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: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is amending the

Investigational Device Exemptions (IDE) regulation. The regulatory

changes are intended to reflect amendments to the Federal Food, Drug,

and Cosmetic Act (the act) by the FDA Modernization Act of 1997

(FDAMA). These amendments provide that the sponsor of an IDE may modify

the device and/or clinical protocol, without approval of a new

application or supplemental application, if the modifications meet

certain criteria and if notice is provided to FDA within 5 days of

making the change. The rule also defines the credible information to be

used by sponsors to determine if the criteria are met.

EFFECTIVE DATE: February 22, 1999.

FOR FURTHER INFORMATION CONTACT: Joanne R. Less, Center for Devices and

Radiological Health (HFZ-403), Food and Drug Administration, 9200

Corporate Blvd., Rockville, MD 20850, 301-594-1190.

SUPPLEMENTARY INFORMATION:

I. Background

Experience has shown that during the course of a clinical

investigation, the sponsor of the study will often want or need to make

modifications to the investigational plan, including changes to the

device and/or the clinical protocol. These changes may be simple

modifications, such as clarifying the instructions for use, or they may

be significant changes, such as modifications to the study design or

device design.

The IDE supplement regulation that has been effect since 1985

(hereinafter referred to as the ``existing regulation''),

Sec. 812.35(a) (21 CFR 812.35(a)), states in part:

A sponsor shall: (1) Submit to FDA a supplemental application if

the sponsor or an investigator proposes a change in the

investigational plan that may affect its scientific soundness or the

rights, safety, or welfare of subjects and (2) obtain FDA approval

under Sec. 812.30(a) of any such change, and IRB approval when the

change involves the rights, safety, or welfare of subjects (see

Secs. 56.110 and 56.111), before implementation. * * *

Under Sec. 812.25 Investigational plan (21 CFR 812.25), the

investigational plan includes: (1) The purpose of the study, (2) the

clinical protocol, (3) a risk analysis, (4) a description of the

investigational device, (5) monitoring procedures, (6) labeling, (7)

informed consent materials, and (8) institutional review board (IRB)

information. Although written guidance on the types of modifications

that can be made without prior FDA approval has not previously been

developed, the agency has permitted changes to all parts of the

investigational plan, without new or supplemental IDE application

approvals, if the changes did not affect the scientific soundness of

the plan or the rights, safety, or welfare of the subjects, and if such

changes were reported to FDA in the upcoming annual report under

Sec. 812.150(b)(5) (21 CFR 812.150(b)(5)).

On November 21, 1997, the President signed into law FDAMA. Section

201 of FDAMA (Pub. L. 105-115) amended the act by adding new section

520(g)(6) to the act (21 U.S.C. 360j(g)(6)). Section 520(g)(6) of the

act permits, upon issuance of a regulation, certain changes to be made

to either the investigational device or the clinical protocol without

prior FDA approval of an IDE supplement. Specifically, this section of

the statute permits:

(i) developmental changes in the device (including manufacturing

changes) that do not constitute a significant change in design or in

the basic principles of operation and that are made in response to

information gathered during the course of an investigation; and

(ii) changes or modifications to clinical protocols that do not

affect--

(I) the validity of the data or information resulting from the

completion of an approved protocol, or the relationship of likely

patient risk to benefit relied upon to approve a protocol;

(II) the scientific soundness of an investigational plan

submitted [to obtain an IDE]; or

(III) the rights, safety, or welfare of the human subjects

involved in the investigation.

The existing IDE regulation and the new statute both permit certain

changes to be made to the investigational plan without prior agency

approval. FDA views the changes and modifications allowed under section

520(g)(6) of the act as consistent with the way the agency has

previously interpreted existing Sec. 812.35(a).

Section 520(g)(6) of the act, as added by FDAMA, also specifies

that the implementing rule provide that such changes or modifications

may be made without prior FDA approval if the IDE sponsor determines,

on the basis of credible information (as defined by the Secretary of

Health and Human Services (the Secretary)) that the previous conditions

are met and if the sponsor submits, not later than 5 days after making

the change or modification, a notice of the change or modification.

Lastly, section 520(g)(6) of the act requires that FDA issue a final

regulation implementing this section no later than 1 year after the

date of enactment of FDAMA.

On July 15, 1998 (63 FR 38131), FDA issued a proposal to implement

section 520(g)(6) of the act. FDA provided interested persons an

opportunity to comment on the proposed rule by September 28, 1998. FDA

received comments from five entities; one medical device manufacturer's

association, two medical device manufacturers, one law firm, and one

consumer. Most of the comments stated that the proposed regulation

increased the economic and regulatory burden and lacked flexibility

compared to the existing regulation. FDA has revised the proposed

regulation in several significant respects to address these concerns.

The following is a summary of the comments and FDA's response to them.

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

A. General Comments

1. Several comments objected to FDA's proposal because it would

require that notices be submitted within 5 days of implementing

protocol and device changes that had previously been

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submitted in annual reports under the existing Sec. 812.35(a)(1).

Comments stated that the regulation should instead have required 5-day

notices for changes that were formerly submitted as IDE supplements.

These comments asserted that the proposed rule was not consistent with

the intent of the statute which was to reduce the burden on industry by

decreasing the number of submissions requiring prior agency approval.

Another comment contended that submitting a notice within 5 days of

implementation of a change rather than in an annual report would pose a

regulatory and economic burden for industry.

FDA recognizes that some of the protocol and device changes that

were previously submitted in IDE annual reports will now need to be

submitted in a 5-day notice under the new regulation. For the reasons

described in the following paragraphs, however, FDA believes that the

language in new section 520(g)(6) of the act clearly requires this, but

does not believe that the new regulation will impose any appreciable

additional burden.

Prior to the enactment of section 520(g)(6) of the act, the

criteria that had been used to determine whether a change to an

investigational plan required approval of an IDE supplement were

described in existing Sec. 812.35(a)(1). This section of the IDE

regulation required a supplement if the change to the investigational

plan ``may affect its scientific soundness or the rights, safety, or

welfare of such subjects.'' All changes that were deemed not to affect

scientific soundness or the rights, safety, or welfare of the subjects

could be implemented without FDA approval of an IDE supplement, and

instead were reported to the agency in an annual report under

Sec. 812.150(b)(5).

As stated in the preamble to the proposed rule, the agency has

permitted changes to all parts of the investigational plan, including

the device, manufacturing process, and clinical protocol, without new

or supplemental IDE application approvals if the changes were made in

compliance with existing Sec. 812.35(a)(1) and if the changes were

reported to FDA in the upcoming annual report. Because written guidance

specifying the types of modifications that could be made without prior

approval has never been issued, there was some inconsistency in the

determination of which types of changes could be permitted without the

submission of a supplement. Therefore, some changes which may have met

the criteria for submission in an annual report were submitted for

prior approval in an IDE supplement.

