing a system of
drug approval and monitoring that maintains a balance between the
benefits of an innovative, potentially life-saving drug and the risks
associated with its widespread use in the population. The current drug
safety system can be improved through increased regulation, but it is
important to realize that no system will succeed without the commitment
and proper training of healthcare professionals and the understanding
of patients of medication risks and benefits.
As you move forward with legislation to address drug safety, we
would urge you to continue to evaluate the essential role that
healthcare professionals and especially pharmacists play in ongoing
post-marketing surveillance and in managing known risks. As medication-
use experts and frontline providers of medication management services,
pharmacists are necessary and fundamental to the drug safety system,
with a responsibility to assist patients, physicians, and other
healthcare professionals.
As the committee pursues its legislative strategy, we would ask
that you consider several points in key areas:
POST-MARKETING SURVEILLANCE STRATEGY & RESTRICTED DRUG
DISTRIBUTION SYSTEMS
The ``Enhancing Drug Safety and Innovation Act'' (S. 3807) does
permit the establishment of new Restricted Drug Distribution Systems
(RDDS) in some limited circumstances. While ASHP values and
acknowledges the critical role that an RDDS plays in managing drug
safety, the use of such systems should not compromise timely and
appropriate patient care and should not be overly burdensome to
healthcare practitioners who are attempting to meet patient needs. This
is especially of concern in hospital settings where pharmacists are
trying to deliver medications and manage the therapy for high-risk
patients.
While we understand that new RDDS programs will only occur in
limited circumstances, they do have a cumulative effect on health-
system pharmacy practice and patients directly. Many ASHP members have
reported that RDDS programs are burdensome and confusing for
practitioners and that they at times result in delayed care and
inconvenience for patients and disrupt the continuity of care.
In order to simplify these programs while maintaining their intent,
we urge the committee to work with ASHP and other stakeholders to
develop legislation that would standardize RDDS programs, require
pharmacist input into each program's development, and improve access to
information for clinicians and patients about the types of restricted
distribution systems.
DIRECT-TO-CONSUMER ADVERTISING
ASHP policy supports direct-to-consumer advertising of drug
products only when the following requirements are met: (1) such
advertising is delayed until post-marketing surveillance data are
collected and assessed, (2) the benefits and risks of therapy are
presented in an understandable format at an accepted literacy level for
the intended population, (3) that such advertising promotes medication
safety and allows informed decisions, and (4) that a clear relationship
between the medication and the disease state is presented.
While ASHP is pleased to see that S. 3807 permits FDA to place
certain requirements on manufacturers' drug advertising efforts, we
would recommend that the committee permit the FDA to extend any
moratorium period over 2 years should additional delays be required to
collect and assess essential post-marketing surveillance data.
CLINICAL TRIALS REGISTRY AND CLINICAL TRIALS RESULTS DATABASE
ASHP policy supports the disclosure of the most complete
information possible on the safety and efficacy of drug products and
has recommended the establishment of a mandatory results registry for
all Phase II, III and IV clinical trials that are conducted on drugs
intended for use in the United States. All clinical trials undertaken,
but not yet completed, should be added to the registry and, upon
completion, the results should be posted electronically with
unrestricted access as quickly as possible after FDA approval but
before marketing commences. Strong enforcement mechanisms are necessary
to ensure compliance.
ADDITIONAL FDA FUNDING NEEDED FOR POST-MARKETING SURVEILLANCE
While we acknowledge funding is not in the jurisdiction of this
committee, we cannot discuss enhancing FDA's ability to meet its public
health mission without expressing support for increased resources for
the agency. It is startling that the resources designated for all food
and drug regulatory activities in the United States are equivalent to
the budget of the Montgomery County, Maryland, public school system
($1.85 billion for 2007), which is the county where the agency is
located. ASHP is a member of the FDA Alliance and supports funding
increases for the agency for the 2008 fiscal year.
BETTER UTILIZATION OF PHARMACISTS SHOULD BE FOSTERED
Increased Federal regulations of drug approval and marketing alone
will not result in an improved drug safety system. We urge the
committee to look carefully at methods to better prepare healthcare
professionals for playing a larger role in post-marketing surveillance
and in managing known risks. ASHP believes pharmacists have a crucial
role in fostering improved medication-use safety. Postgraduate pharmacy
residency training is especially designed to prepare pharmacists for
this role. Unfortunately, there are an insufficient number of such
accredited programs to meet the Nation's needs. Additional Federal
support for pharmacy residency training would have a major effect on
improving the outcomes from medication use, especially in high-risk
patients.
As medication-use experts and frontline providers of medication
management services, pharmacists are necessary and fundamental to the
drug safety system. All medications have associated risks, and
pharmacists have a responsibility to assist patients, physicians, and
other healthcare professionals in managing medicines with risk profiles
that require careful patient selection and monitoring. Products that
are safe and effective only in certain patients, but not in others,
have been withdrawn from the market due to inappropriate management of
well-known risks and a lack of ability to differentiate appropriately
among patients. If a pharmacist, as part of the healthcare team, had
monitored and adjusted the therapy to minimize or eliminate risks, a
subset of patients could have continued to receive benefits from the
withdrawn medications.
CONCLUSION
We appreciate the opportunity to share our views on how to improve
the drug safety system in this country. It is essential that the
American public have confidence in our Nation's ability to maintain the
integrity of our drug supply and protect patient health through
appropriate drug approval and monitoring systems. ASHP and its members
are committed to working with the Congress, FDA and other stakeholders
to achieve this goal.
Prepared Statement of the National Association of Chain
Drug Stores (NACDS)
Chairman Enzi, Ranking Member Kennedy, and Members of the Health,
Education, Labor, and Pensions Committee. The National Association of
Chain Drug Stores (NACDS) appreciates this opportunity to provide the
committee with a statement for your hearing, ``Building a 21st Century
FDA: Proposals to Improve Drug Safety and Innovation.''
NACDS represents the Nation's leading retail chain pharmacies and
suppliers, helping them to better meet the changing needs of their
patients and customers. Chain pharmacies operate more than 37,000
pharmacies, employ 114,000 pharmacists, fill more than 2.3 billion
prescriptions yearly, and have annual sales of nearly $700 billion.
The chain pharmacy industry agrees with the need to enhance the
safety of medication use in the United States, and shares the
committee's goal of improving public safety and helping patients and
healthcare providers make informed decisions about healthcare. Because
the methods in which community pharmacies protect the safety of their
patients would be directly impacted by drug safety legislative changes,
we are providing comments to you on two specific elements of drug
safety proposals: Medication Guides and restricted distribution
systems.
MEDICATION GUIDES
Over the past 2 years, the Food and Drug Administration (FDA) has
significantly increased the number of pharmaceutical products which
require a Medication Guide (``MedGuide'') to be dispensed with each new
and refilled prescription. Currently, there are over 1,500
individually-manufactured products with different National Drug Codes
(NDCs) that require the dispensing of a MedGuide.
With over 1,500 individual products needing to be dispensed with
MedGuides, we are concerned about proposals that could lead to the
unnecessary approval of MedGuides outside the scope of the FDA's
original intention to require them only for a few products which pose a
``serious or significant concern.'' Requiring the use of a MedGuide as
part of all Risk Evaluation and Mitigation Strategies (REMS) may result
in overuse of MedGuides.
All pharmacies already provide patients with comprehensive written
information on their medications. This information, which is updated
continuously, is provided to pharmacies electronically by database
companies and then printed by pharmacies. To enhance the distribution
of MedGuides, we suggest a similar procedure be developed for
MedGuides, in which pharmacies are permitted to print MedGuides through
their computer systems. This will enhance the percentage of patients
that receive Medguides that are consumer friendly and easy to read.
NACDS supports educating patients on their medications. However,
the use of MedGuides may not be the most effective way to educate
patients for all medications. MedGuides should remain a resource only
for medications which pose a serious or significant concern. It is
important to note that while the FDA has significantly increased the
number of MedGuides recently, there is no evidence which demonstrates
that MedGuides enhance patients' understanding of medication risks.
Although manufacturers are required to provide MedGuides in
``sufficient quantities'' to pharmacies, there is no standard method of
distribution used throughout the industry. Instead, each manufacturer
of a product with a required MedGuide can choose from an unlimited
number of methods. Most commonly, manufacturers provide pharmacies with
small MedGuide documents which are difficult to handle for pharmacists
and even more difficult to read for patients. In most cases, this
results in a MedGuide which does not achieve its intended goal of
educating patients on their medications.
We suggest that drug safety proposals enhance the process by which
MedGuides are provided by manufacturers and dispensed to patients. FDA
should use its authority to require manufacturers to use identical
procedures for producing MedGuides and distributing them to pharmacies.
In order to determine whether or not MedGuides are meeting the
goals of educating patients on their medications, we suggest that the
FDA assess the benefits of different types of written information,
including MedGuides. This information will be very helpful in
determining how to best educate patients on their medications so they
can use them safely and effectively.
RESTRICTED DISTRIBUTION PROGRAMS
NACDS and the community pharmacy industry believe there is a need
for significant changes to the manner in which restricted distribution
programs are developed, approved, and monitored. We support proposals
to provide the FDA with more authority over the development of these
programs so that they are effectively and efficiently implemented by
healthcare providers.
Community pharmacies have extensive experience with many restricted
distribution programs, including one of the largest programs, the
iPledge program for isotretinoin (Accutane). As a result, we have
several recommendations for drug safety legislation as it relates to
restricted distribution programs.
As evidenced through the challenges with the recently implemented
iPledge risk management program for isotretinoin, if restricted
distribution programs are not developed properly, patient access can be
hindered significantly. As a result, a delay in patient access to
medications in restricted distribution programs can have negative
consequences on health outcomes.
To help limit burdens on patients, NACDS suggests that drug
manufacturers and the FDA obtain the input of stakeholders, including
patients, pharmacies, and physicians that will ultimately implement the
restricted distribution program. This will result in a more effective
program which builds upon the risk management strategies already put
into place in the private sector. Programs developed using industry
capabilities will also result in enhanced compliance by all
participants with fewer interruptions in patient care.
Although NACDS recognizes the necessity of training practitioners,
pharmacists, and other healthcare providers as part of restricted
distribution programs, it is important to note that there are already
rigorous requirements on pharmacists and pharmacies in order to be
licensed by States to dispense medications. We believe pharmacists and
pharmacies should not be subject to certification requirements to
participate in restricted distribution programs.
NACDS also urges restricted distribution programs to provide all
dispensing locations, including community pharmacies, with the
opportunity to participate. There are some medications that are only
appropriately dispensed in the institutional setting because of
specific monitoring necessities, but these prescription drugs are the
exception. Many patients prefer to use their local community pharmacy
for their prescription needs. Also, having patients fill all of their
prescriptions at one location helps assure that their pharmacy is able
to identify and prevent any potential adverse drug reactions (ADRs) or
complications between the restricted distribution medication and the
other medications the patient is taking. Participation by pharmacies or
other healthcare providers in a restricted distribution program should
only be limited if a dispensing location cannot meet the program
requirements.
CONCLUSION
Thank you for the opportunity to provide this statement to the
hearing record. We look forward to working with the committee on
advancing legislation that improves drug safety and public health.
Response to Questions of Senators Enzi, Kennedy, Murray,
and Clinton by Sheila Burke
QUESTIONS OF SENATOR ENZI
Question 1. Do you believe that comparative effectiveness studies
for drugs should be done by the FDA or by payers?
Answer 1. Such studies can be done by FDA, by payers, or by both
working collaboratively on some or all aspects of study design and
execution.
Question 2. Do you think that user fees affect product approval
decisions by FDA?
Answer 2. The committee did not attempt to conduct a systematic
analysis of the impact of user fees on product approval decisions by
FDA. However, the committee recognizes that a perception exists that
user fees influence approval decisions. Also, in its information
gathering, the committee has learned that the time pressures associated
with the user fees program requirements may contribute to an inability
to examine pre-approval safety issues as closely or thoroughly as a
reviewer may believe is necessary. The committee also noted that the
attention and resources devoted to the pre-approval (review) process
are substantially greater than those available to monitor and
effectively react to a drug's post-approval performance.
