[Federal Register: November 23, 1998 (Volume 63, Number 225)]
[Rules and Regulations]
[Page 64617-64626]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr23no98-15]

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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: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is amending the
Investigational Device Exemptions (IDE) regulation. The 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 rule also defines the credible information to be
used by sponsors to determine if the criteria are met.

EFFECTIVE DATE: February 22, 1999.

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.
    The IDE supplement regulation that has been effect since 1985
(hereinafter referred to as the ``existing regulation''),
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 existing IDE regulation and the new statute both 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 existing Sec. 812.35(a).
    Section 520(g)(6) of the act, as added by FDAMA, 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 (the Secretary)) 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.
    On July 15, 1998 (63 FR 38131), FDA issued a proposal to implement
section 520(g)(6) of the act. FDA provided interested persons an
opportunity to comment on the proposed rule by September 28, 1998. FDA
received comments from five entities; one medical device manufacturer's
association, two medical device manufacturers, one law firm, and one
consumer. Most of the comments stated that the proposed regulation
increased the economic and regulatory burden and lacked flexibility
compared to the existing regulation. FDA has revised the proposed
regulation in several significant respects to address these concerns.
The following is a summary of the comments and FDA's response to them.

II. Summary and Analysis of Comments and FDA's Responses

A. General Comments

    1. Several comments objected to FDA's proposal because it would
require that notices be submitted within 5 days of implementing
protocol and device changes that had previously been

[[Page 64618]]

submitted in annual reports under the existing Sec. 812.35(a)(1).
Comments stated that the regulation should instead have required 5-day
notices for changes that were formerly submitted as IDE supplements.
These comments asserted that the proposed rule was not consistent with
the intent of the statute which was to reduce the burden on industry by
decreasing the number of submissions requiring prior agency approval.
Another comment contended that submitting a notice within 5 days of
implementation of a change rather than in an annual report would pose a
regulatory and economic burden for industry.
    FDA recognizes that some of the protocol and device changes that
were previously submitted in IDE annual reports will now need to be
submitted in a 5-day notice under the new regulation. For the reasons
described in the following paragraphs, however, FDA believes that the
language in new section 520(g)(6) of the act clearly requires this, but
does not believe that the new regulation will impose any appreciable
additional burden.
    Prior to the enactment of section 520(g)(6) of the act, the
criteria that had been used to determine whether a change to an
investigational plan required approval of an IDE supplement were
described in existing Sec. 812.35(a)(1). This section of the IDE
regulation required a supplement if the change to the investigational
plan ``may affect its scientific soundness or the rights, safety, or
welfare of such subjects.'' All changes that were deemed not to affect
scientific soundness or the rights, safety, or welfare of the subjects
could be implemented without FDA approval of an IDE supplement, and
instead were reported to the agency in an annual report under
Sec. 812.150(b)(5).
    As stated in the preamble to the proposed rule, the agency has
permitted changes to all parts of the investigational plan, including
the device, manufacturing process, and clinical protocol, without new
or supplemental IDE application approvals if the changes were made in
compliance with existing Sec. 812.35(a)(1) and if the changes were
reported to FDA in the upcoming annual report. Because written guidance
specifying the types of modifications that could be made without prior
approval has never been issued, there was some inconsistency in the
determination of which types of changes could be permitted without the
submission of a supplement. Therefore, some changes which may have met
the criteria for submission in an annual report were submitted for
prior approval in an IDE supplement.
    Section 520(g)(6) of the act, in describing the types of protocol
changes that were to be subject to 5-day notices, incorporated verbatim
the ``scientific soundness'' and ``rights, safety, or welfare''
criteria in existing Sec. 812.35(a)(1) that distinguished those changes
that required prior approval from those that could have been submitted
in an annual report. This section of the act also sets forth additional
criteria for changes that would qualify for implementation with a 5-day
notice. These additional criteria are consistent with the criteria in
the existing regulation that have been used to determine the effect of
a change on the scientific soundness of the investigational plan and
the rights, safety, and welfare of subjects. Thus, the language in
section 520(g)(6) of the act requires that some changes that had
previously been submitted in annual reports will now need to be
submitted within 5 days of implementation.
    FDA disagrees that the new regulation will be more burdensome for
industry. Section 520(g)(6) of the act and the new implementing
regulation reduce the burden on industry in two important ways. First,
section 520(g)(6) of the act makes mandatory FDA's previous practice of
permitting certain changes to be made to the investigational plan
without prior agency approval. Secondly, this regulation provides
clarification of the types of changes that could be implemented without
prior agency approval, thus eliminating the submission of IDE
supplements that are not needed. For example, prior to this
implementing regulation, an IDE supplement may have been submitted for
any materials change to an investigational device. The new regulation,
however, clarifies that approval of a supplement would only be needed
if the materials change represents a significant change in design
(e.g., new risks) or basic principles of operation.
    Finally, FDA disagrees that notifying the agency of a change within
5 days of implementation, rather than in an annual report, will pose a
regulatory and economic burden on industry. FDA is aware that
submitting a notice within 5 days, as required by section
520(g)(6)(B)(ii) of the act, represents a much shorter response time
compared to submission in an annual report. FDA does not believe,
however, that this reduced timeframe will impose any appreciable
additional burden to industry as the evidence used to determine whether
a change may be made under an annual report or the 5-day notice
provision is the same, and in both cases, would need to be generated
and evaluated before the change is implemented.
    2. One comment stated that section 520(g)(6) of the act should be
interpreted to allow a sponsor to make device changes that
significantly improve safety or effectiveness, yet do not constitute
significant changes in design or in the basic principles of operation
under the 5-day notice provision.
    FDA agrees that section 520(g)(6) of the act allows a sponsor to
make device changes intended to enhance significantly safety or
effectiveness without submitting an IDE supplement, if the
developmental changes in a device do not constitute significant changes
in design or in the basic principles of operation. Although the comment
was not entirely clear, it also seems to suggest that any change
intended to enhance safety or effectiveness should not require an IDE
supplement. If this were the suggestion, FDA does not agree. Consistent
with all other device statutory and regulatory product approval
provisions, section 520(g)(6) of the act does not condition the
submission of an IDE supplement on whether a change will enhance safety
or effectiveness. Section 520(g)(6) of the act conditions the use of
the 5-day notice provision only on whether the change is a significant
change in the design or basic principles of operation. An
interpretation that 5-day notices are allowed any time a sponsor
intends a change to enhance safety or effectiveness would not only be
contrary to the language in section 520(g)(6) of the act, it would
constitute a drastic change in FDA's longstanding position that the
statute and regulations require either a new premarket notification,
new premarket approval application, or new IDE for certain types of
device modifications regardless of whether the sponsor believes the
changes enhance safety or effectiveness. Manufacturers make most
modifications with the intention and belief that the change will make a
safer and/or more effective product. This factor does not obviate the
need for FDA to review changes to ensure that there is scientific
support to show that safety and effectiveness have not been
compromised.
    3. One comment asked that an open public meeting be convened to
discuss the proposed rule with knowledgeable representatives of all
affected entities.
    FDA disagrees that such a meeting is necessary. Detailed comments
were received on virtually every aspect of the proposed regulation, and
the agency has significantly revised the rule in accordance with the
concerns that were expressed in the comments. As

