[Federal Register Volume 60, Number 108 (Tuesday, June 6, 1995)]
[Proposed Rules]
[Pages 29801-29804]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-13886]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 54
[Docket No. 93N-0445]
Financial Disclosure by Clinical Investigators; Public Hearing
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice of public hearing; request for comments.
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SUMMARY: The Food and Drug Administration (FDA) is announcing a public
hearing regarding a proposed regulation that would require disclosure
of certain financial interests and arrangements by clinical
investigators. The proposed regulation would require that sponsors
submitting clinical studies in support of marketing applications for
human drugs, biologics, and medical devices either certify to the
absence of certain financial interests of clinical investigators or
disclose those financial interests. The purpose of the public hearing
is to obtain additional comments and information on specific issues for
use in developing a final rule, and a proposed rule to extend these
requirements to submissions for marketing approval related to human
foods, animal foods, and animal drugs. The public hearing will address
specific issues on which FDA seeks information and comment, and time
will also be set aside after these issues have been addressed during
which participants will have an opportunity to address other aspects of
the proposed regulation.
DATES: The public hearing will be held on July 20, 1995, from 9 a.m. to
5:30 p.m. Submit written notices of participation, including a brief
summary of the presentation and the approximate time requested, by June
30, 1995. Written comments will be accepted until August 20, 1995.
ADDRESSES: The public hearing will be held in the Wilson Auditorium,
National Institutes of Health, 9000 Rockville Pike, Bethesda, MD.
Submit written notices of participation and comments to the Dockets
Management Branch (HFA-305), Food and Drug Administration, rm. 1-23,
12420 Parklawn Dr., Rockville, MD 20857. To expedite processing,
written notices of participation may also be FAXED to 301-594-0113. Two
copies of any comments are to be submitted, except that individuals may
submit one copy. Comments are to be identified with the docket number
found in brackets in the heading of this document. Transcripts of
[[Page 29802]] the hearing will be available for review at the Dockets
Management Branch (address above).
FOR FURTHER INFORMATION CONTACT: Mary Gross, Office of External
Affairs, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD
20857, 301-443-3390, or FAX 301-594-0113.
SUPPLEMENTARY INFORMATION:
I. Background
FDA will sponsor a public hearing to solicit comments and views on
specific aspects of a proposed regulation published in the Federal
Register of September 22, 1994 (59 FR 48708) that would require
disclosure of certain financial information by clinical investigators.
There has been a growing concern for some time, both at FDA and
within the academic and scientific communities, that some financial
arrangements between clinical investigators and product sponsors, as
well as the personal financial interests of clinical investigators, are
a potential source of bias in clinical trials. FDA currently has no
mechanism to collect information concerning specific financial
interests of clinical investigators who conduct studies in support of
product marketing. FDA believes that institution of a system to collect
and analyze this information will strengthen the product review
process.
Under the proposed regulation, every sponsor filing an application
for marketing approval would be required to make one of two alternative
submissions as part of the application: (1) For any clinical study
relied upon by the sponsor to establish that the product meets the
regulatory requirements for approval, the sponsor may certify that: (a)
The sponsor has not entered into any financial arrangement with any
clinical investigator in which the value of financial compensation
received by the clinical investigator for conducting the studies could
be affected by the outcome of the research; (b) the investigator has
not received significant payments of other sorts from the sponsor, such
as a grant to fund ongoing research, compensation in the form of
equipment, a retainer for ongoing consultation, or honoraria; (c) the
clinical investigator has no proprietary interest, such as a patent or
other direct financial interest in the clinically tested product; and
(d) the clinical investigator holds no significant equity interest in
the sponsor's company; or (2) if the sponsor does not provide
certification, the sponsor must disclose the specific financial
arrangements made with the clinical investigator, the investigator's
proprietary and equity interests in the tested product and the
sponsor's company, and significant payments of other sorts, and
describe steps taken to minimize the potential for bias in data
submitted in support of product applications. FDA would refuse to file
any marketing application that does not include either certification or
disclosure.
FDA received 47 comments on the proposed regulation. Many comments
supported the proposed regulation with relatively minor modifications,
while others questioned the substantive provisions of the rule. In view
of the complexity of some of the issues that were raised, and the
diversity of views expressed on these issues, FDA believes that it
would be useful to convene a public meeting to provide interested
parties with an opportunity to present further comment. At this time,
the agency also wishes to provide an opportunity to interested persons
to comment on FDA's intention to propose extending financial disclosure
requirements to submissions for marketing approval related to human
foods, animal foods, and animal drugs.
