[Federal Register Volume 62, Number 50 (Friday, March 14, 1997)]
[Rules and Regulations]
[Pages 12087-12096]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-6475]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
21 CFR Part 812
[Docket No. 92N-0308]
Investigational Device Exemptions; Disqualification of Clinical
Investigators
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is amending its medical
device regulations to include provisions for the disqualification of
clinical investigators. These amended regulations parallel, with minor
exceptions, the regulations for disqualification of clinical
investigators of drugs, biologics, and animal drugs. The agency is
finalizing this regulation to further implement its plan for consistent
bioresearch monitoring procedures for all products regulated by FDA and
to improve the remedies available to deal with clinical investigators
who violate the law. This action is being taken under the Medical
Device Amendments of 1976.
DATES: Effective May 13, 1997.
FOR FURTHER INFORMATION CONTACT: Rodney T. Allnutt, Center for Devices
and Radiological Health (HFZ-310), Food and Drug Administration, 2094
Gaither Rd., Rockville, MD 20850, 301-594-4718.
SUPPLEMENTARY INFORMATION:
I. Background
FDA has long intended to have clinical investigator
disqualification procedures available for medical device
investigations. Although the investigational device exemption (IDE)
regulation part 812 (21 CFR part 812) allows FDA to initiate regulatory
action against a study sponsor due to a noncompliant investigator, such
as terminating the sponsor's IDE or imposing additional restrictions
under the IDE, the IDE regulation did not expressly provide for
clinical investigator disqualification. The proposed IDE regulation,
published in the Federal Register of August 20, 1976 (41 FR 35282 at
35311), contained disqualification provisions for clinical
investigators in proposed Sec. 812.119 that were not included in the
final IDE regulations published on January 18, 1980 (45 FR 3732), which
apply to device investigations generally. Disqualification provisions
were included, however, in part 813 (21 CFR part 813) on
investigational exemptions for intraocular lenses (IOL's) in
Sec. 813.119 (42 FR 58874, November 11, 1977). The preamble to the
final IDE regulation, published in the Federal Register of January 18,
1980 (45 FR 3732 at 3749), noted that proposed Sec. 812.119 was being
removed and would be addressed in FDA's final agency-wide regulation on
the obligations of clinical investigators, which had been proposed in
the Federal Register of August 8, 1978 (43 FR 35186). This agency-wide
regulation, however, was never finalized.
In the Federal Register of October 6, 1993 (58 FR 52142), FDA
issued a proposed rule to remove part 813, the regulation on
investigational exemptions for IOL's. FDA received two comments in
response to the proposed rule. These comments were addressed in the
preamble to the rule that removed part 813, which was published in the
Federal Register of January 29, 1997 62 FR 4164.
In the Federal Register of October 6, 1993 (58 FR 52144), FDA also
published a proposed rule governing disqualification of clinical
investigators of medical devices, to be added to part 812. The proposed
rule was virtually identical to the regulation for disqualification of
clinical investigators of IOL's, which would be removed with the
proposed removal of part 813. In the proposed rule, however, FDA
expressly invited comments on whether the procedures for
disqualification of clinical investigators of medical devices should be
identical, or virtually identical to the regulation for the
disqualification of clinical investigators of drugs and biologics in
Sec. 312.70 (21 CFR 312.70). FDA stated that if comments persuaded the
agency to revise the proposed rule to follow Sec. 312.70 precisely or
closely, the agency might issue a final rule which parallels
Sec. 312.70.
FDA received three comments stating an explicit preference for
rules governing disqualification of investigators of drugs as specified
in Sec. 312.70, over the rules that had been proposed for
disqualification of investigators of devices. Two other comments that
did not specifically mention Sec. 312.70 nevertheless suggested changes
to the proposed rule that would make it more consistent with the drug
investigator disqualification rule. The other three comments FDA
received did not address this issue.
Two comments preferred Sec. 312.70 to the proposed regulation
because Sec. 312.70 does not contain the perceived flaws found in the
proposed regulation. These comments stated, e.g., that the threshold
for disqualification in Sec. 312.70 is set much higher and the terms
are more clearly defined than in the proposed regulation. One of these
comments requested that the Center for Devices and Radiological Health
(CDRH) adopt Sec. 312.70 in its entirety because of the perceived flaws
in the proposed rule. That comment also noted that most medical device
companies and investigators of devices are unfamiliar with Sec. 312.70.
Therefore, the comment recommended that FDA propose a rule similar to
Sec. 312.70 and give interested parties a chance to comment on the
reproposal. The third comment stated that the regulation for
disqualification of investigators of investigational new drugs is a
better model because it is a relatively simple and clear regulation, it
does not impose unfair and potentially harmful presumptions, and it
would give FDA the immediate consistency it desires among product
lines.
FDA has been persuaded by the comments that the regulation
governing disqualification of investigators of medical devices should
parallel the regulation for disqualification of investigators of drugs
and biologics in Sec. 312.70 (as well as the regulation for
disqualification of investigators of animal drugs at Sec. 511.1(c) (21
CFR 511.1(c))). This rule for disqualification of investigators of
medical devices, therefore, adopts regulations that are basically the
same as those governing disqualification of investigators of drugs,
biologics, and animal drugs, with minor exceptions.
The agency has concluded, however, that a reproposal is unnecessary
because the agency received sufficient and adequate comments to make a
reasoned determination about the final rule and because the agency
provided clear notice to interested persons that a final regulation
paralleling Sec. 312.70 would be adopted if the comments persuaded the
agency that this approach represented the best option. (See the Federal
Register of October 6, 1993, that stated ``FDA is giving notice that,
if comments persuade the agency to revise the proposed rule to follow
Sec. 312.70 * * *
[[Page 12088]]
the agency may issue a rule that parallels Sec. 312.70.''( 58 FR
52144).)
In response to the concern that medical device companies and
investigators of medical devices are unfamiliar with Sec. 312.70, the
agency notes that this rule is consistent with FDA's regulatory program
for investigators of drugs, which has existed for more than 30 years,
and that interested persons were provided explicit notice in the
proposal that the same disqualification procedures might be adopted for
investigators of devices. Interested parties who may be unfamiliar with
FDA's bioresearch monitoring activities for clinical investigations may
find useful the description of the agency's investigator
disqualification process that is provided in an FDA publication
entitled ``Food and Drug Administration INFORMATION SHEETS for
Institutional Review Boards and Clinical Investigators'' (October 1995
revision), which is currently available from the Office of the
Associate Commissioner for Health Affairs.
This document explains why FDA was persuaded by the comments to
adopt the approach being codified and also describes the ways in which
the rule has been modified from the proposal in order to incorporate
the changes suggested by the comments. In addition, this document
identifies comments that are now moot because the agency adopted
disqualification procedures that parallel Sec. 312.70. Finally, this
document also explains FDA's basis for not including other suggestions.
II. Summary of the Final Rule
The final rule consists of the following provisions:
A. Grounds for Disqualification
Section 812.119(a) establishes that disqualification proceedings
will only begin if FDA has information indicating that the investigator
has: (1) Repeatedly or deliberately failed to comply with the
requirements of this part, part 50 (21 CFR part 50), or part 56 (21 CFR
part 56); or (2) repeatedly or deliberately submitted false information
either to the sponsor of the investigation or in any required report.
