[Code of Federal Regulations]

[Title 21, Volume 8]

[Revised as of April 1, 2006]

From the U.S. Government Printing Office via GPO Access

[CITE: 21CFR812.35]



[Page 105-107]

 

                        TITLE 21--FOOD AND DRUGS

 

CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN 

                          SERVICES (CONTINUED)

 

PART 812_INVESTIGATIONAL DEVICE EXEMPTIONS--Table of Contents

 

             Subpart B_Application and Administrative Action

 

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 Sec. Sec.  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



[[Page 106]]



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.

    (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;



[[Page 107]]



    (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).

    (b) IRB approval for new facilities. A sponsor shall submit to FDA a 

certification of any IRB approval of an investigation or a part of an 

investigation not included in the IDE application. If the investigation 

is otherwise unchanged, the supplemental application shall consist of an 

updating of the information required by Sec.  812.20(b) and (c) and a 

description of any modifications in the investigational plan required by 

the IRB as a condition of approval. A certification of IRB approval need 

not be included in the initial submission of the supplemental 

application, and such certification is not a precondition for agency 

consideration of the application. Nevertheless, a sponsor may not begin 

a part of an investigation at a facility until the IRB has approved the 

investigation, FDA has received the certification of IRB approval, and 

FDA, under Sec.  812.30(a), has approved the supplemental application 

relating to that part of the investigation (see Sec.  56.103(a)).



[50 FR 25909, June 24, 1985; 50 FR 28932, July 17, 1985, as amended at 

61 FR 51531, Oct. 2, 1996; 63 FR 64625, Nov. 23, 1998]