[Federal Register Volume 61, Number 245 (Thursday, December 19, 1996)]
[Proposed Rules]
[Pages 66954-66961]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-32186]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES
21 CFR Part 812

[Docket No. 96N-0299]


Investigational Device Exemptions; Treatment Use

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing procedures 
to allow for the treatment use of investigational devices. These 
procedures are intended to facilitate the availability of promising new 
therapeutic and diagnostic devices to desperately ill patients as early 
in the device development process as possible, i.e., before general 
marketing begins, and to obtain additional data on the device's safety 
and effectiveness. These procedures would apply to patients with 
serious or immediately life-threatening diseases or conditions for 
which no comparable or satisfactory alternative device, drug, or other 
therapy exists.

DATES: Submit written comments by March 19, 1997. Written comments on 
the information collection requirements should be submitted by January 
21, 1997. FDA proposes that any final rule that may issue based on this 
proposal become effective 30 days after date of publication of the 
final rule.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, 
Rockville, MD 20857. Submit written comments on the information 
collection requirements to the Office of Information and Regulatory 
Affairs, OMB, New Executive Office Bldg., 725 17th St. NW., rm. 10235, 
Washington, DC 20503, Attn: Desk Officer for FDA.

FOR FURTHER INFORMATION CONTACT: Joanne R. Less, Office of Device 
Evaluation (HFZ-403), Center for Devices and Radiological Health, Food 
and Drug Administration, 9200 Corporate Blvd., Rockville, MD 20850, 
301-594-1190.

SUPPLEMENTARY INFORMATION: 

I. Background

    In the Federal Register of May 22, 1987 (52 FR 19466), FDA 
published a final rule that codified procedures authorizing the 
treatment use of investigational new drugs (IND's) (hereinafter 
referred to as the treatment IND regulation). In publishing the 
treatment IND regulation, FDA was responding to an increased demand 
from patients as well as from health professionals to permit broader 
availability of investigational drugs to treat serious diseases for 
which there were no satisfactory alternative treatments. For similar 
reasons, FDA is now proposing to amend its Investigational Device 
Exemption (IDE) regulations (part 812 (21 CFR part 812)). With minor 
exceptions, the proposed rule parallels the regulation for treatment 
use of investigational new drugs and extends those provisions to cover 
the treatment use of investigational devices, including diagnostic 
devices. The proposed rule is intended to facilitate the availability 
of promising new devices to patients as early in the device development 
process as possible while safeguarding against commercialization of the 
devices and ensuring the integrity of controlled clinical trials.

II. Summary of the Proposed Rule

    The proposed rule amends part 812 by adding proposed Sec. 812.36, 
which parallels the IND treatment use provisions contained in 21 CFR 
312.34 and 312.35. The proposed rule consists of the following 
provisions.

A. Purpose

    Proposed Sec. 812.36(a) provides for the treatment use of 
investigational devices in order 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.

B. Criteria

    Proposed Sec. 812.36(b) specifies that treatment use of an 
investigational device would only be considered when the following 
criteria are satisfied: (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 under an approved IDE, or 
all clinical trials have been completed; and (4) the sponsor of the 
controlled clinical trial is pursuing marketing approval/clearance of 
the

[[Page 66955]]

