[Federal Register Volume 62, Number 181 (Thursday, September 18, 1997)]
[Rules and Regulations]
[Pages 48940-48948]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-24735]


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

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 812

[Docket No. 96N-0299]


Investigational Device Exemptions; Treatment Use

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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

SUMMARY: The Food and Drug Administration (FDA) is establishing 
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 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: The regulation is effective January 16, 1998.


[[Page 48941]]


FOR FURTHER INFORMATION CONTACT: Joanne R. Less, Office of Device 
Evaluation (HFZ-403), Center for Devices and Radiological Health 
(CDRH), 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, in the Federal Register of December 19, 1996 (61 FR 66954), 
FDA proposed to amend its Investigational Device Exemptions (IDE) 
regulation (part 812 (21 CFR part 812)) to allow for the treatment use 
of investigational devices (hereinafter referred to as the treatment 
IDE regulation). With minor exceptions, the proposal paralleled the 
treatment IND regulation and extended those provisions to cover the 
treatment use of investigational devices, including diagnostic devices. 
The final rule generally codifies the proposal, with some exceptions 
discussed below. Similar to the proposed rule, this final 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 device and ensuring the 
integrity of controlled clinical trials.
    FDA received six comments on the proposed rule. These comments were 
from an institutional review board (IRB), a medical device consultant, 
a medical device manufacturers' association, a medical device 
manufacturer, an association of surgeons, and a consumer. The comments 
generally supported the agency's proposal to provide for expanded 
access to investigational devices under a treatment IDE. A number of 
comments sought clarification of specific points, or responded to 
specific questions raised in the preamble to the proposed rule. No 
comments opposed codification of the treatment procedures. Interested 
persons were given until March 19, 1997, to comment on the proposed 
rule.

 II. Highlights of the Final Rule

     FDA has retained the basic framework of the proposed rule. 
Treatment use of an investigational device will be considered when: (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 available to treat or diagnose 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 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.
    Each application for treatment use shall 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.
    Treatment use may begin 30 days after FDA receives the treatment 
IDE submission, unless FDA notifies the sponsor earlier than 30 days 
that the treatment use may or may not begin. FDA may approve the 
treatment use as proposed, approve it with modification, disapprove it, 
or withdraw approval of the treatment IDE if FDA finds that certain 
criteria are satisfied.
    Safeguards for treatment use of an investigational device include 
the: Distribution of the device through qualified experts; maintenance 
of adequate manufacturing facilities; the submission of certain 
reports; and compliance with the regulations governing informed consent 
and institutional review boards (IRB's).
    The sponsor of a treatment IDE shall submit progress reports to all 
reviewing IRB's and FDA and shall be responsible for submitting all 
other reports required under Sec. 812.150.
    In response to comments, FDA has made the following changes in the 
final rule.
    FDA has streamlined the reporting requirements in Sec. 812.36(f). 
First, FDA decreased the frequency with which sponsors must submit 
progress reports under Sec. 812.36(f). Under the final rule, the 
sponsor of a treatment IDE is required to submit progress reports on a 
semi-annual basis, rather than quarterly, to all reviewing IRB's and 
FDA. Upon filing of a marketing application, the requirement for 
progress reports is further reduced to annual reporting in accordance 
with Sec. 812.150. Second, FDA limited the type of information that is 
to be submitted in a progress report. Under the final rule, these 
reports are required to include only 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.
    FDA has modified the rule with respect to cost recovery by adding 
new Sec. 812.36(c)(1)(x). In accordance with this provision, if the 
device is to be sold, the price to be charged is to be based on 
manufacturing and handling costs only. This decision was based on the 
fact that under the general IDE, sponsors are permitted to recover, 
among other costs, research and development costs. Because the research 
and development expenditures already are being recovered under the 
general IDE, FDA concluded that cost recovery under the treatment IDE 
should be limited to that of supplying the device for the treatment 
use, i.e., manufacturing and handling costs.
    FDA is clarifying the final rule to state that treatment use must 
be for the same use as that studied under an approved IDE. The preamble 
to the proposed rule addressed this point at 61 FR 66954 at 66955, 
column 3, and FDA believes it is important to include it in the 
codified language. See Sec. 812.36(b)(3). This change reflects the fact 
that it is those indications studied in the controlled clinical trial 
for which the agency would have the preliminary evidence of safety and 
effectiveness needed to support the treatment use.

