[Federal Register Volume 63, Number 251 (Thursday, December 31, 1998)]
[Rules and Regulations]
[Pages 72171-72181]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-34546]
=======================================================================
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 54
[Docket No. 93N-0445]
RIN 0910-AB77
Financial Disclosure by Clinical Investigators
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule; action on petition for reconsideration.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA) is revising the
requirements regarding financial disclosure by clinical investigators
in order to add material to the codified language that was
inadvertently omitted and to clarify the compliance dates to, in some
cases, restrict the retroactive application of certain requirements of
the rule. FDA is making these changes in order to respond to concerns
raised by the Pharmaceutical Research Manufacturers Association
(hereinafter referred to as ``PhRMA''). By making these changes, FDA
will be reducing the administrative burden for manufacturers and other
affected parties while, at the same time, ensuring that the agency
obtains the information that is most relevant to its review of clinical
data submitted in marketing applications.
DATES:
Effective Date: This regulation becomes effective February 2, 1999.
Comment Date: Submit written comments on the information collection
provisions in the rule published on
[[Page 72172]]
February 2, 1998 (63 FR 5233), by February 1, 1999.
Compliance Date: Compliance with collection of information on any
equity interest in a publicly traded corporation that exceeds $50,000
as defined in Sec. 54.2(b) (21 CFR 54.2(b)) as published at 63 FR 5250
(February 2, 1998) is required for covered clinical trials that are
ongoing as of February 2, 1999.
Compliance with collection of information on significant payments
of other sorts as defined in Sec. 54.2(f), as published at 63 FR 5250
(February 2, 1998) is required for those payments made on or after
February 2, 1999.
ADDRESSES: Submit written comments on the information collection
provisions of this final rule to the Office of Information and
Regulatory Affairs, OMB, New Executive Office Bldg., 725 17th St. NW.,
rm. 10235, Washington, DC 20503, Attn: Desk Officer for FDA.
FOR FURTHER INFORMATION CONTACT: Mary C. Gross, Office of External
Affairs (HF-60), Food and Drug Administration, 5600 Fishers Lane,
Rockville, MD 20857, 301-827-3440, FAX 301-594-0113.
SUPPLEMENTARY INFORMATION:
I. Background
In the Federal Register of February 2, 1998 (63 FR 5233), FDA
published a final rule entitled ``Financial Disclosure by Clinical
Investigators'' (hereinafter referred to as ``the February 2, 1998,
final rule''). The February 2, 1998, final rule required the sponsor
(hereinafter referred to as ``the applicant'') of a marketing
application for any drug product, including any biological product, or
any device to submit certain information concerning the compensation
to, and financial interests of, clinical investigators conducting
certain clinical studies. This requirement applied to any covered
clinical study of a drug or device submitted in a marketing application
that the applicant or FDA relies on to establish that the product is
effective, including studies that show equivalence to an effective
product, or that make a significant contribution to evidence of safety.
The February 2, 1998, final rule required applicants to certify to the
absence of certain financial interests of clinical investigators and/or
disclose those financial interests, when covered clinical studies were
submitted to FDA in support of a marketing application. The purpose of
the February 2, 1998, final rule is to help ensure that financial
interests and compensation arrangements of clinical investigators that
could affect the reliability of data submitted to FDA in support of
product marketing are identified and disclosed by the applicant. If the
applicant does not include certification or disclosure, or both if
required, or does not certify that it was not possible to obtain the
information, the agency may refuse to file the application.
In the February 2, 1998, final rule, all reporting requirements
applied to any marketing application submitted on or after February 2,
1999. This final rule will change the reporting requirements by greatly
reducing the need to gather required information retrospectively for
studies already completed. Specifically, information on the equity
interests of investigators in a publicly traded corporation, as
described in Sec. 54.2(b), must be collected only for those covered
clinical studies that are ongoing as of February 2, 1999. In addition,
manufacturers will only be required to report any significant payments
of other sorts as described in Sec. 54.2(f) made on or after February
2, 1999.