investigational device with due diligence.
    An example of approved devices which would have met the proposed 
treatment IDE criteria are nonthoracotomy (transvenous) defibrillation 
leads. These leads would have met the proposed criteria because: (1) 
They are intended to treat immediately life-threatening conditions; 
i.e., sudden cardiac death and ventricular tachyarrhythmia; (2) there 
were no comparable or satisfactory alternative devices (no other leads 
could be placed in the patient without opening the chest cavity); (3) 
the devices were under investigation under controlled clinical trials 
under approved IDE's; and (4) the sponsors of the controlled clinical 
trials pursued marketing approval of the leads with due diligence.
1. Definitions
    Proposed Sec. 812.36(a) defines an ``immediately life-threatening 
disease or condition'' as a stage of a disease or condition 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. Generally, an immediately life-threatening illness or 
condition is one that poses a significant threat that the patient will 
die from the illness or condition unless the course of the disease is 
promptly altered to reduce that possibility.
    As in the treatment IND regulation, this definition does not mean 
that a clinician would have to make a prognosis with exact precision, 
but is meant only to provide a general yardstick for decisionmaking 
purposes (for example, a reasonable expectation of death within 6 
months). (See 52 FR 19466 at 19467.) FDA recognizes that the medical 
judgment of the treating physician must carry considerable weight in 
deciding whether an illness poses a sufficient threat to justify 
treating patients with a device for which safety or effectiveness has 
not yet been fully demonstrated. FDA's statutory responsibility with 
regard to investigational devices, however, necessitates that it retain 
authority to review the appropriateness of treatment use and to ensure 
that such use does not constitute commercialization of the 
investigational device. Therefore, FDA will apply a common sense 
interpretation of the term ``immediately life-threatening,'' in that 
the agency would not normally consider death within more than a year to 
be immediately life-threatening, but would consider death within 
several days or several weeks to be an overly restrictive 
interpretation of the term. (Id.)
    The phrase ``or in which premature death is likely without early 
treatment'' is intended to describe those fatal illnesses or conditions 
where death itself may not be imminent but where immediate treatment is 
necessary to prevent premature death. For example, a ventricular septal 
defect can lead to overloading of the right ventricle, failure of the 
left ventricle, and ultimately result in myocardial infarction (heart 
attack). Use of a septal closure device would help to prevent this 
progression of events and could quality, therefore, for treatment IDE 
use.
    The stage of a disease or condition is important in determining 
whether it should be considered immediately life-threatening, serious, 
or not serious within the context of this treatment IDE regulation. For 
diseases such as multiple sclerosis, where some stages of the disease 
would not be considered serious, the regulation would not be applicable 
to those stages. In approving a treatment IDE, FDA will seek to define 
the intended patient population and, in medically appropriate cases, 
will limit treatment use to particular stages of a disease or condition 
or to patients with a particular set of symptoms.
    To illustrate these categories further, the following diseases or 
conditions or stages of diseases would normally be considered to be 
immediately life-threatening: (1) Certain cardiac arrhythmias; (2) 
arteriovenous malformations; and (3) intracranial aneurysms.
    In addition, the following would normally be considered serious 
diseases or conditions or serious stages of diseases: (1) Early stages 
of breast cancer; (2) proliferative vitreoretinopathy; and (3) advanced 
Parkinson's disease.
    FDA recognizes that these are illustrative and not complete lists. 
The agency solicits suggestions for additional diseases or conditions 
that would provide greater breadth to these illustrative lists.
2. No Comparable or Satisfactory Alternative Device or Other Therapy
    Similar to the treatment IND regulation, the absence of an 
alternative therapy is proposed as a prerequisite to granting a 
treatment IDE because one of the major principles underlying the 
proposed treatment IDE policy is that these devices would be necessary 
to fill an existing gap in the medical therapies available. (See 52 FR 
19466 at 19468.) FDA recognizes that there should be flexibility in 
applying this concept so as to best serve desperately ill patients. The 
fact that the disease in question has existing approved therapies does 
not mean that the approved treatments are satisfactory for all 
patients. FDA will not be unduly restrictive in interpreting this 
criterion. FDA would view the criterion of no comparable or 
satisfactory alternative therapy as being met when there are patients 
who are not adequately treated by available therapies, even if the 
particular disease does respond in some cases to available therapy. 
This criterion would be met, for example, if the intended population is 
patients who have failed on an existing therapy (i.e., the existing 
therapy did not provide its intended therapeutic benefit or did not 
fully treat the condition); patients who could not tolerate the 
existing therapy (i.e., it caused unacceptable adverse effects); or 
patients who had other complicating diseases that made the existing 
therapy unacceptable (e.g., concomitant disease that makes available 
therapy contraindicated). The key is that the device proposed for 
treatment use addresses an unmet medical need in a defined patient 
population.
3. The Device is Under Investigation in a Controlled Clinical Trial 
Under an Approved IDE or All Clinical Trials Have Been Completed
    To ensure that progress is being made towards a marketing 
application, FDA will only permit treatment use of an investigational 
device if the device is being studied or has been studied in a 
controlled clinical trial for the same use under an approved IDE. As in 
the treatment IND regulation, FDA expects that clinical studies will be 
of the kind that can reasonably be expected to provide data acceptable 
to FDA in determining the safety and effectiveness of the 
investigational device for its intended use. (See 52 FR 19466 at 
19470.) Therefore, the agency would interpret the proposed regulation 
to mean that the controlled trial that serves as the underpinning for 
the treatment IDE must be sufficiently well-designed to provide such 
data. The agency anticipates that the controlled clinical trial would 
often be a concurrently controlled trial but recognizes other trial 
designs may be equally appropriate to establish safety and 
effectiveness. In a recent analysis of IDE approvals, the agency found 
more than 40 percent of the key clinical trials used historically 
controlled or self controlled designs. Thus, the term ``controlled 
clinical trial'' is intended to incorporate a number of different trial 
designs, rather than to specify any one particular design.

