[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]
BILLING CODE 4160-01-F