Federal Register / Vol. 63, No. 135 /Wednesday, July 15, 1998 / Proposed Rules 38131

H. Electronic Filing of Data

The Department currently accepts

data submissions either in paper form or

on magnetic disk or tape. Most large

carriers submit the bulk of their data on

magnetic media, with large data

submissions, such as the Passenger

Origin-Destination Survey and T–100

market reports nearly universally

submitted on tape or cassette. Electronic

submission of data can be processed

more quickly, and at lower cost, than

similar data submitted in paper form.

The Department now accepts the

official filing of international fare and

fare rules tariffs electronically (See 14

CFR Part 221 and 61 FR 18070–18075,

April 24, 1996). Given the Department’s

limited resources, it would be

impossible to process the volume of

tariff data received if these data were

filed in a wholly paper environment.

Similarly, the Department is

increasingly burdened by the filing of

required financial and traffic data in

paper form.

We request that respondents provide

specific comments on the following

matters:

[H–1] All air carriers who supply

aviation data to the Department are

requested to comment on their ability to

file data electronically or on magnetic

media, i.e., via tape or disk, or over the

Internet.

[H–2] If certain large database

material now accepted by the

Department in electronic form (e.g., the

T–100/T–100(f), Origin-Destination

Survey, and 298–C reports) are

submitted on paper, relevant carrier

respondents are requested to indicate

why magnetic media are not employed

for their submissions.

Contact Persons

We recognize that formal comments

submitted to the Department on

rulemaking matters are usually

submitted by corporate counsel.

However, we are seeking comments

regarding complex technical issues in

anticipation of a formal rulemaking, in

areas which are generally outside the

area of expertise of legal counsel. It

would aid in our evaluation of any

technical comments to be able to contact

persons with direct knowledge of

technical issues being commented upon.

Respondents are urged to supply the

names, telephone numbers, and

addresses of knowledgeable individuals

who can be contacted for a more

detailed discussion of any technical

matters that the respondent counsel

cannot answer directly. There may be

multiple contact persons for any

particular item, or in total. These

contact persons should be listed on the

last page of any submitted filing, along

with their area(s) of expertise.

Regulatory Process Matters

Executive Orders 12612 and 12866

The Department has determined that

the proposed notice of proposed

rulemaking is not a significant

regulatory action under Executive Order

12866. However, the proposed rule may

be significant under the Department’s

Regulatory Policies and Procedures (44

CFR 11304), because of substantial

industry interest and because it may

result in a reduction in paperwork and

filing burden for U.S. carriers. The

Department has also analyzed the

proposal in accordance with the

principles and criteria contained in

Executive Order 12612 (‘‘Federalism’’),

and has determined that the rule does

not have sufficient federalism

implications to warrant the preparation

of a Federalism Assessment. This rule

would not impose unfunded mandates

as defined by the Unfunded Mandates

Reform Act of 1995.

Regulatory Flexibility Act

The Regulatory Flexibility Act of

1980, 5 U.S.C. 601 et seq., was enacted

by Congress to ensure that small entities

are not unnecessarily and

disproportionately burdened by

government regulations. The Act

requires agencies to review proposed

regulations that may have a significant

economic impact on a substantial

number of small entities. For purposes

of this notice, small entities include air

taxis, commuter air carriers, and smaller

U.S. and foreign airlines.

Although we do not believe the

existing rule imposes a significant

economic impact on a substantial

number of small entities, it does affect

many small entities. For that reason, we

specifically seek public comment on

what steps we can take to lessen or

eliminate any burdens it imposes on

small entities.

Paperwork Reduction Act

Our current rules contain significant

collection-of-information requirements.

Changes we may propose will be subject

to the Paperwork Reduction Act, Public

Law No. 96–411, 44 U.S.C. Chapter 35.

The revised rules are expected to result

in a net paperwork reduction for the

industry.

Regulation Identifier Number

A regulation identifier number (RIN)

is assigned to each regulatory action

listed in the Unified Agenda of Federal

Regulations. The Regulatory Information

Service Center publishes the Unified

Agenda in April and October of each

year. The RIN number contained in the

heading of this document can be used

to cross reference this action with the

Unified Agenda.

Patrick V. Murphy,

Deputy Assistant Secretary for Aviation

International Affairs.

Robert A. Knisely,

Acting Director, Bureau of Transportation

Statistics.

[FR Doc. 98–18855 Filed 7–14–98; 8:45 am]

BILLING CODE 4910–62–P

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.

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.
38132 Federal Register / Vol. 63, No. 135 /Wednesday, July 15, 1998 / Proposed Rules

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, § 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 § 812.30(a) of any such

change, and IRB approval when the change

involves the rights, safety, or welfare of

subjects (see §§ 56.110 and 56.111), before

implementation.

Under § 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 § 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 § 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 § 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 § 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 § 812.35(a)(1) requires that

changes to the investigational plan,

except as provided for in proposed

§ 812.35(a)(2) through (a)(4), be

approved by FDA and the IRB, as

applicable under §§ 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 § 50.24 (21

CFR 50.24) to submit a new IDE

application rather than an IDE

supplement.

B. Changes Effected for Emergency Use

Proposed § 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 § 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
Federal Register / Vol. 63, No. 135 /Wednesday, July 15, 1998 / Proposed Rules 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

§ 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 (§ 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
38134 Federal Register / Vol. 63, No. 135 /Wednesday, July 15, 1998 / Proposed Rules

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 patientuser 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 § 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 sponsorinvestigator incorporates the protocol

change. In addition, proposed

§ 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
Federal Register / Vol. 63, No. 135 /Wednesday, July 15, 1998 / Proposed Rules 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 § 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

§ 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 § 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 § 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

§ 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 § 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 § 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 § 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
38136 Federal Register / Vol. 63, No. 135 /Wednesday, July 15, 1998 / Proposed Rules

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

§ 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, §§ 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

§§ 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

§ 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
Federal Register / Vol. 63, No. 135 /Wednesday, July 15, 1998 / Proposed Rules 38137

an annual progress report under

§ 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 § 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

21 CFR Section No. of

Respondents

Annual

Frequency per

Response

Total Annual

Responses

Hours per

Response Total Hours

812.35(a)(3) 300 1 300 10 3,000

1There 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.
38138 Federal Register / Vol. 63, No. 135 /Wednesday, July 15, 1998 / Proposed Rules

2. Section 812.35 is amended by

revising paragraph (a) to read as follows:

§ 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 § 812.30(a) of any such

change, and IRB approval as applicable

(see §§ 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 § 50.24 of

this chapter, a sponsor shall submit a

separate investigational device

exemption (IDE) application in

accordance with § 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

§ 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 § 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 § 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 (crossreferenced 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 § 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