FDA is also revising the definition of ``covered clinical studies''
in Sec. 54.2(e). With regard to studies that make a significant
contribution to the demonstration of safety, the agency has concluded
that only those studies in which a single investigator makes a
significant contribution to the demonstration of safety will be
included in the definition of covered clinical study. This change would
generally exclude phase 1 tolerance studies or pharmacokinetic studies
(unless they are critical to an efficacy determination), large open
safety studies conducted at multiple sites, treatment protocols and
parallel track protocols from the definition of covered clinical study
and, therefore, eliminate the need to collect and report information on
the financial interests of investigators in those trials. Finally, in
order to obtain information only about investigators who had
significant roles in covered clinical studies, FDA is amending the
definition of ``clinical investigator'' in Sec. 54.2(d) to clarify that
it is intended to include only listed or identified investigators or
subinvestigators who are directly involved in the treatment or
evaluation of research subjects. These changes are being made in part
in response to a petition for reconsideration submitted to the agency
by PhRMA on August 3, 1998. The Health Industry Manufacturers
Association submitted a comment to the rule supporting the petition on
August 17, 1998.
II. Petition for Reconsideration
FDA received a petition for reconsideration on August 3, 1998, from
PhRMA requesting that some provisions of the final rule be reconsidered
and changed. The petition argued that these provisions imposed
substantial logistical and information collection burdens on sponsors
and applicants without providing any significant benefit to the public.
As discussed in section V of this document, PhRMA had also submitted a
comment under the Paperwork Reduction Act of 1995 (the PRA) on the
information collection provisions of the rule. The comment made
essentially the same arguments as the petition, although it was
slightly broader. Aspects of the PhRMA comment not included in the
petition are addressed in section V of this document.
In the petition, PhRMA asked that the agency reconsider requiring
applicants to retrospectively collect information; that is, PhRMA asked
that the final rule be applied only to studies commenced after the
February 2, 1999, effective date of the rule. The petition also sought
to modify the final rule in several respects. Specifically, PhRMA
requested that the rule not apply to large multicenter studies,
subinvestigators who do not have primary responsibility for a clinical
trial, and that it not apply to payments of less than $1,000 to
individuals and less than $2,500 to sponsors' associated institutions
when sponsors are collecting information about ``significant payments
of other sorts'' as defined in Sec. 54.2(f). PhRMA also asked FDA to
respond to the petition by September 28, 1998, or stay the effective
date of the final rule pending reconsideration, with 12 months of lead
time for implementation when the stay is lifted.
Under Sec. 10.33(b) and (g) (21 CFR 10.33(b) and (g)), a petition
for reconsideration must be submitted within 30 days after the date of
the decision involved. However, Sec. 10.33(b) also provides that, for
good cause, the Commissioner of Food and Drugs may consider an untimely
petition for reconsideration. Although PhRMA's petition was submitted
well after the deadline, FDA finds that good cause exists because of
the strength of certain arguments in the petition concerning the
desirability of modifications to some aspects of the February 2, 1998,
rule.
III. Response to Petition
FDA has carefully evaluated the petition for reconsideration and
reviewed the administrative record of the February 2, 1998, final rule
to determine whether the standard in Sec. 10.33(d) for granting a
petition for reconsideration has been met. As explained in the
following paragraphs, the agency concludes that the standard has been
met with respect to some of the actions requested in the petition for
[[Page 72173]]
reconsideration. Specifically, the agency concludes that: (1) The
petitioner's position is not frivolous and is being pursued in good
faith; (2) with respect to certain provisions of the February 2, 1998,
final rule, the agency did not adequately consider certain information
or views in the administrative record; (3) the petition has
demonstrated sound public policy grounds supporting reconsideration of
those provisions; and (4) reconsideration of those provisions is not
outweighed by public health or other public interests. Therefore, the
agency is revising parts of the final rule based on arguments in the
petition for reconsideration. By making these revisions, the agency
will also reduce the information collection burden associated with
implementation of this final rule.
A. Retrospective Collection of Information
FDA received some comments on the proposed rule that asked FDA to
apply the rule prospectively, to avoid penalizing applicants and
clinical investigators whose clinical investigations were concluded or
already in progress. FDA responded in the February 2, 1998, final rule
that it was important to know about the financial arrangements and
payments that were considered to be problematic in a timely manner and
that implementation should not be long deferred. The agency also stated
that in order to give applicants time to comply with the final rule and
to avoid delayed submissions, applicants would not be required to
comply with the final rule until 1 year after the publication date of
the final rule. The agency recognized that there may be times where,
despite the applicant's diligent efforts to collect this information,
the applicant may be unable to obtain it. FDA amended the final rule to
permit an applicant who can show conclusively why this information
could not be obtained to certify that the applicant acted diligently to
obtain the information, but was unable to do so and to include the
reason why such information could not be obtained.