[[Page 66956]]

4. The Sponsor of the Controlled Clinical Trial is Pursuing Marketing 
Approval of the Investigational Device With Due Diligence
    The term ``due diligence'' is intended to refer to an applicant's 
good faith effort to seek timely and expeditious marketing approval 
through actions intended to advance the progress of the clinical study 
or the subsequent marketing application. Pursuing marketing approval 
with due diligence is necessary as a precaution against the artificial 
prolonging of the investigational status of a device. In deciding 
whether a sponsor is pursuing marketing approval with due diligence, 
FDA will take into consideration all relevant factors. For example, 
full enrollment and monitoring of ongoing clinical trials(s); 
compliance with all IDE obligations, especially adverse reaction and 
annual reporting requirements; preparation and filing of a marketing 
application; and moving into compliance with FDA's Current Good 
Manufacturing Practices (CGMP's) would be considered as evidence of a 
sponsor's due diligence to pursue marketing approval.

C. Interpretation of Treatment IDE Criteria

    FDA intends to interpret the above proposed criteria for treatment 
use of investigational devices in the same way FDA's Center for Devices 
and Radiological Health (CDRH) applies the criteria for expedited 
review of premarket approval applications, with which CDRH has 
considerable experience. FDA expects that most requests for treatment 
use would meet the criteria for expedited review, i.e., the device: (1) 
Is intended for a life-threatening or irreversibly debilitating 
condition for which there is no alternative therapy or for which the 
device provides a significant advance in safety and effectiveness over 
the existing alternatives; or (2) meets a specific public health need.
    In addition, however, regardless of whether the device is intended 
to treat an immediately life-threatening or serious disease or 
condition, such devices may be considered for distribution under a 
treatment IDE only when there is promising evidence of safety and 
effectiveness, i.e., relatively late in the IDE process. Therefore, 
information that is relevant to the safety and effectiveness of the 
device for the intended treatment use that is available to a sponsor at 
the time a treatment use is requested should be submitted to the agency 
for review. The evidence should include relevant data gathered under 
the controlled clinical trial, as well as other supporting information 
the sponsor may have.
    The criteria in this proposed rule are independent of, and should 
not be confused with or substituted for, the criteria to categorize IDE 
devices for Medicare coverage purposes. (See 60 FR 48417 at 48425, 
September 19, 1995.) For Medicare coverage purposes, IDE's are 
designated as either Category A (Experimental) or Category B 
(Nonexperimental/Investigational). Accordingly, Category A devices, 
even if given treatment IDE status, would continue to be categorized as 
experimental, and Category B devices would be considered to be 
nonexperimental only when used within the context of an approved 
clinical trial protocol.