B. Informal Conference or Written Explanation and Opportunity for a
Hearing on Proposed Disqualification
In accordance with Sec. 812.119(a), when FDA determines that one of
the grounds for disqualification may exist, CDRH will furnish the
investigator written notice of the matter under complaint and offer the
investigator an opportunity to explain the matter in writing, or, at
the option of the investigator, in an informal conference. If an
explanation is offered and accepted by CDRH, the disqualification
process will be terminated. If an explanation is offered but not
accepted by CDRH, the investigator will be given an opportunity for a
regulatory hearing under part 16 (21 CFR part 16) on the question of
whether the investigator is entitled to continue to receive
investigational devices.
C. Notification of Disqualification
In accordance with Sec. 812.119(b), after evaluating all available
information, including any explanation presented by the investigator,
if the Commissioner of Food and Drugs (the Commissioner) determines
that the investigator has repeatedly or deliberately failed to comply
with the requirements of this part, part 50, or part 56, or has
repeatedly or deliberately submitted false information either to the
sponsor of the investigation or in any required report, the
Commissioner will notify the investigator, the sponsor of any
investigation in which the investigator has been named as a
participant, and the reviewing Institutional Review Board (IRB), that
the investigator is not entitled to receive investigational devices.
The notification will provide a statement of the basis for such
determination.
D. Actions Upon Disqualification
Under Sec. 812.119(c), FDA shall examine each IDE and each cleared
or approved application submitted under subpart E of part 807 (21 CFR
part 807) or part 814 (21 CFR part 814), containing data reported by an
investigator who has been determined to be ineligible to receive
investigational devices to determine whether the investigator has
submitted unreliable data that are essential to the continuation of the
investigation or essential to the clearance/approval of any marketing
application.
Under Sec. 812.119(d), if the Commissioner determines, after the
unreliable data submitted by the investigator are eliminated from
consideration, that the data remaining are inadequate to support a
conclusion that it is reasonably safe to continue the investigation,
the Commissioner will notify the sponsor, who shall have an opportunity
for a regulatory hearing under part 16. If a danger to the public
health exists, however, the Commissioner shall order withdrawal of
approval of the IDE before any hearing. In such case, the sponsor shall
have an opportunity for a regulatory hearing under part 16 on the
question of whether the IDE should be reinstated. (See
Sec. 812.30(c)(2).)
In accordance with Sec. 812.119(e), if the Commissioner determines,
after the unreliable data submitted by the investigator are eliminated
from consideration, that the continued clearance or approval of the
marketing application for which the data were submitted cannot be
justified, the Commissioner will proceed to withdraw approval or
rescind clearance of the medical device in accordance with the
applicable provisions of the act and the agency's regulations.
E. Reinstatement of a Disqualified Investigator
Under Sec. 812.119(f), a disqualified investigator may be
reinstated when the Commissioner determines that the investigator has
presented adequate assurances, through written submissions, that the
investigator will employ investigational devices solely in compliance
with the provisions of parts 812, 50, and 56.
F. Scope
The final rule clarifies that the provisions for disqualification
of investigators of devices apply to all cleared or approved and
pending device applications containing or relying upon any clinical
investigations performed by the disqualified investigator. Such
applications include IDE's, premarket notifications (510(k)'s), and
premarket approval applications (PMA's). Subsequent to publication of
the proposed rule, FDA discovered that 510(k)'s were inadvertently
omitted from proposed Sec. 812.119(a). Because the provisions for
disqualification of a clinical investigators are intended to apply to
all device applications containing or relying upon any clinical
investigations performed by the disqualified investigator, this final
rule clarifies that such provisions apply to 510(k)'s, IDE's, and
PMA's.
The final rule also clarifies that no clinical investigator of
medical devices is exempt from the disqualification regulations. The
exemptions and abbreviated requirements described in part 812 for
certain investigations are intended to relate to those procedures and
requirements under part 812 associated with submitting an IDE
application or obtaining an IDE prior to conducting an investigation.
Section 812.2 is not intended to eliminate the responsibility of
clinical investigators of devices to abide by procedures and standards
associated with good scientific practice. Whether or not an
investigation requires an IDE, every
[[Page 12089]]
clinical investigator whose work may be considered in connection with a
marketing application is expected to comply with the agency's
regulations and scientific standards relating to informed consent, IRB
oversight, inspections, adherence to investigational protocols, and
pertinent reports and recordkeeping. The final rule amends Sec. 812.2
to clarify that the provisions governing disqualification of
investigators apply to all clinical investigations of devices,
including those that do not require FDA approval of an IDE, e.g.,
clinical investigations involving nonsignificant risk devices, and
those categories of exempted devices identified in the IDE regulation.
III. Identification and Explanation for the Differences Between the
Regulation for Disqualification of Investigators of Devices and the
Regulation for Investigators of Drugs and Biologics
Section 812.119(a) establishes that FDA may begin the
disqualification process ``if FDA has information indicating that an
investigator has repeatedly or deliberately submitted false information
either to the sponsor of the investigation or in any required report.''
This language is somewhat different from the parallel provision for
investigators of drugs and biologics (Sec. 312.70(a)), which states
that a disqualification process may begin when there is information
that the investigator ``has submitted to the sponsor false information
in any required report.'' (The parallel regulation for investigators of
animal drugs (Sec. 511.1(c)), requires FDA to have information
indicating that the investigator ``has submitted false information
either to the sponsor of the investigation or in any required
report.'') FDA believes that the language in the final rule for
disqualification of investigators of devices more clearly states the
intent of both the drug and animal drug provisions.
As discussed in section IV. of this document, several comments
raised concern that investigators would be unfairly penalized for
submitting false information inadvertently or when it was beyond their
individual control. The agency does not intend isolated or inadvertent
failures to be the basis for disqualification and the addition of the
phrase ``repeatedly or deliberately'' clarifies that the agency's
threshold for taking action against a clinical investigator requires
the submission of false information to be either deliberate or frequent
enough to call into question the individual's eligibility to continue
the investigation.
Section 812.119(b) establishes that, in addition to notifying the
investigator and the sponsor of any investigation in which a
disqualified investigator has been named as a participant
(Sec. 312.70(b)), FDA will also notify the reviewing IRB of a final
disqualification determination. FDA has made this addition in response
to several comments received on the proposed rule and after concluding
that this notification will better enable the reviewing IRB to meet an
obligation for continuing review to ensure the protection of the rights
and well-being of the subject.
Section 812.119(d) establishes that in addition to notifying the
sponsor of any investigation (Sec. 312.70(d)), FDA will also notify the
reviewing IRB that the Commissioner has determined that a danger to
public health exists and has ordered withdrawal of approval of the IDE.
FDA has considered the comments received on the proposed rule that
prompted the adoption of notification of IRB's as provided under
Sec. 812.119(a), and has concluded that this notification will better
enable IRB's to monitor an investigation that is ordered terminated to
ensure continued protection of the rights and well-being of the
subject.