Question 3. The IOM report addresses some communication issues
within FDA and their impacts on drug safety. Are communications between
FDA and other agencies on drug safety issues effective? If not, how
might they be improved?
Answer 3. The committee was not asked specifically to consider
interagency communication on drug issues, but the committee did comment
on the existing and increasing data available from publicly funded
healthcare programs (those of CMS and VA), and the need for better
communication and especially greater resources to support collaborative
efforts among FDA and other agencies. For example, collecting and
analyzing relevant Medicare part D data for FDA drug safety
surveillance purposes requires funds for staff, information technology,
etc.
Question 4. I agree with you and with some of the other witnesses
that, absent increased appropriations, we should expand what activities
may be covered by user fees. However, approximately half of CDER's
budget is currently derived from user fees. If we increase this figure,
do we run the risk of undermining the perceived independence of the
agency?
Answer 4. That is a legitimate concern. In acknowledgement of the
high likelihood of PDUFA reauthorization, the committee has called for
removing the restrictions on how user fee funds are used, in the belief
that these not only create hardships for certain CDER programs
important to drug safety, but also reinforce the perception that the
sponsors unduly influence the process. It is also incumbent on the
Commissioner and center director to clearly explain the science based
behind the decisions that are made in order to dispel any inaccurate
assumptions or interpretations of what motivated certain regulatory
decisions. In other words, it is important that agency leadership ``go
the extra mile'' in the area of transparency.
QUESTION OF SENATOR KENNEDY
Question. There has been a lot of debate on whether to establish a
safety center at FDA that is separate from the office that approves new
drugs, but your report rejected this idea. Why did you conclude that
this was not the right approach?
Answer. There are two reasons for the committee's discomfort with
the idea of a separate safety center. First, the committee believes
strongly that safety and efficacy must be considered together during a
drug's lifecycle by professionals who can work collaboratively to piece
together a complex and evolving puzzle--what was known before approval,
and what is learned about a drug's risks and benefits after it has been
on the market for some time. Staff in the Office of New Drugs and those
in the Office of Surveillance and Epidemiology (formerly Office of Drug
Safety) each possess information and skills that are important to the
process. For example, reviewers of new drugs know a lot about (classes
of) drugs that never make it to market. Separating post-marketing
safety staff from review staff would break down and complicate the
lines of communication and it could compromise the institutional memory
about drugs reviewed in the past and those that were actually approved.
Second, the reasons that have been given for creating a separate safety
center have included the claim that the staff who were responsible for
approving a drug have a built-in bias against overturning their
previous decision once safety problems arise. There have not been in-
depth studies to support this theory, but the committee in its
information gathering activities found no reason to suspect this would
be the case. In fact, the committee found that drug reviewers are
deeply aware of and sensitive to the reality that the risk-benefit
analysis that leads to a drug approval is frequently based on limited
information, and that only more extensive and prolonged experience with
a drug in a real-life setting will either solidify the earlier position
on a drug, or lead to identifying and then confirming serious safety
problems with the drug.
QUESTION OF SENATOR MURRAY
Question. I know that the IOM did not look at the over-the-counter
application and review process. However, we know that the recent
experience on the Plan B OTC application did impact morale and that
reviewers who supported this application were silenced. Dr. Susan Wood
is probably the most visible casualty of this process and I truly hope
that no one else ever feels that they must resign in protest at the
FDA. How can we legislate a better culture and improve morale at FDA as
is proposed by the IOM? How can we create a structure to allow for
scientific disagreement without undermining the agency?
Answer. This is an enormously difficult question to answer.
Unfortunately, it seems difficult if not impossible to legislate a
better culture. However, the committee believes that it is possible to
put in place some of the elements management literature has shown may
help support organizational change and lead to good morale and a
healthy organization. The committee believes that stability at the top
may help contribute to this, as well as a group of experienced
leadership advisors to help support agency and center leadership,
systematic management efforts to facilitate communication and
collaboration, and addressing some of the imbalances that may
exacerbate polarization among offices and disciplines. The committee is
aware of the recent efforts at CDER to establish mechanisms for dispute
resolution, but it believes that management must make such issues a
priority and consistently demonstrate that they are not simply empty
words on paper, but evidence of support for a true spirit of open-
minded scientific inquiry. Finally, and most importantly, the
Commissioner and the center director need to make it clear to all staff
that a healthy organizational culture is a high priority, and that
specific actions will be implemented to facilitate and maintain an
atmosphere of transparency, inclusion, optimal communication, and
mutual trust.
QUESTIONS OF SENATOR CLINTON
Question 1. The IOM report recommends giving the FDA increased
authority to revise labels, require conditions on distribution, and
changes in promotional materials. It also recommends increasing the
range of tools available to ensure that this new authority can be
effectively enforced. Yet we know that the agency relies heavily upon
drug agency user fees, and have seen examples of when scientists were
pressured to lessen their criticism of products. How can we change the
culture at FDA to ensure that new enforcement authority is used? What
kinds of enforcement mechanisms would be most effective in combating
these cultural issues and helping to improve consumer safety?
Answer 1. It is difficult to make a direct link between culture and
authority. However, the committee believes that agency leadership can
play an absolutely essential role in organizational culture change. The
Commissioner and center director must send a clear message that agency
leadership expects (and will support) staff in exercising authorities
available to them when the scientific evidence calls for certain
regulatory decisions. However, in order to be able to base decisions on
the best science, staff require the funding, skills, information
technology, and institutional relationships to access and analyze the
necessary data which then justifies use of specific authorities.
Adequate resources (preferably from appropriations) are key. The
committee believes that the heavy workloads and tight review timelines
(linked to user fees) of drug reviewers make it difficult for them to
thoroughly attend to safety issues, and their counterparts in the
Office of Surveillance and Epidemiology are so few in number and so
severely underfunded that safety concerns may slip through the cracks.
Question 2. In recent years, the agency's employees have been
suffering a crisis of morale. Career scientists report being pressured
to change their findings by senior level officials. Ideological
concerns, not scientific data, delayed the decision on the over-the-
counter application for Plan B. We have seen multiple examples where
political and commercial interests were given higher priority than
consumer safety.
The IOM report recommends establishing a fixed 6-year term for the
Commissioner, to isolate him or her from political pressures. Could you
comment on the ways in which this fixed term will help address the
concerns over the current FDA culture? What other reforms might be
necessary to address the concerns expressed about senior-level
management, in addition to the Commissioner's post?
Answer 2. The fixed-term appointment of a thoroughly qualified
individual may help to set the tone for the organizational culture. A
commissioner who is ``here to stay'' for several years would have the
opportunity to support center directors and other agency leaders and to
ensure that his or her leadership philosophy and priorities are
implemented.
Some of the management literature cited in the report refers to
past leaders of government agencies who were effective in bringing
about profound cultural changes through their vision and their
leadership style (participatory, encouraging of transparent and
frequent communication among all levels of the agency, respectful of
the diversity of disciplines and viewpoints in the organization, etc.).
The report states,
``Assessments of government agency performance and examples
from the management literature have shown repeatedly that
organizational cultures that stifle dissent, exclude staff from
decisions about the organization's vision, and allow cultural
problems to linger unaddressed are not healthy cultures, and
those problems interfere with their ability to achieve their
goals (Weick and Sutcliffe, 2001; O'Leary R, 2006; Return to
Flight Task Group, 2005; Heifetz and Laurie, 1998; Khademian,
2002; Kotter, 2005).''
Question 3. The Drug Safety Oversight Board (DSOB) currently has no
patient or provider representatives. Patient input into this process
could help to improve public oversight on issues that will have
significant impact on patients and to restore public trust in the drug
safety system. What recommendations does the IOM have for improving
public input into the FDA's drug safety oversight process?
Answer 3. The committee believes that FDA did not communicate
clearly about the nature of the DSOB and its role. Although the board
seemed to be ``offered'' as a solution to the drug safety problems of
the several years, one of its functions is to provide internal
oversight of how safety issues are handled within the agency (tracking
of issues, resolution, etc.)--a function that needs to be performed by
an internal group. Obviously, this is not the type of group that could
be expected to address public concerns and tackle the difficult issues
of external communication (although the DSOB's job description does
include the latter, the committee finds this to be inappropriate--see
Chapter 3).
The Drug Safety and Risk Management Advisory Committee is the
external body that could (and already does to some extent) advise CDER
on drug safety issues. DSaRM, not the DSOB, may be the type of group
that could demonstrate agency commitment to receiving and acting on
public input. Furthermore, in Chapter 6 of its report, the committee
recommended the creation of a new advisory committee to focus on
patient and consumer communication issues. Such a group, representing
patient and consumer views and relevant professional expertise, could
play a dramatic role in improving the quantity, quality, and timeliness
of agency communication to and with the public.
Question 4. The IOM report recommends that civil monetary penalties
be available to FDA as an enforcement tool for various forms of non-
compliance. The report also recommends that industry sponsors be
required to register and submit clinical trial data. What kind of
enforcement mechanisms would the IOM consider appropriate to ensure
that industry sponsors comply with such submission and registry
requirements?
Answer 4. The committee did not describe the enforcement mechanisms
that could be used, other than civil monetary penalties (and offered no
specifics in this regard). However, such mechanisms are clearly
needed--the agency's enforcement authorities are extremely limited.
Response to Questions of Senators Enzi, Kennedy, Murray, and Clinton
by Diane E. Thompson
QUESTIONS OF SENATOR ENZI
Question 1. Some have suggested that the drug safety system is
broken. Do you agree? Are we seeing drugs being approved that truly
shouldn't have been?
Answer 1. Several recent high profile drug safety incidents have
highlighted the need for a stronger drug safety system. However, as
Institute of Medicine (IOM) has pointed out, the fact that these
instances uncovered safety risks after a drug was already on the market
doesn't mean FDA shouldn't have approved it. Most new drugs are studied
in fewer than 3,000 patients. And, most often those patients are far
from a representative sample of the U.S. population. Consequently,
adverse events that occur even as often as 1 in 10,000 patients are not
likely to be discovered until the product is on the market. The answer
to improving drug safety is not to return to the days of significant
delays in access to new therapies for life-threatening illnesses.
Instead, we need to continue to study drugs in real life situations in
larger groups of people in phase IV trails and after FDA approval. It
is clear that our current drug safety paradigm poses considerable,
avoidable danger, where the flow of risk-benefit information between
drug manufacturers and the FDA occurs pre-approval and is extremely
limited post-approval. This is one of the unintended consequences of
the Prescription Drug User Fee Act (PDUFA). As the IOM report notes,
continuing formal evaluations after a drug is approved is necessary. We
have a historic opportunity to correct the current imbalance in our
Nation's drug safety system. A reformed drug safety system that, as the
IOM suggests, takes a life-cycle approach to assessing drug risks and
benefits is in the best interest of all stakeholders.
Question 2. Your testimony calls for giving FDA the authority to
require studies of ``significant'' off-label uses. I expect these post-
market trials of off-label uses would be rather expensive. I worry
about the impact on patients if companies start discouraging off-label
uses to avoid having to conduct a set of new and expensive trials. You
also noted that there are existing incentives to encourage pediatric
studies of off-label uses. These incentives were created through the
Best Pharmaceuticals for Children Act, which is due to be reauthorized
next year. Have you considered ways we could amend that law to create
better incentives for conducting studies of off-label uses in children?
Answer 2. Since off-label prescriptions are such a large proportion
of medicines being prescribed by doctors, granting FDA authority to
require studies of off-label uses is a necessary safety requirement. It
is especially critical to children, who already are being placed at
considerable risk because \3/4\ of pediatric prescribing is off-label.
The expense of such studies needs to be balanced against the expense of
treating patients with medicines that have not been proved to be safe
or effective for the prescribed use.