[[Page 64619]]

discussed in detail in the following paragraphs, the final rule
provides for more flexibility than the proposed rule and addresses the
concerns regarding the economic and regulatory burden posed by the
proposed regulation.

B. Proposed Sec. 812.35(a)(1) Changes Requiring Prior Approval

    4. One comment stated that the first sentence of this proposed
section is awkward and suggested that it be revised to read:
    Except as described in paragraphs (a)(2) through (a)(4) of this
section, a sponsor must receive approval of a supplemental
application under Sec. 812.30(a), and IRB approval when appropriate
under 21 CFR Part 56, prior to implementing a change to an
investigational plan for a device which is subject to an approved
IDE.
    FDA agrees that the proposed sentence could be simplified and more
clearly stated. Therefore, the agency has revised the sentence to read:
    Except as described in paragraphs (a)(2) through (a)(4) of this
section, a sponsor must obtain approval of a supplemental
application under Sec. 812.30(a), and IRB approval when appropriate
(see Secs. 56.110 and 56.111 of this chapter), prior to implementing
a change to an investigational plan.
    5. One comment objected that proposed Sec. 812.35(a)(1) would
require IDE supplements for changes where only annual reports had been
required under the existing regulation. Specifically, the comment
objected to the language in proposed Sec. 812.35(a)(1) which states
that a supplement is required when ``the sponsor or an investigator
proposes a change in the investigational plan.'' The comment stated
that the language in the existing regulation only required supplements
for changes in an investigational plan that ``may affect its scientific
soundness or the rights, safety, or welfare of subjects.''
    FDA does not intend new Sec. 812.35(a)(1) to require the submission
of an IDE supplement for changes that would have been submitted in an
annual report under the existing regulation. Proposed and final
Sec. 812.35(a)(1) states ``Except as described in paragraphs (a)(2)
through (a)(4) of this section, * * *.'' Section 812.35(a)(3) and
(a)(4) provide that sponsors do not have to submit an IDE supplement
for changes to an investigational plan that do not affect the
scientific soundness, rights, safety, or welfare of subjects, risk to
benefit relationship relied upon to approve the protocol, or validity
of the data. As stated in the preamble to the proposed rule, FDA
considers the two additional criteria, i.e., risk to benefit
relationship and validity of the data, to be consistent with the
agency's general criteria under the existing regulation that permits
changes to the investigational plan as long as the changes do not
compromise patient rights, safety, or welfare or the integrity of the
clinical trial.

C. Proposed Sec. 812.35(a)(3)(i) Developmental Changes

    6. In the proposed rule, the first sentence of Sec. 812.35(a)(3)(i)
stated ``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) * * *.'' FDA
has modified this sentence to remove the phrase ``and IRB.'' Therefore,
the sentence now reads ``The requirements in paragraph (a)(1) of this
section regarding FDA approval of a supplement do not apply to
developmental changes in the device (including manufacturing changes) *
* *.''
    The agency has modified the regulation in this manner as the
proposed language indicated that IRB approval and/or notification to
the IRB of device/manufacturing changes in an annual report was not
required. This language not only conflicted with the language in
proposed Sec. 812.35(a)(3)(iv), but also conflicted with 21 CFR
56.108(a)(4) which indicates that IRB's may require review of changes
to approved research. FDA would like to clarify that while
developmental changes that are made in accordance with section
520(g)(6) of the act do not need FDA approval, they must still be
reported to the IRB in the sponsor's annual report. Moreover, the
changes may be subject to IRB review under Sec. 56.110 (21 CFR 56.110).