FDA believes that these changes improve the medical device
regulations for disqualification of clinical investigators without
creating significant discrepancies between those procedures and the
regulations that are now in place for clinical investigators of drugs,
biologics, and animal drugs. FDA intends to consider making similar
changes to Sec. 312.70 in order to make the investigator
disqualification regulations as consistent as possible.
IV. Comments
FDA published a proposed rule to revise its medical device
regulations to include provisions for the disqualification of clinical
investigators (58 FR 52144). Because of an inadvertent error, the date
for submission of comments was incorrectly published as November 5,
1993, even though the preamble to the proposed rule provided an
opportunity for interested persons to submit comments on the proposed
rule until December 6, 1993. A correction notice was published in the
Federal Register of October 14, 1993 (58 FR 53245). Subsequently, in
the Federal Register of December 6, 1993 (58 FR 64209), FDA extended
the comment period for the proposed rule from December 6, 1993, until
January 5, 1994, in response to a request for an extension from a trade
association.
The agency received a total of eight comments from trade
associations, manufacturers, law offices, a medical device consultant,
a medical center, and FDA's Center for Drug Evaluation and Research
(CDER). A summary of the comments and the agency's response to them is
provided below:
A. Secondary Studies; Proposed Sec. 812.119(a)(2)
1. A comment suggested that the proposed provisions authorizing
disqualification of secondary studies, i.e., clinical studies by the
same investigator other than the one in which misconduct is shown,
should be limited. The comment recommended that limits should be placed
on retrospective disqualification of secondary studies because FDA has
authority to monitor the integrity and performance of secondary
studies. For instance, FDA has the opportunity to inspect clinical
study sites, to review sponsor's monitoring of studies, and to analyze
the results of studies. Because the agency already has the authority to
monitor the integrity and performance of secondary studies, the comment
requested FDA to establish the following provisions relating to
disqualification of secondary studies: (1) Secondary studies should be
disqualified only when there is specific, demonstrable basis for a
charge of misconduct; (2) the burden of proof relative to
disqualification of a secondary study should be with FDA; (3) sponsors
of secondary studies should be notified of disqualification of
investigators; and (4) the basis for disqualification of a secondary
study should be limited to issues which represent ongoing threats to
the safety of current or future users of the product.
Another comment suggested that proposed Sec. 812.119(a)(2) should
not apply to other ongoing IDE's in which the investigator is involved,
unless particular information establishes that a potential problem
exists with respect to that specific clinical investigation.
The agency agrees with these comments and is persuaded that the
approach set forth in Sec. 312.70 and now being adopted in part 812 is
preferable to the proposal because it addresses these concerns. The
final rule does not automatically disqualify all IDE's or secondary
studies. Instead, Sec. 812.119 establishes that FDA will examine each
IDE to determine whether the disqualified investigator has submitted
unreliable data that are essential to the continuation of any
investigation in which the investigator has been named a participant.
(See Sec. 812.119(c).) If the Commissioner determines, after the
[[Page 12090]]
unreliable data submitted by the investigator are eliminated from
consideration, that the data remaining are inadequate to support a
conclusion that it is reasonably safe to continue the investigation,
the Commissioner will notify the sponsor, who shall have an opportunity
for a regulatory hearing under part 16. (See Sec. 812.119(d).)
Thus, in accordance with Sec. 812.119(c) and (d), FDA may terminate
``secondary'' clinical investigations in which the disqualified
investigator has been involved only after FDA: (1) Has determined that
the disqualified investigator has submitted unreliable data that are
essential to the continuation of any investigation in which the
investigator has been named a participant; (2) eliminates the
unreliable data from consideration and determines that the data
remaining are inadequate to support a conclusion that it is reasonably
safe to continue the investigation; and (3) provides the sponsor with
an opportunity for a regulatory hearing.
In accordance with Sec. 812.119(d), the initial burden of proof
relative to disqualification of secondary studies/IDE's rests with the
agency. If FDA's initial determination is that the data remaining are
inadequate to support a conclusion that it is reasonably safe to
continue the investigation, the sponsor will be provided with an
opportunity to challenge FDA's findings during a regulatory hearing.
The comment's suggestion that sponsors of secondary studies be
notified of the disqualification of investigators has already been
incorporated into Sec. 812.119(b), which requires, among other things,
notification of the sponsor of any clinical investigation in which the
disqualified investigator has been named as a participant.
B. Proposed Sec. 812.119(a)
2. One comment requested that Sec. 812.119(a), which was drafted to
apply to the disqualification of an investigator ``who has failed to
comply with any'' of the regulations applicable to clinical
investigators, be changed to apply only to investigators who have
engaged in serious violations.
The agency agrees with the basic concern raised by this comment and
believes that the decision to adopt a final regulation that parallels
Sec. 312.70 has addressed this concern. Section 812.119(a) replaces
``has failed to comply with any of the regulations set forth in this
part'' with ``has repeatedly or deliberately failed to comply with the
requirements of this part, part 50, or part 56 * * *.'' An
investigator's failure to repeatedly or deliberately comply with the
requirements of this part, part 50, or part 56 constitutes a serious
violation.
C. Proposed Sec. 812.119(a)(1)
3. One comment noted that the use of the term ``necessarily'' in
proposed Sec. 812.119(a)(1) implies that a disqualification decision
may or may not constitute a finding or recommendation that the
investigator is not qualified to practice or teach medicine or should
be subject to other sanctions by third parties. The comment suggested
that these areas are outside the disqualification proceeding purview.
As a result, the word ``necessarily'' should be omitted from
Sec. 812.119(a)(1) to ensure that a disqualification decision would not
affect these areas of the investigator's life.
Proposed Sec. 812.119(a)(1) has not been adopted in the final
regulation. However, under Sec. 812.119(b), the disqualification
notification issued by the agency constitutes only a finding that the
investigator is not entitled to receive investigational devices and a
statement of the basis for a determination by the agency that the
investigator is disqualified from participation in clinical
investigations. The agency's disqualification does not constitute any
other finding.
D. Proposed Sec. 812.119(b)(1)
4. Proposed Sec. 812.119(b)(1) provided that an investigator could
be disqualified if he or she ``caused false information to be
submitted'' to FDA or a sponsor. According to one comment, this
language allows an investigator to be held responsible even if the
investigator were unaware that the information was false. The comment
said that this provision fails to recognize that all clinical studies
have some degree of unavoidable error. Another comment stated that an
investigator should not be disqualified because he or she submitted
false information generated by a third person, unless the investigator
knew of the falsehood. A third comment requested that proposed
Sec. 812.119(b)(1) be rewritten as follows: An investigator should be
disqualified if ``the investigator deliberately caused false
information to be submitted to FDA or to the sponsor of a study with
the understanding that information may be submitted to FDA.''
It is not FDA's intention to disqualify an investigator for a
single submission of false data for which the investigator was not
responsible. The agency would not seek to disqualify investigators
under such circumstances and FDA believes that the adoption of
Sec. 812.119(a) ensures against such situations.
