Federal Register, Volume 63 Issue 135 (Wednesday, July 15, 1998)

[Federal Register Volume 63, Number 135 (Wednesday, July 15, 1998)]
[Proposed Rules]
[Pages 38131-38138]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-18754]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 812

[Docket No. 98N-0394]
RIN 0910-ZA14

Medical Devices; Investigational Device Exemptions

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend
the Investigational Device Exemptions (IDE) regulation. The proposed
regulatory changes are intended to reflect amendments to the Federal
Food, Drug, and Cosmetic Act (the act) by the FDA Modernization Act of
1997 (FDAMA). These amendments provide that the sponsor of an IDE may
modify the device and/or clinical protocol, without approval of a new
application or supplemental application, if the modifications meet
certain criteria and if notice is provided to FDA within 5 days of
making the change. The proposed rule also defines the credible
information to be used by sponsors to determine if the criteria are
met.

DATES: Submit written comments on or before September 28, 1998. Written
comments on the information collection provisions should be submitted
by August 14, 1998.

ADDRESSES: Submit written comments on the proposed rule to the
Documents Management Branch (HFA-305), Food and Drug Administration,
5630 Fishers Lane, rm. 1061, Rockville, MD 20852. Submit written
comments on the information collection requirements to the Office of
Information and Regulatory Affairs, OMB, New Executive Office Bldg.,
725 17th St. NW., rm. 10235, Washington, DC 20503, Attn: Desk Officer
for FDA.

[[Page 38132]]

FOR FURTHER INFORMATION CONTACT: Joanne R. Less, Center for Devices and
Radiological Health (HFZ-403), Food and Drug Administration, 9200
Corporate Blvd., Rockville, MD 20850, 301-594-1190.

SUPPLEMENTARY INFORMATION:

I. Background

Experience has shown that during the course of a clinical
investigation, the sponsor of the study will often want or need to make
modifications to the investigational plan, including changes to the
device and/or the clinical protocol. These changes may be simple
modifications, such as clarifying the instructions for use, or they may
be significant changes, such as modifications to the study design or
device design.
Currently, Sec. 812.35(a) (21 CFR 812.35(a)) states, in part:
A sponsor shall: (1) Submit to FDA a supplemental application if
the sponsor or an investigator proposes a change in the
investigational plan that may affect its scientific soundness or the
rights, safety, or welfare of subjects, and (2) obtain FDA approval
under Sec. 812.30(a) of any such change, and IRB approval when the
change involves the rights, safety, or welfare of subjects (see
Secs. 56.110 and 56.111), before implementation.
Under Sec. 812.25 Investigational plan (21 CFR 812.25), the
investigational plan includes: (1) The purpose of the study, (2) the
clinical protocol, (3) a risk analysis, (4) a description of the
investigational device, (5) monitoring procedures, (6) labeling, (7)
informed consent materials, and (8) institutional review board (IRB)
information. Although written guidance on the types of modifications
that can be made without prior FDA approval has not previously been
developed, the agency has permitted changes to all parts of the
investigational plan, without new or supplemental IDE application
approvals, if the changes did not affect the scientific soundness of
the plan or the rights, safety, or welfare of the subjects, and if such
changes were reported to FDA in the upcoming annual report under
Sec. 812.150(b)(5) (21 CFR 812.150(b)(5)).
On November 21, 1997, the President signed into law FDAMA. Section
201 of FDAMA (Pub. L. 105-115) amended the act by adding new section
520(g)(6) to the act (21 U.S.C. 360j(g)(6)). Section 520(g)(6) of the
act permits, upon issuance of a regulation, certain changes to be made
to either the investigational device or the clinical protocol without
prior FDA approval of an IDE supplement. Specifically, this section of
the statute permits:
(i) developmental changes in the device (including manufacturing
changes) that do not constitute a significant change in design or in
the basic principles of operation and that are made in response to
information gathered during the course of an investigation; and
(ii) changes or modifications to clinical protocols that do not
affect--
(I) the validity of the data or information resulting from the
completion of an approved protocol, or the relationship of likely
patient risk to benefit relied upon to approve a protocol;
(II) the scientific soundness of an investigational plan
submitted [to obtain an IDE]; or
(III) the rights, safety, or welfare of the human subjects
involved in the investigation.
The current IDE regulation and the new statute permit certain
changes to be made to the investigational plan without prior agency
approval. FDA views the changes and modifications allowed under section
520(g)(6) of the act as consistent with the way the agency has
previously interpreted Sec. 812.35(a).
Section 520(g)(6) of the act, which is a result of the new law,
also specifies that the implementing rule provide that such changes or
modifications may be made without prior FDA approval if the IDE sponsor
determines, on the basis of credible information (as defined by the
Secretary of Health and Human Services), that the previous conditions
are met and if the sponsor submits, not later than 5 days after making
the change or modification, a notice of the change or modification.
Lastly, section 520(g)(6) of the act requires that FDA issue a final
regulation implementing this section no later than 1 year after the
date of enactment of FDAMA.
To implement new section 520(g)(6), FDA is proposing to amend
Sec. 812.35(a) to permit changes to the investigational device,
including manufacturing changes, or to the clinical protocol, in
accordance with the statutory criteria. This proposed rule also
implements the 5 day notice requirement and defines the credible
information to be used by sponsors to determine if the statutory
criteria are met. The agency is soliciting comments on the proposal
and, in particular, on the definition of credible information. Finally,
the amended regulation codifies existing agency practice regarding the
types of changes that could be made to other parts of the
investigational plan (i.e., other than changes to the device or
clinical protocol) and be reported in the annual progress report
without prior agency approval.