D. Proposed Sec. 812.35(a)(3)(iii)(A) Definition of Credible
Information (Device/Manufacturing Changes)

    7. In this section of the proposed regulation, FDA defined
``credible information,'' upon which sponsors are to rely in assessing
device/manufacturing changes, as the information generated under the
design control provisions Sec. 820.30 (21 CFR 820.30) of the Quality
System (QS) Regulation. (The QS regulation implements FDA's good
manufacturing practice (GMP) authority of section 520(f) of the act.)
One comment contended that the agency does not have the authority to
require IDE sponsors to comply with design controls. Specifically, the
comment said that while Sec. 812.1(a) (21 CFR 812.1(a)) states that
``investigational devices are exempt from section 520(f) of the Act,
except for the requirements under 21 CFR 820.30, most device counsels
advise their clients that this regulation does not take precedence over
the explicit exemption from section 520(f) found in section
520(g)(2)(A) of the statute.''
    FDA does not agree. It interprets the act as authorizing it to
require IDE sponsors to comply with the design control procedures, as
stated in Sec. 812.1(a). Contrary to the comment's assertion, section
520(g)(2)(A) of the act does not categorically exempt investigational
devices from all GMP requirements. Section 520(g)(2)(A) of the act
states that FDA shall issue regulations that ``prescribe procedures and
conditions under which devices intended for human use may upon
application be granted an exemption from the requirements of * * *
subsection (f) of this section * * *'' (Emphasis added). Section
520(g)(2)(A) of the act does not mandate that FDA issue regulations
that exempt investigational devices from the act's other requirements,
but rather it allows FDA discretion in issuing IDE's from other
statutory requirements. Under this discretionary authority, FDA has
chosen to retain design control requirements for investigational
devices as stated in Sec. 812.1(a). The agency believes that it would
be illogical to exclude investigational devices used in clinical trials
from the design control provision of the QS regulation because clinical
trials are an integral part of the device development process.
    8. Other comments generally supported the use of design controls
but stated that, while design controls may be one acceptable method of
supporting developmental changes in a device, sponsors should not be
limited to or required to use design controls to support this type of
change. Two comments suggested that FDA should follow more closely the
definition of ``credible information'' in the legislative history,
namely: ```credible information' shall mean information upon which a
reasonable person in a manufacturer's position would rely upon in
making a decision to change or modify an investigational device'' (Food
and Drug Administration Modernization and Accountability Act of 1997,
S. Rept. No. 105-43, at 32 (July 1, 1997)). One comment suggested that
the definition be revised to include ``any other reasonable and
reliable means,'' while a second comment recommended ``literature,
design controls, validation studies, or other appropriate means.''
    FDA agrees that limiting the definition of credible information for
developmental changes for a device to the information generated under
design

[[Page 64620]]

controls procedures is overly restrictive and recognizes that other
information may serve as the credible information. Therefore, rather
than limit the definition of credible information for device/
manufacturing changes to design controls, the agency has revised the
definition to also include information such as preclinical/animal
testing, peer reviewed published literature, or other reliable
information such as clinical information gathered during the trial or
from marketing experience gained in other countries. FDA believes this
new definition is consistent with the legislative history discussing
the term ``credible information,'' but provides more specific guidance
to IDE sponsors.
    9. Several other comments questioned specific aspects of the design
control process, such as the need for the completion of all
verification and validation testing prior to implementation of the
change, the apparent requirement that a device's original design input
requirements cannot be modified, and FDA's definition of ``new types of
risks.''
     FDA agrees, in part, with the comments. With regard to the
assertion that FDA is requiring that all verification and validation
testing be completed before a device/manufacturing change is
implemented, the agency recognizes that verification and validation
testing depends upon the type of change that is made, and that for some
minor changes, no such testing may be needed. In addition, the agency
acknowledges that the clinical trial itself may be part of the
validation testing. Thus, it would be impractical to require that this
testing, or other verification or validation testing that would
reasonably occur after the clinical trial, be completed before a
device/manufacturing change is implemented. In response to the
comments, the regulation has been modified to state ``verification and
validation testing, as appropriate.''
    FDA believes that the comment that asserted that the proposed
regulation requires that a device's original design input requirements
remain unchanged, reflects a misunderstanding of the proposed
regulation. FDA recognizes that if a sponsor is modifying the device
design and/or the manufacturing process, the design input requirements
would need to be modified until the design is finalized. Thus, the
sponsor should conduct the appropriate verification and validation
testing and this testing should indicate that the design outputs meet
the modified design input requirements. The agency believes that this
explanation will serve to clarify the issue and no change to the
regulation is necessary.
    With respect to the agency's interpretation of the term ``new types
of risks,'' FDA is providing the following clarification. In the
preamble to the proposed rule, FDA stated that if a sponsor determined
that no new types of risks were introduced by the device/manufacturing
change and the subsequent verification and validation testing
demonstrated that the design outputs met the design input requirements,
then the change could be made without prior agency approval. An example
of two materials changes in a catheter was provided to illustrate this.
One change, from polyvinylchloride (PVC) to silicone, would be
permitted under a 5-day notice because no new types of risks resulted
from the change; and one, from PVC to latex, would require prior
approval because a new type of risk, i.e., possible latex sensitivity,
would result from the change. A comment stated that the example was
unclear because changing from PVC to silicone and from PVC to latex
presented the same two types of risks (biocompatibility and materials
sensitivity). The comment requested that a definition of ``new types of
risks'' be provided since, in the example, the agency failed to
recognize materials sensitivity in the PVC to silicone change as a new
type of risk.
    FDA acknowledges that this example was not clear and that for both
materials changes, materials sensitivity should have been identified as
a new type of risk. The agency agrees with the comment's assessment of
``new types of risks'' in the previous example. Because the evaluation
of whether new types of risks are presented will vary depending on the
type of device and the type of change, FDA does not believe that this
term should be defined in the regulation.
    10. One comment objected to a statement in the preamble that
indicated that manufacturers should also conduct other testing that
addresses concerns that may have been identified to the IDE sponsor in
a ``recognized standard.'' The comment stated standards are strictly
voluntary and FDA should not require manufacturers to conform with
them.
    FDA agrees that standards are voluntary and thus, FDA cannot
require IDE sponsors to conform to them. FDA did not state, however,
that the sponsor is required to conform to a voluntary standard,
instead FDA stated only that a sponsor ``should 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.'' (Emphasis added). Although FDA
recognizes that compliance with a voluntary standard is not required to
address safety or performance concerns, compliance with standards may
be one way, among others, of addressing those concerns. It should be
noted, however, that if a manufacturer chooses a recognized standard as
a device input requirement, the device output should meet that
standard.
    11. Comments were received both in support of and in opposition to
the agency's reference to the guidance document entitled ``Deciding
When to Submit a 510(k) for a Change to an Existing Device.'' Two
comments agreed that this guidance would be helpful to sponsors when
deciding what types of changes could be made under the 5-day notice
provision. One comment questioned the relevance of the guidance to the
proposed rule as changes that can be made to marketed devices without
affecting their safety and effectiveness may not be appropriate types
of changes for investigational devices. Lastly, one comment appears to
have misunderstood the agency's intent in referring to the guidance. It
was asserted that the document would be helpful in determining the
significance of a change, but would be overly restrictive in the types
of changes that would be permitted under the 5-day notice provision.
    In response to the comments which opposed the agency's reference to
the guidance document, FDA is offering the following clarification. As
stated in section 520(g)(6)(A)(i) of the act, only those changes to the
investigational device that do not constitute a significant change in
design or basic principles of operation are eligible for implementation
under this provision. In an effort to describe the types of device and
manufacturing changes that may be eligible for implementation without
FDA approval, reference was made to the 510(k) guidance document. This
guidance was referenced only for its list of generic types of device
and manufacturing changes that the agency believes apply to all
devices, marketed or investigational. The list includes 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). In referencing these types of
changes, the agency was not indicating