In accordance with Sec. 812.119(a), an investigator may be
disqualified ``If FDA has information indicating that an investigator
has * * * deliberately or repeatedly submitted false information either
to the sponsor of the investigation or in any required report, * * *.''
Requiring submission of false information to be ``deliberately''
submitted ensures that investigators will not be held responsible for a
single submission of false information if the investigator were unaware
that the information was false.
Although the ``repeated submission of false information'' basis for
disqualification does not ensure that an investigator will not be
disqualified for the submission of false information if the
investigator were unaware that the information was false, FDA believes
that such a basis for disqualification is necessary. A clinical
investigator who repeatedly causes false information to be submitted to
FDA, whether through carelessness or mismanagement, jeopardizes the
integrity of the study and safety of the patients. The agency believes
that investigators who repeatedly submit false information should be
disqualified from participation in such investigations.
E. Proposed Sec. 812.119(b)(3)
5. Five comments suggested modifying the language in proposed
Sec. 812.119(b)(3) in order to clarify the grounds for disqualification
and to afford clinical investigators and FDA a less severe remedy than
disqualification for less serious violations. One comment recommended
that FDA incorporate the standard used in Sec. 312.70, which states
that investigators may be disqualified for repeated or deliberate
failures to comply with regulations.
The final rule addresses the concerns raised by these comments by
adopting Sec. 812.119(a), which parallels, with minor modifications,
Sec. 312.70(a). Section Sec. 812.119(a) states that clinical
investigators may be disqualified only under the following situations:
(1) Repeated or deliberate failure to comply with the requirements of
parts 812, 50, or 56; or (2) repeated or deliberate submission of false
information either to the sponsor of the investigation or in any
required report.
The agency believes that the concern regarding affording clinical
investigators a remedy other than disqualification for less serious
violations has also been addressed in Sec. 812.119(a). Section
812.119(a) provides the investigator with an opportunity to explain the
[[Page 12091]]
matter in writing, or in an informal conference with the center. FDA
believes that this opportunity is the appropriate time for a clinical
investigator to dispute or explain any of the allegations cited in the
written notice proposing disqualification. Based on the explanation
given, CDRH may determine that the investigator's disqualification is
not necessary and terminate the proceeding. The clinical investigator
also may decide to enter into a consent agreement with the agency that
terminates the disqualification proceeding.
F. Proposed Sec. 812.119(c) and (d)
6.A comment requested that, in addition to the investigator
receiving written notice, the sponsor of the clinical investigation, as
well as IRB, should be informed about any written notice by FDA to the
clinical investigator of an allegation involving noncompliance with
regulations that may be grounds to justify disqualification of the
investigator. Another comment requested that FDA be required to notify
the sponsor, IRB, and other sponsors who are employing or have
previously employed the investigator to conduct clinical studies
requiring prior FDA review, that a potential problem exists at the same
time FDA notifies the investigator about the opportunity for a written
explanation, an informal conference, or a hearing. The comment
contended that giving such notification will allow the sponsors to take
actions to minimize the potential effect of disqualification.
One comment suggested adding the following provision to
Sec. 812.119(c):
The written notice to the investigator will be copied to the
sponsor of the investigation, as well as the IRB reviewing the
investigation. Sponsors of other clinical studies requiring prior
FDA review which are being or have been conducted by the
investigator will also be notified. FDA will issue this notice to
the IRB and sponsors within 15 working days after the notice is
issued to the clinical investigator.
Furthermore, it was requested that the disqualification process
termination notice to the clinical investigator, provided for in
Sec. 812.119(c)(2), be required to be copied to the sponsor of the
investigation, the IRB reviewing the investigation, and sponsors of
other clinical studies requiring prior FDA review which are being or
have been conducted by the investigator.
The agency does not believe that additional notification of
preliminary findings should be required routinely as part of the
investigation of an investigator who may be disqualified because
further investigation may determine the investigator to be in
compliance with the relevant regulations, and also because sponsors and
IRB's have access to Form FD-483 and warning letters relating to their
clinical investigators. The agency does recognize, however, that there
are times when it is reasonable or necessary for FDA to notify the
sponsor of a study and the reviewing IRB prior to a final
disqualification determination in order to ensure the integrity of a
study or the rights and well-being of a subject. While there are
circumstances that may warrant early notification to sponsors or IRB's,
this final regulation, like its counterparts for investigators of
drugs, biologics, and animal drugs, does not explicitly address this
issue. However, separate from this rulemaking, the agency is
establishing a working group, representing all FDA centers, to
establish a uniform policy on the issue of prior disclosure to sponsors
and IRB's.
The agency has adopted Sec. 812.119(b), which parallels the
language used in Sec. 312.70(b) of the investigational new drug (IND)
regulations for disqualification of investigators, and provides that
``any sponsor of an investigation in which the investigator has been
named as a participant and the reviewing IRB'' shall be notified of the
agency's final decision on the disqualification of the investigator and
the basis for the disqualification. The agency has also adopted
Sec. 812.119(d), which parallels the language used in Sec. 312.70(d) of
the IND regulations, and provides that sponsors and IRB's shall be
notified and sponsors given an opportunity for a hearing, when FDA
intends to withdraw approval for an IDE, or if a danger to public
health warrants immediate termination of an investigation, that the
Commissioner shall order the immediate withdrawal of approval of the
IDE and the sponsor shall be offered an opportunity for a hearing on
whether the IDE should be reinstated.
G. Proposed Sec. 812.119(c)(1) and (d)
7. A comment suggested that the written notice in
Sec. 812.119(c)(1) and (d) should describe the noncompliance with
sufficient detail and particularity so that the investigator is
informed fully of the alleged violation. An investigator cannot provide
an informed response unless sufficient detail is provided.
The agency agrees with the concern expressed by this comment and
has adopted Sec. 812.119(a), which establishes the agency's
responsibility to provide adequate details. Section 812.119(a) provides
that ``* * * the Center for Devices and Radiological Health will
furnish the investigator written notice of the matter under complaint *
* *.'' FDA intends that such notices include a full description of the
alleged violation(s) that are the basis for disqualification.
H. Proposed Sec. 812.119(c)(2)
8. Proposed Sec. 812.119(c)(2) provides for the termination of the
proceeding if the investigator offers an explanation for the
noncompliance that is accepted by FDA. One comment suggested that
Sec. 812.119(c)(2) be rewritten to allow for the termination of the
proceeding if the investigator demonstrates that no regulatory
violations actually occurred. Another comment recommended that the term
``alleged'' be placed before the word noncompliance in
Sec. 812.119(c)(2) to indicate that a noncompliance determination has
not been made at this preliminary stage.
The agency believes that these modifications are unnecessary with
the adoption of the final rule. In accordance with Sec. 812.119(a),
when FDA furnishes the investigator with a written notice of the matter
under complaint, FDA will also offer the investigator an opportunity to
explain the matter in writing, or at the option of the investigator, at
an informal conference. If an explanation is offered by the
investigator and accepted by CDRH, the disqualification process will be
terminated. The scope of an investigator's explanation is not limited
and may include a showing that no regulatory violations actually
occurred.