II. Discussion of Proposed Amendments

The proposed rule amends part 812 by revising Sec. 812.35(a) to
track the new statutory language and to define the credible information
to be used by IDE sponsors to determine if the statutory criteria are
met. This proposal consists of the following provisions:

A. Changes Requiring Prior Approval

Proposed Sec. 812.35(a)(1) requires that changes to the
investigational plan, except as provided for in proposed
Sec. 812.35(a)(2) through (a)(4), be approved by FDA and the IRB, as
applicable under Secs. 56.110 and 56.111 (21 CFR 56.110 and 56.111),
before being implemented. In addition, this section continues to
require an IDE sponsor who intends to conduct an investigation that
involves an exception to informed consent under Sec. 50.24 (21 CFR
50.24) to submit a new IDE application rather than an IDE supplement.

B. Changes Effected for Emergency Use

Proposed Sec. 812.35(a)(2), which parallels the existing
regulation, addresses deviations from the investigational plan to
protect the life or physical well-being of a subject in an emergency.
Such deviations would not require prior FDA approval but must be
reported to the agency by the sponsor within 5 working days of when the
sponsor learns of the deviation. A detailed discussion of this
provision was provided in the guidance document entitled, ``Guidance
for the Emergency Use of Unapproved Medical Devices'' (50 FR 42866,
October 22, 1985).

C. Changes Effected With Notice to FDA Within 5 Days

Proposed Sec. 812.35(a)(3) describes the statutory criteria under
which developmental changes to the investigational device, including
manufacturing changes, and changes to the clinical protocol may be made
without prior approval by FDA. As stated in section 520(g)(6) of the
act, developmental changes to the device or manufacturing process may
be made if the changes do not constitute a significant change in design
or basic principles of operation and are made in response to
information gathered during the course of the investigation.
Changes to the clinical protocol may be made if the modifications
do not affect the validity of the data or information resulting from
the study, the likely risk to benefit relationship that was used to
approve the protocol, the scientific soundness of the investigational
plan, or the rights, safety, or welfare of the subjects in the trial.
As noted previously, the current IDE regulation allows sponsors to
modify the investigational plan without prior agency approval if the

[[Page 38133]]

modification does not affect the scientific soundness of the plan or
the rights, safety, or welfare of the subjects. The new statute
specifies that, in addition to these criteria, IDE sponsors who change
the clinical protocol must also consider the impact that the change may
have on the validity of the data resulting from the study and the risk
to benefit relationship that was used to approve the protocol. FDA
believes that these additional criteria are consistent with the
agency's general criteria under the current regulation that provide
that changes may be made to the investigational plan as long as such
changes ensure the protection of patient safety and rights and the
integrity of the clinical trial.