[[Page 64621]]

that any specific change within a particular type would or would not be
appropriate under the 5-day notice provision because changes in each of
these categories could range from minor to significant depending upon
the particular device, the type of modification, and the extent of the
modification. FDA maintains that IDE sponsors should refer to the list
as a starting point for the types of changes which may qualify for
implementation under this provision. The impact of the change, however,
would still need to be determined by information generated by design
controls or other appropriate means to assess the significance of the
change to the device design or manufacturing process and the
appropriateness of a 5-day notice submission.
    FDA notes, however, that it believes one type of change should be
submitted in an IDE supplement. In the preamble to the proposed rule,
the agency stated that it would consider any change to the basic
principles of operation of a device to be highly likely to constitute a
significant change requiring prior approval and solicited comments on
this premise. FDA received no comments on this issue. The agency
advises that it considers all changes to the basic principles of
operation of a device to be significant changes that should be
submitted in an IDE supplement.

E. Proposed Sec. 812.35(a)(3)(iii)(B) Definition of Credible
Information (Protocol Changes)

    12. Several comments questioned the agency's definition of credible
information for protocol changes as defined in proposed
Sec. 812.35(a)(3)(iii)(B). In general, the comments stated that the
requirement to obtain the approval of an IRB chairperson (or designee)
or of a data safety monitoring board (DSMB) will result in considerable
expense, is unduly burdensome and time consuming, and is less flexible
than the current regulation. The comments asserted that FDA did not
adequately consider the cost of imposing such a requirement. In
addition, the comments contended that section 520(g)(6)(B)(i) of the
act identifies the sponsor as the party responsible for determining
whether a protocol change needs FDA approval, not a third party. In
addition to the general concerns, specific concerns were raised
regarding the use of DSMB's. It was asserted that since DSMB's are
neither required nor recognized in the IDE regulation and FDA has no
regulatory authority over them, DSMB's should not be included in the
agency's definition of credible information for protocol changes.
    Upon further consideration of this statutory provision, the agency
agrees that requiring approval of the IRB chairperson (or designee)
and/or concurrence of a DSMB in the definition of credible information
for protocol changes could prove more burdensome than Congress
intended. FDA also agrees that the act indicates that the sponsor is
responsible for initially determining if the change meets the statutory
criteria. Therefore, FDA has modified the regulation to state that
credible information to support changes to the clinical protocol is
defined as the sponsor's documentation supporting its conclusion that
the change does not have a significant impact on the study design or
planned statistical analysis, and that the change does not affect the
rights, safety, or welfare of the subjects. Such a determination should
be made by the person in the company responsible for such decisions and
should be based upon information such as peer reviewed published
literature, the recommendation of the clinical investigator(s), and or
data collected during the clinical trial or marketing in other
countries.
    As an example of this, consider a case in which preliminary
information gathered during the clinical trial indicates that the
inclusion/exclusion criteria should be modified to better define the
target patient population. This change could be made after the sponsor
concludes and documents that the change would not have a significant
impact on the study design or planned statistical analysis and that the
change does not affect the rights, safety, or welfare of the study
subjects. Similarly, if the clinical investigators recommended that the
protocol be modified to lengthen the subject followup, this change
could be implemented after the previous assessments are performed that
support a determination that the change is not significant.
    As discussed in the preamble to the proposed rule, other examples
of protocol modifications that could be made under the 5-day notice
provision include: Increasing the frequency at which data or
information is gathered, modifying the protocol to include additional
patient observations/measurements, and modifying the secondary
endpoints. Alternatively, FDA believes that the following types of
protocol changes would not generally be appropriate for implementation
without prior agency approval because they are likely to have a
significant effect on the scientific soundness of the trial design and/
or validity of the data resulting from the trial: Change in indication,
change in type or nature of study control, change in primary endpoint,
change in method of statistical evaluation, and early termination of
the study (except for reasons related to patient safety).
    FDA notes that, contrary to statements in the proposed rule (63 FR
38131 and 38134), protocol changes involving study expansions should
not be made without prior agency approval. In the proposed rule, FDA
stated that sponsors could increase either the number of
investigational sites or study subjects participating in a clinical
investigation without approval of an IDE supplement. Upon
reconsideration, the agency believes that expanding the study in either
manner affects the rights, safety, and welfare of the subjects. Thus,
FDA believes that this type of protocol change does not meet the
statutory criteria and may not be implemented without submission and
approval of an IDE supplement.
    Finally, it should be noted that while FDA is not requiring IRB
approval or DSMB concurrence to be used as the credible information to
support protocol changes, sponsors may use this information if they so
wish. In addition, depending upon the type of protocol change being
considered, approval by the IRB may be required under Sec. 56.110.

