[Federal Register Volume 65, Number 128 (Monday, July 3, 2000)]
[Notices]
[Pages 41073-41076]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-16760]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Office of the Secretary
Human Subject Protection and Financial Conflict of Interest:
Conference
AGENCIES: OASPE, OPHS, NIH, FDA, and CDC, HHS.
ACTION: Notice of conference; request for comments.
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SUMMARY: A Conference on Human Subject Protection and Financial
Conflict of Interest will be held at Natcher Auditorium, NIH Campus on
August 15-16, 2000. The issue of financial conflict of interest is one
of the 5 main issues identified by the Secretary of Health and Human
Services in her announcement of steps being taken to strengthen human
subject protection during clinical trials. In that announcement, the
Secretary stated that there would be a public process to review this
issue. She said that HHS would undertake an extensive public
consultation to identify new or improved means to manage financial
conflicts of interest that could threaten the safety of research
subjects or the objectivity of the research itself. Emphasis will be
placed on the informed consent process and how it might be clarified
and enhanced in dealing with issues related to financial conflict of
interest.
The Conference will review the current regulatory requirements and
guidance, serve as a forum for presentations of current approaches
being taken for dealing with real and potential financial conflict of
interest at the institution, IRB, and clinical investigator levels.
This conference will help the government refine its current guidance
and may lead to other changes. NIH has developed a set of issues to
consider related to its regulations which is now available as
background for the conference. Further guidance will be issued based on
the responses to questions posed in this Notice and the conference
deliberations.
To facilitate review of current policies, regulations, and guidance
documents, these documents are cited as references at the end of this
Notice. The references cited are also available electronically at the
OASPE Website (http://aspe.hhs.gov/sp/coi/index.htm).
To maximize the efficiency of this process, six questions (see
below) have been developed. Please address these in writing by August
1, 2000. This will help in organizing the plenary and concurrent work
group sessions. There will be a public session where brief comments on
these topics can be addressed during the conference.
DATES: Conference on Human Subject Protection and Financial Conflict of
Interest: The Conference will be held on Tuesday August 15, 2000 from
8:30 AM to 5:30 PM and Wednesday August 16, 2000 from 8:30 AM to 1:00
PM. Although the entire conference is open to the public and there will
be no registration fee, it is requested that all those who wish to
participate in the conference register by August 1, 2000. This will
allow us to prepare an adequate number of conference background
materials and to make appropriate assignments for the breakout
sessions.
Request for Comments: Written responses to the six questions are
requested by all parties, whether or not they will be attending the
conference, by August 1, 2000 as described below.
Opportunity for Public Comment during the Conference on August 15,
2000, 2:15-3:30 PM. There will be an opportunity to make brief
presentations during this session set aside for public comments. The
comments should be responses to any or all of the six questions listed
below. Anyone wishing to make comments should file a written Notice of
Participation as described below by August 1, 2000. You will be
contacted after all the requests are reviewed and given information
about the time of your presentation and other details.
ADDRESSES: The Conference will be held at Natcher Auditorium, Building
45, NIH Campus, 9000 Rockville Pike, Bethesda, MD 20892.
Registration Information: To register for the conference please
contact Mr. Mark Brown, CMP, MasiMax Resources, Inc., phone 240-632-
5618, FAX 240-632-0519, e-mail: [email protected]. Please register by
August 1, 2000.
Comments and Notices of Participation in Public Session: Written or
electronic responses to the six questions as well as submissions of
written or electronic Notices of Participation to speak during the
Public Session of the Conference should both be addressed to: Stuart L.
Nightingale, M.D., Office of the Assistant Secretary for Planning and
Evaluation, Department of Health and Human Services, 200 Independence
Avenue, SW, Washington, DC 20101, Fax: 202-205-8835 email:
[email protected]
Notices of Participation to present during the Public Session
should include name, affiliation, (whether person is from an IRB, an
institution,
[[Page 41074]]
industry, is a clinical investigator, etc.), main points of
presentation, how much time requested (no more than 5 minutes), and
telephone number and other contact information.
FOR FURTHER INFORMATION CONTACT: Stuart L. Nightingale, FAX 202-205-
8835, e-mail: [email protected].
SUPPLEMENTARY INFORMATION:
A. Background
In recent years, clinical research has generally become ever more
complex--which, in turn, has engendered a new degree of complexity in
accompanying ethical and conflict of interest considerations. Financial
conflict of interest in clinical trials has been of concern for a
number of years, both from the perspective of research objectivity and
human subject protection. Both the PHS and FDA have requirements/
regulations and guidance in place relating to financial conflict of
interest. Recently, financial arrangements between commercial interests
and institutions have become more common and some institutions have
arrangements with the same commercial organizations as investigators.
This has been highlighted in the area of gene transfer research.
Additionally, although IRBs are required to deal with conflict of
interest issues, these have been understood to be directed more toward
members' own conflict of interest rather than those of investigators or
institutions. There is little guidance to IRB's and a recent HHS
Inspector General's Report found that only 25 percent of IRBs review
these issues and consider them for inclusion in the informed consent
document.