D. Definition of Credible Information

To help sponsors decide if the criteria set forth in section
520(g)(6) of the act have been met, and in accordance with FDAMA, the
agency is defining what it would consider to be credible information to
support a decision by the sponsor that prior agency approval for a
proposed change to a device, manufacturing process, or protocol is not
required and that a notice within 5 days of effecting a change will be
sufficient. As described in the following paragraph, FDA believes that
the definition of credible information will be different depending upon
whether the sponsor is modifying the device (or manufacturing process)
or the clinical protocol.
1. Device and Manufacturing Changes
For changes to the device, including manufacturing changes, FDA
believes that the data generated by design control procedures during
the device development process will help manufacturers distinguish
those changes that could be implemented without prior approval from
those that would require approval. Under Sec. 812.1(a) (21 CFR
812.1(a)), manufacturers of investigational devices are exempt from the
good manufacturing practice (GMP) requirements of section 520(f) of the
act, except for the design control procedure requirements (Sec. 820.30
(21 CFR 820.30)), if applicable. Design control procedures consist of a
system of inter-related checks and balances that make the systematic
assessment of design an integral part of the device development
process. Under the design-control section of the quality system
regulation, manufacturers are required to have in place a systematic
set of requirements and activities for the management of design and
development, including documentation of design inputs, appropriate risk
analysis, design output, test procedures, verification and validation
procedures, and documentation of formal design reviews. Use of design
controls in the development process for medical devices contributes to
the protection of the public in general, as well as of patients
involved in clinical trials, from potentially unsafe devices. By using
the information generated by design controls, IDE sponsors are able to
assess the potential impact of changes in the device design or
manufacturing process prior to implementing them in their clinical
investigations.
Under the new law and this proposed implementing regulation,
certain developmental changes to the investigational device (including
manufacturing changes), which are made in response to information
gathered during the course of the investigation, are eligible for
implementation without prior agency approval. Modifications that
constitute a significant change in design or basic principles of
operation, however, may not be made without prior approval of an IDE
supplement. Through the data generated by the appropriate risk analysis
and the subsequent verification and validation testing done as a part
of the design control process, sponsors should be able to judge whether
a change to the device would constitute a significant change in design
or one that changes the basic principles of operation. The agency
believes that any change that could significantly affect the safety
and/or effectiveness of the device is a significant change. FDA also
believes that any change to the basic principles of operation of a
device would be highly likely to constitute a significant change;
however, the agency is soliciting comments on this premise.
In determining whether a change to the design of the device would
be considered significant and require agency approval prior to
implementation, FDA is proposing that IDE sponsors rely upon
information generated by design controls to supply the credible
information that would be the basis of that decision. Specifically, the
manufacturer should conduct an appropriate risk analysis, followed by
verification and validation testing, as required by design control
procedures. If it is determined that no new types of risks are
introduced by the change and that the subsequent testing demonstrates
that the design outputs meet the design input requirements, then the
change could be made without prior agency approval, if the sponsor
notifies FDA within 5 days of implementation. If, however, the risk
analysis identifies new types of risks, the verification/validation
testing indicates that the design input requirements are no longer
satisfied, or the design input requirements need to be modified, then
the change would require prior approval.
As an example, consider a change in material from polyvinylchloride
(PVC) to silicone in a catheter. In accordance with design control
procedures, the manufacturer would conduct the appropriate risk
analysis. Assuming that the risk analysis did not identify any new
types of risks for this device compared to the unmodified device, then
the manufacturer would proceed to conduct the verification and
validation testing. As a part of these activities, the manufacturer
should also conduct any other performance testing that addresses a
safety or performance concern that may have been identified to the IDE
sponsor in a recognized standard or other agency correspondence for
this device. If the results of the testing demonstrate that all of the
risks (those identified in the risk analysis and those identified by
the agency in its previous correspondence to the firm) have been
adequately addressed and that the design output meets the design input
requirements, then the change could be implemented without prior FDA
approval. Alternatively, if the manufacturer had proposed a change from
PVC to latex, the risk analysis should have indicated a new type of
risk, e.g., possible latex sensitivity. In this case, the change should
not be made without prior FDA review and approval.
Using the same device in a second example, consider a change in the
diameter of the lumen of the catheter. If no new types of risks are
identified in the risk analysis, the manufacturer could proceed to
conduct the verification and validation testing. If the testing
demonstrates that the design input requirements are met, the change
could be implemented without prior FDA approval. If, however, during
the testing, it is determined that the intended flow rate was
compromised by the change in diameter, then the manufacturer would have
two options. The manufacturer could adjust the modification so that the
original intended flow rate is still achieved or the manufacturer could
submit an IDE supplement, including a justification for the change, and
pursue FDA approval.
By using the data generated by design control procedures, the
manufacturer should be able to identify significant changes to the
investigational device or manufacturing process, i.e., those that
introduce new types of risks or cause

[[Page 38134]]

