Guidance
Financial Disclosure by Clinical Investigators
Comments and suggestions regarding this document may be submitted
any time. Submit comments to the Dockets Management Branch (HFA-305),
Food and Drug Administration, 5630 Fishers Lane, rm 10-61, Rockville,
MD 20857. All comments should be identified with the docket number
listed in the notice of availability that publishes in the Federal
Register.
For further information, contact (OC) Ms. Mary Gross, (301) 827-3450,
(CDER) Ms. Linda Carter, (301) 594-6758, (CBER) Dr. Jerry Donlon,
(301) 827-3028, or (CDRH) Dr. Joanne Less, (301) 594-1190.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research
Center for Biologics Evaluation and Research
Center for Devices and Radiological Health
March 20, 2001
GUIDANCE FOR INDUSTRY
Financial Disclosure by Clinical Investigators
This guidance represents the Food
and Drug Administration's current thinking on this topic. It
does not create or confer any rights for or on any person and
does not operate to bind FDA or the public. An alternative approach
may be used if such approach satisfies the requirements of the
applicable statute, regulations, or both.
I. Introduction
On February 2, 1998, FDA published a final rule requiring anyone
who submits a marketing application of any drug, biological product
or device to submit certain information concerning the compensation
to, and financial interests of, any clinical investigator conducting
clinical studies covered by the rule. This requirement, which became
effective on February 2, 1999, applies to any clinical study submitted
in a marketing application that the applicant or FDA relies on to
establish that the product is effective, and any study in which
a single investigator makes a significant contribution to the demonstration
of safety. This final rule requires applicants to certify to the
absence of certain financial interests of clinical investigators
or to disclose those financial interests. If the applicant does
not include certification and/or disclosure, or does not certify
that it was not possible to obtain the information, the agency may
refuse to file the application. On December 31, 1998, FDA published
an amended final rule that reduced the need to gather certain financial
information for studies completed before February 2, 1999. On October
26, 1999, FDA published a draft guidance to provide clarification
in interpreting and complying with these regulations. The burden
hours required for Section 21 CFR Part 54 are reported and approved
under OMB Control Number 0910 0396.
II. Financial Disclosure Requirements
Under the applicable regulations (21 CFR Parts 54, 312, 314, 320,
330, 601, 807, 812, 814, and 860), an applicant is required to submit
to FDA a list of clinical investigators who conducted covered clinical
studies and certify and/or disclose certain financial arrangements
as follows:
1. Certification that no financial arrangements with an investigator
have been made where study outcome could affect compensation; that
the investigator has no proprietary interest in the tested product;
that the investigator does not have a significant equity interest
in the sponsor of the covered study; and that the investigator
has not received significant payments of other sorts; and/or
2. Disclosure of specified financial arrangements and any steps
taken to minimize the potential for bias.
Disclosable Financial Arrangements:
- Compensation made to the investigator in which the value of
compensation could be affected by study outcome. This requirement
applies to all covered studies, whether ongoing or completed
as of February 2, 1999.
- A proprietary interest in the tested product, including,
but not limited to, a patent, trademark, copyright or licensing
agreement. This requirement applies to all covered studies,
whether ongoing or completed as of February 2, 1999.
- Any equity interest in the sponsor of a covered study,
i.e., any ownership interest, stock options, or other
financial interest whose value cannot be readily determined through
reference to public prices. This requirement applies to all
covered studies, whether ongoing or completed;
- Any equity interest in a publicly held company that exceeds
$50,000 in value. These must be disclosed only for covered
clinical studies that are ongoing on or after February
2, 1999. The requirement applies to interests held during the
time the clinical investigator is carrying out the study
and for 1 year following completion of the study;
and
- Significant payments of other sorts, which are payments
that have a cumulative monetary value of $25,000 or
more made by the sponsor of a covered study to the investigator
or the investigators' institution to support activities of the investigator
exclusive of the costs of conducting the clinical study or other
clinical studies, (e.g., a grant to fund ongoing research,
compensation in the form of equipment or retainers for
ongoing consultation or honoraria) during the time the clinical
investigator is carrying out the study and for 1 year following
completion of the study. This requirement applies to
payments made on or after February 2, 1999.