B. The Secretary's Initiatives To Strengthen Human Subject
Protection
Notwithstanding the many successes over the years in protecting
human research subjects from undue and undisclosed risks, we recognize
that the protection system itself needs to be enhanced. In this regard,
we agree with the finding of the HHS Inspector General that
Institutional Review Boards (IRBs)--the central element of the system--
often have difficulty fulfilling even their fundamental
responsibilities because many of them are overworked and few have been
accorded adequate resources by their parent institutions. These
findings have been reinforced over the last two years by a series of
inspections by the HHS Office for Protection from Research Risks
(OPRR). Several inspections resulted in complete or partial cessation
of human subjects research until the institutions involved took
appropriate actions.
In response to these developments, Secretary Shalala recently
announced five initiatives designed to enhance protection for human
research subjects.
First, HHS will take steps to require that clinical investigators
and IRB members and staff undergo continuing education in issues
relating to human subjects.
Second, HHS will issue guidance making clear that research
institutions and clinical trial sponsors are expected to take stringent
continuing review actions, such as audits of research records, to
promote compliance with current informed consent requirements.
Third, HHS will expand its requirements for study monitoring--
thereby improving the oversight of even small-scale clinical trials.
Large-scale phase III clinical trials, already have the requirement to
have data and safety monitoring.
Fourth, HHS will undertake an extensive public consultation to
identify new or improved means to manage financial conflict of interest
that could threaten the safety of research subjects or the objectivity
of the research itself. The insights gained from this process will be
expressed in new guidance for the research community regarding what
information about the financial interests of investigators and research
institutions should be disclosed to research subjects and others. The
objective of this guidance will be to make current conflict of interest
regulations more effective.
Fifth, HHS will seek new legislation to enable FDA to level civil
money penalties for violation of informed consent and other important
regulatory requirements so that they can be applied to clinical
investigators and institutions. This new authority would fill a
significant gap in the current spectrum of sanctions against those who
fail to obey Federal regulations for protection of human research
subjects.
C. HHS/PHS Grant Award Requirements for Dealing With Financial
Conflict of Interest
In 1995 the Public Health Service promulgated regulations
establishing standards and procedures to be followed by institutions
that apply for research funding to ensure that the design, conduct and
reporting of research under PHS grants, contracts or cooperative
agreements would not be biased by any conflicting financial interest of
those investigators responsible for the research. These regulations
require that investigators disclose to an institutional official a
listing of significant financial interests (and those of his/her spouse
and dependent children) that would reasonably appear to be affected by
the research. The institutional official must review the disclosures
and determine whether any of the reported financial interests could
directly and significantly affect the design, conduct or reporting of
the research and, if so, the institution must, prior to any expenditure
of funds, report the existence of any conflicting interests to the PHS
awarding component and assure that the conflict of interest has been
managed, reduced or eliminated in accordance with the regulations.
D. FDA Regulations Requiring Financial Disclosure by Clinical
Investigators
On February 2, 1998, FDA published a final rule requiring that
financial interests and arrangements of clinical investigators that
could affect the reliability of data submitted to FDA be identified and
disclosed to FDA by the applicant. Clinical research data provide the
basis for FDA's assessment of whether a product is approvable under
statutory requirements. It is essential that these data be reliable and
that steps be taken to minimize possible effects on the data resulting
from potential bias on the part of any investigator. This regulation,
which became effective on February 2, 1999, applies to any applicant
who submits a marketing application or reclassification petition for a
human drug, biological product, or medical device and who submits any
clinical study of a drug or device in humans that the applicant or FDA
relies on to establish that the product is effective, or any study in
which a single investigator makes a significant contribution to the
demonstration of safety. The regulation requires applicants to certify
to the absence of certain financial interests of clinical investigators
or to disclose those financial interests. If the applicant does not
include certification and/or disclosure, or does not certify that it
was not possible to obtain the information, the agency may refuse to
file the application. On December 31, 1998, FDA published an amended
final rule that reduced the need to gather certain financial
information for studies completed before February 2, 1999.
E. Purpose of This Conference
As discussed above, the issue of financial conflict of interest in
research is one of the 5 main areas identified by the Secretary of
Health and Human Services in her announcement of steps being taken to
strengthen human subject protection during clinical trials. In that
[[Page 41075]]
announcement, the Secretary stated that HHS will hold public
discussions this summer to find new ways to manage conflicts of
interest so that research subjects are appropriately informed, and to
further ensure that research results are analyzed and presented
objectively. In addition, these public discussions also will focus on
clarifying and enhancing the informed consent process.
This Conference Will:
Implement one of the Secretary's five initiatives to strengthen
human subject protection in clinical research.
Remind participants of current PHS/FDA regulations, guidelines and
guidance through documents and presentations.
Present examples of how the issue of financial conflict of interest
is dealt with at the level of: Institutions, IRBs, and Clinical
Investigators (including Sponsor/Investigators), and Industry/Sponsors.
Receive public comments on questions posed in the Federal Register
announcing the conference.
Provide information for the Department of Health and Human Services
to develop more useful and detailed guidance to implement current
regulatory requirements.