the design outputs to no longer meet the design input requirements. In
the guidance document entitled, ``Deciding When to Submit a 510(k) for
a Change to an Existing Device,'' the agency has identified generic
types of device and manufacturing modifications. The previous guidance
may be found on the World Wide Web at ``http://www.fda.gov/cdrh''.
Although this guidance applies to modifications of marketed devices,
the types of changes identified in the document are also applicable to
investigational devices. These include changes to the control
mechanism, principle of operation, energy type, environmental
specifications, performance specifications, ergonomics of patient-user
interface, dimensional specifications, software or firmware, packaging
or expiration dating, sterilization, and the manufacturing process
(including the manufacturing site). Such changes can range from minor
to significant, depending upon the particular device, the type of
modification, and the extent of the modification. As discussed
previously, significant changes of any of the previous types would not
be eligible for the 5 day notice provision, but rather would require
prior FDA approval.
2. Protocol Changes
The new statute also permits changes to the clinical protocol to be
made and reported within 5 days of implementation if the changes do not
affect the validity of the data or information that will result from
the clinical trial, the likely patient risk to benefit relationship
used to approve the study, the scientific soundness of the
investigational plan, or the rights, safety, or welfare of the
subjects. FDA is proposing that the credible information relied upon to
support this change should consist of a statistical analysis performed
by the sponsor and independent confirmation by the IRB chairperson, the
data safety monitoring board (DSMB), or published literature. For a
modification to be eligible for implementation under this provision,
FDA believes the IDE sponsor should conduct an assessment of the impact
of the proposed change on the study design and planned statistical
analysis and determine that they would not be adversely affected. In
addition to this assessment, FDA is proposing that the credible
information that is the basis of the sponsor's determination include
approval by the IRB chairperson (or designee) or concurrence of the
DSMB. For certain types of changes, peer reviewed published literature
also could be the additional credible evidence to support a protocol
modification. Generally, FDA would rely upon the IRB chairperson to
review changes that are related to the rights, safety, or welfare of
the subjects in the trial, while the approval/recommendation of the
DSMB or the peer reviewed published literature would be relied upon for
changes that are related to the scientific soundness of the
investigational plan or validity of the data. Several examples of these
types of changes are provided as follows.
1. Increasing the frequency at which data or information is
gathered or lengthening the subject follow-up period. Assuming that the
sponsor's assessment of the impact of the proposed change on the study
design and planned statistical analysis demonstrates that they would
not be adversely affected, FDA believes this type of modification could
be implemented without agency approval if the IRB chairperson agrees
that the rights, safety, and welfare of the subjects would not be
affected.
2. Modifying the protocol to include additional patient
observations/measurements or modifying the inclusion/exclusion criteria
to better define the target patient population. After confirming that
the proposed change would not have a significant impact on the study
design or planned statistical analysis, this type of change could be
implemented if the DSMB either recommends the change or approves it.
Approval by the IRB chairperson or peer reviewed published literature
that supports the change may be substituted for the DSMB's concurrence,
depending upon the extent of these types of changes.
3. Increasing the number of investigational sites or number of
subjects to be enrolled in the study. Again, after determining that the
proposed change would not have a significant impact on the study design
or planned statistical analysis, the sponsor could increase the number
of investigational sites or subjects in the trial if the DSMB
overseeing the clinical investigation either recommends or concurs with
the study expansion. If such a change to the protocol is implemented,
however, IDE sponsors are reminded that the study, as expanded, would
need to be completed before the marketing application could be
submitted. Furthermore, under 21 CFR 812.7(c), sponsors are prohibited
from unduly prolonging a clinical investigation, i.e., commercializing
an investigational device. Therefore, sponsors should ensure that the
study expansion is well justified.
4. Modifying the secondary endpoint(s). Following the assessment of
the impact of the proposed change on the study design and planned
statistical analysis, the secondary endpoint(s) could be modified if
the DSMB or peer reviewed published literature supports the change. For
example, eliminating the assessment of post-void residuals in a benign
prostatic hyperplasia (BPH) study could be implemented if peer review
published literature supported the change, i.e., if the literature
indicated that this is not a significant outcome measure for the
intervention being studied.
Alternatively, FDA believes that the following types of protocol
modifications would not generally be eligible for implementation
without prior agency approval because they are likely to have a
significant effect on the validity of the data resulting from the trial
and/or on the scientific soundness of the trial design:
Change in indication
Change in type or nature of study control
Change in the primary endpoint variable
Change in the method of statistical evaluation
Early termination of the study (except for reasons related
to patient safety)

E. Notice of IDE Change

Proposed Sec. 812.35(a)(3)(iv) would require IDE sponsors who have
determined, based on the credible evidence as defined by FDA, that
changes to their device and/or clinical protocol do not require prior
agency approval to notify the agency within 5 days of making the
change. To be in compliance with this requirement, sponsors would be
required to submit the notice within 5-calendar days of the date the
device, incorporating the change, is first distributed to the
investigator(s). For protocol changes, the notice would need to be
submitted within 5-calendar days of the sponsor's notification to the
clinical investigators that the protocol has been modified or, for
sponsor-investigator studies, within 5-calendar days of when the
sponsor-investigator incorporates the protocol change. In addition,
proposed Sec. 812.35(a)(3)(iv) states that the notification shall be
identified as a ``Notice of IDE Change.'' FDA is proposing to require
that the notices be identified in this manner so that they can be
easily distinguished from IDE supplements being submitted for agency
approval.
This proposed section of the regulation also describes the

[[Page 38135]]

information to be included in the notice. For a device or manufacturing
change, FDA is proposing that the notice include: (1) A summary of the
relevant information gathered during the course of the investigation
upon which the change was based; (2) a description of the change that
has been made to the device or manufacturing process, including a
cross-reference to appropriate sections of the original device
description or manufacturing process; and (3) a statement that no new
risks were identified by the appropriate design control risk analysis
and that the verification/validation testing demonstrated that the
design outputs met the design input requirements. For a protocol
change, FDA is proposing that the notice include: (1) A description of
the change that has been made to the clinical protocol, including a
cross-reference to appropriate sections of the original protocol, and
(2) an assessment supporting the conclusion that the change does not
have a significant impact on the study design or planned statistical
analysis of safety and effectiveness. As discussed in the previous
section, protocol changes that relate to the rights, safety, or welfare
of the subjects would be required to be supported by a letter from the
IRB chairperson (or designee) stating that the change is acceptable.
Protocol changes that relate to the scientific soundness of the
investigational plan or validity of the data would require the support
of a data safety monitoring board overseeing the investigation or peer
reviewed published literature, as appropriate.

