[Federal Register Volume 67, Number 27 (Friday, February 8, 2002)]
[Notices]
[Pages 6039-6042]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-3078]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 01N-0308]


Agency Information Collection Activities; Submission for OMB 
Review; Comment Request; Financial Disclosure by Clinical Investigators

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing that the 
proposed collection of information listed below has been submitted to 
the Office of Management and Budget (OMB) for review and clearance 
under the Paperwork Reduction Act of 1995.

DATES: Submit written comments on the collection of information by 
March 11, 2002.

ADDRESSES: Submit written comments on the collection of information to 
the Office of Information and Regulatory Affairs, OMB, New Executive 
Office Bldg., 725 17th St. NW., rm. 10235, Washington, DC 20503, Attn: 
Stuart Shapiro, Desk Officer for FDA.

FOR FURTHER INFORMATION CONTACT: Karen L. Nelson, Office of Information 
Resources Management (HFA-250), Food and Drug Administration, 5600

[[Page 6040]]

Fishers Lane, Rockville, MD 20857, 301-827-1482.

SUPPLEMENTARY INFORMATION: In compliance with 44 U.S.C. 3507, FDA has 
submitted the following proposed collection of information to OMB for 
review and clearance.

Financial Disclosure by Clinical Investigators (OMB Control No. 
0910-0396)

    Respondents are sponsors of marketing applications that contain 
clinical data from studies covered by the regulations. These sponsors 
represent pharmaceutical, biologic, and medical device firms. The 
applicant will incur reporting costs in order to comply with the final 
rule. Applicants will be required to submit, for example, the complete 
list of clinical investigators for each covered study, not employed by 
the applicant and/or sponsor of the covered study, and either certify 
to the absence of certain financial arrangements with clinical 
investigators or disclose the nature of those arrangements to FDA and 
the steps taken by the applicant or sponsor to minimize the potential 
for bias. The clinical investigator will have to supply information 
regarding financial interests or payments held by the sponsor of the 
covered study. FDA has said that it has no preference as to how this 
information is collected from investigators and that sponsors/
applicants have the flexibility to collect the information in the most 
efficient and least burdensome manner that will be effective.
    FDA estimated that the total reporting costs of sponsors would be 
less than $450,000 annually. Costs could also occur after a marketing 
application is submitted if FDA determines that the financial interests 
of an investigator raise significant questions about the integrity of 
the data.
    FDA estimates the burden of this collection of information as 
follows:

                                 Table 1.--Estimated Annual Reporting Burden\1\
----------------------------------------------------------------------------------------------------------------
                            No. of       Annual Frequency per   Total Annual
   21 CFR Section        Respondents           Response           Responses     Hours per Response   Total Hours
----------------------------------------------------------------------------------------------------------------
54.4(a)(1) and              1,000                  5               5,000                 1             5,000
 (a)(2)
54.4 and 54.4(a)(3)           100                  1                 100                20             2,000
54.4                       46,000                  1              46,000                  .10          4,600
----------------------------------------------------------------------------------------------------------------
Total                                                                                                 11,600
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\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.

