|[Code of Federal Regulations]|
|[Title 21, Volume 8]|
|[Revised as of April 1, 2016]|
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION
DEPARTMENT OF HEALTH AND HUMAN SERVICES
SUBCHAPTER H--MEDICAL DEVICES
|PART 812||INVESTIGATIONAL DEVICE EXEMPTIONS
Subpart B--Application and Administrative Action
(a) Submission. (1) A sponsor shall submit an application to FDA if the sponsor intends to use a significant risk device in an investigation, intends to conduct an investigation that involves an exception from informed consent under 50.24 of this chapter, or if FDA notifies the sponsor that an application is required for an investigation.
(2) A sponsor shall not begin an investigation for which FDA's approval of an application is required until FDA has approved the application.
(3) A sponsor shall submit three copies of a signed "Application for an Investigational Device Exemption" (IDE application), together with accompanying materials, by registered mail or by hand to the address in 812.19. Subsequent correspondence concerning an application or a supplemental application shall be submitted by registered mail or by hand.
(4)(i) A sponsor shall submit a separate IDE for any clinical investigation involving an exception from informed consent under 50.24 of this chapter. Such a clinical investigation is not permitted to proceed without the prior written authorization of FDA. FDA shall provide a written determination 30 days after FDA receives the IDE or earlier.
(ii) If the investigation involves an exception from informed consent under 50.24 of this chapter, the sponsor shall prominently identify on the cover sheet that the investigation is subject to the requirements in 50.24 of this chapter.
(b) Contents. An IDE application shall include, in the following order:
(1) The name and address of the sponsor.
(2) A complete report of prior investigations of the device and an accurate summary of those sections of the investigational plan described in 812.25(a) through (e) or, in lieu of the summary, the complete plan. The sponsor shall submit to FDA a complete investigational plan and a complete report of prior investigations of the device if no IRB has reviewed them, if FDA has found an IRB's review inadequate, or if FDA requests them.
(3) A description of the methods, facilities, and controls used for the manufacture, processing, packing, storage, and, where appropriate, installation of the device, in sufficient detail so that a person generally familiar with good manufacturing practices can make a knowledgeable judgment about the quality control used in the manufacture of the device.
(4) An example of the agreements to be entered into by all investigators to comply with investigator obligations under this part, and a list of the names and addresses of all investigators who have signed the agreement.
(5) A certification that all investigators who will participate in the investigation have signed the agreement, that the list of investigators includes all the investigators participating in the investigation, and that no investigators will be added to the investigation until they have signed the agreement.
(6) A list of the name, address, and chairperson of each IRB that has been or will be asked to review the investigation and a certification of the action concerning the investigation taken by each such IRB.
(7) The name and address of any institution at which a part of the investigation may be conducted that has not been identified in accordance with paragraph (b)(6) of this section.
(8) If the device is to be sold, the amount to be charged and an explanation of why sale does not constitute commercialization of the device.
(9) A claim for categorical exclusion under 25.30 or 25.34 or an environmental assessment under 25.40.
(10) Copies of all labeling for the device.
(11) Copies of all forms and informational materials to be provided to subjects to obtain informed consent.
(12) Any other relevant information FDA requests for review of the application.
(c) Additional information. FDA may request additional information concerning an investigation or revision in the investigational plan. The sponsor may treat such a request as a disapproval of the application for purposes of requesting a hearing under part 16.
(d) Information previously submitted. Information previously submitted to the Center for Devices and Radiological Health, the Center for Biologics Evaluation and Research, or the Center for Drug Evaluation and Research, as applicable, in accordance with this chapter ordinarily need not be resubmitted, but may be incorporated by reference.
Sec. 812.25 Investigational plan.
The investigational plan shall include, in the following order:
(a) Purpose. The name and intended use of the device and the objectives and duration of the investigation.
(b) Protocol. A written protocol describing the methodology to be used and an analysis of the protocol demonstrating that the investigation is scientifically sound.
(c) Risk analysis. A description and analysis of all increased risks to which subjects will be exposed by the investigation; the manner in which these risks will be minimized; a justification for the investigation; and a description of the patient population, including the number, age, sex, and condition.