F. Review of the Notices

Under proposed Sec. 812.35(a)(3), it is the sponsor's
responsibility to determine if a change made to the device or the
manufacturing process would affect the safety and effectiveness of the
device and thus would be considered a significant change requiring
prior agency approval. Similarly, the sponsor must decide if a change
to the clinical protocol would affect the validity of the data
resulting from the clinical trial, the likely risk to benefit
relationship relied upon to approve the study, the scientific soundness
of the investigational plan, or the rights, safety, or welfare of the
subjects. Under proposed Sec. 812.35(a)(3)(iii), the agency has defined
the type of credible information IDE sponsors should use in determining
if the change meets the statutory criteria.
Under proposed Sec. 812.35(a)(3)(v), however, FDA reserves the
right to question the sponsor's determination that the change met the
statutory criteria. Thus, if the agency has reason to believe, based on
the information submitted in the Notice of IDE Change or on other
available information, such as reports of adverse events, that the
modification did not meet the criteria, FDA will notify the sponsor
that the change should have been reviewed and approved before being
implemented. Upon receipt of such a communication from FDA, the sponsor
would have the option of suspending the investigation until approval is
obtained for the change or of reverting to the unmodified device,
manufacturing process, or protocol. FDA recognizes the potential impact
that this action could have on the IDE sponsor and the clinical trial
and, therefore, intends to take such action only if the agency
determines that the modification to the device, manufacturing process,
or clinical protocol could jeopardize patient safety, the scientific
soundness of the investigation, or the validity of the data resulting
from the trial. Such determinations would be made by the individuals
authorized to approve IDE's.

G. Changes Submitted in the Annual Report

Under proposed Sec. 812.35(a)(4), changes to certain portions of
the investigational plan other than to the device, manufacturing
process, or clinical protocol may continue to be submitted in an IDE
annual report under Sec. 812.150(b)(5). Changes to the purpose of the
study, the risk analysis, monitoring procedures, labeling for the
investigational device, informed consent materials, and IRB information
may continue to be submitted in an IDE annual report if the changes do
not affect the validity of the data/information resulting from the
trial, the risk to benefit relationship relied upon to approve the
protocol, the scientific soundness of the investigational plan, or the
rights, safety, or welfare of the subjects. The types of changes that
would normally satisfy these criteria would be those that would serve
to increase patient safety, e.g., clarifying the instructions for use,
providing additional information in the informed consent document, or
enhancing the monitoring procedures.
Each of the following parts of the investigational plan is
discussed as follows and specific examples are provided to illustrate
the types of changes that would usually be considered appropriate for
submission in an annual report.
1. Purpose. Under Sec. 812.25(a), the purpose of the study includes
the name and intended use of the device as well as the objectives and
duration of the investigation. Examples of changes that may be made to
this section of the investigational plan and reported in the annual
report include:
Changes to the name of the device. This type of change can
be made provided that the new name does not imply a new intended use.
Name changes that are made in conjunction with a modification to the
device, however, should be submitted either as an IDE supplement or as
a notice within 5 days of implementation, as appropriate for the device
modification.
Clarifications to the intended use of the device. Such
changes may be made if the modifications do not implicitly or
explicitly affect the intended use.
Minor modifications to the study objectives. Such changes
include clarifying the study objectives as long as the intent of the
objectives and the study endpoints are not changed. Study objectives
related to future labeling claims for the device may be added under the
annual report requirements if the change is minor, as described in
proposed Sec. 812.35(a)(4). If, however, the change in the objectives
requires protocol modifications, the change should be submitted as an
IDE supplement or a notice within 5 days of implementation, as
appropriate for the protocol modification.
Changes in the duration of the investigation. If the
investigation will take less time or more time to complete than was
anticipated at the time the IDE application was submitted, this
information may be submitted in the annual report.
2. Risk Analysis. If information to be added to the risk analysis
does not affect the risk to benefit relationship, it may be reported in
the annual report. For example, modifying the risk analysis to include
foreign data that confirms the original patient risk to benefit
relationship could be submitted in the annual report. If, however,
during the course of the investigation, the sponsor becomes aware of
information that may adversely affect the risk analysis, this
information should be submitted as a supplement under Sec. 812.35
indicating that the risk to benefit relationship has changed.
3. Monitoring Procedures. A change in the name and/or address of
the monitor may be submitted in the annual report. In addition, changes
in the monitoring procedures that are consistent with the ``Guideline
for the Monitoring of Clinical Investigations'' are eligible for this
type of reporting mechanism.
4. Labeling. Labeling changes that clarify the instructions for use
or serve to increase subject safety may be

[[Page 38136]]

implemented without prior agency approval and submitted in the annual
report. Adding contraindications, hazards, adverse effects, interfering
substances/devices, warnings, or precautions to the labeling, however,
may require concomitant changes to the protocol (e.g., modifications to
the exclusion criteria) and should be submitted in an IDE supplement or
notice within 5 days of implementation, as appropriate for the protocol
modification.
5. Informed Consent. Revisions to the informed consent materials
may be made without prior approval and submitted in the annual report
if the changes are, for example, to include preliminary results from
the trial (if in agreement with expected outcome(s)), clarify the risks
and/or potential benefits of the investigational device, or clarify the
procedures/tests to which the subjects may be subject.
6. IRB Information. A change in the IRB chairperson or address may
be reported in the annual report. Changes in approval status of the
study, however, must be reported to FDA, all reviewing IRB's, and
participating investigators in accordance with Sec. 812.150(b)(2).

III. Environmental Impact

The agency has determined under 21 CFR 25.30(h) 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.