D. Applications for Treatment Use

    As in the treatment IND regulation, the proposed requirements for 
applications for treatment use would be minimal, but must be consistent 
with patient safety and proper use. (See 48 FR 26720 at 26729.) Each 
application would include, among other things, an explanation of the 
rationale for the use of the device; the criteria for patient 
selection; a description of clinical procedures, laboratory tests, or 
other measures to be used to monitor the effects of the device and to 
minimize risk; written procedures for monitoring the treatment use; 
information that is relevant to the safety and effectiveness of the 
device for the intended treatment use; and a written protocol 
describing the treatment use. The protocol should be written by the 
device firm supplying the device, with input from the clinical 
community and FDA as necessary to aid patient safety and proper use.
    The agency recognizes that most of the information needed for a 
treatment IDE should already be available in the sponsor's IDE. 
Therefore, the additional supporting information to be submitted by the 
sponsor of the treatment IDE should focus on the safety and 
effectiveness of the device for the proposed treatment use. 
Applications for treatment use of an investigational device should be 
clearly identified as a ``Treatment IDE.''

E. FDA Action on Treatment IDE Applications

1. Approval of Treatment IDE's
    Similar to the treatment IND regulations, proposed 
Sec. 812.36(d)(1) provides that treatment use may begin 30 days after 
FDA receives the treatment IDE submission, 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
    Under proposed Sec. 812.36(d)(2)(i), FDA would have the authority 
to disapprove a treatment IDE if the threshold criteria proposed in 
Sec. 812.36(b) are not met or the treatment IDE is incomplete, i.e., 
does not contain all the information proposed in Sec. 812.36(c). FDA 
may also disapprove or withdraw approval of a treatment IDE if any of 
the grounds for disapproval or withdrawal of approval listed in 
Sec. 812.30(b)(1) through (b)(5) apply.
    Two additional proposed reasons for disapproval or withdrawal of 
approval of a treatment IDE relate to the amount of evidence necessary 
to support the intended treatment use. Under proposed 
Sec. 812.36(d)(2)(iii), FDA may disapprove or withdraw approval of a 
treatment IDE for a serious disease if there is insufficient evidence 
of safety and effectiveness to support such use. In addition, under 
proposed Sec. 812.36(d)(2)(iv), FDA may disapprove or withdraw approval 
of a treatment IDE for an immediately life-threatening illness if the 
available scientific evidence, taken as a whole, fails to provide a 
reasonable basis for concluding that the device: (1) May be effective 
for its intended use in its intended patient population; or (2) would 
not expose the patients to whom the device is to be administered to an 
unreasonable or significant additional risk of illness or injury.
    As in the treatment IND regulation, FDA believes that the severity 
of the disease or condition needs to weigh heavily in the decision on 
whether to approve the investigational device for treatment use. This 
is because of the different risk-benefit considerations involved in 
treating patients under different disease conditions; the consequences 
of denying treatment use for a patient in an immediately life-
threatening situation are much graver than for a patient with a 
serious, but not immediately life-threatening condition. The agency 
believes that this standard needs to be interpreted so that the level 
of evidence needed to support treatment use in diseases that are 
immediately life-threatening is significantly less than that needed for 
device approval and may be less than what would be needed to support 
treatment use in diseases that are serious, but not immediately life-
threatening.
    In order to reflect this continuum, the agency is proposing that 
FDA may deny

[[Page 66957]]

