[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: <a href="/cdn-cgi/l/email-protection#baf7d8c8d5cdd4fad7dbc9d3d7dbc294d9d5d7"><span class="__cf_email__" data-cfemail="eda08f9f829a83ad808c9e84808c95c38e8280">[email protected]</span></a>. 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: 
<a href="/cdn-cgi/l/email-protection#f6b5b9bfb697858693d8929e9e85d8919980"><span class="__cf_email__" data-cfemail="e5a6aaaca584969580cb818d8d96cb828a93">[email protected]</span></a>
    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: <a href="/cdn-cgi/l/email-protection#8eede1e7cec1ddcfdddecba0eae6e6fda0e9e1f8"><span class="__cf_email__" data-cfemail="9af9f5f3dad5c9dbc9cadfb4fef2f2e9b4fdf5ec">[email protected]</span></a>.

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)

[[Page 41076]]

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]
BILLING CODE 4151-05-P


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