IV. Analysis of Impacts

FDA has examined the impact of this proposed rule under Executive
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612) (as
amended by subtitle D of the Small Business Regulatory Fairness Act of
1996 (Pub. L. 104-121)), and the Unfunded Mandates Reform Act of 1995
(Pub. L. 104-4). Executive Order 12866 directs agencies to assess all
costs 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 proposed rule is consistent with the regulatory
philosophy and principles identified in the Executive Order. This
proposed rule has been determinated to be a significant regulatory
action as defined by the Executive Order and so is subject to review
under the Executive Order.
Unless the head of the agency certifies that the rule would not
have a significant economic impact on a substantial number of small
entities, the Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. This proposed rule amends existing regulations to
implement section 520(g)(6) of the act.
FDAMA added new section 520(g)(6) to permit certain changes to a
device, manufacturing processes, or clinical protocols during the
course of a clinical investigation without having to obtain prior FDA
approval of a new IDE or an IDE supplement. In addition to specifying
the types of changes to clinical studies allowed without prior
approval, section 520(g)(6) provides that the sponsor must provide
notice within 5 days of making the change, and that the agency define,
by regulation, the term ``credible information'' that the sponsor must
use as a basis to decide that the types of changes meet the criteria
for implementation without prior FDA approval.
Under the existing regulations and policy, Secs. 812.35 and
812.150(b)(5), a sponsor is allowed to make certain changes in its
investigational device or protocol without prior FDA approval, provided
that such changes are reported in an annual progress report. Under the
proposed regulation, such changes would be reported in a 5 day notice
report, instead of an annual report. Accordingly, the proposed
regulation does not require industry to submit a new type of report
because a change in a device or protocol triggers a reporting
requirement under both the existing and proposed regulation.
FDA's interpretation of the types of changes that are allowed
without prior approval in annual reports under the existing regulation,
and the proposed regulation's criteria to allow changes without prior
approval in 5-day notice reports are consistent. Accordingly, the
criteria stated in the proposed regulation does not affect the types of
changes that sponsors will be allowed to implement without prior
approval, and, therefore, would not add any additional burden to
industry.
The kind of credible information that the proposed regulation would
require as a basis to determine that a change can be made without prior
FDA approval is either currently required under existing regulations,
or will not add additional costs. The proposed regulation provides that
the type of credible information depends on the type of change.
For design and manufacturing changes, the proposed regulation
provides that credible information must be information generated by
design controls. The generation of this information currently is
required under Secs. 812.1 and 820.30. Moreover, this type of
information is already required to be submitted in annual progress
reports. Under the current regulation, sponsors provide testing data to
support the device change. Under the proposed regulation, sponsors are
allowed to provide summary information generated by design control
procedures. Therefore, sponsors will be able under the proposed
regulation to provide less detailed testing information than currently
provided in annual progress reports. Accordingly, the proposed
regulation's definition of credible information that must be used as a
basis to file a 5 day notice does not add any additional burden to
industry.
For clinical protocol type changes, the proposed regulation
provides that credible information consists of an assessment of the
impact of the change on the study design and planned statistical
analysis, and approval from the IRB chairperson, a recommendation or
concurrence from a DSMB, or published literature that supports the
change. The proposed regulation's requirement for an assessment of the
impact of the change on the study design and planned statistical
analysis is consistent with the analysis performed by sponsors under
the current regulation when assessing whether their protocol
modification does not affect the scientific soundness. Consultation
with an IRB and a DSMB is customary for protocol modifications. Under
current regulatory authority, sponsors must report changes to the IRB.
See 21 CFR 56.108(a)(3), 56.110(b)(2), 812.40 and 812.150(b)(5). Since
the current regulations already require that information relating to
the study would be generated and provided to IRB's, the generation of
this information under the proposed regulation does not add any add
additional costs. Although the proposed regulation would add the
requirement of IRB chairperson approval, or DSMB recommendation or
concurrence, these entities are not paid by the sponsors, and would not
generate additional costs.
Similarly, the proposed regulation's requirement for providing FDA
with published literature supporting a change does not add additional
costs. Under Sec. 812.27(b), sponsors are currently required to submit
all publications, whether adverse or supportive, in an IDE application.
Supporting publications for changes after approval of an IDE
application are submitted in

[[Page 38137]]

an annual progress report under Sec. 812.150(b)(5).
The only additional burden posed by the proposed rule would be the
timing of the submission. Section 520(g)(6) of the act, as added by
FDAMA, requires that the sponsor submit a notice within 5 days of the
change. As stated previously, the type of information in the 5 day
notice in the proposed regulation would be submitted annually in a
progress report under the current regulatory authority. FDA believes
that the additional cost of submitting information on each change when
that change is made, is not significantly greater than compiling the
information and sending it in one annual report. The primary additional
costs will be minimal mailing costs.
For the reasons stated previously, the Commissioner of Food and
Drugs certifies that this proposed rule will not have a significant
economic impact on a substantial number of small entities.
Additionally, this proposed rule does not trigger the requirement for a
written statement under section 202(a) of the Unfunded Mandates Reform
Act because it does not impose a mandate that results in an expenditure
of $100 million or more by State, local, or tribal governments in the
aggregate, or by the private sector, in any 1 year.