Section 520(g)(6) of the act, in describing the types of protocol

changes that were to be subject to 5-day notices, incorporated verbatim

the ``scientific soundness'' and ``rights, safety, or welfare''

criteria in existing Sec. 812.35(a)(1) that distinguished those changes

that required prior approval from those that could have been submitted

in an annual report. This section of the act also sets forth additional

criteria for changes that would qualify for implementation with a 5-day

notice. These additional criteria are consistent with the criteria in

the existing regulation that have been used to determine the effect of

a change on the scientific soundness of the investigational plan and

the rights, safety, and welfare of subjects. Thus, the language in

section 520(g)(6) of the act requires that some changes that had

previously been submitted in annual reports will now need to be

submitted within 5 days of implementation.

FDA disagrees that the new regulation will be more burdensome for

industry. Section 520(g)(6) of the act and the new implementing

regulation reduce the burden on industry in two important ways. First,

section 520(g)(6) of the act makes mandatory FDA's previous practice of

permitting certain changes to be made to the investigational plan

without prior agency approval. Secondly, this regulation provides

clarification of the types of changes that could be implemented without

prior agency approval, thus eliminating the submission of IDE

supplements that are not needed. For example, prior to this

implementing regulation, an IDE supplement may have been submitted for

any materials change to an investigational device. The new regulation,

however, clarifies that approval of a supplement would only be needed

if the materials change represents a significant change in design

(e.g., new risks) or basic principles of operation.

Finally, FDA disagrees that notifying the agency of a change within

5 days of implementation, rather than in an annual report, will pose a

regulatory and economic burden on industry. FDA is aware that

submitting a notice within 5 days, as required by section

520(g)(6)(B)(ii) of the act, represents a much shorter response time

compared to submission in an annual report. FDA does not believe,

however, that this reduced timeframe will impose any appreciable

additional burden to industry as the evidence used to determine whether

a change may be made under an annual report or the 5-day notice

provision is the same, and in both cases, would need to be generated

and evaluated before the change is implemented.

2. One comment stated that section 520(g)(6) of the act should be

interpreted to allow a sponsor to make device changes that

significantly improve safety or effectiveness, yet do not constitute

significant changes in design or in the basic principles of operation

under the 5-day notice provision.

FDA agrees that section 520(g)(6) of the act allows a sponsor to

make device changes intended to enhance significantly safety or

effectiveness without submitting an IDE supplement, if the

developmental changes in a device do not constitute significant changes

in design or in the basic principles of operation. Although the comment

was not entirely clear, it also seems to suggest that any change

intended to enhance safety or effectiveness should not require an IDE

supplement. If this were the suggestion, FDA does not agree. Consistent

with all other device statutory and regulatory product approval

provisions, section 520(g)(6) of the act does not condition the

submission of an IDE supplement on whether a change will enhance safety

or effectiveness. Section 520(g)(6) of the act conditions the use of

the 5-day notice provision only on whether the change is a significant

change in the design or basic principles of operation. An

interpretation that 5-day notices are allowed any time a sponsor

intends a change to enhance safety or effectiveness would not only be

contrary to the language in section 520(g)(6) of the act, it would

constitute a drastic change in FDA's longstanding position that the

statute and regulations require either a new premarket notification,

new premarket approval application, or new IDE for certain types of

device modifications regardless of whether the sponsor believes the

changes enhance safety or effectiveness. Manufacturers make most

modifications with the intention and belief that the change will make a

safer and/or more effective product. This factor does not obviate the

need for FDA to review changes to ensure that there is scientific

support to show that safety and effectiveness have not been

compromised.

3. One comment asked that an open public meeting be convened to

discuss the proposed rule with knowledgeable representatives of all

affected entities.

FDA disagrees that such a meeting is necessary. Detailed comments

were received on virtually every aspect of the proposed regulation, and

the agency has significantly revised the rule in accordance with the

concerns that were expressed in the comments. As

[[Page 64619]]

discussed in detail in the following paragraphs, the final rule

provides for more flexibility than the proposed rule and addresses the

concerns regarding the economic and regulatory burden posed by the

proposed regulation.

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

4. One comment stated that the first sentence of this proposed

section is awkward and suggested that it be revised to read:

Except as described in paragraphs (a)(2) through (a)(4) of this

section, a sponsor must receive approval of a supplemental

application under Sec. 812.30(a), and IRB approval when appropriate

under 21 CFR Part 56, prior to implementing a change to an

investigational plan for a device which is subject to an approved

IDE.

FDA agrees that the proposed sentence could be simplified and more

clearly stated. Therefore, the agency has revised the sentence to read:

Except as described in paragraphs (a)(2) through (a)(4) of this

section, a sponsor must obtain approval of a supplemental

application under Sec. 812.30(a), and IRB approval when appropriate

(see Secs. 56.110 and 56.111 of this chapter), prior to implementing

a change to an investigational plan.

5. One comment objected that proposed Sec. 812.35(a)(1) would

require IDE supplements for changes where only annual reports had been

required under the existing regulation. Specifically, the comment

objected to the language in proposed Sec. 812.35(a)(1) which states

that a supplement is required when ``the sponsor or an investigator

proposes a change in the investigational plan.'' The comment stated

that the language in the existing regulation only required supplements

for changes in an investigational plan that ``may affect its scientific

soundness or the rights, safety, or welfare of subjects.''

FDA does not intend new Sec. 812.35(a)(1) to require the submission

of an IDE supplement for changes that would have been submitted in an

annual report under the existing regulation. Proposed and final

Sec. 812.35(a)(1) states ``Except as described in paragraphs (a)(2)

through (a)(4) of this section, * * *.'' Section 812.35(a)(3) and

(a)(4) provide that sponsors do not have to submit an IDE supplement

for changes to an investigational plan that do not affect the

scientific soundness, rights, safety, or welfare of subjects, risk to

benefit relationship relied upon to approve the protocol, or validity

of the data. As stated in the preamble to the proposed rule, FDA

considers the two additional criteria, i.e., risk to benefit

relationship and validity of the data, to be consistent with the

agency's general criteria under the existing regulation that permits

changes to the investigational plan as long as the changes do not

compromise patient rights, safety, or welfare or the integrity of the

clinical trial.

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

6. In the proposed rule, the first sentence of Sec. 812.35(a)(3)(i)

stated ``The requirements in paragraph (a)(1) of this section regarding

FDA and IRB approval of a supplement do not apply to developmental

changes in the device (including manufacturing changes) * * *.'' FDA

has modified this sentence to remove the phrase ``and IRB.'' Therefore,

the sentence now reads ``The requirements in paragraph (a)(1) of this

section regarding FDA approval of a supplement do not apply to

developmental changes in the device (including manufacturing changes) *

* *.''