II. Public Hearing
Consistent with FDA regulations at 21 CFR 10.40(f)(2), the agency
is holding a hearing under part 15 (21 CFR part 15) to discuss the
proposed rule. Presentations submitted and comments received at the
hearing will be included in the administrative record for that
regulation. In addition, written comments submitted to the Dockets
Management Branch (address above) by August 20, 1995, will also be part
of the administrative record.
The format of the hearing is one in which specific issues, as
listed below, are dealt with one at a time in the order listed. A block
of time will be allotted to discussion of additional issues by
participants once the listed issues have been addressed. Issues to be
addressed are as follows:
(1) In the proposed regulation, FDA specified four specific
financial arrangements or interests of a clinical investigator that
would be required to be disclosed, including any significant equity
interest in the applicant held by a clinical investigator. For purposes
of the regulation, a significant equity interest was defined as any
ownership interest, stock options, or other financial interest whose
value cannot be readily determined through reference to public prices,
or any equity interest in a publicly traded corporation that exceeds 5
percent of total equity. With respect to an equity interest in a
publicly traded corporation, a number of comments requested
clarification as to whether ``5 percent'' refers to 5 percent of the
investigator's equity, or 5 percent of the equity of the corporation.
Other comments argued that a dollar threshold should be set for
disclosure of an equity interest in a publicly traded corporation.
These comments suggested threshold amounts ranging from $5,000 to
$50,000. In specifying an equity interest that exceeds 5 percent of
total equity, FDA was referring to equity of a corporation. FDA
initially considered specific dollar amounts that might be used to
trigger disclosure, but wanted to avoid setting an amount that would be
so small as to trigger excessive and not particularly meaningful
disclosure. On the other hand, the agency acknowledges that the value
of 5 percent of equity in publicly traded companies could vary widely.
FDA is interested in further discussion as to what would constitute a
reasonable threshold for disclosure of an equity interest in a publicly
traded corporation.
(2) The proposed regulation would require disclosure of
``significant payments of other sorts,'' which were defined for
purposes of the regulation as payments that exceed $5,000 (e.g., grants
to fund ongoing research, compensation in the form of equipment or
retainers for ongoing consultation or honoraria) or that exceed 5
percent of the total equity in a publicly held or widely traded
company. Comments were divided as to the need to require disclosure of
arrangements that would fall under this definition. Some comments held
that only payments directly related to the conduct of covered studies
should be required to be disclosed. It should also be noted that a
number of comments stated that the regulation was intrusive and
burdensome, particularly with respect to the need to obtain extensive
information from investigators, adding that much of the need to query
investigators would be associated with accessing ``significant payments
of other sorts.'' FDA seeks additional discussion and views on whether
such arrangements should be disclosed, and the value of such disclosure
to the intent of the regulation.
(3) In proposed Sec. 54.2(e), FDA defined a clinical study as:
Any study involving human subjects, including a study to
establish bioavailability or bioequivalence, submitted in a
marketing application subject to this part, that either: (1) The
sponsor identifies as one that the sponsor relies on to establish
that the product meets the regulatory requirements for marketing, or
(2) FDA identifies as one that it intends to rely on to support its
decision to permit the marketing of the product * *
*. [[Page 29803]]
Comments suggested that the definition of a covered study be
narrowed by exempting, for example, phase 1 safety studies, because
they are not as important to evaluation for marketing as phase 2 and 3
studies, and bioavailability and pharmacokinetic studies, because they
generally result in quantitative, objective results based on tangible
data that are not especially vulnerable to bias. It was also suggested
that covered studies be limited to open label (unblinded) studies of a
nonpharmacokinetic nature, study designs with subjective endpoints, and
single investigator studies. FDA is interested in further discussion as
to what should constitute a covered study and whether the scope of the
proposed definition might be narrowed.
(4) In proposed Sec. 54.2(d), FDA defined ``clinical
investigator'' as any investigator who is: ``(i) Directly involved in
the treatment or evaluation of research subjects, or (ii) Could
otherwise influence the outcome of the research; * * *.'' Some comments
stated that this definition was overly broad. It was suggested that FDA
use for the purposes of this regulation the definition of ``clinical
investigator'' relied on by the agency's investigational drug
application regulations at 21 CFR 312.3(b), as follows:
Investigator means an individual who actually conducts a
clinical investigation (i.e., under whose immediate direction the
drug is administered or dispensed to a subject). In the event an
investigation is conducted by a team of individuals, the
investigator is the responsible leader of the team.
``Subinvestigator'' includes any other individual member of that
team.
FDA notes that the term ``clinical investigator,'' was defined in a
Public Health Service (PHS) proposed rule on objectivity in research
that published in the Federal Register of June 28, 1994 (59 FR 33242),
as the principal investigator and any other person who is responsible
for the design, conduct, or reporting of research. Both FDA's proposed
rule and the PHS final rule defined ``investigator'' as including the
spouse and dependent children of the investigator. FDA is interested in
obtaining additional views on the definition of ``clinical
investigator'' for purposes of financial disclosure.