Currently, companies cannot advertise or encourage off-label use,
since these uses are not included on the label nor included during
label negotiations between FDA and drug companies. It may actually be
of significant benefit for companies to conduct off-label studies,
because if studies confirm safety and efficacy for the off-label use,
companies could then have an opportunity to advertise and market the
drug for the new use once it is negotiated onto the label. Overall,
patients stand to benefit greatly from new safety and efficacy
information, where the public health impact of the off-label use was
unknown before.
The reauthorizations of the Best Pharmaceuticals for Children Act
(BPCA) and the Pediatric Research Equity Act (PREA), both of which
expire next year, are extremely important to children's health.
Although BPCA creates incentives to encourage manufacturers to study
their products for children, these incentives are voluntary. We're
seeing that manufacturers are increasingly opting not to conduct the
studies FDA requests. Unambiguous authority to require such studies
when the off-label use is significant will help ensure that children
too can reap the benefits of an improved drug safety system. In both
BPCA and PREA, the balance between incentive and mandate needs careful
review to ensure that we accomplish the objective of the statute and
fairly compensate the company for their investment. We look forward to
working with the committee to further explore this.
Question 3. Do you think the timeframes for FDA action proposed in
S. 3807 are reasonable?
Answer 3. It is very important that when new safety issues arise,
there be quick and decisive action to address these concerns. Patients
should not have to choose between safety and access. Safety assessments
must be incorporated into the approval process so as not to slow the
process down. This can only happen if FDA has adequate resources to
address safety issues. Through the Risk Evaluation and Mitigation
Strategy (REMS) plan, S. 3807 proposes that when new safety information
demonstrates significant risk, FDA reassess REMS and enter into
discussions with the manufacturer. We support the requirement that
action on new safety information be completed in a timely way.
S. 3807 also establishes a dispute resolution process for resolving
disagreements between FDA and drug companies related to REMS, referring
such disputes to the closed-door Drug Safety Oversight Board (DSOB),
which would review cases swiftly. In our view, transparency and patient
input into this process is critical, both to ensure that there is
public oversight on issues that will have significant impact on
patients and to restore public trust in the drug safety system. We
recommend that patient and consumer representatives be included on any
such boards.
Question 4. Do you believe mandatory reporting of clinical trial
results would compromise proprietary company information?
Answer 4. The release of proprietary information is not required in
order to establish a clinical trials and results database. It's
important to note that while drug manufacturers invest their resources
and expertise into the clinical trial process, patients make an
investment of their own, of their health and their lives. In that
sense, they also ``own'' the data. Understanding the results of
clinical trails is of critical importance to participants who, in some
cases, have heard about trial results via the media rather than the
trial sponsor. In addition, community members who may not have been
eligible for a trial but might benefit from the therapy in development
are also invested in trial outcomes. A clinical trial results registry
would provide a central, credible source for information, much of which
currently is widely shared within patient communities. These informal
communication mechanisms that have developed out of necessity must be
replaced with a credible, comprehensive, and reliable registry. Access
to reliable information about drug trials should not be dependent on
whether a patient has the right contacts.
To the extent a manufacturer can make the case that the release of
some piece of data would severely compromise their research efforts,
the release of such information could be examined on a case-by-case
basis. If the information is provided to each study patient on the
trial it should be considered in the public domain for all intents and
purposes. We should start from the premise that all parties benefit if
we can restore trust in the clinical trials system, which will only
come from more transparency in the process. Moreover, the availability
of clinical trials information will serve to accrue more patients into
studies more quickly, resulting in faster trial results and FDA
approval forthcoming sooner. This provides a clear benefit to both
sponsors and patients.
QUESTION OF SENATOR KENNEDY
Question. Outcomes of studies that are negative or that suggest
toxicity in patients are often not published. The legislation I
introduced with Senator Enzi requires publishing clinical trial
results, both positive and negative, in a public database. What impact
do you think this would have for patients, healthcare providers, and
the research community?
Answer. Several events over the past few years involving selective
reporting of clinical trials data and more specifically, the
suppression of negative research have generated concern over whether
enough is being done to ensure that important information about ongoing
and completed scientific studies of drugs and devices is easily
accessible to patients, healthcare providers, and researchers. While
the NIH currently operates a clinical trials database, it was designed
solely to help patients find ongoing trials and does not contain trial
results.
Creating a mandatory and publicly accessible registry of clinical
trials and their results is important, to not only provide the public
with access to critical information affecting their health, but also
for improving patients' trust in the clinical trial process. As IOM
notes, the results of trials of not yet approved products is also of
value to patients and researchers. For example, a drug may be a new
member of a class of products already on the market and safety signals
from the trial can help to highlight potential concerns with the
already approved products. Information from trials on new uses of
existing products can also be valuable, particularly if the new use is
one that is already in practice. Furthermore, in our view, for the
database to be of greatest use to patients, researchers, and healthcare
providers, it will be critical that it be as comprehensive as possible,
and that it include trials completed prior to enactment of the proposed
S. 3807 legislation as well as medical device trials.
QUESTIONS OF SENATOR MURRAY
Question 1. One of my goals for FDA has always been trying to find
the right balance between getting new drugs to patients without delay
while ensuring safety and effectiveness. I know it's a tough balance
and we always have to be concerned about unintended consequences for
any actions we take legislatively. I also think we need to be concerned
about making sure that patients get good information--not conflicting
information or even information that simply focuses on risks and not
benefits. We have to be sure not to scare patients away from
potentially beneficial treatments. There are risks with any drug or
device, and we could raise safety flags on any new treatment, but this
could also deter access. How can we achieve this balance and do you
have concerns about the impact of the IOM recommendations or the Enzi/
Kennedy bill as it relates to access?
Answer 1. In our view, patients should not have to choose between
safety and access. There should be equal focus on speedy access to new
lifesaving drugs and safer, more effective medicines. As the AIDS
epidemic has shown, patients are thirsty for greater access to
information that affects their health and are both very capable of
absorbing this information and better informed to make decisions
regarding their health because of it. For example, access to
information in a clinical trials and results database goes a long way
toward ensuring that patients have access to unbiased information and
to a full body of trial results for a condition or drug--a vast
improvement over the fragmented, promotional sources too frequently
relied on now. In addition, patients aren't alone in the decisionmaking
process. As always when the decision involves the prescribing of a new
course of treatment, providers will have a role in navigating new
information.
Question 2. As the IOM report noted, 21 percent of prescriptions in
2001 were for off-label uses, meaning of course that these uses were
never reviewed or approved by FDA. Many patients often are not even
aware of off-label use. However, as you pointed out, off-label use is
extremely important for pediatric patients as well as patients with
rare diseases. I agree that additional safety data is warranted for
off-label use, but are you concerned about efforts to discourage off-
label use? Once again is there a way we can encourage greater safety
data on off-label use without jeopardizing access or impeding the
practice of medicine?
Answer 2. As you mentioned above, a substantial number of
prescriptions are written for off-label uses. Any effort to reform the
drug safety system that fails to address \1/5\ of the use of drugs in
real-world settings would create a significant safety gap. Requiring
that companies conduct clinical trials of off-label uses would not
jeopardize or impede access or the practice of medicine. Instead, it
would inform medical practice by providing the necessary safety and
efficacy information to better assess the impact on public health in an
area where both efficacy and safety have heretofore been unaddressed.
Question 3. It has become very clear that we need a more uniform
mechanism for collecting safety data. Currently the process for
reporting adverse events is fragmented and there is little role for the
patient. In fact, FDA does not even have a database of reported adverse
events.
As an early champion, with Senator DeWine, of 1-800 Mr. Yuck, a
national poison control center hotline that provides real time,
accurate information to parents and providers in response to accidental
poison exposure, I know how difficult it is to create a national
database of real time information. But, we did succeed. We now have a
national poison control database that can provide information to any
caller across the country regarding accidental exposure to poisons.
Using the data mined from this database we can also find information on
increases in exposure to certain poisons and even local trends that
could indicate widespread problems.
I think we need to consider a national reporting structure for
adverse events associated to all medications. Many patients don't even
know what an adverse event is and when a side effect may or may not be
a concern. This kind of database could provide a great early warning
system as well.
What steps can we take to improve the collection of adverse events
and how can we be sure that patients are included in this process?
Answer 3. S. 3807 creates a Risk Evaluations and Management
Strategy (REMS) system that would allow FDA and manufacturers to
develop a plan to adapt and integrate new safety information about a
drug, including regular review of adverse events reports by FDA.
Because adverse events are not likely to be discovered until the
product is on the market, it is critical that they be addressed post-
approval. IOM recommends improving the current adverse event reporting
system, through systemic review, to increase its usefulness in post-
market surveillance, which we support. This approach is in-line with
the idea of taking an overall ``life-cycle'' approach to drug safety,
allowing for periodic reassessment of the risk-benefit of a drug over
time. We also recommend that the process be amended to include patient
representation in the dispute resolution process.
QUESTION OF SENATOR CLINTON
Question. Ms. Thompson, in your testimony, you discuss the ways in
which the protections in Pediatric Research Equity Act and the Best
Pharmaceuticals for Children Act have resulted in safer drugs for our
children.
With these protections, we can ensure that drugs that are labeled
for use by children have first been tested to determine effects in
pediatric populations.
However, you note that there is significant off-label use of
medications among pediatric populations, meaning that many children are
still exposed to unknown risks at the very moments when we are trying
to improve their health.
Could you please elaborate on the ways in which giving FDA the
authority to require studies for off-label utilization of drugs would
improve children's health? What impact would this authority have on
adult health outcomes?
Answer. As the IOM report notes, a recent study found that 21
percent of prescriptions written in 2001 were for off-label uses.
Children are placed at particular risk, since as much as \3/4\ of
pediatric prescribing is off-label and children are prescribed drugs
for uses different than the adult use. Any safety and efficacy
information for off-label uses would be extremely useful for children's
health. Thanks to your efforts and those of Senators Dodd and DeWine,
there are incentives available to encourage manufacturers to study
their products for children. However, they are voluntary--and we're
seeing that manufacturers are increasingly opting not to conduct the
studies FDA requests. Unambiguous authority to require such studies
when the off-label use is significant will help ensure that children
too can reap the benefits of an improved drug safety system. Whether
focusing on children or adults, the effect of off-label studies is the
same. Health outcomes are improved when prescribing is guided by safety
and efficacy for any use of a drug. There would also be an added
benefit for adult populations who would know with much more certainty
the benefits and risks of medicine they may be now taking without such
vital information.
As valuable as comprehensive drug safety reform improvements would
be in improving FDA's ability to monitor and act on safety signal once
drugs are on the market, they don't obviate the need for renewal of
BPCA and PREA--both of which expire next year. Most importantly, PREA
creates the presumption that drugs to treat conditions that occur in
children will be tested in children before approval or soon thereafter.
This critical authority is not addressed by the proposed general drug
safety reforms and should not be allowed to expire. In addition, both
BPCA and PREA extend beyond simply a focus on safety data. Because
children are not small adults and their bodies can respond very
differently to a drug than adults, FDA can use the carrot and stick
combination of PREA and BPCA to also generate critical data on dosing
and efficacy.
Responses to Questions of Senators Enzi, Kennedy, Murray, and Clinton
by Steve E. Nissen, M.D.
QUESTIONS OF SENATOR ENZI
Question 1. Can you comment on the feasibility of the Enhancing
Drug Safety and Innovation Act (S. 3807) to simultaneously shorten the
time to bring new medications to patients, while improving the safety
of drugs?
Answer 1. I remain strongly convinced that the Enhancing Drug
Safety and Innovation Act (S. 3807) can simultaneously shorten the time
to develop new medications, while improving drug safety. Because the
current regulatory environment does not facilitate robust post-
marketing surveillance, the FDA and its Advisory Committees must
necessarily be cautious in approving new medications. This caution is
warranted because we lack confidence that emerging drug safety problems
will be promptly identified and addressed. The Enzi-Kennedy bill
strengthens the post-marketing risk mitigation, which will increase
confidence that the Agency can rapidly identify any unforeseen drug
safety problems. This enhanced confidence will allow more rapid
approval of innovative new therapies, while protecting against
unexpected post-marketing risks.