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

A. General Comments

    1. One comment stated that the example FDA provided in the preamble 
to the proposed rule of an approved device that would have met the 
treatment IDE criteria, i.e., nonthoracotomy (transvenous) 
defibrillation leads, was inappropriate. According to the comment, 
unless patients in need of such leads had a complicating disease or 
condition that prevented surgery, the surgical placement of approved 
defibrillation leads would have been a satisfactory alternative to the 
nonthoracotomy (transvenous) defibrillation leads. The

[[Page 48942]]

comment stated that placement of the transvenous leads may present less 
risk to the patient than the surgical placement of defibrillation 
leads. The comment noted, however, that the regulation does not 
incorporate risk considerations. If the intent of the regulation is to 
permit the use of a device based on risk, then the comment suggested 
that Sec. 812.36(b)(2) be rewritten to include risk-benefit 
considerations.
    FDA agrees that risk/benefit considerations should be part of 
treatment IDE decisionmaking, but believes that the agency has already 
addressed this concern adequately in the criteria established under 
Sec. 812.36(b)(1) and (b)(2), in conjunction with the bases for 
disapproval or withdrawal of a treatment IDE under 
Sec. 812.36(d)(2)(iii) and (d)(2)(iv). In the example FDA provided, 
clinical data from the general IDE showed that nonthoracotomy 
(transvenous) defibrillation leads addressed an unmet medical need in a 
defined patient population, i.e., those patients with postradiation 
mediastinal fibrosis who could not undergo surgical placement of the 
approved defibrillation leads. FDA's evaluation of a treatment IDE in 
this context would necessarily include full consideration of the 
potential risks and benefits of the device, given the clinical and 
other scientific information known to date, in light of the seriousness 
of the disease or condition and availability of alternative therapies.
    In addition, FDA notes that once a treatment IDE is made available 
generally, there still remains a risk/benefit consideration for 
individual patients within the intended patient population. In this 
situation, the physician and patient would need to decide, based on the 
available clinical information and the individual patient's condition, 
whether the treatment use device would expose that patient to an 
acceptable level of risk. This is a case-by-case decision to be made by 
the doctor and the patient.
     2. A comment stated that the preamble to the proposed rule could 
be improved by providing fewer ``disease'' examples, and providing more 
examples of surgical uses, implants, or injury/accident references, 
where devices might be utilized.
    In response to the recommendation, the agency is providing the 
following examples to better explain when a treatment IDE would be 
appropriate.
    One example of an approved device that would have met the treatment 
use criteria is an interactive wound and burn dressing indicated for 
use as a temporary covering for surgically excised full-thickness and 
deep partial-thickness thermal burns in patients who require such a 
temporary covering prior to autograft placement. This device would have 
met the treatment IDE criteria because: (1) The device is intended to 
treat immediately life-threatening conditions, i.e., full-thickness and 
deep partial-thickness thermal burns; (2) there were no comparable or 
satisfactory alternative devices (the only alternative therapy (cadaver 
skin) is severely limited in supply and has a risk of disease 
transmission); (3) the device was under investigation in a controlled 
clinical trial for the same use under an approved IDE; and (4) the 
sponsor of the controlled clinical trial was pursuing marketing 
approval of the device with due diligence.
    Another example of an approved device that would have met the 
treatment use criteria is the low density lipoprotein (LDL) apheresis 
system indicated for use in performing low density lipoprotein 