Agency Actions
If FDA determines that the financial interests of any clinical
investigator raise a serious question about the integrity of the
data, FDA will take any action it deems necessary to ensure the
reliability of the data including:
Initiating agency audits of the data derived from the clinical
investigator in question;
Requesting that the applicant submit further analyses of data,
e.g., to evaluate the effect of the clinical investigator's data
on the overall study outcome;
Requesting that the applicant conduct additional independent
studies to confirm the results of the questioned study; and
Refusing to treat the covered clinical study as providing data
that can be the basis for an agency action.
Definitions
Clinical Investigator - means any 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.
Covered clinical study - means any study of a drug, biological
product 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 (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 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. An applicant may consult with FDA
as to which clinical studies constitute "covered clinical studies" for
purposes of complying with financial disclosure requirements.
Applicant - means the party who submits a marketing application
to FDA for approval of a drug, device or biologic product or who
submits a reclassification petition. The applicant is responsible
for submitting the required certification and disclosure statements.
Sponsor of the covered clinical study - means the party providing
support for a particular study at the time it was carried out.
III. PURPOSE
The financial disclosure regulations were intended to ensure that
financial interests and arrangements of clinical investigators that
could affect the reliability of data submitted to FDA are identified
and disclosed by the applicant. FDA has received many questions
concerning the implementation of this final rule. The agency is
issuing this guidance to respond to these questions. FDA encourages
applicants and sponsors to contact the agency for advice concerning
specific circumstances that may raise concerns as early in the product
development process as possible.
IV. QUESTIONS AND ANSWERS
- Q. Why did FDA develop financial disclosure regulations?
A: In June 1991, the Inspector General of the Department
of Health and Human Services submitted a management advisory
report to FDA stating that FDA's failure to have a mechanism
for collecting information on "financial conflicts of
interest" of clinical investigators who study products
that undergo FDA review could constitute a material weakness
under the Federal Manager's Financial Integrity Act. Although
FDA determined that a material weakness did not exist, the
agency did conclude that there was a need to address this
issue through rulemaking. During the rulemaking process, FDA
also learned about potentially problematic financial arrangements
through published newspaper articles, Congressional inquiries,
public testimony, and comments. Based on the information gathered,
FDA determined that it was appropriate to require the submission
of certain financial information with marketing applications
that include certain types of clinical data.
- Q: Are applicants required to use FDA forms 3454 and
3455 in reporting this information?
A:Yes. The regulations require that the applicant submit
one completed Form 3454 for all clinical investigators certifying
to the absence of financial interests and arrangements. The
applicant may append a list of investigator names to Form
3454 for those investigators certifying that those investigators
hold none of the identifiable disclosable financial arrangements.
For any clinical investigator for whom the applicant does
not submit the certification, the applicant must submit a
completed Form 3455 disclosing the financial interests and
arrangements and steps taken to minimize the potential for
bias.
Where an applicant cannot provide a blanket certification
for all investigators because of the existence of disclosable
financial arrangements for one or more investigators, an applicant
should complete a disclosure form 3455 for each investigator
having disclosable financial arrangements. The applicant should
identify the specific covered clinical study (or studies)
at issue and provide detailed information about the specific
relationship that is being disclosed, (e.g., the nature of
the contingent payment or the equity holdings of the investigator
or the investigator's spouse or dependent child that exceeded
the threshold). This disclosure needs to be linked to the
specific covered clinical study (or studies) in which the
investigators participated.
In those instances where the applicant cannot provide complete
certification or disclosure on all arrangements (e.g., the
applicant has information about 2 of the 4 requirements but
has been unable to obtain the rest of the information), the
applicant should certify that despite the applicant's due
diligence in attempting to obtain the information, the applicant
was unable to obtain the information and should include an
explanation of how the applicant attempted to obtain the information
and why the information was not obtainable.
- Q: What does FDA mean by the term "due diligence"?
A: "Due diligence" is a measure of activity expected from
a reasonable and prudent person under a particular circumstance.
In complying with these rules, sponsors and applicants should
use reasonable judgement in deciding how much effort needs
to be expended to collect this information. If sponsors/applicants
find it impossible to obtain the financial information in
question, applicants should explain why this information was
not obtainable and document attempts made in an effort to
collect the information.
- Q:Who, specifically, is responsible for signing the financial
certification/disclosure forms?
A: The forms are to be signed and dated by a responsible
corporate official or representative of the applicant (e.g.,
the chief financial officer)
- Q. Where in a drug/biologic application should an applicant
include certification that financial arrangements of concern
do not exist or the disclosure of those arrangements that
do exist? Where should the information be included in a device application?