In addition, the requirement for transparency in reporting the
results of late stage clinical trials can also help to speed new drug
development. Currently, enormous resources are expended in the
development of agents that are often similar to failed compounds.
Because companies developing these therapies are unaware of the
problems that led to failure of similar agents, enormous resources are
wasted exploring failed or nonproductive pathways. The increased
transparency afforded by S. 3807 will help companies to focus their
development efforts on truly innovative approaches, while avoiding
pathways likely to lead to failure. This concentration of resources on
the most promising therapies should serve to speed drug development.
Question 2. You suggest a new type of new drug approval that you
describe as ``provisional.'' Some have suggested that a provisional or
conditional approval could have very negative market effects, but you
suggest that it might in fact improve innovation and drug safety. Could
you elaborate?
Answer 2. Making provisional approval work in the current market
environment is possible with creative regulatory strategies.
Provisional approval would be appropriate for important potentially
life-saving therapies for which there is inadequate data, particularly
with respect to long-term benefits vs. risks. For lethal disorders such
as AIDS or cancer, permitting more rapid access to potentially
breakthrough medications makes good sense, even if there are remaining
safety and efficacy concerns. It would be necessary to provide
legislative support empowering the FDA to mandate that certain Phase IV
trials must be completed by the end of the provisional approval period.
If the studies were not performed, approval would automatically be
rescinded.
To compensate companies for the shortened period of exclusivity
that would likely result from provisional approval, legislation could
adjust the exclusivity period to provide an economic incentive to seek
provisional approval. This would be similar to the additional 6 months
of exclusivity that is provided for companies that study therapies in
pediatric populations. With the proper incentives, new therapies could
be made available to the public without compromising safety or
resulting in economic disincentives for industry to seek provisional
approval.
Question 3. Do you believe mandatory reporting of clinical trial
results would compromise proprietary company information?
Answer 3. In my view, when patients are asked to participate in
randomized clinical trials, there is a moral and ethical obligation to
translate their participation into the advancement of scientific
knowledge. We owe this obligation to our patients who selflessly
consent to participate in clinical trials. Therefore, I strongly
disagree with the contention that mandatory reporting of clinical trial
results would compromise proprietary company information. Most of the
studies that go unreported are clinical trials in which the agent
either failed to show benefit or exhibited unacceptable toxicity. In
either case, there is little or no proprietary information involved.
The results of clinical trials affect the health and even the survival
of many of our citizens. It is just simply unacceptable to withhold
such knowledge under the guise of proprietary interest.
If a drug fails during Phase II or Phase III due to toxicity, it is
essential that the scientific community be informed of the nature of
that toxicity, so that patients treated with related agents can be
appropriately protected. Similarly, if toxicity is experienced in Phase
IV trials, physicians must be provided with such information to
optimally protect their patients from the hazards of such therapies.
Interestingly, there is dissociation between release of information for
studies that are reviewed by FDA Advisory Panels and those that are
not. Currently, the FDA posts the briefing documents for advisory
panels on the ``worldwide web'' the night before advisory committee
meetings. But if studies never come to an advisory committee, the
information is withheld. Since both types of trials contribute to
knowledge and release of the results always serves the public interest.
Question 4. Can professional medical societies play a greater role
in communicating the benefits and risks of drugs to their physician
members and to the general public? If so, how?
Answer 4. I believe that professional societies have been under-
utilized as a contributing source for information on the benefits and
risks of drugs. Professional societies can serve as impartial sources
of information independent of both the FDA and the pharmaceutical
industry. Members and leaders of these professional societies include
individuals with great expertise on the clinical application of
pharmaco-
therapy. They provide a source for objective information and balanced
recommendations for practitioners and the public at large.
In addition, many professional societies operate databases that
include unique information about outcomes for patients treated with
pharmacological agents. I am currently President of the American
College of Cardiology, an organization with 33,000 members that
includes more than 90 percent of the cardiovascular practitioners in
the United States. We operate a database known as the National
Cardiovascular Database Registry (NCDR) that has information on several
million patients who have undergone various interventional procedures,
including cardiac catheterization, intervention, carotid stenting and
implantation of cardioverter-defibrillators (ICDs). This information
provides vital opportunities for post-marketing surveillance of safety,
but is currently not generally utilized by regulatory agencies as a
source for unbiased information. Rather than have the Federal
Government recreate such databases through the FDA, partnership
opportunities with professional societies can enable access to this
information to enhance quality and patient safety.
Question 5. You conduct large safety trials. Could you give us a
sense of what is involved in tracking down a safety issue that occurs
in, say, 1 in 10,000 people who take a drug?
Answer 5. Evaluating serious or potentially lethal risks that have
a low frequency of occurrence represents the single greatest challenge
in post-marketing surveillance. Such risks can virtually never be
determined prior to drug approval, since most approval packages involve
treatment of substantially less than 10,000 patients.
Several strategies have been employed in the past to assess these
low frequency risks. For example, in the case of rare liver failure
events, certain biochemical markers can be used to predict which drugs
will likely have a risk and can estimate with reasonable precision the
likely rates of occurrence of fatal outcomes. However, for many
idiosyncratic drug reactions, there exist no predictive biochemical
markers.
Ultimately, detection of these low frequency events requires a very
robust post-marketing surveillance system. The best sources of
information are patient databases that record clinical outcomes and
adverse events for larger populations. Several health maintenance
organizations such as Kaiser Permanente maintain such large databases,
which have been used successfully in the past to detect low frequency
risks. I also believe that partnership with professional societies can
be very helpful since many of these societies maintain ongoing
databases for monitoring quality and health outcomes.
Other innovations, available in the near future, may be helpful.
For example, electronic medical records (EMR's) allow rapid and
reliable assessment of patient outcomes. EMR's are much easier and less
expensive to evaluate than abstraction of outcomes information from
paper records. Current legislative initiatives designed to enhance the
electronic medical record have the potential to greatly enhance drug
safety. EMR's make possible nearly automated reporting of outcomes, a
potentially powerful approach to identification of unanticipated risks.
Finally, the current Adverse Event Reporting System (AERS) has
proven inadequate for assessing low frequency events even when they are
serious or fatal. There are considerable burdens upon the practicing
physicians to report these rare events. Currently, there exists no
incentive for voluntary reporting. Perhaps there is an opportunity to
create incentives for physicians to take the time to report unusual
events to the FDA. Perhaps, a provision of Continuing Medical Education
(CME) credits might encourage reporting.
QUESTION OF SENATOR KENNEDY
Question. Outcomes of studies that are negative or that suggest
toxicity in patients are often not published. The legislation I
introduced with Senator Enzi requires publishing clinical trial
results, both positive and negative, in a public database. What impact
do you think this would have for patients, healthcare providers, and
the research community?
Answer. The requirement in S. 3807 for mandatory registration
reporting of clinical trial results represents one of the most
important and valuable provisions of this bill. During the past several
decades, there has been an enormous proliferation of clinical trials
throughout most medical disciplines. Increasingly, these trials are
directed by pharmaceutical companies, often working in conjunction with
independent operators known as contract research organizations (CRO's).
It is also becoming increasingly clear that such trials are promptly
published when they show benefits for a pharmacological therapy, but
are often never published if the study shows no benefits or serious
toxicity. This practice, known as negative publication bias, has a
catastrophic effect on the practice of medicine. For example, if 10
clinical trials are conducted to study a class of medications and 9 of
the 10 studies show either lack of efficacy or toxicity, it is highly
likely that the therapy is not beneficial. Yet, if a 10th study is
conducted and it shows a marginal, but statistically significant
evidence of benefit, this may be the only study of the therapy that is
ever published. Physicians unaware of the 9 failed studies may
prescribe this ineffective or potentially risky therapy because they
have no knowledge of the studies that failed to show benefit or showed
toxicity.
Negative publication bias also has major negative effects on drug
development. Many companies are unaware that a competitor has studied a
drug and found it ineffective or showed unacceptable toxicity. As a
result, they may proceed with clinical trials of a very similar
compound. This exposes patients to risky drugs, when such exposure
could have been avoided had the company developing the drug been aware
of poor outcomes for similar drugs in the class. I strongly believe
that when we ask patients to consent to participate in a clinical
trial, there is a moral and ethical obligation to ensure that their
participation results in the advancement of science. Science cannot
advance if the results of this study are never published. Accordingly,
I strongly support the provision of bill S. 3807 requiring registration
and publication of all late stage clinical trials. This provision is
essential to restoring an adequate balance between safety and efficacy
in drug development.
QUESTIONS OF SENATOR MURRAY
Question 1. One of my goals for FDA has always been trying to find
the right balance between getting new drugs to patients without delay
while ensuring safety and effectiveness. I know it's a tough balance
and we always have to be concerned about unintended consequences for
any actions we take legislatively. I also think we need to be concerned
about making sure that patients get good information--not conflicting
information or even information that simply focuses on risks and not
benefits. We have to be sure not to scare patients away from
potentially beneficial treatments. There are risks with any drug or
device, and we could raise safety flags on any new treatment, but this
could also deter access. How can we achieve this balance and do you
have concerns about the impact of the IOM recommendations or the Enzi/
Kennedy bill as it relates to access?
Answer 1. I understand and share your concerns about achieving the
right balance between bringing new medicines forward and ensuring
public safety. I am very comfortable that S. 3807 will achieve both
goals in a balanced fashion. There is nothing in the bill that directly
affects patients' perception about the safety of beneficial therapies.
We have seen a series of drugs withdrawn from the market or come under
serious scrutiny because of drug safety problems. This has seriously
undermined public confidence in the safety of medications. As a
consequence of this series of safety revelations, many patients are
reluctant to accept life saving therapies. Improving drug safety has
the potential to improve public confidence and access to innovative
therapies. If we can improve the approval process and post-marketing
surveillance, we will avoid the kind of public attention that has
undermined confidence in drug safety.
In addition, I believe the FDA has a great opportunity to do a
better job of communicating the issues of benefit versus risk. In
several recent FDA advisory panels, I recommended the development of
``Patient Guides.'' These are mandatory brochures provided to patients
at the time of dispensing certain risky medications. These Guides
explain to patients both the benefits and risks of these drugs. The
Guides are written in language easily understood by the general public
and carefully explain to patients what side effects to look for and how
to report these adverse effects to their physicians. I believe that an
informed public is much more likely to accept the benefits of
therapies. A public that is suspicious about the relative benefits and
risks may not comply with therapy. The enhanced transparency of the
Enzi-Kennedy bill in making certain that we have all the information
necessary within the public domain can help to improve, rather than
undermine public confidence.
Question 2. As the IOM report noted, 21 percent of prescriptions in
2001 were for off-label uses, meaning of course that these uses were
never reviewed or approved by FDA. Many patients often are not even
aware of off-label use. However, as Diane Thompson pointed out, off-
label use is extremely important for pediatric patients as well as
patients with rare diseases. I agree that additional safety data is
warranted for off-label use, but are you concerned about efforts to
discourage off-label use? Once again is there a way we can encourage
greater safety data on off-label use without jeopardizing access or
impeding the practice of medicine?
Answer 2. Off label use of medications is an important issue and
must be addressed in a thoughtful fashion. Nothing in the Enzi-Kennedy
bill restricts the rights of physicians to make individual choices
about which therapies would be beneficial for their patients. I
strongly support the notion of physician and patient choice. There are
many examples where so called ``off label'' therapies have become the
treatments of choice for important medical conditions. Examples include
the use of b-blocking agents for angina and clopidigrel to prevent
thromboses following coronary stent placement.
However, it is important to distinguish between physician choice
and active commercial promotion of off-label treatments. Therefore, I
strongly support the current approach that precludes marketing drugs
for off-label indications. If a medical therapy is effective, it should
be demonstrated in an appropriate clinical trial.