(d) Description of device. A description of each important component, ingredient, property, and principle of operation of the device and of each anticipated change in the device during the course of the investigation.
(e) Monitoring procedures. The sponsor's written procedures for monitoring the investigation and the name and address of any monitor.
(f) Labeling. Copies of all labeling for the device.
(g) Consent materials. Copies of all forms and informational materials to be provided to subjects to obtain informed consent.
(h) IRB information. A list of the names, locations, and chairpersons of all IRB's that have been or will be asked to review the investigation, and a certification of any action taken by any of those IRB's with respect to the investigation.
(i) Other institutions. The name and address of each institution at which a part of the investigation may be conducted that has not been identified in paragraph (h) of this section.
(j) Additional records and reports. A description of records and reports that will be maintained on the investigation in addition to those prescribed in subpart G.
Sec. 812.27 Report of prior investigations.
(a) General. The report of prior investigations shall include reports of all prior clinical, animal, and laboratory testing of the device and shall be comprehensive and adequate to justify the proposed investigation.
(b) Specific contents. The report also shall include:
(1) A bibliography of all publications, whether adverse or supportive, that are relevant to an evaluation of the safety or effectiveness of the device, copies of all published and unpublished adverse information, and, if requested by an IRB or FDA, copies of other significant publications.
(2) A summary of all other unpublished information (whether adverse or supportive) in the possession of, or reasonably obtainable by, the sponsor that is relevant to an evaluation of the safety or effectiveness of the device.
(3) If information on nonclinical laboratory studies is provided, a statement that all such studies have been conducted in compliance with applicable requirements in the good laboratory practice regulations in part 58, or if any such study was not conducted in compliance with such regulations, a brief statement of the reason for the noncompliance. Failure or inability to comply with this requirement does not justify failure to provide information on a relevant nonclinical test study.
Sec. 812.30 FDA action on applications.
(a) Approval or disapproval. FDA will notify the sponsor in writing of the date it receives an application. FDA may approve an investigation as proposed, approve it with modifications, or disapprove it. An investigation may not begin until:
(1) Thirty days after FDA receives the application at the address in 812.19 for the investigation of a device other than a banned device, unless FDA notifies the sponsor that the investigation may not begin; or
(2) FDA approves, by order, an IDE for the investigation.
(b) Grounds for disapproval or withdrawal. FDA may disapprove or withdraw approval of an application if FDA finds that:
(1) There has been a failure to comply with any requirement of this part or the act, any other applicable regulation or statute, or any condition of approval imposed by an IRB or FDA.
(2) The application or a report contains an untrue statement of a material fact, or omits material information required by this part.
(3) The sponsor fails to respond to a request for additional information within the time prescribed by FDA.
(4) There is reason to believe that the risks to the subjects are not outweighed by the anticipated benefits to the subjects and the importance of the knowledge to be gained, or informed consent is inadequate, or the investigation is scientifically unsound, or there is reason to believe that the device as used is ineffective.
(5) It is otherwise unreasonable to begin or to continue the investigation owing to the way in which the device is used or the inadequacy of:
(i) The report of prior investigations or the investigational plan;
(ii) The methods, facilities, and controls used for the manufacturing, processing, packaging, storage, and, where appropriate, installation of the device; or
(iii) Monitoring and review of the investigation.
(c) Notice of disapproval or withdrawal. If FDA disapproves an application or proposes to withdraw approval of an application, FDA will notify the sponsor in writing.
(1) A disapproval order will contain a complete statement of the reasons for disapproval and a statement that the sponsor has an opportunity to request a hearing under part 16.
(2) A notice of a proposed withdrawal of approval will contain a complete statement of the reasons for withdrawal and a statement that the sponsor has an opportunity to request a hearing under part 16. FDA will provide the opportunity for hearing before withdrawal of approval, unless FDA determines in the notice that continuation of testing under the exemption will result in an unreasonable risk to the public health and orders withdrawal of approval before any hearing.
