Financial Disclosure by Clinical Investigators

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

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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

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\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

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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

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\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]

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