With respect to rare diseases, I also favor ``lowering the bar''
for development of therapies for these indications. I served on the FDA
Advisory Board that approved a drug therapy for a rare fatal disease
known as pulmonary arterial hypertension. I and other members of this
panel strongly supported approval of this drug despite a clinical trial
that provided less statistically robust demonstration of efficacy than
would ordinarily be required. This adjustment to the standards for
approval represents good regulatory policy and should be encouraged in
selected circumstances. This is particularly advisable when the disease
is potentially lethal and there are few, if any, accepted therapies.
Question 3. It has become very clear that we need a more uniform
mechanism for collecting safety data. Currently the process for
reporting adverse events is fragmented and there is little role for the
patient. In fact, FDA does not even have a database of reported adverse
events.
As an early champion, with Senator DeWine, of 1-800 Mr. Yuck, a
national poison control center hotline that provides real time,
accurate information to parents and providers in response to accidental
poison exposure, I know how difficult it is to create a national
database of real time information. But, we did succeed. We now have a
national poison control database that can provide information to any
caller across the country regarding accidental exposure to poisons.
Using the data mined from this database we can also find information on
increases in exposure to certain poisons and even local trends that
could indicate widespread problems.
I think we need to consider a national reporting structure for
adverse events associated to all medications. Many patients don't even
know what an adverse event is and when a side effect may or may not be
a concern. This kind of database could provide a great early warning
system as well.
What steps can we take to improve the collection of adverse events
and how can we be sure that patients are included in this process?
Answer 3. The current AERS is ineffective. Reporting of adverse
events is voluntary which limits effective analysis. We need to find
creative approaches to the collection and evaluation of adverse event
data. I am convinced that the electronic medical record can help
substantially. If patient outcomes are recorded electronically, it
becomes much easier to collect and report outcomes data, including
adverse effects for a wide range of therapies. My own institution, the
Cleveland Clinic, has very effectively used our EMR in this way.
Similarly, many professional medical societies maintain large
prospective databases that record outcomes for quality initiatives.
Providing support for the FDA to partner with medical societies
represents a truly innovative opportunity. Similar opportunities exist
for large health maintenance organizations, such as Kaiser Permanente,
which has played an important role providing independent data during
several recent drug safety discussions.
Finally, I support your concept of involving the patient in adverse
event reporting. We must recognize that such reporting may not have the
scientific quality of physician reporting, but it is very useful
nonetheless. There may be an opportunity to provide a vehicle for
patients to express their observations and have the opportunity for the
FDA to evaluate such reports.
QUESTION OF SENATOR CLINTON
Question. The IOM report notes that direct-to-consumer (DTC)
advertising has been shown to have an impact on physician prescribing
practices, and you stated in your testimony that such advertising
should be more heavily regulated, with companies required to
demonstrate a compelling public health benefit for this communication.
However, we also face challenges from advertising targeted to
physicians, such as conferences or lunches, at which favorable studies
and journal articles can be highlighted.
As a doctor yourself, what are your recommendations for addressing
pharmaceutical marketing efforts that target physicians? How do we
ensure that such efforts do not also result in the over-prescription of
therapies that may be more expensive without being more effective?
Answer. I share your concerns about the effect of very aggressive
advertising directed at physicians and other healthcare providers by
the pharmaceutical industry. Through voluntary restrictions, there has
been some improvement in these practices in recent years. However, in
my opinion, these reforms have not gone far enough. Pharmaceutical
companies now dominate medical education. For example, in smaller
hospitals ``Grand Rounds'' is typically a weekly conference in which
emerging educational topics are discussed. In most cases,
pharmaceutical companies sponsor such Grand Rounds and provide the
speakers. Often such lecturers are scientifically unbalanced,
presenting highly promotional material under the guise of medical
education.
In addition, there has been a proliferation of so-called ``medical
education companies.'' Although these entities are loosely regulated by
the Accreditation Council for Continuing Medical Education, such
voluntary regulation is largely ineffective. ``Scientific'' symposia
sponsored by most medical education companies often consist of
promotional material in which speakers favorable to a particular
therapy dominate the activity.
In many hospitals with post-graduate training programs,
pharmaceutical companies provide lunches and other perquisites for the
physicians in training, along with a variety of ``educational
materials'' that are largely promotional. As a consequence of these
practices, newer and expensive therapies are often favored over older,
generically available treatments. In some cases, the earlier treatments
are actually better, but in most cases they are simply more cost-
effective.
Determining how to regulate physician-targeted advertising is a
challenging problem. Obviously, we must respect the principles of the
first amendment in which ``commercial speech'' is traditionally
considered privileged. Nonetheless, I think we will need to consider
creative strategies for curtailing inappropriate physician targeted
advertising. Drugs are not ``widgets'' and the manner in which they are
marketed affects the health of all 300 million Americans. The standards
for promotion of drugs should be higher than any other industry.
Currently, they are not.
Response to Questions of Senators Enzi, Kennedy, and Murray
by Adrian Thomas, M.D.
QUESTIONS OF SENATOR ENZI
Question 1a. I would like to ask you some questions about clinical
trials, particularly clinical trial registries and results databases.
What is an ``adequately designed and well-controlled clinical trial?''
Answer 1a. An adequately designed and well-controlled clinical
trial is a clinical study that has the following characteristics:
Clear objectives and a measurable hypothesis;
Study design that distinguishes treatment effects from
other influences;
Enrolls patients that have evidence of the disease under
study or of susceptibility;
Uses methods for assessing patient outcomes that are
reproducible and valid;
Has an appropriate control;
Is adequately powered to achieve the objective of the
study;
Has adequate measures to minimize bias such as blinding of
patients, investigators and data analysts;
Has random assignment to the test therapy or control
group; and
Produces an analysis of the results of the study that is
adequate to assess the effects of the drug.
Adequately designed and well-controlled clinical trials are the
primary basis upon which the FDA determines whether there is
substantial evidence of effectiveness for a new drug. (Reference: 21
CFR 314.126 adequate and well-controlled studies)
Question 1b. What clinical studies does Johnson & Johnson register
with ClinicalTrials.gov?
Answer 1b. We publicly register all adequate and well-controlled
studies of both marketed and investigational drugs regardless of
location. For studies related to serious and life threatening diseases,
we register all that include efficacy endpoints, regardless of trial
design or location. Registration is made to the National Library of
Medicine's Website, http://www.clinicaltrials.gov.
We believe that both patients and healthcare providers can benefit
from knowledge of clinical trials that are open for enrollment, and our
policy is intended to provide this information to consumers in a manner
that is as clear and easy to access as possible.
Question 1c. What clinical study results does Johnson & Johnson
currently disclose?
Answer 1c. For marketed medicines, we publish the results of all
adequate and well-controlled studies regardless of outcome. We also
publish results of any other clinical studies of our marketed medicines
that are material and relevant to the clinical use of the medicine or
to the care and safety of patients.
Question 1d. How are these results disclosed?
Answer 1d. These trial results appear either in peer-reviewed
medical literature or in the form of a clinical study report synopsis
in the ICH-E3 format, which is designed to present data for a
standardized scientific regulatory review. At present, our clinical
study results are posted as links from the protocols we have registered
on http://www.clinicaltrials.gov.
Question 2. Do you think the timeframes for FDA action proposed in
S. 3807 are reasonable?
Answer 2. Yes, as long as we understand that these are minimum
timelines and companies should engage with FDA and relevant
stakeholders earlier if possible.
Question 3. S. 3807 requires generic drugs to have REMS that are
identical to the REMS for the innovator product. However, some very
stringent RiskMAPS are based on patents. I would hope that in such
cases the patent holder would be amenable to licensing, but that may
not always be possible. How might this requirement be filled for
generic versions of these products, without compulsory licensure of the
patent?
Answer 3. This is a difficult situation that may not be able to be
addressed simply. Innovation necessary to address safety concerns
should not be undervalued, and incentives for this innovation must be
maintained. There are elements of RiskMAPS such as the ``STEPS''
program for thalidomide, which has been patented, and thus a product or
molecule patent may not be what is at issue, but rather the risk
management plan itself. It may not even be the company marketing the
drug that owns a REMS-related patent, but a contract research
organization, commercial vendor or other third party. This issue is
complex and we recommend that the committee engage other interested
stakeholders in this debate.
Question 4. In your testimony you suggest that the Reagan-Udall
Institute should not be associated with the FDA and should report
directly to the HHS Secretary and that intense interaction with the
pharmaceutical industry is needed for success. Finding the right place
for the Institute has been a challenge. Could you discuss the benefits
of placing the Institute outside of the FDA, and if it were placed
outside the FDA, how would you ensure that what is learned at the
Institute is integrated into FDA safety reviews?
Answer 4. The Reagan-Udall Institute could contribute much more
broadly than to FDA and its output should be optimized by placing it at
the correct level within the framework of HHS. This would allow it to
pursue valuable areas of research, for example into effectiveness and
outcomes areas that are not directly the focus of FDA. In addition, one
potentially exciting output of this institute could be research into
methodologies for improving the approval processes. Such research could
be conflicted if the Institute were placed within the FDA as the
current process reflects the regulatory tools now used by the agency in
its activities. Placing this institute at the level of reporting to the
Secretary of HHS would give this organization appropriate independence
from FDA, visibility and stature and does not undermine the agency's
ability to implement output from the institute. Also, industry funding
partners would be able to distance themselves from the regulatory
approval process and potential for criticisms that would result if the
organization were placed within the FDA.
QUESTION OF SENATOR KENNEDY
Question. Outcomes of studies that are negative or that suggest
toxicity in patients are often not published. The legislation I
introduced with Senator Enzi requires publishing clinical trial
results, both positive and negative, in a public database. What impact
do you think this would have for patients, healthcare providers, and
the research community?
Answer. We believe that physicians, patients and the research
community have a legitimate interest in clinical trial results
regardless of whether the results show an advantage for an intervention
or not.
In recent months, the traffic to clinicaltrials.gov has grown
illustrating an interest in the availability of trial information, but
not necessarily reflecting the utility of the information. A patient or
treating physician needs to know how to interpret the information
(either positive or negative) in order for it to be useful.
During the period from May until October 2005 there was a
73 percent increase in the number of trials registered to
www.clinicaltrials.gov--from 13,153 to 22,714 (see graph).
During the period from September 2005 until November 2006
there was a more than a hundred-fold increase in the number of browsers
to Johnson & Johnson's postings on www.clinicaltrials.gov from 37 to
more than 4,000 in November of this year (see graph).
In order for patients and physicians to effectively use the
information they learn from clinicaltrials.gov, it is important to
understand the strength of the clinical evidence. The strength of the
clinical evidence is related to the scientific method that was used to
produce the results. In the case of a consumer encountering postings of
negative information, there could be unintended consequences in terms
of misinterpretation, or cessation of use of a needed medicine. A
consumer must know how to interpret the information they read and this
should be through the assistance of a learned intermediary who can
evaluate the relevance of the information to a specific situation and
guide the decisions on the course of treatment. The importance of the
contribution of the learned intermediary in this context should not be
underestimated.
When apparently similar studies, with similar populations and
ostensibly the same intervention, give apparently conflicting results,
physicians and even other researchers may not be in a position to
reconcile and integrate the findings in such a way that meaningful
conclusions can be drawn.
There is genuine scientific benefit in having results from all
studies available to members of the scientific research community, who
can bring sophisticated skill to evaluating complex and often
preliminary and exploratory data from early clinical trials. These
experts often specialize within specific therapeutics areas, use
sophisticated statistical methods, and apply experience and judgment of
the principles of evidence-based medicine to weigh the strengths and
weaknesses of various types of trials and their resulting data. This
skill is needed to be able to assess varying and sometimes conflicting
data into an interpretable body of evidence.
For experts who synthesize research findings, particularly when
they calculate a quantitative summary of results, the unavailability of
unpublished results may produce misleading summary evaluations. This
would be the case if the publication of certain types of results (e.g.,
those not favoring the intervention of interest, or those showing harm
resulting from an intervention), were systematically suppressed from
the scientific literature, either through the researchers' failure to
submit the papers for publication or through the failure of journals to
publish what editors might view as ``uninteresting'' results (e.g.,
results showing no difference between two treatments).