For drugs and biological product applications, applicants
should include the financial certification/disclosure forms
as part of item 19 (other) of the application. See form
356h. FDA is revising the current form 356h and upon completion
of this revision, financial certification and disclosure
information will become number 19 and (other) will become
number 20. For device applications, applicants should submit
the financial certification/disclosure forms according to
the format outlined in the appropriate submission checklist.
- Q: What obligations do IND and IDE sponsors have regarding
information collection prior to study start?
A: The regulations, 21 CFR 312.53 and 21 CFR 812.43, provide
that before permitting an investigator to begin participation
in an investigation, the IND/IDE sponsor shall obtain sufficient
accurate financial information that will allow an applicant
to submit complete and accurate certification or disclosure
statements required under Part 54. The sponsor is also required
to obtain the investigator's commitment to promptly update
this information if any relevant changes occur during the
course of the investigation and for one year following completion
of the study. By collecting the information prior to study
start, the sponsor will be aware of any potential problems,
can consult with the agency early on, and take steps to minimize
the potential for bias. See question and answer 7 for additional
information.
- Q: What is the responsibility of the IND/IDE sponsor
for obtaining financial information from investigators
at the IND/IDE stage when the IND/IDE sponsor is not the
party who will be submitting a marketing application?
The term "sponsor" has somewhat different meanings in the
regulations at 312.53/812.43 and 54.2. An applicant must report
financial interests in the sponsor of the covered study. Under
21 CFR 54.2, "sponsor" is defined as the party "supporting
a particular study at the time it was carried out." FDA interprets
support to include those who provide "material support",e.g.,
monetary support or test product under study. The sponsor
of an IND or IDE, as defined in 21 CFR 312 and 812 is the "party
or parties who take responsibility for and initiate a clinical
investigation". The term "sponsor" is also used in 312.53
and 812.43 to refer to the party who will be submitting a
marketing application (who is also responsible for submitting
the certification and disclosure statement required by Part
54).
In most cases, the IND/IDE sponsor, the sponsor of the covered
study, and the applicant company are the same party, but there
are times where they may be different. For example, when an
academic or government institution or CRO conducts a covered
study and is the IND/IDE sponsor (Part 312/812 sponsor), a
drug or device company that provides funding or the test article
used in the study is a Part 54 sponsor, and is likely to be
the applicant if a marketing application is submitted to FDA.
If the drug or device company that was a sponsor of the covered
study sold the drug/device to another company, the applicant
could be neither the IND/IDE sponsor nor a Part 54 sponsor.
The responsibility for reporting financial information to
FDA falls upon the applicant; that is, the final rule (Part
54) requires that the applicant company submit financial information
on clinical investigators at the time the marketing application
is submitted to the agency. The information that the applicant
must report, apart from compensation that may be affected
by study outcome and proprietary interests is:
- equity interests in a Part 54 sponsor of a covered
study (e.g., any interest that cannot be valued through
reference to public prices and interest in excess of $50,000
in a publicly held company), and
- significant payments of other sorts by a Part 54
sponsor of a covered study.
Although reporting to the FDA is the responsibility of the
applicant, the IND/IDE holder (part 312/812 sponsor) is required
to collect the financial information before permitting an
investigator to participate in a clinical study (312.53 and
812.43). The purpose of this requirement is two fold:
- to alert the IND/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.
The IND/IDE sponsor, who is in contact with the investigator,
is best placed to inquire as to the financial arrangements
of investigators, and this obligation applies to any IND/IDE
sponsor (e.g., commercial, government or CRO). The IND/IDE
sponsor shall maintain complete and accurate records showing
any financial interest as described in Section 54.4 (a) (3)
(i-iv) in a sponsor of the covered study. The IND/IDE sponsor
is responsible for ensuring that required financial information
is collected and is made available to the applicant company,
so that, the information can be included in the NDA/BLA/PMA
submission.
- Q. The applicant is obligated to disclose financial interests
related only to >covered studies,
specifically those relied upon to provide support for the effectiveness
of a product and certain others. An IND holder (IND sponsor),
acting much earlier, must inquire into investigator financial
interests before the ultimate role of a study in the application
is determined. How will the IND sponsor determine which studies will
ultimately require certification/disclosure statements?