The agency has modified the regulation in this manner as the

proposed language indicated that IRB approval and/or notification to

the IRB of device/manufacturing changes in an annual report was not

required. This language not only conflicted with the language in

proposed Sec. 812.35(a)(3)(iv), but also conflicted with 21 CFR

56.108(a)(4) which indicates that IRB's may require review of changes

to approved research. FDA would like to clarify that while

developmental changes that are made in accordance with section

520(g)(6) of the act do not need FDA approval, they must still be

reported to the IRB in the sponsor's annual report. Moreover, the

changes may be subject to IRB review under Sec. 56.110 (21 CFR 56.110).

D. Proposed Sec. 812.35(a)(3)(iii)(A) Definition of Credible

Information (Device/Manufacturing Changes)

7. In this section of the proposed regulation, FDA defined

``credible information,'' upon which sponsors are to rely in assessing

device/manufacturing changes, as the information generated under the

design control provisions Sec. 820.30 (21 CFR 820.30) of the Quality

System (QS) Regulation. (The QS regulation implements FDA's good

manufacturing practice (GMP) authority of section 520(f) of the act.)

One comment contended that the agency does not have the authority to

require IDE sponsors to comply with design controls. Specifically, the

comment said that while Sec. 812.1(a) (21 CFR 812.1(a)) states that

``investigational devices are exempt from section 520(f) of the Act,

except for the requirements under 21 CFR 820.30, most device counsels

advise their clients that this regulation does not take precedence over

the explicit exemption from section 520(f) found in section

520(g)(2)(A) of the statute.''

FDA does not agree. It interprets the act as authorizing it to

require IDE sponsors to comply with the design control procedures, as

stated in Sec. 812.1(a). Contrary to the comment's assertion, section

520(g)(2)(A) of the act does not categorically exempt investigational

devices from all GMP requirements. Section 520(g)(2)(A) of the act

states that FDA shall issue regulations that ``prescribe procedures and

conditions under which devices intended for human use may upon

application be granted an exemption from the requirements of * * *

subsection (f) of this section * * *'' (Emphasis added). Section

520(g)(2)(A) of the act does not mandate that FDA issue regulations

that exempt investigational devices from the act's other requirements,

but rather it allows FDA discretion in issuing IDE's from other

statutory requirements. Under this discretionary authority, FDA has

chosen to retain design control requirements for investigational

devices as stated in Sec. 812.1(a). The agency believes that it would

be illogical to exclude investigational devices used in clinical trials

from the design control provision of the QS regulation because clinical

trials are an integral part of the device development process.

8. Other comments generally supported the use of design controls

but stated that, while design controls may be one acceptable method of

supporting developmental changes in a device, sponsors should not be

limited to or required to use design controls to support this type of

change. Two comments suggested that FDA should follow more closely the

definition of ``credible information'' in the legislative history,

namely: ```credible information' shall mean information upon which a

reasonable person in a manufacturer's position would rely upon in

making a decision to change or modify an investigational device'' (Food

and Drug Administration Modernization and Accountability Act of 1997,

S. Rept. No. 105-43, at 32 (July 1, 1997)). One comment suggested that

the definition be revised to include ``any other reasonable and

reliable means,'' while a second comment recommended ``literature,

design controls, validation studies, or other appropriate means.''

FDA agrees that limiting the definition of credible information for

developmental changes for a device to the information generated under

design

[[Page 64620]]

controls procedures is overly restrictive and recognizes that other

information may serve as the credible information. Therefore, rather

than limit the definition of credible information for device/

manufacturing changes to design controls, the agency has revised the

definition to also include information such as preclinical/animal

testing, peer reviewed published literature, or other reliable

information such as clinical information gathered during the trial or

from marketing experience gained in other countries. FDA believes this

new definition is consistent with the legislative history discussing

the term ``credible information,'' but provides more specific guidance

to IDE sponsors.

9. Several other comments questioned specific aspects of the design

control process, such as the need for the completion of all

verification and validation testing prior to implementation of the

change, the apparent requirement that a device's original design input

requirements cannot be modified, and FDA's definition of ``new types of

risks.''

FDA agrees, in part, with the comments. With regard to the

assertion that FDA is requiring that all verification and validation

testing be completed before a device/manufacturing change is

implemented, the agency recognizes that verification and validation

testing depends upon the type of change that is made, and that for some

minor changes, no such testing may be needed. In addition, the agency

acknowledges that the clinical trial itself may be part of the

validation testing. Thus, it would be impractical to require that this

testing, or other verification or validation testing that would

reasonably occur after the clinical trial, be completed before a

device/manufacturing change is implemented. In response to the

comments, the regulation has been modified to state ``verification and

validation testing, as appropriate.''

FDA believes that the comment that asserted that the proposed

regulation requires that a device's original design input requirements

remain unchanged, reflects a misunderstanding of the proposed

regulation. FDA recognizes that if a sponsor is modifying the device

design and/or the manufacturing process, the design input requirements

would need to be modified until the design is finalized. Thus, the

sponsor should conduct the appropriate verification and validation

testing and this testing should indicate that the design outputs meet

the modified design input requirements. The agency believes that this

explanation will serve to clarify the issue and no change to the

regulation is necessary.

With respect to the agency's interpretation of the term ``new types

of risks,'' FDA is providing the following clarification. In the

preamble to the proposed rule, FDA stated that if a sponsor determined

that no new types of risks were introduced by the device/manufacturing

change and the subsequent verification and validation testing

demonstrated that the design outputs met the design input requirements,

then the change could be made without prior agency approval. An example

of two materials changes in a catheter was provided to illustrate this.

One change, from polyvinylchloride (PVC) to silicone, would be

permitted under a 5-day notice because no new types of risks resulted

from the change; and one, from PVC to latex, would require prior

approval because a new type of risk, i.e., possible latex sensitivity,

would result from the change. A comment stated that the example was

unclear because changing from PVC to silicone and from PVC to latex

presented the same two types of risks (biocompatibility and materials

sensitivity). The comment requested that a definition of ``new types of

risks'' be provided since, in the example, the agency failed to

recognize materials sensitivity in the PVC to silicone change as a new

type of risk.

FDA acknowledges that this example was not clear and that for both

materials changes, materials sensitivity should have been identified as

a new type of risk. The agency agrees with the comment's assessment of

``new types of risks'' in the previous example. Because the evaluation

of whether new types of risks are presented will vary depending on the

type of device and the type of change, FDA does not believe that this

term should be defined in the regulation.

