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


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 812

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


Medical Devices; Investigational Device Exemptions

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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

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

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


[[Page 38132]]


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

SUPPLEMENTARY INFORMATION:

I. Background

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

II. Discussion of Proposed Amendments

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

A. Changes Requiring Prior Approval

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

B. Changes Effected for Emergency Use

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

C. Changes Effected With Notice to FDA Within 5 Days

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

[[Page 38133]]

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

D. Definition of Credible Information

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

[[Page 38134]]

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

E. Notice of IDE Change

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

[[Page 38135]]

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

F. Review of the Notices

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

G. Changes Submitted in the Annual Report

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

[[Page 38136]]

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

III. Environmental Impact

    The agency has determined under 21 CFR 25.30(h) that this action is 
of a type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

IV. Analysis of Impacts

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

[[Page 38137]]

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

V. Paperwork Reduction Act of 1995

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

                                  Table 1.--Estimated Annual Reporting 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 of these notices of IDE changes will 
be submitted each year. Based upon discussions with sponsors of IDE's 
and FDA's own experience in reviewing these types of documents, FDA 
estimates that it will take approximately 10 hours for a sponsor to 
prepare a Notice of IDE Change. Therefore, FDA estimates that the total 
annual burden for preparation of these notices will be 3,000 hours.
    As required by section 3507(d) of the Paperwork Reduction Act of 
1995 (44 U.S.C. 3507(d)), the agency has submitted the information 
collection provisions of this proposed rule to OMB for review. 
Interested persons are requested to send comments regarding the 
information collection by August 14, 1998 to the Office of Information 
and Regulatory Affairs, OMB (address above).

VI. Comments

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

List of Subjects in 21 CFR Part 812

    Health records, Medical devices, Medical research, Reporting and 
recordkeeping requirements.
    Therefore, under the Federal Food, Drug, and Cosmetic Act, and 
under authority delegated to the Commissioner of Food and Drugs, it is 
proposed that 21 CFR part 812 be amended as follows:

PART 812--INVESTIGATIONAL DEVICE EXEMPTIONS

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

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


[[Page 38138]]


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

Sec. 812.35  Supplemental applications.

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

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