    In the Federal Register of July 25, 2001 (66 FR 38712 ), the agency 
requested comments on the proposed collections of information. Three 
comments were received. Two comments were not on the proposed 
information collection and will be addressed separately. The third 
comment had concerns whether the proposed collection of information is 
necessary for the proper performance of FDA's functions, including 
whether the information will have practical utility.
    The comment states that member companies reported that in calendar 
year 2000, less than 1 percent of all investigators, subinvestigators 
and their spouses and dependent children reported any financial 
arrangement with the sponsor. According to the comment, large global 
companies almost never pay investigators with proprietary interests in 
the product or give compensation that is affected by study outcome.
    FDA's Center for Drug Evaluation and Research (CDER) surveyed the 
rate of disclosure of financial information according to numbers of 
applications. CDER reviewed 129 total applications, including 119 new 
drug applications (NDAs) and 10 abbreviated new drug applications. Out 
of the original 129 applications, 33 applications or 25 percent of the 
total number of applications included the disclosure form (FDA 3455), 
meaning that at least one investigator had a disclosable interest. Out 
of those reporting, 12 applications included disclosable equity 
interests in the sponsor, 18 applications reported significant payments 
of other sorts (SPOOS) and 3 included information about clinical 
investigations who held proprietary interests in the product under 
study. FDA did not break down submission of financial information 
according to individual investigators, but it is, as the comment 
states, clearly a small minority.
    FDA agrees with the comment that it would be very unlikely for a 
company to compensate investigators differentially, depending on study 
outcome or to include investigators who hold proprietary interests in 
the product under study, and we did not expect to encounter many such 
financial arrangements. Providing assurance that such financial 
interests do not exist, however, imposes almost no collection burden on 
companies because they can certify that investigators hold none of 
these types of financial interest without asking the investigators.
    These financial interests represent an unusual occurrence, but 
other interests also deserve attention. FDA has found that it is not 
unusual for investigators to have received significant payment of other 
sorts and to hold equity interest in the sponsor exceeding $50,000. 
Collecting this information is clearly more difficult. For both of 
these cases, however, FDA has amended the final rule (21 CFR 54.2(b) 
and (f)) in order to help reduce the collection burden and has lifted 
the retroactive requirement on studies completed before February 2, 
1999, on SPOOS and equity interests in publicly held companies, thereby 
relieving the sponsor from contracting the investigators retroactively. 
With regard to SPOOS, FDA has asked for information on payments made on 
or after February 2, 1999, and for equity interests in publicly held 
companies whose value exceeds $50,000 in value, FDA has asked only for 
those financial holdings relating to ongoing studies after February 2, 
1999.
    Another concern was the accuracy of FDA's estimate of the burden of 
the proposed collection of information, including the validity, 
methodology, and assumptions used.
    Some companies report that it takes approximately 15 workweeks to 
collect, compile, and verify the information about financial 
relationships for a single phase 3 study involving 50 sites. According 
to the comment, these figures translate into an average low of 
approximately 3 and a high of 26 workweeks to collect, compile, and 
verify the information. Also, according to the comment, an additional, 
but a smaller amount of staff time is necessary to compile and verify 
information for phase 2 and phase 1 studies; the comment concluded that 
FDA's estimates of 1 to 4 hours to complete a response is unrealistic.
    FDA held extensive discussions with the drug, device, and 
biotechnology

[[Page 6041]]

companies as well as discussion with the academic medicine community 
and individual investigators, including numerous public meetings. Six 
extensions were permitted for public comment. Based on this input, FDA 
estimates the effort needed for the data collection requirement would 
not be unduly burdensome. FDA expected that the data collection would 
become easier as mechanisms to collect it routinely under the 
investigational new drug (IND) became established. A factor that may 
have complicated collection of this information is the multiple drug 
company acquisition and mergers that have taken place in recent years. 
In addition, subsequent to the issuance of the rule, FDA learned that 
many companies had no organized records of total monies distributed to 
investigators (e.g., SPOOS).
    Companies, therefore, have to ask the investigators about SPOOS or 
develop new tracking systems for such payments. Because no organized 
tracking systems existed in many companies, large companies through the 
public comment process and during meetings asked FDA whether it would 
be acceptable for a company to use a questionnaire to collect 
information on SPOOS from an investigator. FDA said it had no 
preference as to how the information is collected and that sponsor/
applicants may collect the information in the most efficient and least 
burdensome manner that is still effective. Although FDA did make a good 
faith estimate of the data collection burden based on extensive 
discussions with the affected communities, FDA will revise its burden 
estimate upward to reflect the fact that companies could not easily 
access some of the information, particularly relating to SPOOS 
payments. FDA noted that industry queries to investigators about SPOOS 
payments may be made in the initial letter that inquires about equity 
interests held by clinical investigators and that both could also be 
updated through the same inquiry.
    In the comment, concerns were raised on the issue of ways to 
enhance the quality, utility, and clarity of the information to be 
collected. The comment has said some companies collect, compile, and 
report investigator financial interest information for all studies, 
whether or not they are covered by the rule. They have asked that we 
clarify the definition of covered study and ensure that reviewers apply 
a consistent definition of what studies are covered. They have asked 
that FDA exclude all large, multicenter studies in which no single 
investigator contributes more than 20 percent of the data. The comment 
also said that companies report difficulties locating investigators who 
have already left the study prior to completion and also during the 1-
year period following completion of the study. The comment asked that 
FDA define what constitutes due diligence in attempting to locate those 
investigators. The comment also recommended that FDA clarify and limit 
the definition of investigator and subinvestigator because some 
companies are interpreting the definition very broadly.
    In response to the concerns above, a covered clinical study means 
any study of drug, biologic, or device in humans submitted in a 
marketing application or reclassification petition that the applicant 
or FDA relies on to establish efficacy of a product or any study where 
a single investigator makes a significant contribution to the 
demonstration of safety. This, in general, does not include phase 1 
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. FDA continues to 
strongly encourage companies to consult with FDA early on about which 
clinical studies constitute ``covered clinical studies'' for purposes 
of complying with these requirements. Regarding comments about ensuring 
that reviewers apply a consistent definition of covered study, FDA has 
provided clarification through the guidance process. In addition, FDA 
has extensively discussed these requirements with review staff in 
training sessions; FDA will also issue Manuals of Practices and 
Procedures (MaPPs) to CDER staff to help further ensure consistent 
interpretation of the financial disclosure requirements by FDA staff.
    Large scale, multicenter efficacy studies with many investigators 
are considered covered clinical studies within the meaning of the final 
rule. (See 21 CFR 54.4(c)). Data from an investigator having only a 
small percentage (20 percent) of the total subject population (in a 
study with large numbers of investigators and multiple sites) could 
still affect the overall study results. FDA has, therefore, declined to 
exclude all large, multicenter studies in which no single investigator 
contributes less than 20 percent of the data.
    The comment also mentioned difficulty in locating clinical 
investigators who leave the study or clinical trial site prior to 
completion of the study or completion of the 1-year followup period and 
asked for clear parameters in defining the term due diligence to search 
out these investigators. With regard to the definition of due 
diligence, FDA has suggested through guidance that sponsors and 
applicants should use reasonable judgment in deciding how much effort 
should be expended to collect this information. This suggestion was 
made in an effort to provide flexibility to sponsors and applicants and 
encourage them to use their best judgment while complying with the 
requirements.
    However, based on the comment, FDA is now providing more specific 
advice on due diligence in seeking information from investigators who 
have left the study prior to its completion, or 1 year following 
completion of the study period. FDA recommends that sponsors and 
applicants try to locate the investigator through at least two 
telephone calls and include written memoranda of telecons. In addition, 
they should followup in writing and send no fewer than two certified 
letters in an effort to locate lost investigators. For all clinical 
trials begun after February 2, 1999, which is the effective date of the 
regulation, information should be collected from clinical investigators 
prior to study start, which should prevent the difficulty in collecting 
the information retrospectively.
    Regarding the comment requesting additional clarification on the 
definition of clinical investigator. FDA would like to reiterate once 
again the definition of clinical investigator and subinvestigator. The 
definition of clinical investigator in 21 CFR part 54 is intended to 
identify the individuals who should be considered investigators for 
purposes of reporting under the rule, generally, the people taking 
responsibility for the study at a given study site. (For purposes of 
this rule, the term investigator also includes the spouse and each 
dependent child of the investigator and subinvestigator). For drugs and 
biologics, clinical investigator means the individual(s) who actually 
conduct(s) and take(s) responsibility for an investigation, i.e., under 
whose immediate direction the drug or biologic is administered to a 
subject or who is directly involved in the evaluation of research 
subjects. Where an investigation is directed by more than one person at 
a site, there may be more than one investigator who must report. These 
definitions could, in some cases, leave uncertainty about whether a 
particular individual was an investigator for purposes of the rule. The 
agency has, therefore, recommended specific criteria that should be 
considered for determining