The agency also believes that modifying Sec. 812.119(a) by
inserting the term ``alleged'' in the regulatory text is unnecessary
because Sec. 812.119(a), unlike proposed Sec. 812.119(c)(2), does not
indicate that a final noncompliance determination will be made at this
preliminary stage.
I. Proposed Sec. 812.119(c)(2) and (c)(3)
9. A comment requested that the terms ``FDA'' and ``agency'' in
Sec. 812.119(c)(2) and (c)(3) be replaced with ``Center for Devices and
Radiological Health,'' in order to clarify that informal conferences
would not be held at the Commissioner's level.
The concern raised by this comment has been addressed with the
adoption of Sec. 812.119(a), which references CDRH, FDA. Also, FDA is
taking this opportunity to notify interested persons that CDRH's
Division of Compliance Operations has been eliminated through
reorganization. The informal conferences will be held by the Division
of Bioresearch Monitoring, Office of Compliance, CDRH.
[[Page 12092]]
J. Proposed Sec. 812.119(d)
10. A comment stated that the text of proposed Sec. 812.119(d)
failed to mention that an opportunity for a hearing exists for an
investigator who has received a proposed notice of disqualification.
This concern also has been addressed with the adoption of
Sec. 812.119(a). Section 812.119(a) specifically states, ``If an
explanation is offered but not accepted by the Center for Devices and
Radiological Health, the investigator will be given an opportunity for
a regulatory hearing under part 16 * * *.''
K. Proposed Sec. 812.119(f)(1)
11. Under Sec. 812.119(a) and paragraph (f)(1) as proposed, a
hearing on the disqualification of an investigator shall be conducted
in accordance with the requirements for a regulatory hearing as set
forth in part 16. One comment maintained that conducting a regulatory
hearing under part 16 does not adequately protect the investigator's
due process rights. The comment requested FDA to follow the procedures
set forth in part 12 (21 CFR part 12) for a formal evidentiary public
hearing when determining whether an investigator should be
disqualified.
The agency disagrees with the comment that a part 16 regulatory
hearing does not provide adequate due process. A part 16 regulatory
hearing is initiated by a notice of opportunity for hearing from FDA.
This notice specifies, among other things, the facts and the action
that are the subject of the hearing and states the time in which a
hearing may be requested. In accordance with part 16, if a hearing is
requested, the Commissioner will designate a presiding officer, and the
hearing will take place at a time and location agreed upon by the party
requesting the hearing, FDA, and the presiding officer. A part 16
regulatory hearing, therefore, adequately protects an investigator's
due process rights by providing the investigator with notice and an
opportunity to be heard. Moreover, FDA has had extensive experience in
the use of part 16 hearings for disqualification proceedings of
clinical investigators of new drugs under part 312. FDA's experience
has established that part 16 hearings are appropriate in these
circumstances and protect the investigator's due process rights.
Finally, a part 16 regulatory hearing is more streamlined than a part
12 evidentiary public hearing and will provide a quicker resolution of
issues for both FDA and the investigator.
L. Proposed Sec. 812.119(f)(3)
12. Section 812.119(f)(2) provides that a final order disqualifying
a clinical investigator will be copied to the sponsor of each clinical
investigation subject to requirements for prior submission to FDA that
was or is being conducted by the investigator. A comment suggested
adding a similar provision to Sec. 812.119(f)(3) so that sponsors will
be notified of any final order terminating the disqualification
proceeding. Additionally, the comment suggested that FDA provide a copy
of such orders to IRB's as well.
The agency has adopted Sec. 812.119(b), which provides for
notification of the interested parties after the Commissioner has made
a final determination that an investigator is disqualified. After a
final disqualification decision has been made, the investigator, the
sponsors of any investigations in which the investigator was named as a
participant, and the reviewing IRB shall be notified that the
investigator is disqualified.
The agency's response to comments concerning notification of
interested parties prior to a final disqualification decision has been
provided previously. (See the response to comment 6 in section IV.F. of
this document.)
M. Proposed Sec. 812.119(g)
13. One comment said that proposed Sec. 812.119(g), actions upon
disqualification, may be interpreted to mean that the Commissioner is
authorized to make decisions that directly affect the rights and
responsibilities of sponsors even though sponsors may not be aware of
the disqualification process or be given the opportunity to participate
in the disqualification decisions. Another comment maintained that this
section may violate sponsors' due process rights. The comment
recommended that sponsors be given the opportunity to present their
views before the agency takes any of the actions described in proposed
Sec. 812.119(g).
The agency has addressed these concerns with the adoption of
Sec. 812.119(d), which provides sponsors with the opportunity to
participate in proceedings regarding termination of clinical
investigations. Under this section, if the Commissioner determines,
after the unreliable data submitted by the disqualified investigator
are eliminated from consideration, that the data remaining are
inadequate to support a conclusion that it is reasonably safe to
continue the investigation, the Commissioner will notify the sponsor,
who shall have an opportunity for a regulatory hearing under part 16.
If a danger to the public health exists, however, the Commissioner
shall terminate the clinical investigation immediately and notify the
sponsor of that determination. In such case, the sponsor shall have an
opportunity for a regulatory hearing under part 16 on the question of
whether the clinical investigation should be reinstated.
The agency's adoption of Sec. 812.119(e), which parallels Sec. 312
.70(e), also addresses the concerns about sponsors' rights raised by
these comments. This new section provides that if the Commissioner
determines, after the unreliable data submitted by the disqualified
investigator are eliminated from consideration, that the continued
clearance or approval of the device for which the data were submitted
cannot be justified, the Commissioner will proceed to rescind clearance
or withdraw approval of the marketing application in accordance with
the applicable provisions of the act and regulations. These provisions
provide adequate due process protections to the sponsor whose clinical
investigations are subject to termination and/or whose marketing
applications are subject to rescission of clearance or withdrawal of
approval following disqualification of clinical investigators.
N. Proposed Sec. 812.119(g)(2)
14. A comment suggested that proposed Sec. 812.119(g)(2) was overly
broad because it would allow FDA to terminate an entire study based on
the disqualification of a single investigator.
The agency believes that the concern raised by this comment has
been addressed with the adoption of Sec. 812.119(d), which, like
Sec. 312.70(d), provides a sponsor with notification that the
Commissioner has determined that the data are inadequate to support a
conclusion that it is reasonably safe to continue the investigation,
and an opportunity for a hearing under part 16, as indicated
previously. (See the response to comment 13 in section IV.M. of this
document.)
15. A comment suggested that there was an inconsistency between
proposed Sec. 812.119(g)(2) and proposed Sec. 812.119(b). The comment
stated that, under Sec. 812.119(b), the Commissioner must base a
disqualification order upon findings that address only limited factual
issues. In contrast, Sec. 812.119(g)(2) directed FDA to consider
information that goes beyond the scope of the administrative record
created during the disqualification proceedings. For example, nothing
in proposed Sec. 812.119(b) related to ``the risks of the
[[Page 12093]]
subjects from suspension of the study,'' and yet FDA, under
Sec. 812.119(g)(2), would consider that factor. The comment recommended
that this inconsistency be rectified.