Based on arguments presented in the petition for reconsideration,
FDA is revising this final rule with regard to collection of
information on equity interests in a publicly traded company when such
interests exceed $50,000 in value as defined in Sec. 54.2(b). Sponsors
will be required to collect information regarding such interests only
in those covered clinical studies that are ongoing as of February 2,
1999. FDA is also revising the final rule with regard to collection of
information concerning significant payments of other sorts, defined
under Sec. 54.2(f), so that submission of this information is required
only for payments made on or after February 2, 1999.
Collection of information described under Sec. 54.2(a),
``compensation affected by the outcome of clinical studies'', and
Sec. 54.2 (c), ``proprietary interests in the tested product'', will be
required for investigators participating in covered clinical studies,
whether they are ongoing or already completed, if the studies are used
to support applications that are submitted on or after February 2,
1999. In addition, sponsors will be required under Sec. 54.2(b) to
collect information on any ownership interest whose value cannot be
readily determined through reference to public prices (generally
interests in a nonpublicly traded corporation) for investigators
participating in all covered clinical studies, whether they are ongoing
or already completed, if they are used to support applications that are
submitted on or after February 2, 1999. FDA is not changing these
requirements because the agency believes that the information required
under Sec. 54.2(a), (b), (with regard to any ownership interest whose
value cannot be readily determined through reference to public prices)
and (c) is the most critical to the agency and therefore, its
collection should not be deferred. By modifying the compliance dates of
Sec. 54.2(b) (equity interests that exceed $50,000 in a publicly traded
corporation) and (f) (significant payments of other sorts), FDA has
eliminated the potential administrative burden to sponsors of
reconstructing records after the fact, thereby reducing the information
collection burden on regulated industry without compromising the
integrity of the final rule.
B. Clinical Investigator Definition
In the September 22, 1994 (59 FR 48708) proposed rule, FDA defined
clinical investigator to mean any investigator who is directly involved
in the treatment or evaluation of research subjects, or who could
otherwise influence the outcome of the research. Spouses and dependent
children were also included under the definition of clinical
investigator. The proposed rule asked for comment on whether the
definition of clinical investigator should include business partners of
the investigator who might share in profits from the investigator's
arrangements or financial interests. Most comments objected to
including business partners under the definition of clinical
investigator. Several comments on the proposed rule found the
definition to be too broad and stated that, as proposed, the definition
would involve all study personnel and pose an enormous administrative
burden. One comment recommended limiting the scope of the definition to
the principal investigator only.
In the February 2, 1998, final rule, FDA agreed with comments that
stated that including business partners under this definition was
unnecessary and potentially burdensome. FDA also agreed with those
comments that supported narrowing the definition. The February 2, 1998,
final rule defined clinical investigator to mean any listed or
identified investigator who is directly involved in the treatment or
evaluation of research subjects. The definition also included the
investigator's spouse and dependent children. It was not intended to
include hospital or office staff who may provide occasional care to
subjects.
In the petition for reconsideration, PhRMA argued that the final
rule should not apply to subinvestigators because it would be too
burdensome to collect and report financial information concerning
subinvestigators. In addition, the petition asserted that
subinvestigators often play a limited role in the conduct of a trial
and do not have a significant effect on the trial's outcome and
therefore should be excluded.
After careful consideration of this request, the agency disagrees
with the reasoning in the petition about subinvestigators and declines
to adopt the request that they all be excluded from the final rule. FDA
believes that it is appropriate to clarify the definition of clinical
investigator, however, in light of this request. The agency wishes to
make clear that individuals included in the definition of clinical
investigator are only those who actually and directly participate in
the conduct of the trial and not those who may occasionally provide
treatment to subjects.
The agency believes that most of the individuals participating in
the conduct of a clinical trial could be described as subinvestigators.
If the position recommended in the petition were adopted, the agency
would likely receive financial information for no more than a handful
of individuals for each trial, regardless of how many individuals were
actually directly involved in the treatment or evaluation of research
subjects. FDA believes that subinvestigators generally perform a
significant amount of the work involved in the conduct of a trial and
can therefore influence its results. It would not be prudent to exclude
all subinvestigators because to do so would mean that much of the most
meaningful
[[Page 72174]]
and relevant information would not be reported which, in turn, would
greatly weaken the agency's ability to assess the reliability of
clinical trial data. For this reason, FDA will not eliminate
subinvestigators from the definition of ``clinical investigator.''