A: The IND sponsor will need to consider the potential role
of a particular study based on study size, design and other
considerations. Almost any controlled effectiveness study
could, depending on outcome, become part of a marketing application,
but other studies might be critical too, such as a pharmacodynamic
study in a population subset or a bioequivalence study supporting
a new dosage form.
- Q. If a Contract Research Organization (CRO) is conducting
a covered clinical study on behalf of another company, should
the CRO collect the financial information from investigators?
Is it necessary to collect financial information from investigators
who have financial interests in CROs?
A: With regard to CRO and commercial sponsor arrangements,
the same principles as articulated in answer 6 would apply.
For example, if a CRO meets the definition of an IND/IDE sponsor
or has contracted to collect financial information from investigators
on behalf of an IND/IDE sponsor, the CRO must collect financial
information on clinical investigators' interests in Part 54
sponsors (312.53, 812.43). If the CRO provides material support
for a covered study, financial information on clinical investigators'
interests in the CRO is to be collected. If another entity
provided material support for the study, the CRO also would
collect financial information relative to that entity.
- Q: Suppose a public or academic institution conducts
a study without any support from a commercial sponsor, but
the study is then used by an applicant to support its marketing
application. In that case, who is the "sponsor" of the study
and what information should the applicant submit?
A: In this case, the Part 54 sponsor of the study is the
public or academic institution. Because such institutions
are not commercial entities, in many instances, there will
not be relevant equity interests to report. However, any relevant
interests under 54.4, such as any proprietary interest in
the tested product, including but not limited to a patent,
trademark, copyright or licensing agreement are to be reported.
- Q: Does FDA have expectations about how the financial
information should be collected? Will FDA consider it acceptable
practice for a company to use a questionnaire to collect
financial information from investigators rather than constructing
an internal system to collect and report this information?
A: FDA has no preference as to how this information is collected
from investigators. Under this rule, sponsors/applicants have
the flexibility to collect the information in the most efficient
and least burdensome manner that will be effective, for example,
through questionnaires completed by the clinical investigators
or by using information already available to the sponsor. FDA
does not require sponsors to establish elaborate tracking systems
to collect the information.
- Q. What does FDA mean by the definition of clinical investigator
and subinvestigator? Is it necessary to collect financial
information on spouses and dependent children of subinvestigators?
A: The definition of "clinical investigator" in 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
drugs, biological products and devices, it should be noted that
hospital staff, including nurses, residents, or fellows and office
staff who provide ancillary or intermittent care but who do not
make direct and significant contribution to the data are not meant
to be included under the definition of clinical investigator.
For purposes of this financial disclosure regulation, the term
investigator also includes the spouse and each dependent child
of the investigator and subinvestigator.
For drugs and biological products, 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 or dispensed 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.
For purposes of this rule, the terms investigators and subinvestigators
include persons who fit any of these criteria: sign 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/BLA. For studies not conducted under an IND, the sponsor
will need to identify the investigators and subinvestigators they
consider covered by the rule in form 3454 and/or 3455. We expect
that there will be at least one such person at each clinical site.
If, however, there are other persons who are responsible for a
study at a site, those persons should also be included as investigators.
For medical devices, clinical investigators are defined as individual(s),
under whose immediate direction the subject is treated and the
investigational device is administered, including follow-up evaluations
and treatments. Where an investigation is conducted by a team
of individuals, the investigator is the responsible leader of
the team. In general, investigators and subinvestigators sign "investigator
agreements" in accordance with 21 CFR 812.43(c ) and it is these
individuals whose interests should be reported. For studies not
conducted under an FDA-approved IDE, (that is, a non-significant
risk IDE or an exempt study), the sponsor would need to identify
the investigators and subinvestigators they considered covered
by the rule in form 3454 and 3455. We expect that there will be
at least one such person at each site.
- Q: Do the reporting requirements apply to efficacy studies
that include large numbers of investigators and multiple
sites? Will the agency consider a waiver mechanism to
exempt applicants from collecting information from clinical investigators
conducting these kinds of studies?
A: Large multi-center efficacy studies with many investigators
are considered covered clinical studies within the meaning of
the final rule. See 21 CFR 54.2(c). Data from investigators having
only a small percentage of the total subject population (in a
study with large numbers of investigators and multiple sites)
may still affect the overall study results. For example, if a
sponsor submitted data collected during a large, multi-center,
double blind study that included several thousand subjects and
a single clinical investigator at one of the largest sites enrolled
one percent of subjects, that investigator could still be responsible
for a significant number of subjects. If the investigator fabricated
data or otherwise affected the integrity of the data, remaining
data for the drug may not meet the statistical criteria for efficacy
as defined prospectively in the protocol.