cholesterol (LDL-C) apheresis to acutely remove LDL-C from the plasma 
of the following high risk patient populations for whom diet has been 
ineffective and maximum drug therapy has either been ineffective or not 
tolerated: functional hypercholesterolemic homozygotes with LDL-C > 
500/mg/dl; functional hypercholesterolemic heterozygotes with LDL-C 
 300 mg/dl; and functional hypercholesterolemic 
heterozygotes with LDL-C  200 mg/dl and documented coronary 
heart disease. This device would have met the treatment IDE criteria 
because: (1) The device is intended to treat serious conditions, i.e., 
functional hypercholesterolemic homozygotes/heterozygotes with certain 
LDL-C levels; (2) there were no comparable or satisfactory alternative 
devices (the only alternative therapies available to treat these high 
risk patients are diet, which can be ineffective, and maximum drug 
therapy, which can be either ineffective or not tolerated); (3) the 
device was under investigation in a controlled clinical trial for the 
same use under an approved IDE; and (4) the sponsor of the controlled 
clinical trial was pursuing marketing approval of the device with due 
diligence.
    Again, these are illustrative examples only.
    3. Two comments requested that FDA discuss the differences and 
relationships among treatment IDE's, emergency use devices, the Office 
of Device Evaluation's (ODE) memorandum on ``Continued Access to 
Investigational Devices During Premarket Approval Application (PMA) 
Preparation and Review,'' expedited review, and custom devices. One of 
the comments recommended that CDRH issue separate guidance delineating 
the differences and relationships among these policies/regulations.
    With the exception of custom devices, FDA has issued guidance on 
all of the topics identified in the previous comments. The agency has 
provided the following summary of each of these policies and has also 
identified key similarities and differences between them and the 
treatment IDE regulation.
1. ``Guidance for the Emergency Use of Unapproved Medical Devices''
    Under FDA's ``Guidance for the Emergency Use of Unapproved Medical 
Devices'' (hereinafter referred to as the Emergency Use Policy), that 
appeared in the Federal Register of October 22, 1985 (50 FR 42866), an 
unapproved medical device is a device that is utilized for a purpose, 
condition, or use for which the device requires, but does not have, an 
approved application for premarket approval under section 515 of the 
Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 360e) or an 
approved IDE under section 520(g) of the act (21 U.S.C. 360j(g)). 
Normally, an unapproved device may be used in human subjects only if it 
is approved for clinical testing under an IDE. Emergency use of an 
unapproved device, however, may occur when an IDE for the device does 
not exist, when a physician wants to use the device in a way not 
approved under the IDE, or when a physician or institution is not 
approved under the IDE.
    The Emergency Use Policy is different from the treatment IDE 
regulation in significant ways. First, the Emergency Use Policy is 
designed for just that--emergencies--and is applied on an individual 
patient basis. To qualify for emergency use, the treating physician 
must conclude that: (1) The patient has a life-threatening condition 
that needs immediate treatment; (2) no generally acceptable alternative 
treatment for the condition exists; and (3) there is no time to obtain 
FDA approval due to the immediate need of the patient.
    By contrast, treatment use of an investigational device is designed 
to operate prospectively under a protocol that may cover a large number 
of patients, so that a treatment IDE application would be submitted to 
and approved by the agency before patients are treated with the device. 
Also, the Emergency Use Policy is limited to life-threatening 
situations, whereas a treatment IDE allows use of the device for 
serious diseases in addition to those that are immediately life-
threatening.

[[Page 48943]]