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 812.30(a), and IRB approval when appropriate (see 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 50.24 of this chapter, the 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-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 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 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 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 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 812.30(a), has approved the supplemental application relating to that part of the investigation (see 56.103(a)).
Sec. 812.36 Treatment use of an investigational device.
(a) General. A device that is not approved for marketing may be under clinical investigation for a serious or immediately life-threatening disease or condition in patients for whom no comparable or satisfactory alternative device or other therapy is available. During the clinical trial or prior to final action on the marketing application, it may be appropriate to use the device in the treatment of patients not in the trial under the provisions of a treatment investigational device exemption (IDE). The purpose of this section is to facilitate the availability of promising new devices to desperately ill patients as early in the device development process as possible, before general marketing begins, and to obtain additional data on the device's safety and effectiveness. In the case of a serious disease, a device ordinarily may be made available for treatment use under this section after all clinical trials have been completed. In the case of an immediately life-threatening disease, a device may be made available for treatment use under this section prior to the completion of all clinical trials. For the purpose of this section, an "immediately life-threatening" disease means a stage of a disease in which there is a reasonable likelihood that death will occur within a matter of months or in which premature death is likely without early treatment. For purposes of this section, "treatment use"of a device includes the use of a device for diagnostic purposes.
(b) Criteria. FDA shall consider the use of an investigational device under a treatment IDE if:
(1) The device is intended to treat or diagnose a serious or immediately life-threatening disease or condition;
(2) There is no comparable or satisfactory alternative device or other therapy available to treat or diagnose that stage of the disease or condition in the intended patient population;
(3) The device is under investigation in a controlled clinical trial for the same use under an approved IDE, or such clinical trials have been completed; and
(4) The sponsor of the investigation is actively pursuing marketing approval/clearance of the investigational device with due diligence.
(c) Applications for treatment use. (1) A treatment IDE application shall include, in the following order:
(i) The name, address, and telephone number of the sponsor of the treatment IDE;
(ii) The intended use of the device, the criteria for patient selection, and a written protocol describing the treatment use;
(iii) An explanation of the rationale for use of the device, including, as appropriate, either a list of the available regimens that ordinarily should be tried before using the investigational device or an explanation of why the use of the investigational device is preferable to the use of available marketed treatments;
(iv) A description of clinical procedures, laboratory tests, or other measures that will be used to evaluate the effects of the device and to minimize risk;
(v) Written procedures for monitoring the treatment use and the name and address of the monitor;
(vi) Instructions for use for the device and all other labeling as required under 812.5(a) and (b);
(vii) Information that is relevant to the safety and effectiveness of the device for the intended treatment use. Information from other IDE's may be incorporated by reference to support the treatment use;
(viii) A statement of the sponsor's commitment to meet all applicable responsibilities under this part and part 56 of this chapter and to ensure compliance of all participating investigators with the informed consent requirements of part 50 of this chapter;
(ix) An example of the agreement to be signed by all investigators participating in the treatment IDE and certification that no investigator will be added to the treatment IDE before the agreement is signed; and
(x) If the device is to be sold, the price to be charged and a statement indicating that the price is based on manufacturing and handling costs only.
(2) A licensed practitioner who receives an investigational device for treatment use under a treatment IDE is an "investigator" under the IDE and is responsible for meeting all applicable investigator responsibilities under this part and parts 50 and 56 of this chapter.
(d) FDA action on treatment IDE applications --(1) Approval of treatment IDE's. Treatment use may begin 30 days after FDA receives the treatment IDE submission at the address specified in 812.19, unless FDA notifies the sponsor in writing earlier than the 30 days that the treatment use may or may not begin. FDA may approve the treatment use as proposed or approve it with modifications.