Because the regulations (see 21 CFR 312.10, 812.10, 314.90 and
814.20) allow a sponsor to seek a waiver of certain requirements,
applicants may seek waivers of the financial disclosure requirements.
FDA believes it is highly unlikely, however, that any waivers
will be justified for studies begun after February 2, 1999, because
the sponsor should already have begun collecting the information
on an ongoing basis. FDA will evaluate any request for waiver
on a case-by-case basis.
- Q: The rule requires that investigators provide information
on financial interests during the course of the study and
for one year after completion of the study (see 54.4(b))?
What does "completion of the study" mean?
A: Completion of the study means that all study subjects
have been enrolled and follow up of primary endpoint data
on all subjects has been completed in accordance with the
clinical protocol. Many studies have more than one stage (e.g.,
a study could have a short term endpoint and a longer term
follow up phase). Completion of the study here refers to that
part of the study being submitted in the application. If there
were a subsequent application based on longer term data, completion
of the study would be defined similarly for the new data.
It is not required that an applicant submit updated financial
information to FDA after submission of the application, but
applicants must retain complete records. Where there is more
than one study site, the sponsor may consider completion of
the study to be when the last study site is complete, or may
consider each study site individually as it is completed.
- Q: Do applicant companies need to collect information
for a year after completion of the study? Who is responsible
for collecting/providing this information?
A: According to the February 2, 1998 final rule, the investigator
must provide updated information when the investigator holds
any equity interest in a privately held company or if stock
holdings in a publicly held company exceed $50,000 in value
during the one year period following completion of the study.
In addition, sponsors/applicants must keep records on file
when significant payments of other sorts are paid by the
sponsor of the covered study to the investigator or the
investigator's institution to support activities of the
investigator that have a cumulative monetary value of more
than $25,000, exclusive of the costs of conducting the covered
clinical studies, during the study and for one year following
completion of the study. FDA specified the one-year time
frame because anticipation of payments may be as influential
as payments already received. Applicants need only report
on these arrangements when the marketing application is
submitted, but sponsors/applicants are responsible for keeping
updated financial information from the investigators in
company files.
- Q: What information about a financial interest should
be disclosed to the agency? For example, if an investigator
owns more than $50,000 of stock in a publicly held company,
can the applicant just disclose that there is an interest that
exceeds the $50,000 threshold or is it necessary to disclose
in written detail the arrangement in question?
A: The applicant must disclose specific details of the financial
interest including the size and nature of the financial interest
in question and any steps taken to minimize the potential
for study bias that such an interest represents.
- Q: Is the clinical investigator required to report all fluctuations
above and below the $50,000 level during the course of the
investigation and one year after completion of the study?
A: The rule requires sponsors/applicants to obtain financial
information from clinical investigators and a commitment from
clinical investigators to promptly update financial information,
if any relevant changes occur during the course of the covered
clinical study and for one year following the completion of
the study [21 CFR 312.53(c)(4), 312.64(d), 812.43(c)(5), 812.110(d)].
In light of the potential volatility of stock prices, FDA
recognizes that the dollar value of an investigator's equity
holding in a sponsoring/applicant company is likely to fluctuate
during the course of a trial. Clinical investigators should
report an equity interest when the investigator becomes aware
that the holding has exceeded the threshold and the investigator
should use judgement in updating and reporting on fluctuations
in equity interests exceeding $50,000. FDA does not expect
the investigator to report when that equity interest fluctuates
below that threshold.
- Are equity interests in mutual funds and 401K(s) reportable?
A: Because an investigator would not have control over buying
or selling stocks in mutual funds, these would not be reportable.
In most circumstances, interests in 401K(s) would not be reportable,
although equity interest in a product over $50,000 would be
reportable if it is a holding in a self directed 401K.
- Q: Does the rule include ANDAs? Does the rule include
510(k)s that do not include clinical data?
A: The rule applies to any clinical study of a drug (including
a biological product) or device submitted in a marketing application
that the applicant or FDA relies on to establish that the product
is effective, including studies of drugs that show equivalence
to an approved product. This means that ANDAs are covered by the
final rule. 510(k)s that do not include clinical data would not
contain covered studies and therefore, no financial information
from device manufacturers is needed for those applications.