At the same time, information from clinical trials may well be
difficult for patients, and indeed, some healthcare professionals, to
assess accurately. Significant patient education will be necessary in
order to avoid unintended and potentially harmful effects to patients.
Congress should consider how best to ensure patients are educated
before raw results are made broadly available. Laypersons, as well as
many healthcare professionals who are not experts in clinical trial
analysis may misinterpret data in two ways:
First, by interpreting data from early stages of human
research as if it were from later stages of research. The research
methodology of early trials is not robust enough to formally test for
benefits, but rather is designed to evaluate adverse experiences or
assess maximum tolerated doses. A related issue is interpreting data
from a study in one indication as if it is in a different indication.
It would be unfortunate for patients who are receiving potentially life
saving treatment for one indication to cease therapy because they
become aware of toxicity data in another newly tested indication or
population.
Second, promising but preliminary data from dose ranging
studies, or hypotheses-generating studies may be misinterpreted as
implying benefits that cannot be proved by the study design. Benefit
cannot be formally evaluated in other than definitive studies, such as,
for example, mortality studies in cardiovascular disease. By assuming
benefit that has not been proven, patients could be exposed to
potentially harmful untested therapies.
Organizations conducting new drug development studies invest
significant research time and resources in exploring potentially
beneficial uses of novel therapies. Typically this involves the
exploration of multiple indications, populations, dose ranges over
increasing numbers of patients treated in clinical trials. Much
negative trial data is to be expected from such research and this
should be well understood. If early clinical trial data is made broadly
available, it will be necessary to educate patients so that they can
better communicate with their physicians about these data.
One final caution is that there is a major investment in innovation
associated with investigating novel therapies. This investment could be
compromised through early release of commercially sensitive data from
clinical trials. Sufficient protections to support these investments
must be considered.
QUESTIONS OF SENATOR MURRAY
Question 1. One of my goals for FDA has always been trying to find
the right balance between getting new drugs to patients without delay
while ensuring safety and effectiveness. I know it's a tough balance
and we always have to be concerned about unintended consequences for
any actions we take legislatively. I also think we need to be concerned
about making sure that patients get good information--not conflicting
information or even information that simply focuses on risks and not
benefits. We have to be sure not to scare patients away from
potentially beneficial treatments. There are risks with any drug or
device, and we could raise safety flags on any new treatment, but this
could also deter access. How can we achieve this balance and do you
have concerns about the impact of the IOM recommendations or the Enzi-
Kennedy bill as it relates to access?
Answer 1. Senator Murray raises very real issues about the loss of
balance potentially resulting from a singular focus on safety, and not
benefit/risk. The issues at hand are especially pertinent to the
inherent tension between early approval and availability of products
for unmet medical needs and the fact that we will always know less
about risks than is ideal in this situation. The balance needs to be
achieved through avoiding legislation that may result in inadvertently
denying access to therapies (i.e., distribution restrictions) but
focusing more on ensuring the agency has administrative mechanisms for
evaluating potential risks and negotiating with companies on the
product and population-specific methods of minimizing those risks.
Overall, the IOM report and the Enzi-Kennedy bill recognize the need
for this balance, but Congress should consider carefully before
legislating periods of restrictions such as fixed moratoriums on DTC,
distribution restrictions, or REMS that are template in nature. A
preferable alternative would be for Congress to direct FDA to consider
these matters through administrative procedures that ensure an
appropriate risk-based scientific evaluation guides such restrictions.
Question 2. As the IOM report noted, 21 percent of prescriptions in
2001 were for off-label uses, meaning of course that these uses were
never reviewed or approved by FDA. Many patients often are not even
aware of off-label use. However, as Diane Thompson pointed out, off-
label use is extremely important for pediatric patients as well as
patients with rare diseases. I agree that additional safety data is
warranted for off-label use, but are you concerned about efforts to
discourage off-label use? Once again is there a way we can encourage
greater safety data on off-label use without jeopardizing access or
impeding the practice of medicine?
Answer 2. In the opinion of treating physicians the use of products
in unapproved, or off-label, indications may be in the best interest of
the patient because it is consistent with the best science at the time.
That said, it may not be a priority for an innovator company focusing
its limited research resources on areas of larger medical need and
where more safety data exist to support development programs. The FDA
can always discuss with companies, as can any scientific organization,
the potential for areas of research in unapproved indications, and
these need to be balanced against other research opportunities and
priorities of the company. With respect to pediatric indications,
encouraging specific research through offering data exclusivity and
other programs has been a very useful path forward, and is now also
being followed in the EU as a way of generating these data. We should
be very careful not to inadvertently expose patients to unethical or
unsafe exposure to products in unapproved indications outside the
protections provided under an IND. The matter of unapproved uses is an
important area for continued discussion.
Question 3. It has become very clear that we need a more uniform
mechanism for collecting safety data. Currently the process for
reporting adverse events is fragmented and there is little role for the
patient. In fact, FDA does not even have a database of reported adverse
events.
As an early champion, with Senator DeWine, of 1-800 Mr. Yuck, a
national poison control center hotline that provides real time,
accurate information to parents and providers in response to accidental
poison exposure, I know how difficult it is to create a national
database of real time information. But, we did succeed. We now have a
national poison control database that can provide information to any
caller across the country regarding accidental exposure to poisons.
Using the data mined from this database we can also find information on
increases in exposure to certain poisons and even local trends that
could indicate widespread problems.
I think we need to consider a national reporting structure for
adverse events associated to all medications. Many patients don't even
know what an adverse event is and when a side effect may or may not be
a concern. This kind of database could provide a great early warning
system as well.
What steps can we take to improve the collection of adverse events
and how can we be sure that patients are included in this process?
Answer 3. There are a number of very important steps that can be
taken to improve the collection and analysis of adverse events. A key
issue is to collect high quality information and ensure appropriate
followup. This balance can be achieved, although with the following
potential considerations:
The current FDA Adverse Event Reporting System (AERS)
database needs to be updated and maintained. One option would be to
streamline this by private/
public partnerships to ensure that cutting edge technologies, validated
and maintained current with dictionary and database oversight, are
implemented to allow consistent reproducible searching of data.
Physicians and healthcare professionals need to be
encouraged to report adverse events, perhaps through incentives linked
to performance measures specifically in this area. Considerations such
as how to streamline this activity are critical as disruption to
clinical workflow will need to be avoided.
Opportunities to gather rich clinical data and safety
information from claims and clinical databases should be accelerated,
once again through public/private initiatives while protecting patient
privacy. We need to move away from passive, spontaneous reporting to
automated systems of surveillance.
Thank you for the opportunity to provide input on these important
issues before the Senate HELP Committee. Please let me know if I can
provide any further information.
Response to Questions of Senators Enzi, Kennedy, Murray,
and Clinton by Jim Guest
QUESTIONS OF SENATOR ENZI
Question 1. You suggest increasing the opportunity for and
transparency of scientific dissent within FDA. One of the
recommendations you make is that dissenters be offered whistleblower
protections. However, dissent and discussion are an inherent part of
the scientific enterprise. Rarely is there complete certainty based on
the data. Do you really think it helps the FDA scientists to equate
dissent with whistle-blowing?
Answer 1. Of course dissent and debate should be part of the
scientific process. However, there is a distinction between an honest,
competent scientific discussion--including disagreement--and a
whistleblower who reports on an illegal or improper action which
threatens the public interest. In a very real sense, in a scientific
agency like the FDA, allowing and encouraging public scientific dissent
(and making such dissent public in a timely manner) will eliminate many
or even most of the need for public servants to become whistleblowers.
What I am suggesting in the way of additional views and dissent is
elaborated on in my response to Senator Kennedy's question. Our concern
is that, for example, a junior staffer might feel that a dissent from
the opinion held by, say, a section head would destroy future promotion
opportunities. Assuming that the dissent (or additional views) were
based on reasonable science, what guarantees can we give to younger
civil servants that raising red flags is acceptable within the FDA?
There should be a civil service appeals process in which staffers who
believe their career path is harmed by speaking out can seek review and
redress. To ensure objectivity in that appeals system, the office of
review should have some independence--like a whistleblower/ombudsmen
office would have. As you indicate, names are important, and perhaps it
should be called something like ``Office of Scientific Integrity.''
It is worth noting the December 1, 2006, Wall Street Journal
article ``Virulent Strain: Inside FDA, a Battle Over Drug to Treat
`Darth Vader' Bacteria.'' The report describes the issues over the
approval of the anti-heart valve infection drug Cubicin. It concludes
with the following paragraph:
``An internal e-mail sent out to staffers who worked on the
Cubicin application by an FDA administrator said, `this has
been a very difficult application,' and promised that
dissenting reviewers could note their disagreement for the
record, with no retribution. . . .''
In short, there is precedent for this idea of dissent, but it
should go without saying that there is ``no retribution,'' and a system
should be institutionalized to make that promise a guarantee.
There is language in the FDA regulations that seems ignored, but
which, if codified and made prominent in the agency's culture, could
address many of the morale and scientific problems that have plagued
the FDA in recent years. We urge you to codify and put some teeth into
compliance with 21 CFR 10.70, which currently reads as follows:
(1) Appropriate documentation of the basis for the decision,
including relevant evaluations, reviews, memoranda, letters, opinions
of consultants, minutes of meetings, and other pertinent written
documents; and
(2) The recommendations and decisions of individual employees,
including supervisory personnel, responsible for handling the matter.
(i) The recommendations and decisions are to reveal
significant controversies or differences of opinion and their
resolution.
(ii) An agency employee working on a matter and, consistent
with the prompt completion of other assignments, an agency
employee who has worked on a matter may record individual views
on that matter in a written memorandum, which is to be placed
in the file.
The type of serious concerns identified by the Union of Concerned
Scientists (and by the HHS OIG) in their poll of FDA scientists could
also be addressed by institutionalizing respect for science. S. 1358
(Senators Durbin and Lautenberg), the ``Restore Scientific Integrity to
Federal Research and Policymaking Act,'' has language we urge you to
consider which would prevent political interference with science and
punish managers who violate such non-interference provisions. One of
the reasons for the culture/morale problems in the FDA is the
widespread belief that senior managers regularly have ex parte contacts
with industry applicants and then use these undocumented contacts to
overrule line staff. We hope that you could also codify the idea that
ex parte contacts are prohibited, or if they occur, must be documented.
Question 2. You suggest that the clinical trial results disclosure
provisions in the Enzi-Kennedy drug safety proposal allow too much time
for study sponsors to seek publication of their results. But don't we
want to encourage publication in peer-
reviewed medical journals?
Answer 2. We must find a way to move this science into the public
domain sooner. Certainly, if there are findings of danger, or warnings
of danger that call for additional research, the findings should be
posted immediately or within a set period of time, such as 2 working
days.
We urge your consideration of an exciting article in
www.plosclinicaltrials.org, October 2006 e31, by Elizabeth Wager and
entitled ``Publishing Clinical Trial Results: The Future Beckons.'' The
article makes a moral case for publication of trial results, points to
the many problems with the current journal system, and basically
concludes:
``A new model might therefore be for investigators or
sponsors to make results available on publicly accessible
Websites using standard templates and for journals to add value
by publishing peer-reviewed commentary and synthesis.''
Wager notes that ``it is ironic that medical journals, for so long
the bastion of publishing research findings, may now prevent or delay
other, possibly better, forms of publication.''
A 1-year limit in your bill on the publication of results should
help force changes in this sector that we believe would be in the
public interest.
Question 3. Where is the line between the FDA limiting the
marketing and use of a new drug and the FDA interfering in the practice
of medicine?
Answer 3. Your bill encourages the practice of good medicine. There
have been repeated studies showing that despite black box warnings and
other strong guidance to the medical community, very potent drugs are
repeatedly prescribed inappropriately. Physicians are busy and errors
happen. For drugs that can be dangerous (e.g., accutane in a pregnant
woman), your bill systemizes safeguards that will reduce mortality and
morbidity in the future. We see nothing in your bill that interferes
with the good practice of medicine, though it does interfere with the
bad practice of medicine. Physicians should thank you for reducing the
chance for errors that may harm their patients.