(2) Disapproval or withdrawal of approval of treatment IDE's. FDA may disapprove or withdraw approval of a treatment IDE if:
(i) The criteria specified in 812.36(b) are not met or the treatment IDE does not contain the information required in 812.36(c);
(ii) FDA determines that any of the grounds for disapproval or withdrawal of approval listed in 812.30(b)(1) through (b)(5) apply;
(iii) The device is intended for a serious disease or condition and there is insufficient evidence of safety and effectiveness to support such use;
(iv) The device is intended for an immediately life-threatening disease or condition and the available scientific evidence, taken as a whole, fails to provide a reasonable basis for concluding that the device:
(A) May be effective for its intended use in its intended population; or
(B) Would not expose the patients to whom the device is to be administered to an unreasonable and significant additional risk of illness or injury;
(v) There is reasonable evidence that the treatment use is impeding enrollment in, or otherwise interfering with the conduct or completion of, a controlled investigation of the same or another investigational device;
(vi) The device has received marketing approval/clearance or a comparable device or therapy becomes available to treat or diagnose the same indication in the same patient population for which the investigational device is being used;
(vii) The sponsor of the controlled clinical trial is not pursuing marketing approval/clearance with due diligence;
(viii) Approval of the IDE for the controlled clinical investigation of the device has been withdrawn; or
(ix) The clinical investigator(s) named in the treatment IDE are not qualified by reason of their scientific training and/or experience to use the investigational device for the intended treatment use.
(3) Notice of disapproval or withdrawal. If FDA disapproves or proposes to withdraw approval of a treatment IDE, FDA will follow the procedures set forth in 812.30(c).
(e) Safeguards. Treatment use of an investigational device is conditioned upon the sponsor and investigators complying with the safeguards of the IDE process and the regulations governing informed consent (part 50 of this chapter) and institutional review boards (part 56 of this chapter).
(f) Reporting requirements. The sponsor of a treatment IDE shall submit progress reports on a semi-annual basis to all reviewing IRB's and FDA until the filing of a marketing application. These reports shall be based on the period of time since initial approval of the treatment IDE and shall include the number of patients treated with the device under the treatment IDE, the names of the investigators participating in the treatment IDE, and a brief description of the sponsor's efforts to pursue marketing approval/clearance of the device. Upon filing of a marketing application, progress reports shall be submitted annually in accordance with 812.150(b)(5). The sponsor of a treatment IDE is responsible for submitting all other reports required under 812.150.
Sec. 812.38 Confidentiality of data and information.
(a) Existence of IDE. FDA will not disclose the existence of an IDE unless its existence has previously been publicly disclosed or acknowledged, until FDA approves an application for premarket approval of the device subject to the IDE; or a notice of completion of a product development protocol for the device has become effective.
(b) Availability of summaries or data. (1) FDA will make publicly available, upon request, a detailed summary of information concerning the safety and effectiveness of the device that was the basis for an order approving, disapproving, or withdrawing approval of an application for an IDE for a banned device. The summary shall include information on any adverse effect on health caused by the device.
(2) If a device is a banned device or if the existence of an IDE has been publicly disclosed or acknowledged, data or information contained in the file is not available for public disclosure before approval of an application for premarket approval or the effective date of a notice of completion of a product development protocol except as provided in this section. FDA may, in its discretion, disclose a summary of selected portions of the safety and effectiveness data, that is, clinical, animal, or laboratory studies and tests of the device, for public consideration of a specific pending issue.
(3) If the existence of an IDE file has not been publicly disclosed or acknowledged, no data or information in the file are available for public disclosure except as provided in paragraphs (b)(1) and (c) of this section.
(4) Notwithstanding paragraph (b)(2) of this section, FDA will make available to the public, upon request, the information in the IDE that was required to be filed in Docket Number 95S-0158 in the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852, for investigations involving an exception from informed consent under 50.24 of this chapter. Persons wishing to request this information shall submit a request under the Freedom of Information Act.
(c) Reports of adverse effects. Upon request or on its own initiative, FDA shall disclose to an individual on whom an investigational device has been used a copy of a report of adverse device effects relating to that use.
(d) Other rules. Except as otherwise provided in this section, the availability for public disclosure of data and information in an IDE file shall be handled in accordance with 814.9.
Authority: 21 U.S.C. 331, 351, 352, 353, 355, 360, 360c-360f, 360h-360j, 371, 372, 374, 379e, 381, 382, 383; 42 U.S.C. 216, 241, 262, 263b-263n.
Source: 45 FR 3751, Jan. 18, 1980, unless otherwise noted.