2. ``Continued Access to Investigational Devices During Premarket 
Approval Application (PMA) Preparation and Review''
    Under ODE's policy entitled ``Continued Access to Investigational 
Devices During PMA Preparation and Review'' (hereinafter referred to as 
the Continued Access Policy), sponsors of clinical investigations are 
permitted to continue to enroll subjects while a marketing application 
is being prepared by the sponsor or reviewed by ODE if there is: (1) A 
public health need for the device; or (2) preliminary evidence that the 
device is likely to be effective and no significant safety concerns 
have been identified for the proposed indication. By allowing sponsors 
to continue to enroll patients while a marketing application is being 
prepared and/or reviewed, the Continued Access Policy allows increased 
patient access and the collection of additional safety and 
effectiveness data to support the marketing application or address new 
questions regarding the investigational device. The Continued Access 
Policy may be applied to any clinical investigation that meets the 
criteria identified above; however, it is intended to be applied late 
in the device development process, i.e., after the controlled clinical 
trial has been completed.
    There is significant overlap between the treatment IDE regulation 
and the Continued Access Policy. Both the Continued Access Policy and 
the treatment IDE regulation are intended to provide additional access 
to an unapproved device, once preliminary evidence regarding safety and 
effectiveness is available to FDA. However, because a treatment IDE can 
be submitted earlier in the IDE process, i.e., once promising evidence 
of safety and effectiveness has been collected under the IDE but while 
the clinical study is ongoing, it could provide access to a wider group 
of patients at an earlier stage in the IDE process. The treatment IDE 
regulation also has a more narrow application than the Continued Access 
Policy in that treatment use is intended to address only those patients 
who have an immediately life-threatening or serious disease or 
condition whereas the Continued Access Policy, which is applied later 
in the process, may be considered for any clinical study.
3.``PMA/510(k) Expedited Review''
    According to ODE's ``PMA/510(k) Expedited Review'' policy 
(hereinafter referred to as the Expedited Review Policy), expedited 
review of a marketing application may be considered for a device 
intended for or meeting at least one of the following criteria: (1) 
Life-threatening or irreversibly debilitating condition with no 
alternative modality. The condition or potential condition/disease is 
serious or life-threatening or presents a risk of serious morbidity and 
no alternative legally marketed diagnostic/therapeutic modality exists; 
(2) life-threatening or irreversibly debilitating condition with 
approved alternatives, but where the new device provides for clinically 
important earlier diagnosis or significant advances in safety and/or 
effectiveness over the existing alternatives; (3) a revolutionary 
(breakthrough) device, i.e., the device represents a clear clinically 
meaningful advantage over existing technology defined as having a major 
increase in effectiveness or reduced risk compared to existing 
technology; and (4) a specific public health benefit, i.e., the 
availability of the device is otherwise in the best interest of the 
public health.
    Under the Expedited Review Policy, granting expedited review 
ensures that the marketing application will receive priority review, 
i.e., review before other pending PMA's or 510(k)s. Therefore, the 
Expedited Review Policy differs from the treatment IDE regulation in 
that expedited review pertains to the review priority given to 
marketing applications, whereas treatment use pertains to expanding 
access to patients of a device during the course of the clinical 
investigation.
    As stated previously, FDA intends to interpret the criteria for 
treatment IDE's in the same way CDRH applies the criteria for expedited 
review of marketing applications. FDA anticipates that most requests 
for treatment use would involve devices that 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. These criteria are similar 
because the same public health considerations that justify expanding 
access to an investigational product also justify giving a marketing 
application for that device top priority. In both cases, the likely 
patient benefit warrants special policies.
4. Custom Devices
    FDA has not issued a guidance document concerning custom devices, 
but a custom device is defined in Sec. 12.3(b). A custom device is one 
that:
    (1) Necessarily deviates from devices generally available or 
from an applicable performance standard or premarket approval 
requirement in order to comply with the order of an individual 
physician or dentist; (2) is not generally available to, or 
generally used by, other physicians or dentists; (3) is not 
generally available in finished form for purchase or for dispensing 
upon prescription; (4) is not offered for commercial distribution 
through labeling or advertising; and (5) is intended for use by an 
individual patient named in the order of a physician or dentist, and 
is to be made in a specific form for that patient, or is intended to 
meet the special needs of the physician or dentist in the course of 
professional practice.
Because all the preceding criteria must be met for a device to qualify 
as a custom device and because the use of a custom device is exempt 
from the IDE regulation (Sec. 812.2(c)(7)), the provision usually 
covers only a single device and is not frequently applicable.
    FDA believes that the existing guidance documents on these topics, 
together with the preceding discussion, satisfies the concern raised in 
the comment.
    4. One comment suggested that FDA add a reference to the Emergency 
Use Policy to permit shipment of devices in emergency situations such 
as those in 21 CFR 312.36. The same comment asked FDA to clarify that 
IRB review is not necessary in the case of emergency use for a single 
patient.
     Emergency use for a single patient is governed by FDA's Emergency 
Use Policy. As noted previously in the Emergency Use Policy, an 
unapproved device may be shipped without FDA approval to a physician 
who is faced with an emergency situation that meets the outlined 
criteria.
    The comment's request for clarification regarding IRB review in the 
case of an emergency use for a single patient is also addressed in the 
Emergency Use Policy. Under this guidance, in the event that a device 
is needed to treat a life-threatening disease or condition, FDA would 
expect the physician to follow as many patient protection procedures as 
possible. These include, among other things, obtaining the IRB 
chairperson's concurrence and complying with the institution's 
requirements regarding such use. Therefore, IRB approval for emergency 
use would only be required if such review were necessary under the 
procedures of that particular institution.
    5. One comment raised a concern that the treatment IDE review 
procedures and reporting requirements will create additional work that 
will delay FDA's review of PMA's.
    FDA disagrees. As stated in the preamble to the proposed, FDA 
anticipates a limited number of treatment IDE's and has estimated it is