10. One comment objected to a statement in the preamble that

indicated that manufacturers should also conduct other testing that

addresses concerns that may have been identified to the IDE sponsor in

a ``recognized standard.'' The comment stated standards are strictly

voluntary and FDA should not require manufacturers to conform with

them.

FDA agrees that standards are voluntary and thus, FDA cannot

require IDE sponsors to conform to them. FDA did not state, however,

that the sponsor is required to conform to a voluntary standard,

instead FDA stated only that a sponsor ``should conduct any other

performance testing that addresses a safety or performance concern that

may have been identified to the IDE sponsor in a recognized standard or

other agency correspondence.'' (Emphasis added). Although FDA

recognizes that compliance with a voluntary standard is not required to

address safety or performance concerns, compliance with standards may

be one way, among others, of addressing those concerns. It should be

noted, however, that if a manufacturer chooses a recognized standard as

a device input requirement, the device output should meet that

standard.

11. Comments were received both in support of and in opposition to

the agency's reference to the guidance document entitled ``Deciding

When to Submit a 510(k) for a Change to an Existing Device.'' Two

comments agreed that this guidance would be helpful to sponsors when

deciding what types of changes could be made under the 5-day notice

provision. One comment questioned the relevance of the guidance to the

proposed rule as changes that can be made to marketed devices without

affecting their safety and effectiveness may not be appropriate types

of changes for investigational devices. Lastly, one comment appears to

have misunderstood the agency's intent in referring to the guidance. It

was asserted that the document would be helpful in determining the

significance of a change, but would be overly restrictive in the types

of changes that would be permitted under the 5-day notice provision.

In response to the comments which opposed the agency's reference to

the guidance document, FDA is offering the following clarification. As

stated in section 520(g)(6)(A)(i) of the act, only those changes to the

investigational device that do not constitute a significant change in

design or basic principles of operation are eligible for implementation

under this provision. In an effort to describe the types of device and

manufacturing changes that may be eligible for implementation without

FDA approval, reference was made to the 510(k) guidance document. This

guidance was referenced only for its list of generic types of device

and manufacturing changes that the agency believes apply to all

devices, marketed or investigational. The list includes the control

mechanism, principle of operation, energy type, environmental

specifications, performance specifications, ergonomics of patient-user

interface, dimensional specifications, software or firmware, packaging

or expiration dating, sterilization, and the manufacturing process

(including the manufacturing site). In referencing these types of

changes, the agency was not indicating

[[Page 64621]]

that any specific change within a particular type would or would not be

appropriate under the 5-day notice provision because changes in each of

these categories could range from minor to significant depending upon

the particular device, the type of modification, and the extent of the

modification. FDA maintains that IDE sponsors should refer to the list

as a starting point for the types of changes which may qualify for

implementation under this provision. The impact of the change, however,

would still need to be determined by information generated by design

controls or other appropriate means to assess the significance of the

change to the device design or manufacturing process and the

appropriateness of a 5-day notice submission.

FDA notes, however, that it believes one type of change should be

submitted in an IDE supplement. In the preamble to the proposed rule,

the agency stated that it would consider any change to the basic

principles of operation of a device to be highly likely to constitute a

significant change requiring prior approval and solicited comments on

this premise. FDA received no comments on this issue. The agency

advises that it considers all changes to the basic principles of

operation of a device to be significant changes that should be

submitted in an IDE supplement.

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

Information (Protocol Changes)

12. Several comments questioned the agency's definition of credible

information for protocol changes as defined in proposed

Sec. 812.35(a)(3)(iii)(B). In general, the comments stated that the

requirement to obtain the approval of an IRB chairperson (or designee)

or of a data safety monitoring board (DSMB) will result in considerable

expense, is unduly burdensome and time consuming, and is less flexible

than the current regulation. The comments asserted that FDA did not

adequately consider the cost of imposing such a requirement. In

addition, the comments contended that section 520(g)(6)(B)(i) of the

act identifies the sponsor as the party responsible for determining

whether a protocol change needs FDA approval, not a third party. In

addition to the general concerns, specific concerns were raised

regarding the use of DSMB's. It was asserted that since DSMB's are

neither required nor recognized in the IDE regulation and FDA has no

regulatory authority over them, DSMB's should not be included in the

agency's definition of credible information for protocol changes.

Upon further consideration of this statutory provision, the agency

agrees that requiring approval of the IRB chairperson (or designee)

and/or concurrence of a DSMB in the definition of credible information

for protocol changes could prove more burdensome than Congress

intended. FDA also agrees that the act indicates that the sponsor is

responsible for initially determining if the change meets the statutory

criteria. Therefore, FDA has modified the regulation to state that

credible information to support changes to the clinical protocol is

defined as the sponsor's documentation supporting its conclusion that

the change does not have a significant impact on the study design or

planned statistical analysis, and that the change does not affect the

rights, safety, or welfare of the subjects. Such a determination should

be made by the person in the company responsible for such decisions and

should be based upon information such as peer reviewed published

literature, the recommendation of the clinical investigator(s), and or

data collected during the clinical trial or marketing in other

countries.

As an example of this, consider a case in which preliminary

information gathered during the clinical trial indicates that the

inclusion/exclusion criteria should be modified to better define the

target patient population. This change could be made after the sponsor

concludes and documents that the change would not have a significant

impact on the study design or planned statistical analysis and that the

change does not affect the rights, safety, or welfare of the study

subjects. Similarly, if the clinical investigators recommended that the

protocol be modified to lengthen the subject followup, this change

could be implemented after the previous assessments are performed that

support a determination that the change is not significant.

As discussed in the preamble to the proposed rule, other examples

of protocol modifications that could be made under the 5-day notice

provision include: Increasing the frequency at which data or

information is gathered, modifying the protocol to include additional

patient observations/measurements, and modifying the secondary

endpoints. Alternatively, FDA believes that the following types of

protocol changes would not generally be appropriate for implementation

without prior agency approval because they are likely to have a

significant effect on the scientific soundness of the trial design and/

or validity of the data resulting from the trial: Change in indication,

change in type or nature of study control, change in primary endpoint,

change in method of statistical evaluation, and early termination of

the study (except for reasons related to patient safety).

FDA notes that, contrary to statements in the proposed rule (63 FR

38131 and 38134), protocol changes involving study expansions should

not be made without prior agency approval. In the proposed rule, FDA

stated that sponsors could increase either the number of

investigational sites or study subjects participating in a clinical

investigation without approval of an IDE supplement. Upon

reconsideration, the agency believes that expanding the study in either

manner affects the rights, safety, and welfare of the subjects. Thus,

FDA believes that this type of protocol change does not meet the

statutory criteria and may not be implemented without submission and

approval of an IDE supplement.