a request for treatment use for an immediately life-threatening illness 
if 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 patient population; or 
(b) would not expose the patients in whom the device is to be used to 
an unreasonable or significant additional risk of illness or injury. 
The agency is proposing that FDA may deny a request for treatment use 
for serious, but not immediately life-threatening, disease conditions 
based on a finding of insufficient evidence of safety and effectiveness 
to support such use. For any of these disease conditions, the proposed 
rule provides for a standard of medical and scientific rationality--a 
requirement for sufficient scientific evidence on the basis of which 
experts reasonably could conclude that the device may be effective for 
the intended patient population.
    The scientific evidence to be submitted in support of a treatment 
IDE may arise from a variety of sources. FDA expects that at least an 
early analysis of the data from the controlled clinical trial will 
ordinarily be available at the time a treatment IDE is submitted. 
However, FDA is committed to reviewing and considering all available 
evidence, including results of domestic and foreign clinical trials, 
animal data, and, where pertinent, in vitro data or bench testing. FDA 
will also consider clinical experience from outside a controlled trial, 
where the circumstances surrounding such experience provide sufficient 
indicia of scientific value.
    Under proposed Sec. 812.36(d)(2)(v), FDA may disapprove or propose 
to withdraw approval of a treatment IDE if 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. As in the 
treatment IND regulation, FDA is concerned that the treatment IDE 
process does not become either a substitute for the research necessary 
to bring a device to market or a substitute for marketing itself. 
Therefore, the proposed rule incorporates specific approval criteria as 
well as reasons for disapproval or withdrawal of approval of a 
treatment IDE that reflect these agency concerns. These provisions are 
intended to ensure that the premarket availability of devices for 
treatment use does not impede the controlled clinical trial of the 
device or delay the timely development and submission of marketing 
applications for promising therapies.
    Under proposed Sec. 812.36(d)(2)(vi), FDA may disapprove or propose 
to withdraw approval of a treatment IDE if the device has received 
marketing approval 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. As previously 
discussed in this document, FDA believes that the proposed treatment 
IDE regulation can facilitate the availability of therapeutic or 
diagnostic tools for patients that have no other alternative available 
to them. However, if the treatment use device gains marketing approval/
clearance, or if an alternative device becomes available for this 
specific indication, FDA may determine that the treatment IDE is no 
longer medically necessary, or needs to be restricted to patients for 
whom the recently approved product is not medically appropriate.
    Under proposed Sec. 812.36(d)(2)(vii), FDA may disapprove or 
propose to withdraw approval of a treatment IDE if the sponsor of the 
controlled clinical trial is not pursuing marketing approval/clearance 
with due diligence. As discussed in section II.B.4. of this document, 
pursuing marketing approval/clearance with due diligence is necessary 
as a precaution against the artificial prolonging of the 
investigational status of a device by a sponsor that is unable or 
unwilling to complete the clinical trial(s) and prepare a marketing 
application. Thus, if FDA determines that a sponsor is not 
demonstrating due diligence in pursuing marketing approval/clearance, 
FDA may disapprove or propose to withdraw approval of the treatment 
IDE.
    Under proposed Sec. 812.36(d)(2)(viii), FDA may disapprove or 
propose to withdraw approval of a treatment IDE if approval of the IDE 
for the clinical trial for the device has been withdrawn for reasons 
related to safety and effectiveness of the device. In such a situation, 
if FDA has determined that it is contrary to public health to allow the 
clinical trial of the device to continue due to issues related to 
safety and/or effectiveness of the device, the agency believes that 
treatment use of the device should also be curtailed.
    Under proposed Sec. 812.36(d)(2)(ix), FDA may disapprove a 
treatment IDE if the investigator(s) named in the application are not 
qualified by reason of their scientific training and experience to use 
the investigational device for the intended treatment use. While it is 
primarily the sponsor's responsibility to select only those 
investigators who are qualified to use the device under the treatment 
IDE, FDA may also review the qualifications of a proposed investigator 
if the need arises.
    As with all IDE's, in addition to FDA's authority to disapprove or 
withdraw approval of the treatment IDE, FDA reserves the right to 
impose limits on the number of sites and/or patients who may receive 
the investigational device under a treatment use protocol. If FDA 
determines that it is necessary to impose limits on treatment use or to 
withdraw approval of the treatment IDE, the treatment IDE sponsor is 
responsible for ensuring that no new patients are enrolled and that the 
patients that had already been enrolled are followed in accordance with 
the treatment use protocol.
3. Notice of Disapproval or Withdrawal of Approval of Treatment IDE
    Under proposed Sec. 812.36(d)(3), FDA will follow the procedures 
set forth in Sec. 812.30 if FDA disapproves or proposes to withdraw 
approval of a treatment IDE. In accordance with Sec. 812.30(c), FDA 
will notify the sponsor in writing of FDA's decision to disapprove or 
propose to withdraw approval of a treatment IDE. The notice of 
disapproval or proposed withdrawal of approval of a treatment IDE will 
contain a complete statement of the reasons for disapproval or proposed 
withdrawal and a statement that the sponsor has an opportunity to 
request a part 16 hearing. FDA will provide the opportunity for a 
hearing before withdrawal of approval, unless FDA determines and 
specifies in the notice that continuation of use of the device will 
result in an unreasonable risk to patients and orders withdrawal of 
approval before any hearing.