[[Page 48944]]

likely to receive six annually. (See 61 FR 66954 at 66959.) Although 
these treatment IDE's will create additional work for the agency, such 
a limited number will not cause delays in FDA's review of PMA's. 
Moreover, in the 10 years since the treatment IND rule was issued, the 
agency has not experienced delays in the review of new drug 
applications due to the additional work created by the treatment IND 
review procedures and reporting requirements.

B. Specific Comments

    1. A comment noted that Sec. 812.36(a) defines an ``immediately 
life-threatening disease or condition,'' but does not define a 
``serious disease or condition.'' The comment asserted that the term 
``serious'' disease or condition should either be defined in or omitted 
from the regulation because it is likely to be a ``gray area'' with 
regard to interpretation of the regulation. The comment preferred that 
the term ``serious'' be omitted because the diseases intended to be 
included under this definition, i.e., early stages of breast cancer, 
proliferative vitreoretinopathy, and advanced Parkinson's disease, 
would meet the definition of an ``immediately life-threatening disease 
or condition.''
    FDA does not intend to add a definition of ``serious disease or 
condition'' to the final rule. The agency has concluded that defining 
the term ``serious disease or condition'' could be unduly restrictive 
and limit the agency's discretion when determining whether certain 
stages of a disease or condition are ``serious.'' In addition, the 
agency's experience under the treatment IND regulation demonstrates 
that a definition is unnecessary; the agency has been successful in 
identifying the serious diseases or conditions appropriate to treatment 
IND even though the term is undefined in that regulation. If a sponsor 
is not sure of whether a particular stage of a disease or condition 
would be considered ``serious,'' the sponsor should contact the 
appropriate review division in ODE for clarification.
    FDA did not omit the term ``serious disease or condition'' from the 
regulation because, contrary to the comment's assertion, the diseases 
or conditions intended to be included under the serious disease or 
condition definition would not meet the definition of immediately life-
threatening disease or condition in all circumstances. For example, 
advanced Parkinson's disease would normally be considered a serious 
disease or condition rather than an immediately life-threatening 
disease state, i.e., there is not a reasonable likelihood that death 
will occur within a matter of months nor is premature death likely 
without early treatment.
    2. One comment stated that the definition of ``immediately life-
threatening disease or condition'' is severe in its limitations. As a 
result, the comment suggested that FDA adopt the definition used for 
expedited review, i.e., a condition or disease that is irreversibly 
debilitating with no alternative treatment modalities or meets a 
specific public health need. The comment believed that this would cover 
serious disease states but not restrict those diseases to those likely 
to result in imminent death. The comment stated that this definition is 
appropriate because FDA intends to interpret the criteria for treatment 
use IDE's in the same way FDA applies the criteria for expedited review 
of PMA's.
    FDA disagrees with the recommendation to modify the definition of 
``immediately life-threatening disease or condition.'' As stated in the 
preamble to the proposed rule, with minor exceptions, the treatment IDE 
regulation parallels the treatment IND regulation and extends those 
provisions to cover treatment use of investigational devices. FDA does 
not believe that this definition will be problematic in light of the 
fact that FDA is adopting the same definition in the treatment IDE 
regulation that is used in the treatment IND regulation. Since the 
implementation of the treatment IND regulation in 1987, FDA has not had 
any experience that would indicate that the definition is severe in its 
limitations. The agency also believes that adopting the same definition 
of immediately life-threatening disease or condition in both treatment 
regulations will promote consistency.
    3. One comment recommended that FDA expand the definition of an 
``immediately life-threatening disease or condition'' to include 
diseases or conditions that threaten the integrity of the nervous 
system. According to the comment, an investigational device might 
prevent devastating neurological illness even though death is not 
imminent.
    FDA disagrees with expanding the definition of immediately life-
threatening disease or condition to include neurological illnesses not 
resulting in imminent death because the agency intended that such 
illnesses be included under the definition of a serious disease or 
condition. For example, as stated in the proposed rule, advanced 
Parkinson's disease, which causes severe neurological impairment, would 
be considered a serious disease or condition appropriate for a 
treatment IDE. (See 61 FR 66954 at 66955.) Likewise, advanced multiple 
sclerosis would also be considered a serious disease or condition 
because, although it does not result in imminent death, it causes 
severe neurological impairment.
    4. A comment requested that Sec. 812.36(b)(3) be clarified to read 
that patients who were in the ``parent'' controlled clinical trial 
under the approved IDE be allowed to continue under the treatment IDE, 
after the parent controlled clinical trial has been completed, but 
before FDA approval is received. The comment referred to the July 15, 
1996, memorandum entitled, ``Continued Access to Investigational 
Devices During Premarket Approval Application (PMA) Preparation and 
Review.''
    FDA agrees that patients who were originally enrolled in the 
``parent'' controlled clinical trial, which is now complete, could 
qualify for continued access to the device under the Continued Access 
Policy described in section III.A.2 of this document. The agency does 
not believe a change to the regulation is needed to accommodate this 
situation.
    5. In the preamble to the proposed rule in Sec. 812.36(e), FDA 
solicited comments on the appropriate approach to take with respect to 
charging for devices under treatment IDE's. (See 61 FR 66954 at 66958.) 
Specifically, FDA posed the following questions in connection with 
Sec. 812.36(e):
1. Do the IDE and Treatment IDE Regulations Provide Sufficient 
Protection Against Commercialization?
    FDA received one comment, which stated that the IDE regulation, the 
proposed rule on treatment IDE's, market forces, and expedited review 
procedures, where appropriate, protect against commercialization of 
devices distributed under IDE's or treatment IDE's. First, according to 
the comment, Secs. 812.40 and 812.43 and proposed Sec. 812.36(e) limit 
distribution of investigational devices by ensuring that only qualified 
investigators receive the device. Failure of the manufacturer to 
control distribution often draws attention from competitors who report 
such violations to FDA, thus adding an additional commercialization 
control element. Secondly, the comment pointed out that Sec. 812.7(c) 
and proposed Sec. 812.36(e) prohibit sponsors from unduly prolonging an 
investigation. Thirdly, according to the comment, proposed 
Sec. 812.36(f) adds another layer of control over commercialization of 
treatment investigational devices by requiring sponsors to provide a 
description of their efforts to pursue marketing approval/clearance of 
the device in the progress reports which are