Question 4. Without advertisements, how would consumers learn about
drugs that might help them?
Answer 4. Just as most of us don't need ads to tell us when to eat,
most of us go to a doctor when we feel sick or something doesn't feel
right--and that's the best way to get an appropriate prescription.
Studies have shown that DTC ads prompt people to ask for medicines that
are often inappropriate, and to keep customers happy, doctors all too
often comply with the request.
We are seeing the over-medication of America because of the
enormous profits that flow from direct-to-consumer advertising. I was
nervous testifying before the committee--but I don't think that means I
needed to take a pill, like the television ads keep pushing. In short,
Americans were doing fine before DTC ads, and we will do fine without
them. And remember, the proposal is simply to limit for a few years ads
for drugs which have shown warning signs of trouble.
In cases where there may be a problem that is hard to talk about,
or a new vaccine, such as the one for young women to help prevent
cervical cancer, Public Service Announcements could be run. The PSAs
could be cleared for objectivity and scientific validity by a group
within the FDA or NIH and funded through an industry user fee system.
QUESTIONS OF SENATOR KENNEDY
Question 1. The IOM report discusses the need to encourage a
culture of safety at FDA. Some commentators have argued that FDA needs
better ways to recognize diverse scientific interpretations of data in
its review panels, and to create a climate where scientific debate is
encouraged. What actions need to be taken legislatively to bring about
this cultural change?
Answer 1. I would like to offer two different ideas, either of
which could be legislated and, I believe, would greatly increase the
morale and culture of scientific vigor at the FDA.
Proposal #1: Recently Acting Commissioner Dr. von Eschenbach
responded to a question by Senator Grassley about the need for an
independent office of safety by describing, in detail, all the ways
that the Office of Surveillance and Epidemiology (OSE) works with the
Office of New Drugs (OND), and indicating it would be duplicative and
wasteful to separate the two offices. But we believe that the FDA's
morale and culture of scientific vigor could be improved by a variation
of the separation of offices proposal, and avoid all the problems
raised by Dr. von Eschenbach. Legislation could state:
CDER consists of an OND and an OSE, and such other offices
as the Commissioner may determine necessary.
The Director of the OSE may, at any time, order a REMS
process or an amendment to any REMS process (consistent with some
timeframe for notice to the company, etc.), or order the suspension or
withdrawal of a drug, and shall provide a written brief as to his/her
reasons.
If the Director of the OND disagrees, in whole or part,
and provides a written brief as to his/her reasons within x days, the
Commissioner shall decide the issue(s) within y days, and provide a
written explanation for the decision.
After the decision has been made, the briefs and final
decision explanation shall be public documents.
Nothing else that the OSE does, which Dr. von Eschenbach defends in
his letter to Senator Grassley as coordinating and working with OND,
would change. This proposal would not disrupt anything. What it would
do is make the Director of OSE more responsible for raising questions,
and forcing an FDA-wide debate and decision within a tight timeframe.
It would give him/her co-authority with OND to force a decision at the
Commissioner level. Basically, it would focus more responsibility on
three people, rather than the very diffuse Drug Safety Oversight Board.
Proposal #2: (See also our response to Senator Enzi question #1
relating to codification of current FDA regulations.)
For every NDA (and other significant approval action) the
FDA shall develop a memorandum (to be made public at the point of final
decision) explaining the decision to approve, adjust, or reject an
application, signed by the members of the team working on the NDA.
The memorandum shall include a provision for additional
views, in which any staff member may raise questions, and urge further
studies and clarifications.
It shall also include a provision for dissenting views in
the case of any staff person who believes unresolved questions and
issues outweigh potential benefits.
In determining what level of REMS to establish, the
Commissioner shall give ``weight'' to the additional and/or dissenting
views.
There would be Office of Scientific Integrity language
(see response to Chairman Enzi's first question) to protect those who
participate in additional or dissenting views.
Title IV would be amended to provide that any advisory
committee member can request the presence and participation of any FDA
staffer who signed a NDA memorandum, either in the majority, additional
views, or dissenting views. Any FDA staff that conceals relevant
information from an Advisory Committee should be subject to discipline.
(In the meantime, we have seen press reports (Inside Health Policy,
November 14, 2006, ``HHS Seeks to do Away with Incentives, Protections
for Scientists''), that in on-going labor negotiations between FDA
management and union representatives, that the Administration is trying
to weaken protections for workers who dissent. If these press reports
are true, they take the agency in absolutely the wrong direction, and
we urge you to contact the FDA as soon as possible in opposition to
such a negotiating position.)
There has to be science for there to be scientific dissent, and the
IOM report makes clear that the FDA needs to do more to promote and
advance science. We urge you to do more to encourage original
scientific work within the FDA. The IOM report makes many
recommendations for increasing the level of science within the agency,
both for the public good, and as a way to increase morale and build a
more stable FDA workforce. In addition to resources for continuing
medical education and participation in scientific conferences, more
should be done to encourage scientific publication: pre-clearances and
restrictions on publishing should be dropped (anyone intelligent enough
to be published in a Journal is smart enough to know what is and is not
the policy on proprietary information), and managers and staff should
be measured by and rewarded for the quantity and quality of scientific
publication that comes out of their Office and Center. We urge you to
consider the language in H.R. 5922 which provides encouragement for
scientific publication.
Question 2. Outcomes of studies that are negative or that suggest
toxicity in patients are often not published. The legislation I
introduced with Senator Enzi requires publishing clinical trial
results, both positive and negative, in a public database. What impact
do you think this would have for patients, healthcare providers, and
the research community?
Answer 2. This is a very important provision that will truly save
lives, reduce illness, and speed the rate of scientific research and
knowledge through the world medical community. It is one of the key
improvements in S. 3807.
We hope it can be strengthened even more by covering all Phase 2
results. We hope that you will ask the GAO, or some other appropriate
body, to report on whether some or all Phase 1 results should be made
public at the time the drug involved is either approved or withdrawn
from development. People should not be treated as guinea pigs and then
have the scientific knowledge gained from their participation in
sometimes dangerous trials hidden from the world scientific community.
We urge that the bill also provide for the quicker publication of
results (especially negative results showing dangers). Finally, we
think this data is so important, we hope that you will phase in the
publication in the database of the last 10 years of trial results.
QUESTIONS OF SENATOR MURRAY
Question 1. One of my goals for FDA has always been trying to find
the right balance between getting new drugs to patients without delay
while ensuring safety and effectiveness. I know it's a tough balance
and we always have to be concerned about unintended consequences for
any actions we take legislatively. I also think we need to be concerned
about making sure that patients get good information--not conflicting
information or even information that simply focuses on risks and not
benefits. We have to be sure not to scare patients away from
potentially beneficial treatments. There are risks with any drug or
device, and we could raise safety flags on any new treatment, but this
could also deter access. How can we achieve this balance and do you
have concerns about the impact of the IOM recommendations or the Enzi/
Kennedy bill as it relates to access?
Answer 1. I do not see any way that the IOM recommendations or the
Enzi/Kennedy bill denies access.
I understand your concern that too much negative information may
deter some from trying a drug. But in general, we always support the
right of consumers to full information about products--whether it is
the safety of cars or of prescription drugs. A consumer should have the
right to decide whether a drug's possible side effects, even though
unlikely, might not be worth the risk for the condition in question.
Or, if the consumer has information identifying possible problems with
one drug, it can help them ask whether there are other drugs in the
class or in another class that can work without the risk.
The right of consumers to have full information is particularly
important in this age where so much is spent on slick direct-to-
consumer ads, and so many researchers, journals, and even physicians
have become financially conflicted.
Question 2. As the IOM report noted, 21 percent of prescriptions in
2001 were for off-label uses, meaning of course that these uses were
never reviewed or approved by FDA. Many patients often are not even
aware of off-label use. However, as Diane Thompson pointed out, off-
label use is extremely important for pediatric patients as well as
patients with rare diseases. I agree that additional safety data is
warranted for off-label use, but are you concerned about efforts to
discourage off-label use? Once again is there a way we can encourage
greater safety data on off-label use without jeopardizing access or
impeding the practice of medicine?
Answer 2. We in no way want to discourage responsible off-label
use. We are simply asking for the FDA to obtain studies on the most
commonly prescribed off-label uses to ensure that the science supports
the safe use of these drugs. Ideally, the studies will lead to label
amendments so that the drugs are used ``on-label'' and the science of
pharmaceuticals is expanded and improved. The requirement for studies
is an obligation on the companies (or the FDA/NIH if their budgets
permit) and not on the individual physician or pharmacist. The proposal
does not in any way interfere with the doctor/patient relationship.
As you know, one recent medical journal article found that of the
21 percent prescribed off-label, in 73 percent of those cases there was
no science to support such use. A little more science would be a good
thing. Also, since the hearing, there are major new reports about the
safety of drug-coated stents. These stents have been used extensively
off-label on older, less healthy patients than the FDA approved. The
result is a high level of heart incidents and deaths--and reminds us
once again about the importance of applying more science before drugs
or devices are used widely off-label.
Question 3. It has become very clear that we need a more uniform
mechanism for collecting safety data. Currently the process for
reporting adverse events is fragmented and there is little role for the
patient. In fact, FDA does not even have a database of reported adverse
events.
As an early champion, with Senator DeWine, of 1-800 Mr. Yuck, a
national poison control center hotline that provides real time,
accurate information to parents and providers in response to accidental
poison exposure, I know how difficult it is to create a national
database of real time information. But, we did succeed. We now have a
national poison control database that can provide information to any
caller across the country regarding accidental exposure to poisons.
Using the data mined from this database we can also find information on
increases in exposure to certain poisons and even local trends that
could indicate widespread problems.
I think we need to consider a national reporting structure for
adverse events associated to all medications. Many patients don't even
know what an adverse event is and when a side effect may or may not be
a concern. This kind of database could provide a great early warning
system as well.
What steps can we take to improve the collection of adverse events
and how can we be sure that patients are included in this process?
Answer 3. This is an exciting proposal. I believe that within a few
years, there will be widespread use of electronic Personal Health
Records (PHR), and we hope that there are strong patient privacy and
security built-in. We urge you to include a new section in the bill
which will establish a system that enables a patient (with their
consent) who gets a prescription (especially a new molecular entity or
other new, breakthrough drug) to be queried electronically at, say, 2
weeks, 1 month, 2 months, and at some later dates. The query would ask
for any adverse events and any major medical events in the patient's
life, etc., with responses collected in certain electronic fields. The
electronic response would go to a secure FDA database in a format that
would allow systematic analysis and the search for short- and long-term
problems.
Such a system would be an enormous improvement over today's systems
which we estimate collect only 1 to 10 percent of all ADRs, and which
often miss major problems that are buried in the ``background noise''
of the medical incidents of an aging society.
QUESTIONS OF SENATOR CLINTON
Question 1. In your written testimony, you talk about the need for
legislation that would establish a path for the approval of biogeneric
drugs. Could you elaborate on the ways in which increasing access to
biogenerics could improve access to safe and appropriate treatments for
patients?
Answer 1. Biologics hold much promise for the future, but come with
awesome price tags. Without generics available at the end of the
biologics patent/exclusivity life, there will be little or no price
competition, and some consumers might never be able to afford such
medicines.
We know that the development of safe biogenerics will not be easy,
and it will take time. We hope you will start the process of developing
a biogeneric pathway in this bill, so that there is hope for financial
relief in the future.
Question 2. Consumers Union has been a strong advocate of
comparative effectiveness studies, which allow us to determine the
benefits of a range of treatments for a certain disease and ensure that
providers and patients are making treatment choices that are evidence-
based, and not unduly influenced by direct-to-consumer advertising or
other marketing efforts.
These comparative effectiveness studies complement the drug
approval work of the FDA. The agency's approval process focuses largely
on ensuring that the drugs that come to market are safe for consumers.