Finally, it should be noted that while FDA is not requiring IRB

approval or DSMB concurrence to be used as the credible information to

support protocol changes, sponsors may use this information if they so

wish. In addition, depending upon the type of protocol change being

considered, approval by the IRB may be required under Sec. 56.110.

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

13. Several comments suggested that FDA should make it clear that

the 5-day timeframe consists of 5-working days and not 5-calendar days,

because 5-calendar days is unreasonably short and could consist of as

few as 2-working days. Another comment suggested that the rule should

state that the notice need only be mailed within 5 days and not

necessarily received by FDA within that time.

The agency agrees with the comments regarding working rather than

calendar days and has modified the regulation to indicate that the

notices shall be submitted within 5-working days. FDA also agrees that

sponsors have 5 days from the time a change is implemented to mail the

notice. The agency disagrees, however, that the regulation should be

modified because unless otherwise specified, agency timeframes already

generally indicate the time to mailing rather than the time to receipt.

14. One comment suggested that the requirements for the contents of

a notice of IDE change were unduly burdensome in that the statute

required a notice and not a detailed description of the changes. The

comment further

[[Page 64622]]

suggested that FDA should require only a notice of the change, while

the detailed description would be reported in the annual report.

FDA disagrees with the comment. As modified in the final rule, the

information to be submitted to the agency in the notice is the same

information that the sponsor would have submitted in the annual report

and therefore, should not represent an increased burden. The

recommendation that sponsors should be permitted to submit a simple

notice of the change in 5 days, followed by a full description in the

annual report, would not allow the agency to review the notices in a

timely fashion, as other comments asserted was critical to this

provision (see section II.G of this document).

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

15. Several comments objected that the proposed rule did not

contain any procedures or timeframes within which FDA would review and

respond to the notices. The comments stated that this omission was

unfair to manufacturers and would result in uncertainty that could lead

to the submission of more supplements by manufacturers who wanted

certainty that the data could be used in support of a premarket

application. It was also asserted that the proposed approach does not

serve the public health and recommended that the provision be revised

to include an appropriate timeframe within which the agency would

respond to the IDE sponsor if additional information to support the

change is needed. Comments suggested various time periods in which FDA

should respond to the notices, ranging from 5 days to 30 days.

FDA agrees, in part, with the comments. Upon reconsideration, the

agency agrees that procedures should be identified for the review of

the IDE notices. FDA intends to review the notices in the same

timeframe and manner in which it has customarily reviewed other IDE

submissions of this type, i.e, progress/annual reports. In keeping with

its practice for other submissions of this type, the agency will only

notify the sponsor if questions arise or additional information is

needed.

FDA disagrees that a specific timeframe for review, such as a 5 or

10-day period, should be established in the final rule. The statute

does not require that FDA conduct its review of the notices within a

specific period of time. As stated previously, the agency will make

every effort to review the notices in the same timeframe and manner as

it does other IDE submissions. FDA believes that with the majority of

the notices, it will be readily apparent whether the notice meets the

applicable criteria. In those instances in which questions arise, the

agency will address the issue as expeditiously as possible, thereby

ensuring the protection of public health.

It should be noted that FDA reserves the right to request

additional information if, during the course of the investigation,

information becomes available (e.g., adverse events) that would cause

the agency to question whether the change(s) made in accordance with

Sec. 812.35(a)(3)(i) or (a)(3)(ii) met the applicable criteria. FDA

would normally only take such action if the agency believes that the

modification to the device, manufacturing process, or protocol could

jeopardize patient safety, the scientific soundness of the

investigation, or the validity of the data resulting from the trial.

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

16. One comment stated that proposed Sec. 812.35(a)(4) was

difficult to understand and suggested that it be rewritten to express

in the regulation the preamble's discussion of annual report

requirements.

FDA agrees, in part, with the comment. The agency agrees that this

section of the regulation could be simplified and has revised

Sec. 812.35(a)(4) in the final rule to more clearly indicate the types

of changes to the investigational plan that are suitable for submission

in an annual report. The agency disagrees, however, that the regulation

should include all of the text from the preamble of the proposed rule.

The discussion from the preamble of the types of changes that would be

appropriate for submission in an annual report is too detailed to be

included in a regulation. Furthermore, this list was intended to be

illustrative rather than all inclusive; including it in the regulation

would be overly restrictive.

17. One comment noted that the proposed rule failed to include a

provision that would assure manufacturers that their data could be used

in support of a premarket application as suggested in the legislative

history. Specifically, the comment noted that the proposed rule did not

reference section 515(d)(B)(iii) of the act (21 U.S.C.

360e(d)(B)(iii)), and stated that the agency should modify the

regulation to state: ``FDA will accept and review all data and

information that are derived in accordance with this section in

determining whether to clear or approve a device for commercial

distribution.'' The comment maintains that this addition to the

regulation would clarify that FDA will accept and review the data if

the IDE sponsor determines that no new original or supplemental IDE

application was necessary prior to implementing the change.

FDA agrees that it will accept and review statistically valid and

reliable data and any other information from an investigation that is

conducted under section 520(g) of the act, provided that the data or

information meets the conditions prescribed in section 515(d)(B)(iii).

The comment suggests, however, that the decision about whether the

change meets the criteria of sections 515(d)(B)(iii) and 520(g)(6) of

the act rests solely with the IDE sponsor. FDA does not agree with this

premise. Although section 520(g)(6) of the act states that the sponsor

shall determine whether the device/manufacturing or protocol change

meets the criteria for submitting a notice for FDA review and

acceptance under this provision, the statute does not state that the

sponsor determines whether the data resulting from the clinical trial

meets the criteria for acceptance or review under section

515(d)(B)(iii) of the act. Consistent with FDA's decisions on all other

clearance and approval submissions, the final determination regarding

whether the application contains statistically valid and reliable

information, in accordance with these sections, rests with FDA.

III. Environmental Impact

The agency has determined under 21 CFR 25.30(h) that this action is

of a type that does not individually or cumulatively have a significant

effect on the human environment. Therefore, neither an environmental

assessment nor an environmental impact statement is required.

IV. Analysis of Impacts

FDA has examined the impact of this final rule under Executive

Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the

Unfunded Mandates Reform Act of 1995 (2 U.S.C. 1532). Executive Order

12866 directs agencies to assess all costs of available regulatory

alternatives and, when regulation is necessary, to select regulatory

approaches that maximize net benefits (including potential economic,

environmental, public health and safety, and other advantages;

distributive impacts; and equity). Unless the head of the agency

certifies that the rule would not have a significant economic impact on

a substantial number of small entities, the Regulatory Flexibility Act

[[Page 64623]]

requires agencies to analyze regulatory options that would minimize any

significant impact of a rule on small entities. The Unfunded Mandates

Reform Act requires that agencies prepare a written assessment of

anticipated costs and benefits before proposing any rule that results

in an expenditure of $100 million or more by State, local, or tribal

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

The agency believes that this rule is consistent with the regulatory

philosophy and principles identified in the Executive Order, and these

two statutes.