[[Page 48945]]

to be submitted to both FDA and the IRB's. Finally, the comment noted 
that if a device meets the criteria for a treatment IDE, it will also 
meet the criteria for expedited review of PMA's. Accordingly, the 
comment suggested that in cases where a treatment IDE is approved, 
expedited review of the PMA should be automatically granted. Expedited 
reviews should add another layer of control against clinical trial 
prolongation once the trial has been completed and the PMA is pending 
because it is anticipated that the PMA would be reviewed more quickly.
    FDA agrees that the IDE and treatment IDE regulations should 
provide sufficient protection against commercialization of the 
investigational device. In the general IDE regulation, Sec. 812.7(c) 
prohibits sponsors from unduly prolonging an investigation, 
Sec. 812.43(b) limits distribution of the investigational device to 
qualified investigators, and Sec. 812.150(b)(5) requires the submission 
of progress reports to FDA and the IRB's. Under Sec. 812.36(e), 
sponsors of treatment IDE's are subject to all of the requirements of 
the general IDE regulation. Sponsors of treatment IDE's are also 
subject to Sec. 812.36(f), which requires sponsors to describe their 
efforts to pursue marketing approval/clearance of the device in their 
progress reports.
2. Is It Appropriate for Sponsors to Recover Research and Development 
Costs in Addition to the Costs of Manufacturing and Handling of an 
Investigational Device?
    One comment stated that it is not appropriate for sponsors to 
recover research and development costs when charging for devices under 
a treatment IDE because the assignment of such costs to the limited 
number of devices under the treatment IDE will result in the device 
being extremely costly and, therefore, not used. The comment also 
stated that delaying recovery of the research and development costs 
until device approval will provide an incentive for the sponsor to 
obtain such approval.
    Three other comments stated that sponsors should be able to recover 
research and development costs as well as manufacturing and handling 
costs, as is the case with IDE's in general. According to two of the 
comments, not allowing sponsors to recover these costs will result in a 
reduction of the number of IDE's and treatment IDE's. One of the 
comments noted that charging a lower price for a device under a 
treatment IDE than under the IDE in general could dissuade sponsors 
from submitting treatment IDE applications. According to the second 
comment, the majority of devices that would be under treatment IDE's 
are breakthrough technologies developed by small start-up and medium 
sized companies, which often depend upon venture capital to develop new 
devices. The comment further asserted that these companies cannot 
afford the costs of a clinical trial unless they are compensated. 
Alternatively, the comment noted that larger companies may opt not to 
apply for an IDE or treatment IDE if the costs of research, 
development, manufacturing, and handling as well as the expense of the 
trial itself cannot be adequately recovered by postapproval sales.
    Upon consideration of the comments, FDA has decided that it is not 
appropriate for sponsors to recover research and development costs 
under treatment IDE's. FDA acknowledges that the investment cost of 
developing a device may be high and that the actual cost recovered by 
the sponsor may be a factor in proceeding with development of the 
device. (See 43 FR 20726 at 20742.) Nevertheless, it is a well-
established principle, that no profit should be made on experimental 
devices. (See 45 FR 3732 at 3741, January 18, 1980; Medical Devices; 
Procedures for IDE's; Final rule.) Based on this principle, and on the 