The agency believes that it has addressed the issue raised in the
petition of the burden involved in reporting information concerning
subinvestigators in several ways. First, as will be discussed more
fully as follows, by narrowing the definition of covered clinical study
to exclude large open safety studies conducted at multiple sites,
treatment protocols, and parallel track protocols, the agency has
eliminated the need for collecting and reporting information from the
large number of individuals, many of whom are subinvestigators, who
typically participate in those types of studies. Second, the change
being made to eliminate the need for retrospective reporting of equity
interests in publicly traded companies will also make the information
on subinvestigators easier to collect. With these steps, FDA has
considerably reduced the administrative burden associated with this
final rule while maintaining the agency's ability to obtain the
information it needs to assess the reliability of clinical trial data.
C. Covered Clinical Study Definition
In the September 1994 proposed rule, ``clinical study'' was defined
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 the sponsor identifies as one that
the sponsor relies on to establish that the product meets the
regulatory requirements for marketing, or FDA identifies as one that it
intends to rely on to support its decision to permit the marketing of
the product. Under the proposal, studies submitted as publications or
in brief summary form would generally not be considered ``covered
clinical studies'' unless FDA informed the sponsor otherwise. The
agency further proposed that a sponsor could consult with FDA as to
which clinical studies constituted ``covered clinical studies'' for
purposes of complying with financial disclosure requirements. Several
comments recommended that FDA limit the scope of the rule with respect
to covered studies. One comment said that the rule appeared to include
large-scale open label studies, such as studies involving some
cardiovascular therapies, compassionate use studies and parallel track
studies, all of which might be submitted in support of a new drug
application (NDA). The comment noted that investigators in such studies
could number in the thousands and said that it would be an unwarranted
burden to require an applicant to obtain financial information from
each clinical investigator.
FDA responded in the preamble to February 2, 1998, final rule that
in general, large open studies, treatment protocols, and other such
studies with large numbers of investigators would not be covered
studies. The preamble further states that because these studies
generally have large numbers of investigators, no single investigator
has a major responsibility for the data. The agency said in the
preamble that although it is not impossible that a financial interest
could be important in these studies, it is relatively unlikely, and the
agency has concluded that the effort needed to obtain financial
information for these investigators should not be undertaken. It has
been brought to the agency's attention that the codified language of
the regulation at Sec. 54.2(e) did not fully reflect those preamble
statements. The petitioners have asked FDA to reconsider whether the
final rule should apply to these types of large, multicenter studies.
FDA acknowledges that some material was inadvertently omitted from the
codified language in the February 2, 1998, final rule and accordingly
is adding language to the definition of ``covered clinical study'' to
reflect the agency's original intention. The definition of ``covered
clinical study'' has been amended to indicate that generally it does
not include phase I tolerance studies or pharmacokinetic studies, most
clinical pharmacology studies (unless they are critical to an efficacy
determination), large open safety studies conducted at multiple sites,
treatment protocols, and parallel track protocols.
D. Tracking Small Gifts in Calculating $25,000 Threshold for
``Significant Payments of Other Sorts''
The petitioners have asked that FDA amend the definition of
significant payments of other sorts'' in Sec. 54.2(f) so that sponsors
are not required to collect or report information concerning individual
payments less than $1,000 to physicians or less than $2,500 to
institutions so that such payments are not counted in determining
whether the $25,000 reporting threshold has been reached. The
petitioners argued that the administrative burden of tracking such
payments is unjustified. FDA declines to amend the final rule in this
way. Payments under $1,000 or $2,500 respectively, if numerous or when
added to a fairly large grant or to the value of equipment provided to
the investigator, could bring the total amount of significant payments
of other sorts to $25,000 or more. The agency believes that the
aggregate amount of such payments is important, not the size of
individual payments. In addition, FDA is reluctant to create a
mechanism that could be used to circumvent the reporting requirement
entirely by making many small payments to an investigator or
institution. The agency has changed the compliance date regarding these
payments, however, so that sponsors will begin to collect and report
information regarding ``significant payments of other sorts'' only on
such payments made on or after February 2, 1999. The agency believes
this modification reasonably addresses sponsors' concerns about the
burdensomeness of the requirement.
E. Request for Response by September 28, 1998 or Request to Stay the
Rule
FDA does not believe there is a need to stay the rule indefinitely
because by making the changes described previously, the agency has both
clarified the requirements of the rule and significantly decreased the
administrative burden associated with collecting this information. The
agency finds that the petitioners have not demonstrated a need to delay
the effective date for this rule and therefore declines to grant this
request.