(5) In the preamble to the proposed regulation, FDA stated its
expectation that disclosed financial interests and steps taken to
minimize bias would vary with different applications, and explained
that the agency would therefore evaluate and act on these applications
on a case-by-case basis. As to what actions the agency might take in
response to disclosure of problematic interests, FDA stated that, if a
study design is sufficiently robust as a result of factors such as
independent data monitoring, multiple investigators, blinding, and
independent endpoint assessment, the agency could determine that the
financial interest would not likely introduce bias and the data could
be accepted. In other situations, there might be sufficient replication
of critical results to render questionable data less important, or it
might be possible to carry out further analyses or observations (such
as reexamination of hospital records or patients) that would provide
assurance as to the quality of the data. In still others, intensified
scrutiny by FDA's bioresearch monitoring staff might be sufficient to
permit FDA to accept the data in support of product marketing
applications. In some cases, however, if adequate steps were not taken
to minimize potential bias, FDA stated that it might not be able to
conclude that the data were reliable and might find it necessary to
require sponsors to conduct further studies. This range of actions was
listed in proposed Sec. 54.5(c). A number of comments criticized the
proposed process as subjective. One comment argued that FDA must
develop specific criteria for evaluating the potential impact of
financial interests to avoid ad hoc decisionmaking by reviewers. FDA is
interested in further discussion of how these evaluations might be
conducted, especially with respect to specific criteria that might be
applied.
(6) In the preamble to the proposed rule, FDA stated its intention
to propose the extension of this rulemaking on financial disclosure to
additional products for which sponsors submit data from clinical
investigators, or investigators who conduct the equivalent of clinical
studies in animals, in support of marketing. Examples of these products
include food and color additives, infant formulas, human foods labeled
with health claims, animal foods, and animal drugs. FDA is interested
in hearing comments on this extension from the industries that would be
affected, as well as other interested persons.
III. Notice of Hearing Under 21 CFR Part 15
The Commissioner of Food and Drugs is announcing that the public
hearing will be held in accordance with 21 CFR part 15. The presiding
officer will be Sharon Smith Holston, Deputy Commissioner for External
Affairs. Ms. Holston will be joined by other FDA officials.
Persons who wish to participate must file a written notice of
participation with the Dockets Management Branch (address above) on or
before June 30, 1995. All notices submitted should be identified with
the docket number found in brackets in the heading of this document and
should contain the person's name, address, telephone number, FAX
number, business affiliation, if any, a brief summary of the
presentation, and the approximate time requested for the presentation.
The agency requests that individuals or groups having similar
interests consolidate their comments and present them through a single
representative. FDA may request joint presentations by persons with
common interests. FDA will allocate the time available for the hearing
among persons who properly file a notice of participation.
After reviewing the notices of participation and accompanying
information, FDA will schedule each appearance and notify each
participant by mail, telephone, or FAX, of the time allotted to the
person and the approximate time the person's presentation is scheduled
to begin. The schedule of the public hearing will be available at the
hearing and then placed on file in the Dockets Management Branch
(address above) after the hearing under docket number 93N-0445.
Under Sec. 15.30, the hearing is informal, and the rules of
evidence do not apply. No participant may interrupt the presentation of
another participant. Only the presiding officer and panel members may
question any person during or at the conclusion of their presentation.
Public hearings, including hearings under part 15, are subject to
FDA's guideline (21 CFR part 10, subpart C) concerning the policy and
procedures for electronic media coverage of FDA's public administrative
proceedings. Under Sec. 10.205, representatives of the electronic media
may be permitted, subject to certain limitations, to videotape, film,
or otherwise record FDA's public administrative proceedings, including
presentations by participants. The hearing will be transcribed as
stipulated in Sec. 15.30(b). Orders for copies of the transcript can be
placed at the meeting or through the Dockets Management Branch (address
above).
To the extent that the conditions for the hearing, as described in
this notice, conflict with any provisions set out in part 15, this
notice acts as a waiver of those provisions as specified in
Sec. 15.30(h).
The administrative record of the proposed rule will remain open
until August 20, 1995 to allow comments on matters raised at the
hearing. Persons [[Page 29804]] who wish to provide additional
materials for consideration should file these materials with the
Dockets Management Branch (address above) by August 20, 1995.
Dated: June 1, 1995.
Ronald G. Chesemore,
Associate Commissioner for Regulatory Affairs.
[FR Doc. 95-13886 Filed 6-5-95; 8:45 am]
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