V. Paperwork Reduction Act of 1995

This proposed rule contains information collection provisions which
are subject to review by OMB under the Paperwork Reduction Act of 1995
(the PRA) (44 U.S.C. 3501-3520). A description of these provisions is
given below with an estimate of the annual reporting burden. Included
in the estimate is the time for reviewing instructions, searching
existing data sources, gathering and maintaining the data needed, and
completing and reviewing each collection of information.
FDA invites comments on: (1) Whether the proposed collection of
information is necessary for the proper performance of FDA's functions,
including whether the information will have practical utility; (2) the
accuracy of FDA's estimate of the burden of the proposed collection of
information, including the validity of the methodology and assumptions
used; (3) ways to enhance the quality, utility, and clarity of the
information to be collected; and (4) ways to minimize the burden of the
collection of information on respondents, including through the use of
automated collection techniques, when appropriate, and other forms of
information technology.
Title: Medical Devices; Investigational Device Exemptions;
Supplemental Applications.
Description: Section 201 of FDAMA amended the act by adding new
section 520(g)(6) to the act, which permits a sponsor to implement
certain changes to an investigational device or to a clinical protocol
without prior approval of an IDE supplement if the modifications meet
certain criteria and if notice is provided to FDA within 5 days of
making the change. In order to implement this provision, FDA is
proposing to amend Sec. 812.35(a) to describe which types of changes
may be made without prior approval and to describe the information to
be included in a notice to FDA if this provision is to be exercised.
For developmental or manufacturing changes, sponsors would be required
to submit a summary of the information from the study upon which the
change was based, a description of the change, and a statement that no
new risks were identified and that the device testing demonstrated that
the design outputs met the design input requirements. For a protocol
change, the sponsor must submit a description of the change, an
assessment of the impact of the change, and supporting documentation
from the IRB chairperson, data safety monitoring board, or peer
reviewed published literature, as appropriate. FDA will review the
notices to determine whether they meet the criteria of section
520(g)(6) of the act or whether additional action is necessary to
assure the protection of the public health.
Description of Respondents: Businesses or other for profit
organizations.
FDA estimates the burden for this collection of information as
follows:

Table 1.--Estimated Annual Reporting Burden^{1
----------------------------------------------------------------------------------------------------------------
Annual
21 CFR Section No. of Frequency per Total Annual Hours per Total Hours
Respondents Response Responses Response
----------------------------------------------------------------------------------------------------------------
812.35(a)(3) 300 1 300 10 3,000
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
information.

Based upon a review of IDE's submitted in recent years, FDA
estimates that approximately 300 of these notices of IDE changes will
be submitted each year. Based upon discussions with sponsors of IDE's
and FDA's own experience in reviewing these types of documents, FDA
estimates that it will take approximately 10 hours for a sponsor to
prepare a Notice of IDE Change. Therefore, FDA estimates that the total
annual burden for preparation of these notices will be 3,000 hours.
As required by section 3507(d) of the Paperwork Reduction Act of
1995 (44 U.S.C. 3507(d)), the agency has submitted the information
collection provisions of this proposed rule to OMB for review.
Interested persons are requested to send comments regarding the
information collection by August 14, 1998 to the Office of Information
and Regulatory Affairs, OMB (address above).

VI. Comments

Interested persons may by September 28, 1998, submit to the Dockets
Management Branch (address above) written comments regarding this
proposed rule. Two copies of any comment are to be submitted, except
that individuals may submit one copy. Comments are to be identified
with the docket number found in brackets in the heading of this
document. Received comments may be seen in the office above between 9
a.m. and 4 p.m., Monday through Friday.

List 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, it is
proposed that 21 CFR part 812 be amended as follows:

PART 812--INVESTIGATIONAL DEVICE EXEMPTIONS

1. The authority citation for 21 CFR part 812 continues to read as
follows:

Authority: 21 U.S.C. 331, 351, 352, 353, 355, 356, 357, 360,
360c-360f, 360h-360j, 371, 372, 374, 379e, 381, 382, 383; 42 U.S.C.
216, 241, 262, 263b-263n.

[[Page 38138]]

2. Section 812.35 is amended by revising paragraph (a) to read as
follows:

Sec. 812.35 Supplemental applications.