IV. Analysis of Impact
FDA has examined the impacts of the final rule under Executive
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the
Unfunded Mandates Reform Act (Pub. L. 104-4). Executive Order 12866
directs agencies to assess all costs and benefits of available
regulatory alternatives and, when regulation is necessary, to select
regulatory approaches that maximize net benefits (including potential
economic, environmental, public health and safety, and other
advantages; and distributive impacts and equity). The agency believes
that the final rule is consistent with the regulatory philosophy and
principles identified in the Executive Order and concludes that it is
not a significant regulatory action as defined. The Regulatory
Flexibility Act requires agencies to prepare a regulatory flexibility
analysis for each rule, unless the agency certifies that the rule would
not have a significant economic impact on a substantial number of small
entities. As explained in the February 2, 1998, final rule, the agency
believes that this final rule will
[[Page 72175]]
not have a significant economic impact on a substantial number of small
entities. Nevertheless, the rule may impose significant costs on a few
small businesses. Because FDA cannot adequately quantify all of this
impact, it prepared a regulatory flexibility analysis as part of its
economic assessment. Title II of the Unfunded Mandates Reform Act (in
section 202) requires that agencies prepare a written assessment of
anticipated costs and benefits before proposing any rule that may
result in an expenditure in any 1 year by State, local, and tribal
governments, in the aggregate or by the private sector of $100 million
(adjusted annually for inflation). Because the rule will not result in
expenditures of this amount, FDA is not required to prepare a cost-
benefit analysis under this Act.
FDA is publishing these revisions in response to a petition for
reconsideration of some of the rules' requirements on the grounds that
they imposed a substantial burden on sponsors. The agency has amended
the requirements in the final rule so that the information collection
requirements for reporting equity interests in publicly held
corporations that exceed $50,000 in value will apply to studies ongoing
as of February 2, 1999, and the requirements regarding significant
payments of other sorts will apply to payments made on or after
February 2, 1999 (see section III.A and III.D of this document,
respectively).
These changes will substantially reduce the affected industry's
near term regulatory burden. Nevertheless, the agency has not reduced
its earlier cost estimate, because its original impact analysis did not
fully reflect the cost of collecting retrospective information on
equity interests in publicly held corporations or of making significant
payments of other sorts. The agency now believes that its original
figure of less than $450,000 annually may have understated the
reporting costs of the rule as published on February 2, 1998, but
reasonably reflects that reporting costs of the final rule as amended.
The revised definitions for ``clinical investigator'' and ``covered
clinical study'' do not result in any change to the cost analysis
because they continue to reflect the agency's earlier intent.
V. Paperwork Reduction Act of 1995
This final rule contains information collection provisions that are
subject to review by the Office of Management and Budget (OMB) under
the PRA of 1995 (44 U.S.C. 3501-3520). A description of these
provisions is given as follows with an estimate of the annual reporting
and recordkeeping burden. Included in the estimate is the time for
reviewing instructions, searching existing data sources, gathering and
maintaining the data needed, and completing and reviewing each
collection of information.
Title: Financial Disclosure by Clinical Investigators (21 CFR part
54)
Description: In the February 2, 1998, final rule, FDA issued
regulations requiring the sponsor of any drug (including a biological
product) or device marketing application to submit information
concerning the compensation to, and financial interests of, any
clinical investigator directly involved in the treatment or evaluation
of subjects enrolled in certain clinical studies. This final rule
revises the requirements of the February 2, 1998, final rule to reduce
the information collection burden imposed on sponsors of drug and
medical device products. The revisions are described in section III of
this document.
As modified by this revised final rule, the requirement to disclose
information about compensation to, and financial interests of, clinical
investigators will apply to any study of a drug or device in humans
submitted in a marketing application or reclassification petition that
the applicant or FDA relies on to establish that the product is
effective and to any study in which a single investigator makes a
significant contribution to the demonstration of safety. The
regulations require applicants to certify to the absence of certain
financial interests of clinical investigators or disclose those
financial interests as required, when covered clinical studies are
submitted to FDA in support of product marketing. The purpose of the
regulations is to ensure that financial interests and arrangements of
clinical investigators that could affect the reliability of the data
submitted to FDA in support of product marketing are identified and
disclosed. The regulations will become effective on February 2, 1999.