F. Safeguards

    FDA's objectives in regulating the clinical testing of new devices 
is the same as in regulating the clinical testing of new drugs; that is 
to protect the rights, safety, and welfare of human subjects involved 
in such testing while, at the same time, to facilitate the development 
and marketing of beneficial device therapies. (See 52 FR 19466 at 
19468.) In order to fulfill these objectives, FDA has included in the 
proposed rule certain safeguards that were already in place as part of 
the IDE regulations and other safeguards that have been specifically 
designed for the proposed treatment use.
    Under proposed Sec. 812.36(e), treatment use of an investigational 
device is conditioned upon the sponsor and investigators complying with 
the IDE regulations, including distribution of

[[Page 66958]]

the device through qualified experts, maintenance of adequate 
manufacturing facilities, the submission of certain reports, and with 
the regulations governing informed consent (part 50 (21 CFR part 50)) 
and institutional review boards (21 CFR part 56).
    The most significant of these safeguards are the following:
    1. The IDE regulations. The obligations and responsibilities of the 
sponsor of a clinical trial also apply to the sponsor of a treatment 
IDE. For example, treatment IDE sponsors are responsible for 
maintaining control of the device by ensuring that only qualified 
experts receive the device under the treatment IDE protocol. Similarly, 
the responsibilities of a clinician using an investigational device for 
treatment use are the same as those imposed on an investigator 
participating in a clinical trial. In addition, as with investigational 
devices, the methods, facilities, and controls used for the 
manufacturing, processing, packaging, storage, and when appropriate, 
installation of the treatment use device must be adequate. Finally, as 
with all investigational devices, treatment IDE sponsor(s) or any 
person(s) acting for or on behalf of the treatment IDE sponsor(s) may 
not charge the subjects or investigators a higher price than is 
necessary to recover costs of research, development, manufacturing, and 
handling. However, because FDA is concerned that the existence of 
treatment IDE's may increase the risk of commercialization of 
investigational devices, FDA is soliciting comment on the appropriate 
approach to take with respect to charging for devices under a treatment 
IDE. Specifically, do the IDE and proposed treatment IDE regulations 
provide sufficient protection against commercialization? Is it 
appropriate for sponsors to recover research and development costs in 
addition to the cost of manufacturing and handling an investigational 
device? Should prior FDA approval of charging be required? FDA wants to 
adopt an approach that facilitates the availability of promising new 
devices to treat serious diseases early in the device development 
process, but does not want to undermine the integrity of controlled 
clinical trials or increase the likelihood that investigational 
products will be commercialized before safety and efficacy have been 
established.
    2. Submission of progress reports. Under proposed Sec. 812.36(f), 
in lieu of the annual reports required under 812.150(b)(5), the sponsor 
of a treatment IDE shall submit progress reports on a quarterly basis 
to all reviewing IRB's and FDA. See section G below for further 
explanation.
    3. Informed consent. As in the treatment IND regulation, 
authorization to use an investigational device for treatment use is 
conditioned upon the practitioner obtaining the legally effective 
informed consent of the patient. See 52 FR 19466 at 19469. Clearly, 
there are risks in using experimental devices. Patients must be 
informed of the device's potential benefits and risks to help them 
decide whether the risks are appropriate and acceptable for their 
particular situation. Thus, the regulations governing informed consent, 
part 50, apply to the use of devices under a treatment IDE.
    4. IRB review. Compliance with the IRB regulations will help to 
ensure that the rights, safety, and welfare of human subjects treated 
with an investigational device are protected, whether it be during a 
clinical investigation or under a treatment IDE. Therefore, FDA has 
determined that an IRB, either local or national, shall review and have 
authority to approve, require modifications to, or disapprove the 
treatment use of an investigational device.