FDAMA added new section 520(g)(6) of the act to permit certain

changes to a device, manufacturing processes, or clinical protocols

during the course of a clinical investigation without having to obtain

prior FDA approval of a new IDE or an IDE supplement. In addition to

specifying the types of changes to clinical studies allowed without

prior approval, section 520(g)(6) of the act provides that the sponsor

must provide notice within 5 days of making the change, and that the

agency define, by regulation, the term ``credible information'' that

the sponsor must use as a basis to decide that the types of changes

meet the criteria for implementation without prior FDA approval. This

final rule amends existing regulations to implement section 520(g)(6)

of the act.

Several comments objected that FDA underestimated the economic

effects of the proposed rule and that the proposed requirements were

unduly burdensome. These comments generally stated: (1) FDA

misinterpreted the statute by requiring 5-day reports for changes that

previously were reported in annual reports, thereby making the

reporting requirements more burdensome than those under the existing

regulation; (2) FDA created an unnecessary burden by requiring IRB

approval or DSMB concurrence as ``credible information'' for protocol

changes, and did not take into account in its analysis the costs of

requiring IRB approval or DSMB concurrence; (3) FDA created an

unnecessary burden by requiring solely design control information as

``credible information'' for design and manufacturing modifications to

a device; (4) FDA should allow 5-working days to mail the notice,

instead of 5-calendar days, and (5) the requirements for the contents

of a 5-day notice were unduly burdensome by requiring too much detail

in the description of the changes.

FDA has adopted most of the comments' suggestions on ways to reduce

regulatory burden and provide flexibility and believes that the

resulting final rule is significantly less burdensome and more flexible

than the proposed rule. The responses to the comments related to burden

are discussed in detail in both sections II and V of this document, but

are also described briefly in the following paragraphs.

FDA disagrees with the comment stating the 5-day notice provision

should only be used for changes that were previously filed as IDE

supplements. FDA believes that the statute clearly requires 5-day

notices for some changes that were filed previously as annual reports,

but does not believe that this presents any appreciable additional

burden on manufacturers. The evidence used to determine whether a

change may be made under an annual report or the 5-day notice provision

is the same, and in both cases, would need to be generated and

evaluated before the change is implemented. Moreover, the regulation

should reduce burden by clarifying to sponsors what types of changes

require prior approval, thereby eliminating the submission of

unnecessary IDE supplements.

FDA agrees with comments that stated there were less burdensome

ways of providing credible information for protocol changes than IRB

approval or DSMB concurrence. In response to these comments, the final

rule has removed IRB approval or DSMB concurrence as a basis for

credible information, and instead requires documentation such as peer

reviewed published literature, the recommendation of clinical

investigator(s), and/or a summary of the data gathered during the

clinical trial that supports the sponsor's determination that the

change does not affect the rights, safety, or welfare of the subjects.

These types of information are already generated and evaluated at the

time a sponsor changes a device protocol. Therefore, FDA's definition

in the final rule of credible information provides flexibility and

negligible additional burden in that it requires the submission of

already existing evidence.

FDA also agrees with comments that suggested allowing more

flexibility in the credible information required for design changes. In

response to comments, the final rule allows information, other than

information generated by design controls, to be used as a basis for

credible information to support a design change.

FDA also agrees with the suggestion to allow 5-working days to mail

the notice, instead of 5-calendar days. This will reduce burden by

allowing sponsors more time to submit the notice.

FDA does not agree with the comment that the contents of the notice

were unduly burdensome, and that most of the information should be

submitted subsequently in an annual report. The information that is in

the notice will have already been generated and evaluated at the time

of the change. There is no appreciable burden in submitting information

that is already on hand within a 5-day timeframe. Moreover, many

comments stated that it was important that FDA advise them, within a

short time of the change, if FDA did not believe that the data could be

used to support a premarket application. The comment that suggested

providing FDA with limited information in the notice would preclude FDA

from giving such timely advice.

FDA believes that the revisions in the final rule substantially

reduced the regulatory burden. The information that is now required by

the final rule as a basis for credible information is the type of

information that sponsors should have already generated and evaluated

to fulfill their previous reporting requirements under the existing IDE

and QS regulations. The only additional burden is the shortened

reporting timeframe. As discussed previously, this reporting timeframe

should present no appreciable burden because the contents of the

submission should have been generated and evaluated before a change is

made.

FDA estimates that it will receive 300 5-day reports annually, and

that 200 to 300 manufacturers will submit these notices annually. FDA

believes that this rule will affect a substantial number of small

entities. For the reasons stated previously, however, FDA does not

believe that this rule will have a significant impact on a substantial

number of small entities. FDA believes that there will be some small

additional cost associated with mailing, and training the persons

responsible for submissions about the requirements of this rule. FDA

believes that training the responsible employees will only take a few

hours, and that additional mailing costs are minimal.

Accordingly, the agency certifies that this rule will not have a

significant economic impact on a substantial number of small entities.

Additionally, this rule does not trigger the requirement for a written

statement under section 202(a) of the Unfunded Mandates Reform Act

because it does not impose a mandate that results in an expenditure of

$100 million or more by State, local, or tribal governments in the

[[Page 64624]]

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

V. Paperwork Reduction Act of 1995

This rule contains information collection provisions which are

subject to review by OMB under the Paperwork Reduction Act of 1995 (the

PRA) (44 U.S.C. 3501-3520). The title, description and respondent

description of the information collection provisions are shown below

with an estimate of the annual reporting burden. Included in the

estimate is the time for reviewing instructions, searching existing

data sources, gathering and maintaining the data needed, and completing

and reviewing each collection of information.

Title: Medical Devices; Investigational Device Exemptions;

Supplemental Applications.

Description: Section 201 of FDAMA amended the act by adding new

section 520(g)(6) to the act, which permits a sponsor, based on

``credible information,'' as defined by the Secretary, to implement

certain changes to an investigational device or to a clinical protocol

without prior approval of an IDE supplement if the modifications meet

certain criteria and if notice is provided to FDA within 5-working days

of making the change. In order to implement this provision, FDA is

amending Sec. 812.35(a) to describe which types of changes may be made

without prior approval and to describe the credible information to be

included in a notice to FDA under this provision.