F. Proposed Sec. 812.35(a)(3)(iv) Notice of IDE Change

    13. Several comments suggested that FDA should make it clear that
the 5-day timeframe consists of 5-working days and not 5-calendar days,
because 5-calendar days is unreasonably short and could consist of as
few as 2-working days. Another comment suggested that the rule should
state that the notice need only be mailed within 5 days and not
necessarily received by FDA within that time.
    The agency agrees with the comments regarding working rather than
calendar days and has modified the regulation to indicate that the
notices shall be submitted within 5-working days. FDA also agrees that
sponsors have 5 days from the time a change is implemented to mail the
notice. The agency disagrees, however, that the regulation should be
modified because unless otherwise specified, agency timeframes already
generally indicate the time to mailing rather than the time to receipt.
    14. One comment suggested that the requirements for the contents of
a notice of IDE change were unduly burdensome in that the statute
required a notice and not a detailed description of the changes. The
comment further

[[Page 64622]]

suggested that FDA should require only a notice of the change, while
the detailed description would be reported in the annual report.
    FDA disagrees with the comment. As modified in the final rule, the
information to be submitted to the agency in the notice is the same
information that the sponsor would have submitted in the annual report
and therefore, should not represent an increased burden. The
recommendation that sponsors should be permitted to submit a simple
notice of the change in 5 days, followed by a full description in the
annual report, would not allow the agency to review the notices in a
timely fashion, as other comments asserted was critical to this
provision (see section II.G of this document).

G. Proposed Sec. 812.35(a)(3)(v) Review of the Notices

    15. Several comments objected that the proposed rule did not
contain any procedures or timeframes within which FDA would review and
respond to the notices. The comments stated that this omission was
unfair to manufacturers and would result in uncertainty that could lead
to the submission of more supplements by manufacturers who wanted
certainty that the data could be used in support of a premarket
application. It was also asserted that the proposed approach does not
serve the public health and recommended that the provision be revised
to include an appropriate timeframe within which the agency would
respond to the IDE sponsor if additional information to support the
change is needed. Comments suggested various time periods in which FDA
should respond to the notices, ranging from 5 days to 30 days.
    FDA agrees, in part, with the comments. Upon reconsideration, the
agency agrees that procedures should be identified for the review of
the IDE notices. FDA intends to review the notices in the same
timeframe and manner in which it has customarily reviewed other IDE
submissions of this type, i.e, progress/annual reports. In keeping with
its practice for other submissions of this type, the agency will only
notify the sponsor if questions arise or additional information is
needed.
    FDA disagrees that a specific timeframe for review, such as a 5 or
10-day period, should be established in the final rule. The statute
does not require that FDA conduct its review of the notices within a
specific period of time. As stated previously, the agency will make
every effort to review the notices in the same timeframe and manner as
it does other IDE submissions. FDA believes that with the majority of
the notices, it will be readily apparent whether the notice meets the
applicable criteria. In those instances in which questions arise, the
agency will address the issue as expeditiously as possible, thereby
ensuring the protection of public health.
    It should be noted that FDA reserves the right to request
additional information if, during the course of the investigation,
information becomes available (e.g., adverse events) that would cause
the agency to question whether the change(s) made in accordance with
Sec. 812.35(a)(3)(i) or (a)(3)(ii) met the applicable criteria. FDA
would normally only take such action if the agency believes that the
modification to the device, manufacturing process, or protocol could
jeopardize patient safety, the scientific soundness of the
investigation, or the validity of the data resulting from the trial.