FDA will evaluate the information provided about each covered
clinical study in an application to determine the impact of any
disclosed financial interests on the reliability of the study. If FDA
determines that the financial interests of any clinical investigator
raise serious questions about the integrity of the data, FDA may take
any action it deems necessary to resolve those questions, including
initiating agency audits of the questioned data; requesting that the
applicant submit further analyses of data that evaluate the effect of
the clinical investigator's data on overall study outcome; requesting
that the applicant conduct additional independent studies to confirm
the results of the questioned study; or refusing to consider the data
from the questioned study in deciding whether to approve the
application.
Description of Respondents: Respondents are sponsors of marketing
applications containing clinical data from studies covered by the
regulation. These sponsors represent pharmaceutical, biologic, and
medical device firms. Many of these firms are small entities,
especially those which manufacture medical devices and biotechnology
products. Respondents are also clinical investigators who provide
financial information to the sponsors of marketing applications.
The applicant will incur reporting costs in order to comply with
the final rule. Applicants will be required to submit, for example, a
complete list of clinical investigators for each covered study, a list
that is already submitted in a marketing application. For investigators
not employed by the applicant and/or the sponsor of the covered study,
the applicant must either certify to the absence of certain financial
arrangements with clinical investigators or disclose those arrangements
to FDA.
FDA expects that almost all applicants will submit a certification
statement under 21 CFR 54.4(a)(1) and (a)(2). Preparation of the
statement using the following Form FDA 3454 will represent little
effort and should require no more than 1 hour per study.
BILLING CODE 4160-01-F
[[Page 72176]]
[GRAPHIC] [TIFF OMITTED] TR31DE98.000
BILLING CODE 4160-01-C
[[Page 72177]]
TABLE 1.--Estimated Number of Applications, Clinical Trials, and Investigators Subject to the Proposed Rule by
Type of Application1
----------------------------------------------------------------------------------------------------------------
Number of
Application Type Total Number of Applications Number of Trials Number of
Applications Affected Investigations
----------------------------------------------------------------------------------------------------------------
Drugs
New drug application (NDA), new 35 35 3 to 10 3 to 100
molecular entity (NME)
NDA nonNME 100 100 1 to 3 10 to 30
NDA efficacy supplement 100 100 1 to 3 10 to 30
Abbreviated new drug application 400 240 1.1 2
(ANDA)
ANDA supplement 2,500 120 1 2
Rx switch 20 10 2 4
Biologics
Product license application (PLA) 25 25 3 to 10 3 to 100
PLA efficacy supplement 10 10 1 to 3 3 to 100
Medical Devices
Premarket approval (PMA) 50 50 1 10 to 20
PMA supplement 40 10 1 3 to 10
Reclassification devices 8 4 1 3 to 10
510(k) 6,000 300 1 20
----------------------------------------------------------------------------------------------------------------
\1\ Source: Agency estimates.
When certification is not possible and disclosure is made using the
following Form FDA 3455, the applicant must describe the financial
arrangements or interests and the steps that were taken to minimize the
potential for bias in the affected study. As the applicant will be
fully aware of those arrangements and the steps taken to address them,
describing them will be straightforward. The agency estimates that it
will take about 4 hours to prepare this narrative.
BILLING CODE 4160-01-F
[[Page 72178]]
[GRAPHIC] [TIFF OMITTED] TR31DE98.001
[[Page 72179]]
Until the agency begins to collect information on the financial
arrangements between investigators and applicants, it cannot know the
actual number of disclosable arrangements. Therefore, it is not
possible to predict the total cost to industry of preparing these
explanatory statements with any certainty because the financial
arrangements described in this rule are uncommon. FDA estimates that
from 1 to 10 percent of the applications would need disclosure
statements, and has used the extremely conservative estimate of 10
percent in Table 2 of this document.
Investigators must provide sponsors of the covered studies with
sufficient accurate information to make the required disclosure or
certification. Because much of the information required can be obtained
from the applicant's own records, the costs incurred by the clinical
investigator will be minimal. Clinical investigators are required to do
one of two things: (1) Provide a statement that they, their spouse, and
their dependent children did not have a significant equity interest as
defined in Sec. 54.2(b) in the sponsor of the covered study, or (2)
disclose any such interest. Clinical investigators are accustomed to
supplying such information in even greater detail when applying for
research grants. Most people know the financial holdings of their
immediate family, and records of such interests are generally
accessible because they are needed for preparing tax records. FDA
estimates that the time required for this task may range from 5 to 15
minutes.