For developmental or manufacturing changes, sponsors would be

required to submit credible information that consists of a summary of

the information generated from the design control procedures under

Sec. 820.30, preclinical/animal testing, peer reviewed published

literature, or other reliable information such as clinical information

gathered during the trial or from marketing. For a protocol change, the

sponsor must submit credible information that consists of documentation

such as peer reviewed published literature, the recommendation of the

clinical investigator(s), and/or a summary of the data gathered during

the clinical trial which supports the sponsor's determination that the

change does not affect the rights, safety, or welfare of the subjects.

FDA will review the notices to determine whether they meet the criteria

of section 520(g)(6) of the act or whether additional action is

necessary to assure the protection of the public health.

Description of Respondents: Businesses or other for profit

organizations.

FDA notes that it receives approximately 3,000 supplements annually

for changes to IDE's. As discussed in the Analysis of Impacts in

section IV of this document, FDA anticipates that it will receive

approximately 300 5-day reports annually. In accordance with the

statute, which requires that this rule's procedures be established 1

year from the date of enactment of FDAMA, FDA is requiring that all

changes in investigational studies, including ongoing studies, that

meet the criteria described in this rule, be reported in 5-day notices

if those changes are implemented on or after the effective date of this

rule.

FDA published the proposed rule (63 FR 38131), submitted the

information collection requirements in the proposed rule to the Office

of Management and Budget (OMB) for review, and invited interested

persons to submit comments on the information collection requirements

to OMB. Most comments discussed have an impact, directly or indirectly,

on the information collection requirements. FDA has responded to these

comments in detail in section II of this document.

Several comments stated that 5-day notices should be submitted only

for changes that had been submitted previously in IDE supplements.

These comments stated that the requirement of 5-day notices was more

burdensome if it was required for changes that had been submitted

previously as annual reports.

For the reasons described more fully earlier in this preamble, FDA

believes that the language in section 520(g)(6) of the act clearly

requires that certain changes that previously were submitted as annual

reports now be submitted as 5-day notices. Nonetheless, FDA believes

that the final regulation will reduce burden on industry in two ways.

First, section 520(g) of the act makes mandatory, FDA's previous

practice of allowing certain changes to be implemented by notification

to FDA in an annual report. Second, this regulation provides

clarification on the types of changes that could be implemented without

prior agency approval, thus eliminating the submission of IDE

supplements that are not needed.

Finally, FDA believes that the submission of a 5-day report for

certain changes that previously were submitted in annual reports will

not impose any appreciable additional burden on industry because both

the evidence used to determine whether a change may be made under an

annual report and a 5-day notice provision is the same, and would need

to be generated and evaluated before the change is implemented.

Accordingly, a requirement to send information that is available before

the change is made within 5 days of the change, as opposed to a later

time after the change, is not an appreciable additional burden.

Several comments stated that the proposed definitions of credible

information necessary to support a 5-day notice were unduly burdensome.

For design changes, the proposed rule stated that credible information

would consist of information generated by design controls. For protocol

changes, the proposed rule stated that credible information would

consist of approval of an IRB, concurrence of a DSMB, or peer reviewed

literature.

Many comments objected to the concurrence of IRB's and DSMB's as

credible information because they stated that third party review for

changes that previously had not required such review was burdensome.

Some of the reasons specifically stated that FDA had not adequately

considered the costs to sponsors to obtain this type of review.

In response to these comments, the final rule has eliminated the

requirement for IRB approval or DSMB concurrence as evidence of

credible information, and instead requires documentation such as peer

reviewed published literature, the recommendation of clinical

investigator(s), and/or a summary of the data gathered during the

clinical trial that supports the sponsor's determination that the

change does not affect the rights, safety, or welfare of the subjects.

At the time a sponsor changes a device protocol, this type of evidence

is already generated and evaluated. Therefore, FDA's definition of

credible information in the final rule provides flexibility and

negligible additional burden in that it requires the submission of

already existing evidence.

Other comments objected to the lack of flexibility in the

requirement for credible evidence for design changes. These comments

supported the proposal to use information generated by design controls,

but stated that FDA should also allow other information. FDA has

addressed these concerns in the final rule by allowing other

information to be used as a basis for credible information to support a

design change.

Some comments requested that FDA allow more time for the submission

of reports by allowing reports to be made within 5-working days of the

change instead of 5-calendar days. FDA has

[[Page 64625]]

stated in the preamble to this final rule that 5-working days from the

change is the appropriate timeframe for submissions. This policy should

allow sponsors to reduce costs by allowing them additional time to

prepare notices.

One comment suggested that the requirements for the contents of a

5-day notice were unduly burdensome in that the statute required a

notice and not a detailed description of the changes. The comment

further suggested that FDA should require only a notice of the change

while the detailed description would be reported in the annual report.

As discussed more fully earlier in the preamble of this document,

FDA does not agree with this comment. As modified in the final rule,

the information submitted to the agency in the 5-day notice is the same

information that the sponsor would have submitted in the annual report,

and therefore, should not represent an increased burden. Moreover, the

submission of less information would not allow FDA to notify sponsors

that changes require a full supplement until the time of the annual

report, and therefore may result in sponsors wasting resources

gathering data that ultimately may not be used to support a premarket

application.

One comment stated that FDA's estimate of IDE changes that would be

submitted each year was underestimated. This comment stated that there

were 297 original IDE's filed in 1997 and it was conceivable that as

many as 10 changes for each of these original IDE's could occur per

year. Based on these figures, the comment stated the estimate should be

2,900 responses, instead of 300 responses stated in the proposed rule.

FDA does not agree with these estimates. FDA receives approximately

three supplemental filings per original submission per year. One of

these submissions should always be an annual progress report. Only a

small subset of the two remaining submissions, which FDA estimates as

300 for reasons described herein, would be types of changes reported in

5-day notices.

One comment stated that the annual reporting burden in the proposed

rule did not take into consideration ongoing studies. FDA did take such

ongoing studies into account in arriving at the estimates reported.

FDA estimates the burden for this collection of information as

follows:

Table 1.--Estimated Annual Reporting Burden1

----------------------------------------------------------------------------------------------------------------

Annual

21 CFR Section No. of Frequency per Total Annual Hours per Total Hours

Respondents Response Responses Response

----------------------------------------------------------------------------------------------------------------

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

----------------------------------------------------------------------------------------------------------------

\1\ There are no capital costs or operating and maintenance costs associated with this collection of

information.

Based upon a review of IDE's submitted in recent years, FDA

estimates that approximately 300 notices of IDE changes will be

submitted each year. Of these IDE changes, FDA estimates that 100 of

these changes were previously submitted as supplements and 200 of these

changes would have been submitted in annual reports. Based upon

discussions with sponsors of IDE's and FDA's own experience in

reviewing these types of documents, FDA estimates that it will take

approximately 10 hours for a sponsor to prepare a notice of IDE change.

