[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]


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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.

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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