Table 2.--Estimated Annual Reporting Burden1
----------------------------------------------------------------------------------------------------------------
No. of
21 CFR Section No. of Responses per Total Annual Hours per Total Hours
Respondents Respondent Responses Response
----------------------------------------------------------------------------------------------------------------
54.4(a)(1) and (a)(2) 1,000 1 1 1 1,000
54.4(a)(3) 100 1 1 4 400
54.4 (Clinical Investigators) 46,000 1 1 .10 4,600
Total 6,000
----------------------------------------------------------------------------------------------------------------
\1\ There are capital costs or operating and maintenance costs associated with this collection of information.
The sponsors of covered studies will be required to maintain
complete records of compensation agreements with any compensation paid
to nonemployee clinical investigators, including information showing
any financial interests held by the clinical investigator, for a period
of 2 years after the date of approval of the application. This time is
consistent with the current recordkeeping requirements for other
information related to marketing applications for human drugs,
biologics, and medical devices. FDA judged the incremental costs
associated with this new activity to be negligible because firms
already maintain records of compensation as standard business practice,
and the required records pertaining to the financial interests of the
investigators will typically consist of only one additional piece of
paper per investigator. Currently, sponsors of covered studies must
maintain many records with regard to clinical investigators, including
protocol agreements and investigator resumes or curriculum vitae, and
the inclusion of information required by this rulemaking would add
little to this recordkeeping burden. FDA estimates that on average 15
minutes will be required for each recordkeeper to add this record to
clinical investigators' files.
Table 3.--Estimated Annual Recordkeeping Burden1
----------------------------------------------------------------------------------------------------------------
No. of
21 CFR Section No. of Responses per Total Annual Hours per Total Hours
Recordkeepers Recordkeeping Records Recordkeeper
----------------------------------------------------------------------------------------------------------------
54.6 1,000 1 1,000 .25 250
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
information.
[[Page 72180]]
In the February 2, 1998, final rule (63 FR 5233 at 5249), FDA
requested comments on the information collection provisions of the
final rule. The agency received three comments in response to this
request. As discussed previously, one of the comments was very similar
to the petition for reconsideration to which this revised final rule
responds. The issues raised by that comment that have already been
discussed in earlier sections of this document will not be addressed
again here.
One comment suggested that FDA use different criteria for
disclosure of equity interests depending on the amount of sponsor
capital. FDA disagrees. The $50,000 threshold was chosen to represent a
dollar amount that could be important to an investigator. During the
rulemaking, many comments were received on the issue of the appropriate
threshold. Some suggested that FDA's rule should be made consistent
with the Public Health Service final rule and the National Science
Foundation statement of policy on Objectivity in Research published on
July 11, 1995 (a considerably more stringent requirement than the
disclosure requirement in FDA's final rule); others suggested different
dollar thresholds, such as $10,000, or particular percentages of
company equity. One comment suggested that investigators be banned from
owning an equity interest in a sponsor that exceeded $25,000 a year.
FDA's original proposal of a percent equity threshold was deleted from
the final rule because the agency recognized that for many corporations
this would represent an unrealistically large interest (e.g., 5 percent
of a $10 million company is $500,000). Based on discussions with FDA's
Science Board and comments received on FDA's proposed rule, FDA
continues to believe that a $50,000 disclosure threshold strikes the
appropriate balance between the agency's need to be aware of, and to
help minimize, the potential for bias in clinical data.
This comment also stated that FDA underestimated the amount of time
necessary to collect, analyze, and store the information needed to
comply with the February 2, 1998, final rule. FDA agrees that the time
estimates in that document may have been too low because FDA was not
able to accurately predict the burden associated with collecting
information from past covered clinical trials. FDA continues to believe
that the majority of applicants will certify to the absence of covered
financial interests and that sponsors will incorporate the collection
of this information into the routine administration of their studies.
FDA agrees that additional time would have been needed to gather
information from investigators in past studies prior to the revisions
made by this final rule. As FDA is revising the rule to eliminate most
retrospective reporting, however, the burden will be significantly less
than it would have been under the February 2, 1998, final rule. The
agency has reevaluated its burden estimate and concludes that, although
the estimate in the February 2, 1998, final rule (63 FR 5233 at 5249)
underestimated the burden of retrospective reporting at that time, it
now accurately reflects the lessened burden of the financial disclosure
regulations as revised by this final rule. Therefore, the agency is not
modifying its burden estimate.