[[Page 6042]]

who fits the definition of clinical investigator for purposes of the 
financial disclosure rules. Investigators are persons who fit any of 
these criteria: Have signed the Form FDA 1572, are identified as an 
investigator in initial submissions or protocol amendments under an 
IND, or are identified as an investigator in the NDA/biologic license 
application (BLA).
    The comment raised concerns over ways to minimize the burden of the 
collection of information on the respondents, including through the use 
of automated collection techniques when appropriate, and other forms of 
information technology.
    The comment stated that it is not so much the initial startup costs 
to develop tracking mechanisms but the ongoing costs of collecting, 
compiling, verifying and maintaining the information that are high. In 
the comment, a request was made that FDA limit the scope of people for 
whom sponsors are required to collect financial information. In 
addition, the comment recommended streamlining the data collection 
process by allowing sponsors to use e-mail to communicate with 
potential investigators; allowing investigators to fax completed forms 
to the sponsor, rather than requiring that sponsors retain forms with 
original signatures; and allowing sponsors to collect information at or 
near the start of each investigator's participation in the trial rather 
than prior to initiation of the study.
    FDA has addressed in detail the definition of clinical investigator 
earlier in this response and believes it has provided appropriate 
clarification. The suggested ways of streamlining the data collection 
process are acceptable. It is permissible to communicate through e-mail 
or fax machines with investigators. E-mails should be printed and all 
hard copies of correspondence should be maintained in company files. 
Finally, as has been stated earlier, information must be collected 
prior to study start in order to alert the IND/investigational device 
exemption (IDE) sponsor of the study to any potentially problematic 
financial interest as early in the drug development process as possible 
in order to minimize the potential for study bias and to facilitate 
accurate collection of data that may be submitted many years later.

    Dated: February 1, 2002.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 02-3078 Filed 2-7-02; 8:45 am]
BILLING CODE 4160-01-S