fact that research and development expenditures may be recovered under 
the general IDE, FDA has concluded that cost recovery during a 
treatment IDE should be limited to those direct costs of supplying the 
device for the treatment use, i.e., manufacturing and handling costs. 
In this way, manufacturers would not incur additional costs as a result 
of participating in a treatment IDE. FDA recognizes, however, that 
manufacturing and handling costs per unit may be higher during 
production of a limited number of units than during full commercial 
distribution.
3. Should Prior FDA Approval for Charging Be Required?
    One comment stated that Sec. 812.20(b)(8), which requires a sponsor 
to justify why the price charged for the device does not exceed 
research, development, manufacturing, and handling costs, should also 
be part of the treatment IDE application. Another comment believed that 
sponsors should inform FDA in the treatment IDE application if and how 
much they intend to charge for the device. The comment stated that the 
sponsor should provide a justification for the charge based on actual 
manufacturing and handling costs only, and FDA approval of the charge 
would be implied when FDA approves the treatment IDE application. 
Another comment stated that prior FDA approval of costs is not 
appropriate because such approval would result in a longer treatment 
IDE approval process.
    FDA agrees that, as with IDE's in general, prior approval for 
charging for the treatment use device should be required. Therefore, 
FDA has added Sec. 812.36(c)(1)(x), which states that if the device is 
to be sold, the treatment IDE sponsor is required to submit the price 
charged for the treatment use device and a statement indicating that 
the price is based on manufacturing and handling costs only.
    FDA disagrees that prior approval of costs will result in a longer 
approval process for treatment IDE applications. Under Sec. 812.30(a) 
of the general IDE regulation, FDA is required to notify a sponsor in 
writing of its decision to approve the investigation as proposed, 
approve it with modifications, or disapprove it within 30 days of 
receipt of the application. That review includes a review of the 
sponsor's decision to charge for the device. Under Sec. 812.36(d)(1), 
FDA is also required to review treatment IDE applications within the 
30-day timeframe; there is no reason to assume the approval process for 
treatment IDE's will be protracted.
    6. According to one comment on Sec. 812.36(f), quarterly reports to 
the IRB's and FDA should be subject to restrictions intended to protect 
confidential information.
    FDA agrees that treatment IDE progress reports ordinarily should be 
kept confidential. As provided for under Sec. 812.38(a) of the IDE 
regulation in general, FDA will not disclose the existence of an IDE 
until FDA approves a marketing application for the device unless its 
existence has previously been publicly disclosed or acknowledged. Even 
if the existence of an IDE has been disclosed or acknowledged by the 
sponsor, as is likely with respect to treatment IDE's, the information 
contained in an IDE or treatment IDE, including progress reports 
submitted under Sec. 812.36, is generally protected from disclosure.
    A second comment on proposed Sec. 812.36(f) alleged that quarterly 
reporting is an unnecessary burden on sponsors. The comment noted that 
the parallel IND regulation does not require additional quarterly 
reporting. The comment also alleged that this requirement conflicts 
with the Paperwork Reduction Act, in that it adds a layer of paperwork 
never before required for IDE's. According to the comment, the adverse 
reporting procedures for IDE's would provide enough safeguards for 
treatment IDE's without adding a new layer of paperwork.