The agency believes that the inconsistency indicated by this
comment has been addressed with the adoption of Sec. 812.119(b), which
parallels Sec. 312.70(b) and by the elimination of proposed
Sec. 812.119(g) in the final rule. Under Sec. 812.119(b), a
disqualification decision will be based upon the Commissioner's
determination that the investigator has repeatedly or deliberately
failed to comply with the requirements of this part, part 50 or part
56, or has deliberately or repeatedly submitted false information
either to the sponsor or in any required report, after evaluating all
available information, including any explanation presented by the
investigator.
O. Proposed Sec. 812.119(g)(2)(i)
16. One comment stated that the meaning of the phrase ``another
investigator accepts responsibility for the clinical investigation''
was unclear in this proposed section.
Proposed Sec. 812.119(g)(2)(i) was not adopted in the final rule,
thus eliminating any need for clarification indicated by this comment.
However, FDA believes that if continuation of an investigation is
warranted after an investigator is disqualified, the sponsor of the
investigation is responsible for selecting a qualified investigator who
shall be responsible for the continuation of the investigation at that
site. (See, also, the response to comment 18 in section IV.P. of this
document.)
17. A comment expressed concern that proposed Sec. 812.119(g)(2)(i)
could be interpreted as broad FDA authority to suspend or terminate an
entire clinical investigation, rather than the portion of the
investigation conducted by the disqualified investigator. In order for
the regulation to be explicit on this issue, this comment suggested
that the phrase ``under control of the disqualified investigator''
should be added after ``clinical investigation.'' Additionally, another
comment requested that ``clinical investigation'' should be defined as
that part of an investigation directly under the control of the
disqualified investigator. Furthermore, the comment asked FDA to add
the following sentence to this section for clarity: ``Disqualification
of an investigator or termination of a clinical investigation under
control of a disqualified investigator shall not affect any
investigation not under control of the disqualified investigator.''
The agency has previously addressed other comments concerning the
termination of an entire investigation or other investigations
conducted by the disqualified investigator. (See the responses to
comments 1 and 14 in sections IV.A. and N. of this document.)
P. Proposed Sec. 812.119(g)(2)(iii)
18. One comment stated that it is inappropriate for a disqualified
investigator to continue monitoring subjects. Instead, this comment
recommended that another investigator be appointed to monitor the
subject, or the subject should be withdrawn from the study.
The agency agrees that it is inappropriate for a disqualified
investigator to continue monitoring clinical trial subjects who are
either continuing to receive the test device or are in the followup
phase of the trial. An investigator who is disqualified from
eligibility to receive investigational devices is disqualified from
participation in conducting investigations, including monitoring the
subjects of investigations. Therefore, Sec. 812.119(b) provides that
once the Commissioner makes a final disqualification determination, the
Commissioner will notify the sponsor of any investigation in which the
investigator has been named as a participant and the reviewing IRB that
the investigator is disqualified. Furthermore, the agency believes that
if subjects are currently enrolled or receiving followup visits at the
disqualified investigator's site, the sponsor is responsible for
selecting, as soon as possible, a qualified investigator who shall be
responsible at the site for completing the investigation, including
subject followup.
Q. Proposed Sec. 812.119(g)(2)(v)
19. One comment stated that proposed Sec. 812.119(g)(2)(v) was too
restrictive. Various comments suggested that Sec. 812.119(g)(2)(v) be
expanded to allow continued use if discontinuing use would cause a
life-threatening problem, an immediate health problem, or involve
significant risks to the person's health.
The agency has not adopted the provision that was the basis for
this comment. However, under Sec. 812.119(c) and (d), the Commissioner
will determine whether the remaining data are adequate to support a
conclusion that it is reasonably safe to continue an investigation, or
whether approval should be withdrawn. If there is credible evidence
that discontinuing an investigation would cause a life-threatening
problem, an immediate health problem, or involve significant risks to
the health of a subject, this type of evidence will be considered in
support of such determination.
R. Proposed Sec. 812.119(g)(3)
20. Under proposed Sec. 812.119(g)(3), once an investigator is
disqualified, FDA would examine approved and pending applications
relying on the work of this disqualified investigator. FDA would
determine whether the investigation ``is acceptable,'' notwithstanding
the disqualification. According to several comments, proposed
Sec. 812.119(g)(3) was vague and unfair for various reasons. One
comment suggested that FDA incorporate the language used in the IND
regulations for disqualification of investigators, which provides that
an application will be examined to determine whether the investigator
has submitted unreliable data that are ``essential to the continuation
of the investigation or essential to the approval of any marketing
application.'' (See Sec. 312.70(c).)
The agency agrees with the comments and has adopted
Sec. 812.119(c), which parallels the language used in Sec. 312.70(c) of
the IND regulations, for disqualification of investigators.
21. Another comment said that the wording,
Any investigation done by an investigator before or after
disqualification may be presumed to be unacceptable, and the person
relying on the investigation may be required to establish that the
clinical investigation was not affected by the circumstances which
led to disqualification of the investigator, * * *.
has many flaws. First, the terminology ``any investigation done by an
investigator before or after disqualification may be unacceptable'' is
too broad. The comment recommended that the regulation state that an
investigator's data will not be accepted to support a marketing
application only if the evidence shows that the data are unreliable.
The sponsor should then be given the opportunity to validate the data
if possible, after exclusion of the adversely affected data. The
comment also said that a ``presumption'' of invalidity for any
investigation done by an investigator before or after disqualification
is inappropriate because, under the proposed rule, that presumption
would apply to any clinical investigation performed by the
investigator.
The agency believes that the concerns expressed by this comment
have been minimized with the adoption of a final rule that parallels
Sec. 312.70. Under Sec. 812.119(c), each regulatory submission
containing data reported by a
[[Page 12094]]
disqualified investigator will be examined to determine whether the
investigator has submitted unreliable data that are essential to the
continuation of the investigation or essential to the approval of any
marketing application. It is not unreasonable, however, for FDA to
presume that other work done by a disqualified investigator should be
reviewed. Because this final rule states that a sponsor is entitled to
a hearing before any particular investigation or approval is
terminated, the opportunity to validate data will be available to
sponsors.
22. Another comment stated that the use of the phrase ``the person
relying on the investigation may be required to establish that the
investigation was not affected,'' improperly shifts the burden of proof
to the sponsor; just because an investigator has failed to comply with
the regulations in one study does not imply that all other studies are
tainted. This comment recommended that, once FDA determines that an
investigator has acted improperly, FDA should conduct an investigation
to determine whether other clinical investigations conducted by the
disqualified investigator are unreliable.
This recommendation is incorporated into the final rule, which
parallels Sec. 312.70. Under Sec. 812.119(c), each IDE and each
approved marketing application submitted under part 807 or 814 in which
the disqualified investigator has been a participant will be examined
by FDA. In essence, final Sec. 812.119(c) places on FDA the initial
burden of determining whether any unreliable data have been submitted
by the disqualified investigator that are essential to the continuation
of any other investigation or to the approval or clearance of any
marketing application. (See the agency's responses to comments 1, 13,
and 14 in sections IV.A., M., and N. of this document.)