- Q: Do applicants need to provide information on investigators
who participate in foreign studies?
A: Yes, applicants should include either a certification or disclosure
of information for investigators participating in foreign covered
studies. Where the applicant is unable to obtain the information
despite acting with due diligence, the applicant may submit a
statement documenting its efforts to obtain the information. In
this case, it is unnecessary to submit a certification or disclosure
form.
- Q: Does the rule apply to studies in support of labeling
changes?
A: The rule applies to studies submitted in a supplement when
those studies meet the definition of a covered clinical study.
It also applies to studies to support safety labeling changes
where individual investigators make a significant contribution
to the safety information.
- Q:In the case where a subsidiary company of a larger
parent company is conducting a covered clinical trial, is
the applicant (subsidiary company) required to report information
from clinical investigators about financial interests in only
the subsidiary company, or is the applicant also required
to report financial holdings, if any, of the investigator
in the larger parent company?
A: If the subsidiary company meets the definition of sponsor
of the covered study as defined under Part 54, the IND/IDE
holder is required to collect from clinical investigators
financial information related to the subsidiary company. The
IND/IDE holder also must collect financial information related
to the parent company if the parent company is a Part 54 sponsor
of the study in question. If there are multiple companies
providing material support for a covered study, the IND/IDE
holder is responsible for collecting financial information
from clinical investigators related to all companies providing
that support. The applicant company is ultimately responsible
for submitting financial information to the Agency at the
time the marketing application is submitted.
- Q: Do "actual use studies" to support a request to switch
a drug product from prescription to over-the-counter (OTC)
status fit the definition of covered clinical study?
A: Applicants who file supplements requesting that FDA approve
a switch of a prescription drug to OTC status or who file a new
drug application for direct OTC use often conduct "actual use
studies." These may be intended to demonstrate that the product
is safe and effective when used without the supervision of a licensed
practitioner; in other cases, they may test labeling comprehension
or other aspects of treatment. Actual use studies performed to
support these applications would be considered covered clinical
studies if they were used to demonstrate effectiveness in the
OTC setting or if it is a safety study where any investigator
makes a significant contribution.
- Q: Are clinical investigators of in vitro diagnostics
(IVDs) covered under this regulation since they often involve
specimens, not human subjects?
A: Yes. Applicants who submit marketing applications for
IVDs must include the appropriate financial certification
or disclosure information. Under section 21 CFR 812.3(p), "subject" is
defined as a "human who participates in an investigation,
either as an individual on whom or on whose specimen an investigational
device is used or as a control." Thus, an investigation of
an IVD is considered a clinical investigation and, if it is
used to support a marketing application, it would be subject
to this regulation.
- Q: How do significant payments of other sorts (SPOOS)
relate to the variety of payments the sponsor might make
to an individual or institution for various activities?
A: The term "significant payments of other sorts" was intended
to capture substantial payments or other support provided to an
investigator that could create a sense of obligation to the sponsor.
These payments do not include payments for the conduct of the
clinical trial of the product under consideration or clinical
trials of other products, under a contractual arrangement, but
do include other payments made directly to the investigator or
to an institution for direct support of the investigator. These
payments would include honoraria, consulting fees, grant support
for laboratory activities and equipment or actual equipment for
the laboratory/clinic. This means that if an investigator were
given equipment or money to purchase equipment for use in the
laboratory/clinic, but not in relation to the conduct of the clinical
trial, the payment would be considered a significant payment of
other sorts and should be reported. If however, the investigator
were provided with computer software or money to buy the software
needed for use in the clinical trial, that would not need to be
reported. Finally, payments made to the institution or to other
nonstudy participating investigators that are not made on behalf
of the investigator do not need to be reported.
- Q: Are payments made to investigators to cover travel
expenses (such as transportation, lodgings and meal
expenses) trackable under significant payments of other sorts
(SPOOS)?
A: Generally, reasonable payments made to investigators to
cover reimbursable expenses such as transportation, lodgings
and meals do not fall within the purview of SPOOS and, therefore,
would not need to be tracked. Travel costs associated with
transporting, providing lodgings and meals for family members
of investigators are considered unnecessary and should be
tracked as SPOOS. In addition, other payments that exceed
reasonable expectations, (for example, an investigator is
flown to a resort location for an extra week of vacation)
are considered outside of normal reimbursable expenditures
and are not considered expenses that are necessary to conduct
the study. Therefore, these types of expenses are also reportable
and should be tracked as SPOOS.
