Medical Devices; Investigational Device Exemptions

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.

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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

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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

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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

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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

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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]

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