Who Should Attend?
Institutional Officials, IRB staff and members, Clinical
Investigators, Industry/Sponsors, National Organizations/Health
Professionals, Patient and Advocate groups, Patients and Research
Participants.
General information about the conference, the conference Program is
available on the ASPE Website (http://aspe.hhs.gov/sp/coi) and at the
Website of MasiMax Resources, Inc. (www.masimax.com/coi/index.html).
F. Questions for Comment
Members of the Public who wish to respond to the following
questions, should send their comments by August 1, 2000 or comment at
the Conference during the public session (To comment at the conference
during the session for Public Comment, a Notice of Participation should
be submitted).
1. For each group listed below, what types of financial interests
are associated with human subjects research funded or regulated by HHS
agencies?
Clinical investigators (including sponsor/investigators)
IRB members and staff
Awardee institutions
2. Is there empirical evidence that informing research participants
about financial relationships or financial conflict of interest of the
investigator, the institution, or the IRB:
Can cause or prevent real or perceived harm (physical or
psychological) to human research subjects?
Can compromise the objectivity of the associated research?
Can adversely or positively affect participation in the trial?
Can enhance the informed consent process by more fully informing
potential participants?
Can be understood by and is meaningful to the potential research
participant?
3. If information about financial interests is disclosed to
potential participants in clinical trials, what information should be
disclosed and at what level of detail?
Should potential participants be told of all of the financial
interests of investigators, IRB members, or institutions, or only those
financial interests which constitute a financial conflict of interest
or might constitute a financial conflict of interest? Should potential
participants be told what protections are in place and are working to
ensure that financial conflicts are managed, reduced, or eliminated to
promote objectivity and enhance human subject protection in the trial?
Are the financial limits set forth in current PHS regulations covering
awardee institutions still appropriate for clinical researchers? What
are appropriate levels of reportable financial relationships for IRB
members and institutions?
4. If information about financial interests is disclosed to
potential participants, when and how should information about financial
conflict of interest be provided to them?
If information about financial interests/conflict of interest
involving institutions, IRBs, and investigators should be provided,
what is the optimal point in the process for disclosure?
Should information be provided by the institution, the research
investigator, the IRB, or a third party?
Should disclosure information and institutional policy be provided
in the informed consent document or in an entirely separate document?
5. What are appropriate roles for the institution, the IRB, the
clinical investigator (including sponsor/investigators), and perhaps
other entities in dealing with financial interests or financial
conflict of interest?
What are the responsibilities and obligations of each entity?
How should each entity relate to the other entities?
Should disclosed information on which determinations are made
(including deliberations) be shared with the other entities? If so,
what information should be shared and how and when should the
disclosures be conducted?
What confidentiality protections are/should be in place to
safeguard the privacy and confidentiality of the investigator, IRB
member, and institution?
6. Other than those at the Federal level, what protections exist to
ensure that the financial conflicts are managed, reduced, or eliminated
to promote objectivity in the trial and to enhance human subjects
protection?
References
HHS NEWS, U.S. Department of Health and Human Services, May 23, 2000:
``Secretary Shalala Bolsters Protections for Human Research Subjects''
HHS FACT SHEET, U.S. Department of Health and Human Services, May 23,
2000 ``Protecting Research Subjects''
Code of Federal Regulations, Title 45, Part 46, Subpart A. Federal
Policy for the Protection of Human Subjects (Basic DHHS Policy for
Protection of Human Research Subjects).
Code of Federal Regulations, Title 42, Part 50, Subpart A.
Responsibility of PHS Awardee and Applicant Institutions for Dealing
With and Reporting Possible Misconduct in Science
Code of Federal Regulations, Title 42, Part 50, Subpart F.
Responsibility of Applicants for Promoting Objectivity in Research for
Which PHS Funding Is Sought
Frequently Asked Questions Concerning the Department of Health and
Human Services' Objectivity in Research Regulations and the National
Science Foundation Investigator Financial Disclosure Policy, Federal
Register: July 3, 1996 Volume 61, Number 129, p. 34839.
Required Education in the Protection of Human Research Participants.
NIH Guidance, June 5, 2000
Financial Conflict of Interest and Research Objectivity: Issues for
Investigators and Institutional Review Boards. NIH Guidance, June 5,
2000.
FDA Information Sheets, Guidance for Institutional Review Boards and
Clinical Investigators, 1998 Update, Revised February 1999. Also
available at www.fda.gov
Code of Federal Regulations, Title 21, Part 50. Protection of Human
Subjects (FDA)
Code of Federal Regulations, Title 21, Part 54. Financial Disclosure by
Clinical Investigators (FDA)
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Code of Federal Regulations, Title 21, Part 56. Institutional Review
Boards (FDA)
Code of Federal Regulations, Title 45, Part 76. HHS Debarment
Regulations
Dated: June 27, 2000.
William F. Raub,
Deputy Assistant Secretary for Science Policy, Office of the Assistant
Secretary for Planning and Evaluation, Department of Health and Human
Services.
[FR Doc. 00-16760 Filed 6-30-00; 8:45 am]
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