Finally, this comment requests guidance from FDA on what the
comment characterizes as ambiguities in the final rule. FDA has
provided clarification through revisions made to this final rule. FDA
declines to issue a guidance document before the rule becomes
effective; however, FDA will assess the need for guidance after the
agency and those subject to the rule have gained some experience with
it's implementation.
A second comment suggested that FDA modify section 9 of Form FDA
1572, ``Statement of Investigator,'' to add a commitment that the
investigator will comply with the financial disclosure regulations and
to state whether the investigator holds a significant equity interest
in the sponsor. The comment stated that this change to Form FDA 1572
would eliminate the need for investigators to complete additional
documentation.
FDA does not agree with the comments' recommendation that Form FDA
1572 be changed. Clinical investigators are already required to comply
with the financial disclosure regulations and, as part of this
obligation, must provide financial information to the sponsor under 21
CFR 312.53(c)(4) and 312.64(d) of the final rule. The agency has
developed FDA Forms 3454 and 3455 in an effort to facilitate the
collection of this information. FDA also notes that the proposed change
would not eliminate the need for the investigator to provide the
details of any significant equity interests as required by the final
rule. Therefore, the recommended change would make Form FDA 1572 more
burdensome without reducing the burden under the final rule.
A third comment submitted by two clinical investigators from a
government agency asked that a division within a Federal Government
agency be exempted from reporting financial interests to FDA because it
does not submit marketing applications to FDA for products tested under
its investigational new drug application (IND's) and because, according
to the comment, its phase III studies are designed, monitored, and
assessed in such a way that the studies are not subject to the same
potential bias found in smaller, investigator-initiated or company-
sponsored studies. A government researcher conducting a clinical study
under an IND held by a government agency does not have to report
financial interests or arrangements to FDA, as it is the submission of
a marketing application that triggers the disclosure requirement. If,
however, the study were used to support an application, the applicant
would be required to report any covered financial interests of the
clinical investigators. FDA declines to make a change in response to
this comment.
The information collection provisions of the February 2, 1998,
final rule, as modified by this final rule, have been submitted to OMB
for review. Individuals and organizations may submit comments on the
information collection provisions by February 1, 1999. Comments should
be directed to the Office of Information and Regulatory Affairs, OMB
(address above).
[[Page 72181]]
Prior to the effective date of the final rule, FDA will publish a
notice in the Federal Register announcing OMB's decision to approve,
modify, or disapprove the information collection provisions. An agency
may not conduct or sponsor, and a person is not required to respond to,
a collection of information unless it displays a currently valid OMB
control number.
List of Subjects in 21 CFR Part 54
Biologics, Drugs, Medical devices, Reporting and recordkeeping
requirements.
Therefore, under the Federal Food, Drug, and Cosmetic Act, and
under authority delegated to the Commissioner of Food and Drugs, 21 CFR
part 54 is amended as follows:
PART 54--FINANCIAL DISCLOSURE BY CLINICAL INVESTIGATORS
1. The authority citation for 21 CFR part 54 continues to read as
follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357,
360, 360c-360j, 371, 372, 373, 374, 375, 376, 379; 42 U.S.C. 262.
2. Section 54.2 is amended by revising paragraphs (d) and (e) to
read as follows:
Sec. 54.2 Definitions.
* * * * *
(d) Clinical investigator means only a listed or identified
investigator or subinvestigator who is directly involved in the
treatment or evaluation of research subjects. The term also includes
the spouse and each dependent child of the investigator.
(e) Covered clinical study means any study of a drug or device in
humans submitted in a marketing application or reclassification
petition subject to this part that the applicant or FDA relies on to
establish that the product is effective (including studies that show
equivalence to an effective product) or any study in which a single
investigator makes a significant contribution to the demonstration of
safety. This would, in general, not include phase l tolerance studies
or pharmacokinetic studies, most clinical pharmacology studies (unless
they are critical to an efficacy
determination), large open safety studies conducted at multiple sites,
treatment protocols, and parallel track protocols. An applicant may
consult with FDA as to which clinical studies constitute ``covered
clinical studies'' for purposes of complying with financial disclosure
requirements.
* * * * *
Dated: November 24, 1998.
Michael A. Friedman,
Lead Deputy Commissioner for the Food and Drug Administration.
Donna E. Shalala,
Secretary of Health and Human Services.
[FR Doc. 98-34546 Filed 12-30-98; 8:45 am]
BILLING CODE 4160-01-F