G. Reporting Requirements

    Under proposed Sec. 812.36(f), in lieu of the annual reports 
submitted under Sec. 812.150(b)(5), the sponsor of a treatment IDE 
shall submit progress reports on a quarterly basis to all reviewing 
IRB's and FDA. Similar to IDE progress reports, treatment use progress 
reports shall contain a summary of the safety and effectiveness 
information gathered under the treatment IDE, a summary of anticipated 
and unanticipated adverse device effects, 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. The sponsor of a treatment IDE is also 
responsible for submitting all other reports required under 
Sec. 812.150.

III. Environmental Impact

    The agency has determined under 21 CFR 25.24(a)(8) 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 impacts of the proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612). 
Executive Order 12866 directs agencies to assess all costs and benefits 
of available regulatory alternatives and, when regulation is necessary, 
to select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). The agency believes that 
this proposed rule is consistent with the regulatory philosophy and 
principles identified in the Executive Order. In addition, the proposed 
rule is not a significant regulatory action as defined by the Executive 
Order and so is not subject to review under the Executive Order.
    Treatment use of an investigational device will only be considered 
when the criteria set out in section II.B. of this document are met. 
FDA believes that these limitations are necessary to ensure that 
devices are not commercialized before FDA determines that they are 
reasonably safe and effective for wider distribution.
    Given the limited circumstances in which a treatment use of an 
investigational device may be considered, FDA estimates that about six 
investigational devices per year will meet the criteria for treatment 
use. FDA believes that the requirements for applications for treatment 
use of an investigational device would be minimal, but must be 
consistent with patient safety and proper use. Because relevant 
information already should be available to FDA in the sponsor's IDE, 
limited additional information relative to the safety and effectiveness 
of the device for treatment use would be required in the treatment IDE 
application. In fact, applications for treatment use may be submitted 
as supplements to the IDE for the controlled clinical trial in order to 
eliminate the additional burden that could result if sponsors were 
required to submit new applications. FDA estimates that the annual cost 
of submitting an application for treatment use and the necessary 
progress reports would be about $8,000 per application. Treatment use 
would benefit the public health by permitting wider distribution of 
life-saving devices while marketing approval is pending.
    The proposed rule contains very specific provisions regarding the 
approval criteria as well as the reasons for disapproval or withdrawal 
of approval of a treatment IDE. This will assist sponsors in 
determining whether they have met the criteria for initial and 
continued approval of a treatment use IDE well in advance of their 
applications.

[[Page 66959]]

     For the reasons set forth above, the Commissioner of Food and 
Drugs certifies that the proposed rule will not have a significant 
economic impact on a substantial number of small entities. Therefore, 
under the Regulatory Flexibility Act, no further analysis is required.

V. Paperwork Reduction Act of 1995

    This proposed rule contains information collections which are 
subject to review by the Office of Management and Budget (OMB) under 
the Paperwork Reduction Act of 1995. The title, description, and 
respondent description of the information collection are shown below 
with an estimate of the annual reporting burden. Included in the 
estimate is the time for reviewing instructions, gathering and 
maintaining the data needed, and completing and reviewing the 
collection of information.
    With respect to the following collection of information, FDA 
invites comments on: (1) Whether the proposed collection of information 
is necessary for proper performance of FDA's functions, including 
whether the information will have practical utility; (2) the accuracy 
of FDA's estimate of the burden of the proposed collection of 
information, including the validity of the methodology and assumptions 
used; (3) ways to enhance the quality, utility, and clarity of the 
information to be collected; and (4) ways to minimize the burden of the 
collection of information on respondents, including through the use of 
automated collection techniques, when appropriate, and other forms of 
information technology.
    Title: Investigational Device Exemptions; Treatment Use.
    Description: The proposed rule is intended to permit broader 
availability of investigational devices to treat serious diseases for 
which there are not satisfactory alternative treatments. Under the 
proposed rule, treatment use of an investigational device would only be 
considered when the following criteria are satisfied: (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 
under an approved IDE, or all clinical trials have been completed; and 
(4) the sponsor of the controlled clinical trial is pursuing marketing 
approval/clearance of the investigational device with due diligence.
    The proposed requirements for applications for treatment use would 
be minimal, but must be consistent with patient safety and proper use. 
Each application would include, among other things, an explanation of 
the rationale for the use of the device; the criteria for patient 
selection; a description of clinical procedures, laboratory tests, or 
other measures to be used to monitor the effects of the device and to 
minimize risk; written procedures for monitoring the treatment use; 
information that is relevant to the safety and effectiveness of the 
device for the intended treatment use; and a written protocol 
describing the treatment use. Sponsors of an approved treatment IDE 
would be required to submit quarterly progress reports.
    Description of Respondents: Businesses or other for profit 
organizations.