(a) Changes in investigational plan--(1) Changes requiring prior
approval. Except as described in paragraphs (a)(2) through (a)(4) of
this section, a sponsor shall submit to FDA a supplemental application
if the sponsor or an investigator proposes a change in the
investigational plan and obtains FDA approval under Sec. 812.30(a) of
any such change, and IRB approval as applicable (see Secs. 56.110 and
56.111 of this chapter), before implementation. If a sponsor intends to
conduct an investigation that involves an exception to informed consent
under Sec. 50.24 of this chapter, a sponsor shall submit a separate
investigational device exemption (IDE) application in accordance with
Sec. 812.20(a).
(2) Changes effected for emergency use. The requirements of
paragraph (a)(1) of this section regarding FDA approval of a supplement
do not apply in the case of a deviation from the investigational plan
to protect the life or physical well-being of a subject in an
emergency. Such deviation shall be reported to FDA within 5-working
days after the sponsor learns of it (see Sec. 812.150(a)(4)).
(3) Changes effected with notice to FDA within 5 days. A sponsor
may make certain changes without prior approval of a supplemental
application under paragraph (a)(1) of this section if the sponsor
determines that these changes meet the criteria described in paragraphs
(a)(3)(i) and (a)(3)(ii) of this section, on the basis of credible
information defined in paragraph (a)(3)(iii) of this section, and the
sponsor provides notice to FDA within 5 days of making these changes.
(i) Developmental changes. The requirements in paragraph (a)(1) of
this section regarding FDA and IRB approval of a supplement do not
apply to developmental changes in the device (including manufacturing
changes) that do not constitute a significant change in design or basic
principles of operation and that are made in response to information
gathered during the course of an investigation.
(ii) Changes to clinical protocol. The requirements in paragraph
(a)(1) of this section regarding FDA approval of a supplement do not
apply to changes to clinical protocols that do not affect:
(A) The validity of the data or information resulting from the
completion of the approved protocol, or the relationship of likely
patient risk to benefit relied upon to approve the protocol;
(B) The scientific soundness of the investigational plan; or
(C) The rights, safety, or welfare of the human subjects involved
in the investigation. The requirements in paragraph (a)(1) of this
section regarding IRB approval for such changes are described in
paragraph (a)(3)(iii)(B) of this section.
(iii) Definition of credible information--(A) Credible information
to support developmental changes in the device (including manufacturing
changes) is defined as the information generated from the design
control procedures under Sec. 820.30.
(B) Credible information to support changes to clinical protocols
is defined as the sponsor's documentation supporting the conclusion
that a change does not have a significant impact on the study design or
planned statistical analysis, and evidence of IRB chairperson (or
designee) approval, in accordance with the expedited review procedures
described in Sec. 56.110 of this chapter, the concurrence or
recommendation of a data safety monitoring board, or peer reviewed
published literature supporting the change, as appropriate.
(iv) Notice of IDE Change. Changes meeting the criteria in
paragraphs (a)(3)(i) and (a)(3)(ii) of this section that are supported
by credible information as defined in paragraph (a)(3)(iii) of this
section may be made without prior FDA approval if the sponsor submits a
notice of the change to the IDE not later than 5-calendar days after
making the change. Changes to devices are deemed to occur on the date
the device, manufactured incorporating the design or manufacturing
change, is distributed to the investigator(s). Changes to a clinical
protocol are deemed to occur when a clinical investigator is notified
by the sponsor that the change should be implemented in the protocol
or, for sponsor-investigator studies, when a sponsor-investigator
incorporates the change in the protocol. Such notices shall be
identified as a ``Notice of IDE Change.''
(A) For a developmental or manufacturing change to the device, the
notice shall include a summary of the relevant information gathered
during the course of the investigation upon which the change was based;
a description of the change to the device or manufacturing process
(cross-referenced to the appropriate sections of the original device
description or manufacturing process); and a statement that no new
risks were identified by appropriate risk analysis and that the
verification and validation testing demonstrated that the design
outputs met the design input requirements.
(B) For a protocol change, the notice shall include a description
of the change (cross-referenced to the appropriate sections of the
original protocol); an assessment supporting the conclusion that the
change does not have a significant impact on the study design or
planned statistical analysis, and; for changes related to the rights,
safety or welfare of the subjects, a letter of approval from the IRB
chairperson (or designee). For changes related to the scientific
soundness of the investigational plan or validity of the data,
documentation of the concurrence/recommendation of the data safety
monitoring board, or peer reviewed published literature supporting the
change, as appropriate.
(v) Review of the Notices. If, at any time during the course of the
investigation, FDA has reason to believe that the change(s) made in
accordance with paragraphs (a)(3)(i) or (a)(3)(ii) of this section did
not meet the applicable criteria, the agency will notify the sponsor
that the change(s) required approval under paragraph (a)(1) of this
section before being implemented. Upon receipt of such notification,
the sponsor shall either suspend the investigation or revert to an
investigation of the unmodified device or protocol until the change is
approved under paragraph (a)(1) of this section.
(4) Changes submitted in annual report. The requirements of
paragraph (a)(1) of this section do not apply to minor changes to the
investigational plan that do not involve developmental, manufacturing,
or protocol changes (i.e., the purpose of the study, risk analysis,
monitoring procedures, labeling, informed consent materials, and IRB
information) that do not affect:
(i) The validity of the data or information resulting from the
completion of the approved protocol, or the relationship of likely
patient risk to benefit relied upon to approve the protocol;
(ii) The scientific soundness of the investigational plan; or
(iii) The rights, safety, or welfare of the human subjects involved
in the investigation. Such changes shall be reported in the annual
progress report for the IDE, under Sec. 812.150(b)(5).
* * * * *

Dated: June 16, 1998.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 98-18754 Filed 7-14-98; 8:45 am]
BILLING CODE 4160-01-F}