23. A comment urged that an approval should not be withdrawn unless
there is evidence that the device is unsafe or ineffective. If the
device is found to be safe and effective, the device should remain
available, regardless of irregularities in the investigation which led
to the disqualification of an investigator.
The agency does not intend to withdraw approval or rescind
clearance of devices under Sec. 812.119(e) unless the Commissioner
determines, after the unreliable data submitted by the investigator are
eliminated from consideration, that the continued approval or clearance
of the marketing application for which the data were submitted cannot
be justified. By its very nature, unreliable data bring into question
the safety and effectiveness of the device. If the marketing
application contains data, other than the disqualified data, that
support substantial equivalence or safety and effectiveness, FDA would
have no reason to remove the device from the market. The course of
action taken by FDA with respect to that device will be commensurate
with the results of the agency's review, and may include withdrawal of
approval of a PMA or recision of a 510(k) if that is deemed necessary.
Furthermore, as stated in response to comment 13 in section IV. M. of
this document, Sec. 812.119(e) parallels Sec. 312.70(e) and provides
sponsors with the opportunity to participate in proceedings regarding
withdrawal of approval or recession of clearance of a marketing
application.
24. A comment suggested that the regulation should include a
reasonable time limit in which a sponsor must validate the data used in
a study in which an investigator was disqualified.
The agency agrees with this comment. In accordance with
Sec. 812.119(d) and (e), when FDA has reviewed the remaining data after
the disqualified investigator's data are eliminated and the
Commissioner has determined that the remaining data are inadequate to
support continued approval or clearance of an investigation or
marketing application, the Commissioner will notify the sponsor, who
shall have an opportunity for a regulatory hearing under part 16. The
sponsor may request a hearing to present to FDA any new or additional
factual information which challenges the determination, including any
information that validates the disqualified investigator's data or that
indicates the remaining data are adequate to support approval or
clearance. The time limit for providing such information is governed by
the procedures for conducting a regulatory hearing under part 16.
25. Another comment pointed out that Sec. 812.119(d) and (e)
requires a sponsor, in certain circumstances, to submit validating
information to show that an IDE or PMA containing or relying upon a
clinical investigation performed by a disqualified investigator is not
adversely affected. This comment suggested that FDA should offer the
sponsor periodic opportunities, i.e., quarterly, monthly, etc., to
present validating information for any potentially adversely affected
clinical investigation through segregated analysis, adding additional
sites, or verification of existing data. According to this comment,
offering such periodic opportunities to validate existing data would
allow the sponsor to salvage portions of valid data without having to
gather clinical data through new investigations.
The agency agrees that such an opportunity may be appropriate. As
part of FDA's examination under final Sec. 812.119(c) to determine
whether the disqualified investigator has submitted unreliable data
that are essential to the continuation of an investigation or essential
to the approval of any marketing application, FDA may request that
sponsors submit to the agency, on a periodic basis, validating
information for a potentially adversely affected clinical investigation
or marketing application. Sponsors will receive written notification of
such a request.
S. Proposed Sec. 812.119(g)(4)
26. Under proposed Sec. 812.119(g)(4), the determination that a
clinical investigation may not be considered in support of an
application would not relieve the applicant of any obligation under the
statute to submit the results of the clinical investigation to FDA. A
comment urged that an applicant should not be required to submit the
results of the clinical investigation to FDA because, once a
determination has been made that the clinical investigation will not be
considered in support of an application, the usefulness of the clinical
investigation is questionable.
The agency disagrees with this comment. Although the final rule no
longer includes this explicit provision, it is imperative for FDA to
review all available information collected on the investigational
device, particularly information that may affect the rights, safety, or
welfare of the subjects enrolled. Therefore, regardless of whether the
clinical data will be used to support a marketing application, the
reporting requirements described in other parts of the IDE regulation,
e.g., Secs. 812.40 and 812.150, must be maintained to provide adequate
protection for subjects.
T. Proposed Sec. 812.119(h)(1)
27. Proposed Sec. 812.119(h)(1) would have required the notice of
disqualification to state that the results of any investigations
conducted by the investigator may not be considered by FDA in support
of any IDE or PMA. According to one comment, proposed
Sec. 812.119(h)(1) would not permit validating information to be
presented by a sponsor to save the IDE or PMA. Because of this, the
comment requested that the contents of the disqualification notice not
automatically reflect a determination that the study results are not to
be considered in support of an IDE or PMA. Instead, the comment
[[Page 12095]]
requested that the contents of the disqualification notice state that
the results will be evaluated by FDA to determine the effect of
disqualification, if any, on the IDE or PMA.
Proposed Sec. 812.119(h)(1), which is addressed in this comment,
has not been adopted. However, under Sec. 812.119(b), a
disqualification notice is provided that states that the investigator
is disqualified and the basis for such determination. Final
Sec. 812.119(c), (d), and (e) establish that FDA will review any IDE's,
510(k)'s or PMA's that contain data submitted by the disqualified
investigator. If the agency finds that a withdrawal of approval is
warranted, the sponsor of the application will be notified and offered
an opportunity for a hearing under part 16. The sponsor may request a
part 16 hearing to provide relevant information, such as validating
information, which may influence a final decision.
28. Under proposed Sec. 812.119(h)(1), upon issuance of a final
order disqualifying an investigator or upon entry of a consent decree,
FDA would have discretion to notify all or any interested persons. A
comment recommended that it be a mandatory requirement that sponsors
receive notice of an investigator disqualification both when FDA issues
a final order and when FDA has reason to believe that an investigator
may be subject to disqualification. Another respondent asked FDA to
include in the regulation a provision requiring the notification of the
sponsor by FDA when a consent agreement is executed, with a copy of the
consent agreement included in the sponsor's notification. Three other
respondents suggested that FDA, upon disqualification of a clinical
investigator, inform the approving IRB that the investigator has been
disqualified.
Proposed Sec. 812.119(h)(1), which is addressed by these comments,
has not been adopted in the final rule. However, FDA agrees with these
comments in general and has adopted final Sec. 812.119(b), which
parallels Sec. 312.70(b). This final rule provides that FDA will give
notification of disqualification to the investigator who is
disqualified, the sponsor of any investigation in which the
investigator has been named a participant, and the reviewing IRB.
The agency's response to comments concerning notification of
interested parties prior to a final disqualification decision has been
provided previously. (See response to comment 6 in section IV.F. of
this document.) Records relating to disqualification proceedings, such
as inspectional findings, disqualification determinations,
administrative records of determinations and hearings, consent
agreements, and reinstatement determinations are disclosable to the
public upon request, subject to the provisions of part 20 (21 CFR part
20).
U. Proposed Sec. 812.119(h)(3)
29. According to a comment, proposed Sec. 812.119(h)(3) would not
give sponsors notice that an investigator is facing disqualification
proceedings. This comment requested that the regulation be revised to
require FDA to notify the sponsor if one of its investigators may be
facing disqualification.