H. Proposed Sec. 812.35(a)(4) Changes Submitted in an Annual Report

    16. One comment stated that proposed Sec. 812.35(a)(4) was
difficult to understand and suggested that it be rewritten to express
in the regulation the preamble's discussion of annual report
requirements.
    FDA agrees, in part, with the comment. The agency agrees that this
section of the regulation could be simplified and has revised
Sec. 812.35(a)(4) in the final rule to more clearly indicate the types
of changes to the investigational plan that are suitable for submission
in an annual report. The agency disagrees, however, that the regulation
should include all of the text from the preamble of the proposed rule.
The discussion from the preamble of the types of changes that would be
appropriate for submission in an annual report is too detailed to be
included in a regulation. Furthermore, this list was intended to be
illustrative rather than all inclusive; including it in the regulation
would be overly restrictive.
    17. One comment noted that the proposed rule failed to include a
provision that would assure manufacturers that their data could be used
in support of a premarket application as suggested in the legislative
history. Specifically, the comment noted that the proposed rule did not
reference section 515(d)(B)(iii) of the act (21 U.S.C.
360e(d)(B)(iii)), and stated that the agency should modify the
regulation to state: ``FDA will accept and review all data and
information that are derived in accordance with this section in
determining whether to clear or approve a device for commercial
distribution.'' The comment maintains that this addition to the
regulation would clarify that FDA will accept and review the data if
the IDE sponsor determines that no new original or supplemental IDE
application was necessary prior to implementing the change.
    FDA agrees that it will accept and review statistically valid and
reliable data and any other information from an investigation that is
conducted under section 520(g) of the act, provided that the data or
information meets the conditions prescribed in section 515(d)(B)(iii).
The comment suggests, however, that the decision about whether the
change meets the criteria of sections 515(d)(B)(iii) and 520(g)(6) of
the act rests solely with the IDE sponsor. FDA does not agree with this
premise. Although section 520(g)(6) of the act states that the sponsor
shall determine whether the device/manufacturing or protocol change
meets the criteria for submitting a notice for FDA review and
acceptance under this provision, the statute does not state that the
sponsor determines whether the data resulting from the clinical trial
meets the criteria for acceptance or review under section
515(d)(B)(iii) of the act. Consistent with FDA's decisions on all other
clearance and approval submissions, the final determination regarding
whether the application contains statistically valid and reliable
information, in accordance with these sections, rests with FDA.

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 final rule under Executive
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the
Unfunded Mandates Reform Act of 1995 (2 U.S.C. 1532). 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). 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

[[Page 64623]]

requires agencies to analyze regulatory options that would minimize any
significant impact of a rule on small entities. The Unfunded Mandates
Reform Act requires that agencies prepare a written assessment of
anticipated costs and benefits before proposing any rule 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.
The agency believes that this rule is consistent with the regulatory
philosophy and principles identified in the Executive Order, and these
two statutes.
    FDAMA added new section 520(g)(6) of the act 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) of the act 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. This
final rule amends existing regulations to implement section 520(g)(6)
of the act.
    Several comments objected that FDA underestimated the economic
effects of the proposed rule and that the proposed requirements were
unduly burdensome. These comments generally stated: (1) FDA
misinterpreted the statute by requiring 5-day reports for changes that
previously were reported in annual reports, thereby making the
reporting requirements more burdensome than those under the existing
regulation; (2) FDA created an unnecessary burden by requiring IRB
approval or DSMB concurrence as ``credible information'' for protocol
changes, and did not take into account in its analysis the costs of
requiring IRB approval or DSMB concurrence; (3) FDA created an
unnecessary burden by requiring solely design control information as
``credible information'' for design and manufacturing modifications to
a device; (4) FDA should allow 5-working days to mail the notice,
instead of 5-calendar days, and (5) the requirements for the contents
of a 5-day notice were unduly burdensome by requiring too much detail
in the description of the changes.
    FDA has adopted most of the comments' suggestions on ways to reduce
regulatory burden and provide flexibility and believes that the
resulting final rule is significantly less burdensome and more flexible
than the proposed rule. The responses to the comments related to burden
are discussed in detail in both sections II and V of this document, but
are also described briefly in the following paragraphs.
    FDA disagrees with the comment stating the 5-day notice provision
should only be used for changes that were previously filed as IDE
supplements. FDA believes that the statute clearly requires 5-day
notices for some changes that were filed previously as annual reports,
but does not believe that this presents any appreciable additional
burden on manufacturers. The evidence used to determine whether a
change may be made under an annual report or the 5-day notice provision
is the same, and in both cases, would need to be generated and
evaluated before the change is implemented. Moreover, the regulation
should reduce burden by clarifying to sponsors what types of changes
require prior approval, thereby eliminating the submission of
unnecessary IDE supplements.
    FDA agrees with comments that stated there were less burdensome
ways of providing credible information for protocol changes than IRB
approval or DSMB concurrence. In response to these comments, the final
rule has removed IRB approval or DSMB concurrence as a basis for
credible information, and instead requires documentation such as peer
reviewed published literature, the recommendation of clinical
investigator(s), and/or a summary of the data gathered during the
clinical trial that supports the sponsor's determination that the
change does not affect the rights, safety, or welfare of the subjects.
These types of information are already generated and evaluated at the
time a sponsor changes a device protocol. Therefore, FDA's definition
in the final rule of credible information provides flexibility and
negligible additional burden in that it requires the submission of
already existing evidence.
    FDA also agrees with comments that suggested allowing more
flexibility in the credible information required for design changes. In
response to comments, the final rule allows information, other than
information generated by design controls, to be used as a basis for
credible information to support a design change.
    FDA also agrees with the suggestion to allow 5-working days to mail
the notice, instead of 5-calendar days. This will reduce burden by
allowing sponsors more time to submit the notice.
    FDA does not agree with the comment that the contents of the notice
were unduly burdensome, and that most of the information should be
submitted subsequently in an annual report. The information that is in
the notice will have already been generated and evaluated at the time
of the change. There is no appreciable burden in submitting information
that is already on hand within a 5-day timeframe. Moreover, many
comments stated that it was important that FDA advise them, within a
short time of the change, if FDA did not believe that the data could be
used to support a premarket application. The comment that suggested
providing FDA with limited information in the notice would preclude FDA
from giving such timely advice.
    FDA believes that the revisions in the final rule substantially
reduced the regulatory burden. The information that is now required by
the final rule as a basis for credible information is the type of
information that sponsors should have already generated and evaluated
to fulfill their previous reporting requirements under the existing IDE
and QS regulations. The only additional burden is the shortened
reporting timeframe. As discussed previously, this reporting timeframe
should present no appreciable burden because the contents of the
submission should have been generated and evaluated before a change is
made.
    FDA estimates that it will receive 300 5-day reports annually, and
that 200 to 300 manufacturers will submit these notices annually. FDA
believes that this rule will affect a substantial number of small
entities. For the reasons stated previously, however, FDA does not
believe that this rule will have a significant impact on a substantial
number of small entities. FDA believes that there will be some small
additional cost associated with mailing, and training the persons
responsible for submissions about the requirements of this rule. FDA
believes that training the responsible employees will only take a few
hours, and that additional mailing costs are minimal.
    Accordingly, the agency certifies that this rule will not have a
significant economic impact on a substantial number of small entities.
Additionally, this 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

