[Federal Register Volume 63, Number 225 (Monday, November 23, 1998)]
[Rules and Regulations]
[Pages 64617-64626]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 98-31245]


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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 Burden1
----------------------------------------------------------------------------------------------------------------
                                                      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