A similar comment suggested the following wording:
Whenever FDA has reason to believe that an investigator may be
subject to disqualification, the agency will so notify the sponsor
of the clinical investigation in question, as well as the sponsor of
each clinical investigation subject to requirement of prior
submission to FDA that was or is being conducted by the
investigator, and the IRB's under which the investigation(s) were
conducted. This notification shall occur simultaneously with the
agency's notice to the investigator describing the noncompliance and
request for an explanation of the noncompliance under paragraph (c)
of this section.
Proposed Sec. 812.112(h)(3) addressed in these two comments has not
been adopted in the final rule. However, the agency's response to
similar comments concerning notification of interested parties prior to
a final disqualification decision has been provided previously. (See
response to comment 6 in section IV.F. of this document.)
V. Proposed Sec. 812.119(j)
30. This proposed section would have required sponsors to notify
FDA any time an investigator is removed from further participation in a
clinical investigation. One comment stated that there is no need to
require a sponsor to notify FDA when an investigator is removed from a
study for nonregulatory reasons. Another comment maintained that
requiring sponsors to report a termination, for whatever reasons, could
inhibit sponsors from terminating investigators because of the
reporting requirements.
Proposed Sec. 812.119(j) addressed in these two comments has not
been adopted in the final rule. However, Sec. 812.40 of the existing
IDE regulation currently requires sponsors to inform the agency of
significant new information about an investigation, including any
changes in or terminations of clinical investigators.
W. Publication of a List
31. A comment requested that disqualified investigators be added to
a single list maintained by CDER or the Office of Health Affairs in FDA
so that IRB's and sponsors are not required to search two (or more)
separate lists.
Although the proposed rule did not specifically state that CDRH
would maintain a list of clinical investigators who have been
disqualified under this authority, FDA intends to compile such a list.
This list will be combined with CDER's and the Center for Biologics
Evaluation and Research's (CBER's) list of disqualified investigators.
The newly combined disqualified clinical investigator list will be
maintained by FDA's Office of Regulatory Affairs. This list is
disclosable to the public under part 20. A request for the list should
be sent in writing to the Freedom of Information Staff (HFZ-35), Food
and Drug Administration, 5600 Fishers Lane, rm. 12A-16, Rockville, MD
20857.
V. Environmental Impact
The agency has determined under 21 CFR 25.24(a)(8) that this action
is of a type that does not individually or cumulatively have a
significant effect on the human environment. Therefore, neither an
environmental assessment nor an environmental impact statement is
required.
VI. Analysis of Impacts
FDA has examined the impacts of the final rule under Executive
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612).
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; distributive impacts; and equity). The agency believes that
this final rule is consistent with the regulatory philosophy and
principles identified in the Executive Order. In addition, the final
rule is not a significant regulatory action as defined by the Executive
Order and so is not subject to review under the Executive Order.#
The Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. Because the final rule specifies the procedures to
be followed for investigator disqualification, the rule does not impose
any burden on regulated industry. Procedures themselves are protections
and do not
[[Page 12096]]
impose significant costs beyond what the underlying statute imposes.
Thus, the agency certifies that the final rule will not have a
significant economic impact on a substantial number of small entities.
Therefore, under the Regulatory Flexibility Act, no further analysis is
required.
Lists of Subjects in 21 CFR Part 812
Health records, Medical devices, Medical research, 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
812 is amended as follows:
PART 812--INVESTIGATIONAL DEVICE EXEMPTIONS
1. The authority citation for 21 CFR part 812 continues to read as
follows:
Authority: Secs. 301, 501, 502, 503, 505, 506, 507, 510, 513-
516, 518-520, 701, 702, 704, 721, 801 of the Federal Food, Drug, and
Cosmetic Act (21 U.S.C. 331, 351, 352, 353, 355, 356, 357, 360,
360c-360f, 360h-360j, 371, 372, 374, 379e, 381); secs. 215, 301,
351, 354-360F of the Public Health Service Act (42 U.S.C. 216, 241,
262, 263b-263n).
2. Section 812.2 is amended by revising the introductory text of
paragraph (c) to read as follows:
Sec. 812.2 Applicability.
* * * * *
(c) Exempted investigations. This part, with the exception of
Sec. 812.119, does not apply to investigations of the following
categories of devices: * * *
* * * * *
3. New Sec. 812.119 is added to subpart E to read as follows:
Sec. 812.119 Disqualification of a clinical investigator.
(a) If FDA has information indicating that an investigator has
repeatedly or deliberately failed to comply with the requirements of
this part, part 50, or part 56 of this chapter, or has repeatedly or
deliberately submitted false information either to the sponsor of the
investigation or in any required report, the Center for Devices and
Radiological Health will furnish the investigator written notice of the
matter under complaint and offer the investigator an opportunity to
explain the matter in writing, or, at the option of the investigator,
in an informal conference. If an explanation is offered and accepted by
the Center for Devices and Radiological Health, the disqualification
process will be terminated. If an explanation is offered but not
accepted by the Center for Devices and Radiological Health, the
investigator will be given an opportunity for a regulatory hearing
under part 16 of this chapter on the question of whether the
investigator is entitled to receive investigational devices.
(b) After evaluating all available information, including any
explanation presented by the investigator, if the Commissioner
determines that the investigator has repeatedly or deliberately failed
to comply with the requirements of this part, part 50, or part 56 of
this chapter, or has deliberately or repeatedly submitted false
information either to the sponsor of the investigation or in any
required report, the Commissioner will notify the investigator, the
sponsor of any investigation in which the investigator has been named
as a participant, and the reviewing IRB that the investigator is not
entitled to receive investigational devices. The notification will
provide a statement of basis for such determination.
(c) Each investigational device exemption (IDE) and each cleared or
approved application submitted under this part, subpart E of part 807
of this chapter, or part 814 of this chapter containing data reported
by an investigator who has been determined to be ineligible to receive
investigational devices will be examined to determine whether the
investigator has submitted unreliable data that are essential to the
continuation of the investigation or essential to the approval or
clearance of any marketing application.
(d) If the Commissioner determines, after the unreliable data
submitted by the investigator are eliminated from consideration, that
the data remaining are inadequate to support a conclusion that it is
reasonably safe to continue the investigation, the Commissioner will
notify the sponsor who shall have an opportunity for a regulatory
hearing under part 16 of this chapter. If a danger to the public health
exists, however, the Commissioner shall terminate the IDE immediately
and notify the sponsor and the reviewing IRB of the determination. In
such case, the sponsor shall have an opportunity for a regulatory
hearing before FDA under part 16 of this chapter on the question of
whether the IDE should be reinstated.
(e) If the Commissioner determines, after the unreliable data
submitted by the investigator are eliminated from consideration, that
the continued clearance or approval of the marketing application for
which the data were submitted cannot be justified, the Commissioner
will proceed to withdraw approval or rescind clearance of the medical
device in accordance with the applicable provisions of the act.
(f) An investigator who has been determined to be ineligible to
receive investigational devices may be reinstated as eligible when the
Commissioner determines that the investigator has presented adequate
assurances that the investigator will employ investigational devices
solely in compliance with the provisions of this part and of parts 50
and 56 of this chapter.
Dated: March 3, 1997.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 97-6475 Filed 3-13-97; 8:45 am]
BILLING CODE 4160-01-F