[[Page 64624]]

aggregate or by the private sector, in any 1 year.

V. Paperwork Reduction Act of 1995

    This 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). The title, description and respondent
description of the information collection provisions are shown 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.
    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, based on
``credible information,'' as defined by the Secretary, 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-working days
of making the change. In order to implement this provision, FDA is
amending Sec. 812.35(a) to describe which types of changes may be made
without prior approval and to describe the credible information to be
included in a notice to FDA under this provision.
    For developmental or manufacturing changes, sponsors would be
required to submit credible information that consists of a summary of
the information generated from the design control procedures under
Sec. 820.30, preclinical/animal testing, peer reviewed published
literature, or other reliable information such as clinical information
gathered during the trial or from marketing. For a protocol change, the
sponsor must submit credible information that consists of documentation
such as peer reviewed published literature, the recommendation of the
clinical investigator(s), and/or a summary of the data gathered during
the clinical trial which supports the sponsor's determination that the
change does not affect the rights, safety, or welfare of the subjects.
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 notes that it receives approximately 3,000 supplements annually
for changes to IDE's. As discussed in the Analysis of Impacts in
section IV of this document, FDA anticipates that it will receive
approximately 300 5-day reports annually. In accordance with the
statute, which requires that this rule's procedures be established 1
year from the date of enactment of FDAMA, FDA is requiring that all
changes in investigational studies, including ongoing studies, that
meet the criteria described in this rule, be reported in 5-day notices
if those changes are implemented on or after the effective date of this
rule.
    FDA published the proposed rule (63 FR 38131), submitted the
information collection requirements in the proposed rule to the Office
of Management and Budget (OMB) for review, and invited interested
persons to submit comments on the information collection requirements
to OMB. Most comments discussed have an impact, directly or indirectly,
on the information collection requirements. FDA has responded to these
comments in detail in section II of this document.
    Several comments stated that 5-day notices should be submitted only
for changes that had been submitted previously in IDE supplements.
These comments stated that the requirement of 5-day notices was more
burdensome if it was required for changes that had been submitted
previously as annual reports.
    For the reasons described more fully earlier in this preamble, FDA
believes that the language in section 520(g)(6) of the act clearly
requires that certain changes that previously were submitted as annual
reports now be submitted as 5-day notices. Nonetheless, FDA believes
that the final regulation will reduce burden on industry in two ways.
First, section 520(g) of the act makes mandatory, FDA's previous
practice of allowing certain changes to be implemented by notification
to FDA in an annual report. Second, this regulation provides
clarification on the types of changes that could be implemented without
prior agency approval, thus eliminating the submission of IDE
supplements that are not needed.
    Finally, FDA believes that the submission of a 5-day report for
certain changes that previously were submitted in annual reports will
not impose any appreciable additional burden on industry because both
the evidence used to determine whether a change may be made under an
annual report and a 5-day notice provision is the same, and would need
to be generated and evaluated before the change is implemented.
Accordingly, a requirement to send information that is available before
the change is made within 5 days of the change, as opposed to a later
time after the change, is not an appreciable additional burden.
    Several comments stated that the proposed definitions of credible
information necessary to support a 5-day notice were unduly burdensome.
For design changes, the proposed rule stated that credible information
would consist of information generated by design controls. For protocol
changes, the proposed rule stated that credible information would
consist of approval of an IRB, concurrence of a DSMB, or peer reviewed
literature.
    Many comments objected to the concurrence of IRB's and DSMB's as
credible information because they stated that third party review for
changes that previously had not required such review was burdensome.
Some of the reasons specifically stated that FDA had not adequately
considered the costs to sponsors to obtain this type of review.
    In response to these comments, the final rule has eliminated the
requirement for IRB approval or DSMB concurrence as evidence of
credible information, and instead requires documentation such as peer
reviewed published literature, the recommendation of clinical
investigator(s), and/or a summary of the data gathered during the
clinical trial that supports the sponsor's determination that the
change does not affect the rights, safety, or welfare of the subjects.
At the time a sponsor changes a device protocol, this type of evidence
is already generated and evaluated. Therefore, FDA's definition of
credible information in the final rule provides flexibility and
negligible additional burden in that it requires the submission of
already existing evidence.
    Other comments objected to the lack of flexibility in the
requirement for credible evidence for design changes. These comments
supported the proposal to use information generated by design controls,
but stated that FDA should also allow other information. FDA has
addressed these concerns in the final rule by allowing other
information to be used as a basis for credible information to support a
design change.
    Some comments requested that FDA allow more time for the submission
of reports by allowing reports to be made within 5-working days of the
change instead of 5-calendar days. FDA has