- Q: Under what circumstances would FDA refuse to file
an application?
A: FDA may refuse to file any marketing application that does
not contain either a certification that no specified financial
arrangement exists or a disclosure statement identifying the specified
arrangements or a statement that the applicant has acted with
due diligence to obtain the required information, and an explanation
of why it was unable to do so. The agency does not anticipate
that it will be necessary to use its refuse to file authority
often in the context of this financial disclosure rule. Applicants
are encouraged to discuss their concerns on particular matters
about financial information with FDA.
- Q: Who will review a disclosure of the specified financial
arrangements when such information is submitted in a marketing
application? How will the financial information be handled
during the review of the application?
A: Applicants are required to disclose specified financial
information and any steps taken to minimize the potential
for bias in any drug, biological product or device marketing
application submitted to the agency on or after February 2,
1999. (See 21 CFR 54.4(a)(3)). FDA review staff, including
project managers, consumer safety officers, medical officers
and others in the supervisory chain will review this information
on a case-by-case basis.
- Q: Under what circumstances will FDA publicly discuss financial
arrangements disclosed to the agency?
A:In the preamble to the final rule, FDA stated that
certain types of financial information requested under the
rule, notably clinical investigators' equity interests would
be protected from public disclosure unless circumstances relating
to the public interest clearly outweigh the clinical investigator's
identified privacy interest. FDA cited the example of a financial
arrangement so affecting the reliability of a study as to
warrant its public disclosure during evaluation of the study
by an advisory panel. FDA expects that only rarely would an
investigator's privacy interest be outweighed by the public
interest and thus warrant disclosure of the financial interest.
It is difficult to predict all possible situations that may
result in public disclosure of financial interests of a clinical
investigator. The agency will carefully evaluate each circumstance
on a case-by-case basis.
- Q: Can FDA have access to documents related to financial
disclosure or certification documents during an inspection?
A: Yes, FDA has the authority to have access to and
to copy documents supporting an applicant's certification or disclosure
statement submitted to the agency in a marketing application.
Regulations implementing sections 505(i), 519, and 520(g) of the
Act require sponsors to establish and maintain records of data
(including but not limited to analytical reports by investigators)
obtained during investigational studies of drugs, biological products,
and devices, that will enable the Secretary to evaluate a product's
safety and effectiveness. Under 54.6, applicants must retain certain
information on clinical investigators' financial interests and
permits FDA employees to have access to and copy them at reasonable
times.
- Q: What kind of documentation is necessary for manufacturers
to keep in case questions about certification and/or disclosure
arise?
A: To the extent that applicants have relied on investigators
as the source of information about potentially disclosable
financial interests in any of the four categories, the underlying
documentation -- e.g., copies of executed questionnaires
returned by investigators , correspondence on the subject
of financial disclosure, mail receipts, etc. should be retained.
Likewise, to the extent that applicants who did not sponsor
a covered clinical study rely on information furnished by
the sponsor, the underlying documentation, including all
relevant correspondence with and reports from the sponsor
should be retained. To the extent that applicants rely upon
information available internally, all appropriate financial
documentation regarding the financial interests or arrangements
in question should be retained. For example, in the
case of "significant payments of other sorts," sponsors
should keep documentation including, but not limited to,
check stubs, canceled checks, records of electronic financial
transactions, certified mail deliver receipts, etc.
- Q: Where are forms FDA 3454 and 3455 located on the Web?
The forms are located at the following Internet address:
http://www.fda.gov/opacom/morechoices/fdaforms/cder.html
- Q: Who are the contact persons in each FDA Center to
answer questions during this implementation phase?
The following persons may be contacted: Ms. Linda Carter
in the Center for Drug Evaluation and Research, phone
301-594-6758, Dr. Joanne Less in the Center for Devices
and Radiological Health, phone 301-594-1190, and Dr. Jerome
Donlon in the Center for Biologics Evaluation and Research,
phone 301-827-3028.
1 This guidance has been prepared
by the Implementation Team for Financial Disclosure comprised
of individuals in the Office of the Commissioner, the Center
for Drug Evaluation and Research (CDER), Center Biologics
Evaluation and Research (CBER) and Center Devices and Radiological
Health (CDRH) at the Food and Drug Administration.