                                        Estimated Annual Reporting Burden                                       
----------------------------------------------------------------------------------------------------------------
                                                      Annual                                                    
         21 CFR Section               No. of       Frequency per   Total Annual      Hours per      Total Hours 
                                    Respondents      Response        Responses       Response                   
----------------------------------------------------------------------------------------------------------------
812.36(c)                               6               1               6             120             720       
812.36(f)                               6               4              24              20             480       
Total                                                                                               1,200       
----------------------------------------------------------------------------------------------------------------
There are no operating and maintenance costs or capital costs associated with this information collection.      

    As required by section 3507(d) of the Paperwork Reduction Act of 
1995, FDA has submitted the collections of information contained in the 
proposed rule to OMB for review. Other organizations and individuals 
should submit comments on the information collection requirements by 
January 21, 1997, and should direct them to the Office of Information 
and Regulatory Affairs, OMB (address above).

Lists of Subjects in 21 CFR Part 812

    Health records, Medical devices, Medical research, Reporting and 
recordkeeping requirements.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, it is 
proposed that 21 CFR part 812 be amended as follows:

Part 812--Investigational Device Exemptions

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

    Authority: Secs. 301, 501, 502, 503, 505, 506, 507, 510, 513-
516, 518-520, 701, 702, 704, 721, 801 of the Federal Food, Drug, and 
Cosmetic Act (21 U.S.C. 331, 351, 352, 353, 355, 356, 357, 360, 
360c-360f, 360h-360j, 371, 372, 374, 379e, 381); secs. 215, 301, 
351, 354-360F of the Public Health Service Act (42 U.S.C. 216, 241, 
262, 263b-263n).

    2. New Sec.  812.36 is added to subpart B to read as follows:


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

[[Page 66960]]

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 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 of the device and all other labeling as 
required under Sec. 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 assure compliance of all participating investigators with the 
informed consent requirements of part 50 of this chapter; and
    (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.
    (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 Sec.  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 Sec. 812.36(b) are not met or the 
treatment IDE does not contain the information required in 
Sec. 812.36(c);
    (ii) FDA determines that any of the grounds for disapproval or 
withdrawal of approval listed in Sec. 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 or 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 Sec. 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. In lieu of the annual reports required 
under Sec. 812.150(b)(5), the sponsor of a treatment IDE shall submit 
progress reports on a quarterly basis to all reviewing IRB's and FDA. 
These reports shall be based on the period of time since initial 
approval of the treatment IDE and shall include a summary of the safety 
and effectiveness information gathered under the treatment IDE, a 
summary of anticipated and unanticipated adverse device effects, 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. The sponsor of a treatment IDE is 
responsible for submitting all other reports required under Sec.  
812.150.


Sec. 812.150  [Amended]

    3. Section 812.150 Reports is amended by revising paragraph (b)(5) 
to read as follows:
 * * * * *
    (b) * * *
    (5) Progress reports. At regular intervals, and at least yearly, a 
sponsor shall submit progress reports to all reviewing IRB's. In the 
case of a significant risk device, a sponsor shall also submit progress 
reports to FDA. In lieu of the annual reports, a sponsor of a treatment 
IDE shall submit

[[Page 66961]]

progress reports on a quarterly basis to all reviewing IRB's and FDA in 
accordance with Sec. 812.36(f).
 * * * * *

    Dated: December 11, 1996.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 96-32186 Filed 12-18-96; 8:45 am]
BILLING CODE 4160-01-F