[[Page 64625]]

stated in the preamble to this final rule that 5-working days from the
change is the appropriate timeframe for submissions. This policy should
allow sponsors to reduce costs by allowing them additional time to
prepare notices.
    One comment suggested that the requirements for the contents of a
5-day notice were unduly burdensome in that the statute required a
notice and not a detailed description of the changes. The comment
further suggested that FDA should require only a notice of the change
while the detailed description would be reported in the annual report.
    As discussed more fully earlier in the preamble of this document,
FDA does not agree with this comment. As modified in the final rule,
the information submitted to the agency in the 5-day notice is the same
information that the sponsor would have submitted in the annual report,
and therefore, should not represent an increased burden. Moreover, the
submission of less information would not allow FDA to notify sponsors
that changes require a full supplement until the time of the annual
report, and therefore may result in sponsors wasting resources
gathering data that ultimately may not be used to support a premarket
application.
    One comment stated that FDA's estimate of IDE changes that would be
submitted each year was underestimated. This comment stated that there
were 297 original IDE's filed in 1997 and it was conceivable that as
many as 10 changes for each of these original IDE's could occur per
year. Based on these figures, the comment stated the estimate should be
2,900 responses, instead of 300 responses stated in the proposed rule.
FDA does not agree with these estimates. FDA receives approximately
three supplemental filings per original submission per year. One of
these submissions should always be an annual progress report. Only a
small subset of the two remaining submissions, which FDA estimates as
300 for reasons described herein, would be types of changes reported in
5-day notices.
    One comment stated that the annual reporting burden in the proposed
rule did not take into consideration ongoing studies. FDA did take such
ongoing studies into account in arriving at the estimates reported.
    FDA estimates the burden for this collection of information as
follows:

                                  Table 1.--Estimated Annual Reporting Burden<SUP>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 notices of IDE changes will be
submitted each year. Of these IDE changes, FDA estimates that 100 of
these changes were previously submitted as supplements and 200 of these
changes would have been submitted in annual reports. 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.
Although this was the estimate offered in the proposed rule, FDA
received comments indicating that the burden hours in the proposal were
underestimated. As a result of the changes made in this final rule, the
burden has decreased significantly. Thus, FDA believes that the
estimate of 10 hours per submission is now accurate. FDA therefore
estimates that the total annual burden for preparation of these notices
will be 3,000 hours.
    The information collection provisions of this final rule have been
submitted to OMB for review.
    Prior to the effective date of this final rule, FDA will publish a
document in the Federal Register announcing OMB's decision to approve,
modify, or disapprove the information collection provisions in this
final rule. An agency may not conduct or sponsor, and a person is not
required to respond to, a collection of information unless it displays
a currently valid OMB control number.

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

    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 must obtain approval of a supplemental
application under Sec. 812.30(a), and IRB approval when appropriate
(see Secs. 56.110 and 56.111 of this chapter), prior to implementing a
change to an investigational plan. If a sponsor intends to conduct an
investigation that involves an exception to informed consent under
Sec. 50.24 of this chapter, the 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-working days of making these
changes.
    (i) Developmental changes. The requirements in paragraph (a)(1) of
this section regarding FDA approval of a supplement do not apply to
developmental changes in the device (including manufacturing changes)
that do not constitute a significant change in

[[Page 64626]]

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.
    (iii) Definition of credible information. (A) Credible information
to support developmental changes in the device (including manufacturing
changes) includes data generated under the design control procedures of
Sec. 820.30, preclinical/animal testing, peer reviewed published
literature, or other reliable information such as clinical information
gathered during a trial or marketing.
    (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 that the change does not affect the
rights, safety, or welfare of the subjects. Documentation shall include
information such as peer reviewed published literature, the
recommendation of the clinical investigator(s), and/or the data
gathered during the clinical trial or marketing.
    (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-working 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, if design controls were
used to assess the change, a statement that no new risks were
identified by appropriate risk analysis and that the verification and
validation testing, as appropriate, demonstrated that the design
outputs met the design input requirements. If another method of
assessment was used, the notice shall include a summary of the
information which served as the credible information supporting the
change.
    (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 a summary of the information that
served as the credible information supporting the sponsor's
determination that the change does not affect the rights, safety, or
welfare of the subjects.
    (4) Changes submitted in annual report. The requirements of
paragraph (a)(1) of this section do not apply to minor changes to 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: October 27, 1998.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 98-31245 Filed 11-20-98; 8:45 am]
BILLING CODE 4160-01-F