But newer drugs are not always better drugs, and may not be the
clinically appropriate choice for all patients with a given condition.
Comparative effectiveness studies are not a substitute for thorough
and unbiased safety reviews at the FDA. But the studies completed so
far highlight the shortcomings that we have faced at the agency and the
need for reforms in our drug safety system.
One of the first studies to be carried out under the comparative
effectiveness studies provision of the Medicare Modernization Act was a
systematic review of COX-2 drugs, the class of drugs that includes
Vioxx.
The results of this study, which were released in September, found
no difference in the effectiveness of COX-2 painkillers compared with
over-the-counter pain relieving drugs.
How can comparative effectiveness studies help us to weigh the
risks and benefits of the drugs used by consumers?
Answer 2. We believe one of the long-term hopes for slowing the
unsustainable inflation in American healthcare is through comparative
effectiveness research and trials--not just of pharmaceuticals, but of
medical processes, devices, surgeries, etc. We deeply appreciate your
leadership in the passage of Section 1013 of the Medicare Modernization
Act, which establishes a program of comparative effectiveness research
within the Agency for Healthcare Research and Quality.
The example you provided on COX-2 Inhibitors is an excellent
example of the usefulness of comparative effectiveness studies. Another
example that emerged within weeks of the hearing where I testified was
the report showing that the expensive new generation of anti-psychotic
drugs offers little or no advantage over the older drugs in this field.
For newly diagnosed patients or patients having trouble with one of the
new generation anti-psychotics, this comparative effectiveness analysis
shows that other, much lower cost medicines are available that may be
equally helpful. A third example was illustrated on December 6, 2006,
at a hearing before the Ways and Means Committee, which identified
serious danger to the Nation's hundreds of thousands of end stage renal
disease patients, and hundreds of millions of dollars in excessive
payments for a drug used in kidney dialysis. There had been warnings
for years about the over-use of this drug, but no research had been
undertaken until very lately to determine whether the warnings were
valid, despite the lives at stake and the enormous cost of the drug.
For Americans to receive the safest, most effective, and in the
long run lowest cost medicines (because they work safely), we need to
greatly increase the funding of section 1013 and use the Medicare Part
A, B, and D databases to link various drug and treatment options with
actual successful outcomes. We hope that you will include resources (if
necessary, through user fees) in S. 3807 to fund an aggressive FDA use
of the huge new patient de-identified databases now available to us. In
addition to increased appropriations for section 1013, we hope Congress
will explore through hearings other ways to provide greatly expanded,
reliable sources of funding comparative effectiveness trials. For
example, such funding could be through a very small medical drugs and
devices profit surtax or ``user free'' at the company level, or a penny
fee per prescription and device at the customer level. Even at the
level of a penny per prescription, millions would be raised for section
1013 research which could quickly save billions of dollars in future
healthcare costs.
Response to Questions of Senators Enzi, Kennedy, and Murray
by Greg Simon
Thank you for the opportunity to answer questions based on my
testimony before the HELP Committee on November 16.
QUESTIONS OF SENATOR ENZI
Question 1. How can we design and enforce post-approval studies
that would be early indicators of safety issues to enable earlier
approval of treatments with proven benefits?
Answer 1. The actual design of a safety study is intricately tied
to the nature of the therapy, the intended use, foreseeable off-label
uses and sectors of the population expected to use the drug or device.
The FDA needs access to more reviewers and experts who can give careful
thought to these issues during the pre-approval NDA submissions so that
in the case FDA approves a product, thoughtful post-
approval studies are designed based on the most up to date, available
science.
The FDA's authority to enforce post-approval studies needs to be
strengthened and its budget increased to permit improved continuous
safety monitoring and enable the FDA to balance its obligation to bring
new therapies to the public and to monitor adverse effects that are
inevitable for any therapy in some segment of the population.
As stated in our testimony,
1. The FDA needs to be able to assess a drug's impact
post-approval, weigh both benefits and risks and take appropriate
action to protect the public;
2. To do that the FDA needs much stronger authority to
regulate and enforce how an approved drug enters the market, how it is
advertised, what claims are made for it and how labels are updated to
reflect growing knowledge of a product;
3. To do those things the FDA needs increased
appropriations from Congress and should not be forced to rely on
industry user fees which the FDA is largely restricted from using on
post-approval activities.
Question 2. Can you comment on the balance between increasing
transparency and commercially sensitive information in the context of
clinical trial results disclosure?
Answer 2. It is well established that commercial speech is less
protected under the Constitution than is non-commercial speech. When
there is a conflict between the public's right to know what happened in
a clinical trial affecting human health and safety and a company's
interest in protecting commercial interests, the public should win
every time barring extraordinary circumstances. FasterCures as an
organization advocates for positions that save lives by saving time. We
believe that it is very important to consider and protect patients'
interests at each step of the process of scientific discovery.
We believe that patients should be armed with information that will
help them and their health providers make good treatment decisions for
the individual. Part of this is making available meaningful information
during and after the clinical trial process.
We believe that disclosure of both positive and negative outcomes
is vital to the progress of medical research and to patient safety.
While there is a case to be made to disclose all clinical trials data
starting with Phase 1 trials, FasterCures supports the Enzi-Kennedy
bill requirement of disclosure of aggregated clinical trial data
starting with Phase 2 data. We want companies to be able to compete
adequately in the market place of ideas and to retain proprietary
information that will motivate them to innovate and improve safety
profiles of treatments, but we also want this information to inform
treatment decisionmaking.
We believe one area of this debate that has not had enough thought
and energy is finding policies that will help avoid exposing people to
potential harms that have been shown to have no benefit or to
unnecessarily repeating trials that worked and that need to move
forward into therapies.
Question 3a. I noted in your testimony you expressed support for
the creation of the Reagan-Udall (RU) Institute. Do you have any
thoughts about the placement of the Institute and how to maximize its
chances of it being successful and minimization of conflicts of
interest?
Answer 3a. To keep FDA moving forward and preparing for the science
of tomorrow, we must continue to invest in the infrastructure of
regulatory science. The RU Institute should be located at the FDA and
serve as the FDA's research arm to examine the FDA's extensive
accumulated data of the history of drug development and to identify
best practices and new promising approaches to therapy development.
Question 3b. Do you think the timeframes for FDA action proposed in
S. 3807 are reasonable?
Answer 3b. FasterCures believes the timeframes are reasonable
generally but that the committee should be flexible in this area and
focus more on provisions to strengthen the FDA's authority and budget.
Question 4. Does our current system of approval and post-approval
review take into account the very different perspectives people with
life threatening diseases have about ``risk,'' as compared to the
concerns of the ``well'' population?
Answer 4. Finding a way to adequately balance risk tolerance and
benefit for individual patients is very challenging. Each person
assesses benefit differently based on his or her life experience. We
believe the agency should redouble its effort to communicate its
benefit and risk determinations in the approval process. FasterCures
believes patients should have access to new and innovative medicines
even when they have known risks. The challenge is to inform these
patients and their healthcare providers properly so that they have a
clear understanding of a product's benefit and risk profile and can
make good decisions for that individual patient.
FasterCures believes that properly addressing post-approval safety
issues should allow the FDA to move more expeditiously to approve
therapies for terminal illnesses and conditions, knowing that the
chance of a benefit can outweigh the known threats from the disease or
condition.
We believe properly addressing post-approval safety issues will
help agency reviewers avoid being overly cautious in the pre-approval
stage out of fear that they have few good options to monitor or affect
use of the product post-approval.
QUESTION OF SENATOR KENNEDY
Question. Outcomes of studies that are negative or that suggest
toxicity in patients are often not published. The legislation I
introduced with Senator Enzi requires publishing clinical trial
results, both positive and negative, in a public database. What impact
do you think this would have for patients, healthcare providers, and
the research community?
Answer. At FasterCures, we often talk about the need for a Journal
of Failure. We believe a public database to capture the results of both
positive and negative clinical trials is vital to pursuing cures.
Although this will mean culture change in the research community, it is
the most efficient antidote to the lack of awareness that can exist
when information is not available about who has done what and what has
and has not worked.
QUESTIONS OF SENATOR MURRAY
Question 1. One of my goals for FDA has always been trying to find
the right balance between getting new drugs to patients without delay
while ensuring safety and effectiveness. I know it's a tough balance
and we always have to be concerned about unintended consequences for
any actions we take legislatively. I also think we need to be concerned
about making sure that patients get good information--not conflicting
information or even information that simply focuses on risks and not
benefits. We have to be sure not to scare patients away from
potentially beneficial treatments. There are risks with any drug or
device, and we could raise safety flags on any new treatment, but this
could also deter access. How can we achieve this balance and do you
have concerns about the impact of the IOM recommendations or the Enzi/
Kennedy bill as it relates to access?
Answer 1. Both the Institute of Medicine (IOM) report and S. 3807
will improve access by focusing resources on post-approval safety
studies, thereby improving the FDA's ability to approve needed drugs
knowing they are being well monitored for safety post-approval.
The IOM focus on better labels to communicate with the public is
vital to increasing the public's understanding of the risks and
benefits of new therapies.
Disclosure of clinical trial results is also critical to
communicating to the public, the medical research community, and
physicians the risks and benefits of new proposed therapies.
Question 2. As the IOM report noted, 21 percent of prescriptions in
2001 were for off-label uses, meaning of course that these uses were
never reviewed or approved by FDA. Many patients often are not even
aware of off-label use. However, as Diane Thompson pointed out, off-
label use is extremely important for pediatric patients as well as
patients with rare diseases. I agree that additional safety data is
warranted for off-label use, but are you concerned about efforts to
discourage off-label use? Once again is there a way we can encourage
greater safety data on off-label use without jeopardizing access or
impeding the practice of medicine?
Answer 2. At FasterCures, we believe that off-label use of
medication remains an important option for health providers and their
patients. Those patients with the most intractable and serious diseases
that often have no identified cures need to be able to work with their
healthcare providers to find the best treatment options. Thus, we are
concerned with efforts to discourage off-label use.
With that said, we believe that medical professional societies
should, and can, do more to ensure that doctors are aware of the
latest, unbiased treatment options. Physicians should be encouraged to
share voluntarily their knowledge and experience from off-label usage
of a drug so that we learn how medications are succeeding and failing
in various populations.
Question 3. It has become very clear that we need a more uniform
mechanism for collecting safety data. Currently the process for
reporting adverse events is fragmented and there is little role for the
patient. In fact, FDA does not even have a database of reported adverse
events.
As an early champion, with Senator DeWine, of 1-800 Mr. Yuk, a
national poison control center hotline that provides real time,
accurate information to parents and providers in response to accidental
poison exposure, I know how difficult it is to create a national
database of real time information. However, we did succeed. We now have
a national poison control database that can provide information to any
caller across the country regarding accidental exposure to poisons.
Using the data mined from this database we can also find information on
increases in exposure to certain poisons and even local trends that
could indicate widespread problems.
I think we need to consider a national reporting structure for
adverse events associated to all medications. Many patients don't even
know what an adverse event is and when a side effect may or may not be
a concern. This kind of database could provide a great early warning
system as well.
What steps can we take to improve the collection of adverse events
and how can we be sure that patients are included in this process?
Answer 3. FasterCures supports improving the adverse event
reporting system from both the reporting side and the monitoring and
evaluation side by dedicating significant financial and staff resources
to overhauling the current system.
Currently the United States has a voluntary reporting system for
health professionals. Constraints on physicians' time and a reluctance
to seek out and report adverse events, have contributed to the system's
lack of effectiveness.
We need to identify ways to make reporting more consistent so that
better data is captured. We also need to invest in an electronic real-
time system that allows computer analysis to spot trends and patterns
that might elude a human reviewer. We believe an analysis of the pros
and cons of the ``yellow card'' system in England need to be explored
and examined.
Again, thank you for the opportunity to provide answers to these
questions. Please contact Margaret Anderson at
[email protected] if you have questions before January 8th, as
I will be out of the country. Thank you.
[Whereupon, at 11:53 a.m., the hearing was adjourned.]