Although this was the estimate offered in the proposed rule, FDA

received comments indicating that the burden hours in the proposal were

underestimated. As a result of the changes made in this final rule, the

burden has decreased significantly. Thus, FDA believes that the

estimate of 10 hours per submission is now accurate. FDA therefore

estimates that the total annual burden for preparation of these notices

will be 3,000 hours.

The information collection provisions of this final rule have been

submitted to OMB for review.

Prior to the effective date of this final rule, FDA will publish a

document in the Federal Register announcing OMB's decision to approve,

modify, or disapprove the information collection provisions in this

final rule. An agency may not conduct or sponsor, and a person is not

required to respond to, a collection of information unless it displays

a currently valid OMB control number.

List of Subjects in 21 CFR Part 812

Health records, Medical devices, Medical research, Reporting and

recordkeeping requirements.

Therefore, under the Federal Food, Drug, and Cosmetic Act, and,

under authority delegated to the Commissioner of Food and Drugs, 21 CFR

part 812 is amended as follows:

PART 812--INVESTIGATIONAL DEVICE EXEMPTIONS

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

follows:

Authority: 21 U.S.C. 331, 351, 352, 353, 355, 357, 360, 360c-

360f, 360h-360j, 371, 372, 374, 379e, 381, 382, 383; 42 U.S.C. 216,

241, 262, 263b-263n.

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

follows:

Sec. 812.35 Supplemental applications.

(a) Changes in investigational plan--(1) Changes requiring prior

approval. Except as described in paragraphs (a)(2) through (a)(4) of

this section, a sponsor must obtain approval of a supplemental

application under Sec. 812.30(a), and IRB approval when appropriate

(see Secs. 56.110 and 56.111 of this chapter), prior to implementing a

change to an investigational plan. If a sponsor intends to conduct an

investigation that involves an exception to informed consent under

Sec. 50.24 of this chapter, the sponsor shall submit a separate

investigational device exemption (IDE) application in accordance with

Sec. 812.20(a).

(2) Changes effected for emergency use. The requirements of

paragraph (a)(1) of this section regarding FDA approval of a supplement

do not apply in the case of a deviation from the investigational plan

to protect the life or physical well-being of a subject in an

emergency. Such deviation shall be reported to FDA within 5-working

days after the sponsor learns of it (see Sec. 812.150(a)(4)).

(3) Changes effected with notice to FDA within 5 days. A sponsor

may make certain changes without prior approval of a supplemental

application under paragraph (a)(1) of this section if the sponsor

determines that these changes meet the criteria described in paragraphs

(a)(3)(i) and (a)(3)(ii) of this section, on the basis of credible

information defined in paragraph (a)(3)(iii) of this section, and the

sponsor provides notice to FDA within 5-working days of making these

changes.

(i) Developmental changes. The requirements in paragraph (a)(1) of

this section regarding FDA approval of a supplement do not apply to

developmental changes in the device (including manufacturing changes)

that do not constitute a significant change in

[[Page 64626]]

design or basic principles of operation and that are made in response

to information gathered during the course of an investigation.

(ii) Changes to clinical protocol. The requirements in paragraph

(a)(1) of this section regarding FDA approval of a supplement do not

apply to changes to clinical protocols that do not affect:

(A) The validity of the data or information resulting from the

completion of the approved protocol, or the relationship of likely

patient risk to benefit relied upon to approve the protocol;

(B) The scientific soundness of the investigational plan; or

(C) The rights, safety, or welfare of the human subjects involved

in the investigation.

(iii) Definition of credible information. (A) Credible information

to support developmental changes in the device (including manufacturing

changes) includes data generated under the design control procedures of

Sec. 820.30, preclinical/animal testing, peer reviewed published

literature, or other reliable information such as clinical information

gathered during a trial or marketing.

(B) Credible information to support changes to clinical protocols

is defined as the sponsor's documentation supporting the conclusion

that a change does not have a significant impact on the study design or

planned statistical analysis, and that the change does not affect the

rights, safety, or welfare of the subjects. Documentation shall include

information such as peer reviewed published literature, the

recommendation of the clinical investigator(s), and/or the data

gathered during the clinical trial or marketing.

(iv) Notice of IDE change. Changes meeting the criteria in

paragraphs (a)(3)(i) and (a)(3)(ii) of this section that are supported

by credible information as defined in paragraph (a)(3)(iii) of this

section may be made without prior FDA approval if the sponsor submits a

notice of the change to the IDE not later than 5-working days after

making the change. Changes to devices are deemed to occur on the date

the device, manufactured incorporating the design or manufacturing

change, is distributed to the investigator(s). Changes to a clinical

protocol are deemed to occur when a clinical investigator is notified

by the sponsor that the change should be implemented in the protocol

or, for sponsor-investigator studies, when a sponsor-investigator

incorporates the change in the protocol. Such notices shall be

identified as a ``notice of IDE change.''

(A) For a developmental or manufacturing change to the device, the

notice shall include a summary of the relevant information gathered

during the course of the investigation upon which the change was based;

a description of the change to the device or manufacturing process

(cross-referenced to the appropriate sections of the original device

description or manufacturing process); and, if design controls were

used to assess the change, a statement that no new risks were

identified by appropriate risk analysis and that the verification and

validation testing, as appropriate, demonstrated that the design

outputs met the design input requirements. If another method of

assessment was used, the notice shall include a summary of the

information which served as the credible information supporting the

change.

(B) For a protocol change, the notice shall include a description

of the change (cross-referenced to the appropriate sections of the

original protocol); an assessment supporting the conclusion that the

change does not have a significant impact on the study design or

planned statistical analysis; and a summary of the information that

served as the credible information supporting the sponsor's

determination that the change does not affect the rights, safety, or

welfare of the subjects.

(4) Changes submitted in annual report. The requirements of

paragraph (a)(1) of this section do not apply to minor changes to the

purpose of the study, risk analysis, monitoring procedures, labeling,

informed consent materials, and IRB information that do not affect:

(i) The validity of the data or information resulting from the

completion of the approved protocol, or the relationship of likely

patient risk to benefit relied upon to approve the protocol;

(ii) The scientific soundness of the investigational plan; or

(iii) The rights, safety, or welfare of the human subjects involved

in the investigation. Such changes shall be reported in the annual

progress report for the IDE, under Sec. 812.150(b)(5).

* * * * *

Dated: October 27, 1998.

William B. Schultz,

Deputy Commissioner for Policy.

[FR Doc. 98-31245 Filed 11-20-98; 8:45 am]

BILLING CODE 4160-01-F