[[Page 48946]]

    FDA agrees in part with the comment. Upon reconsideration, FDA has 
concluded that such frequent reporting, in addition to the annual 
reporting requirement under the regular IDE, is not necessary. 
Therefore, FDA has revised the reporting requirements to include those 
elements needed to monitor the size and scope of the treatment IDE, and 
to assess the sponsor's due diligence in seeking marketing approval. 
Under final Sec. 812.36(f), the sponsor of a treatment IDE is required 
to 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 only three items: (1) The number of 
patients treated with the device under the treatment IDE; (2) the names 
of the investigators participating in the treatment IDE; and (3) a 
brief description of the sponsor's efforts to pursue marketing 
approval/clearance of the device. Upon filing of a marketing 
application, progress reports will be required to be submitted annually 
in accordance with Sec. 812.150(b)(5). At the sponsor's option, the 
annual report for the treatment IDE may be combined with the annual 
report for the general IDE or may be submitted separately.
    FDA disagrees that the submission of progress reports conflicts 
with the Paperwork Reduction Act. In accordance with 
Sec. 812.150(b)(4), the sponsor of an IDE is required to submit to FDA, 
at 6-month intervals, a current list of all investigators participating 
in the investigation. Furthermore, under Sec. 812.150(b)(5), at regular 
intervals and at least yearly, the sponsor of an IDE is required to 
submit progress reports to all reviewing IRB's and FDA. Under final 
Sec. 812.36(f), the sponsor of a treatment IDE will be required to 
submit reports on the treatment use at 6 month intervals, the same 
frequency required for updating information about investigators of 
controlled clinical trials. Although the content of the semi-annual 
report differs, the information required is minimal, but nevertheless 
necessary, to maintain control over the treatment use. Therefore, FDA 
believes that semi-annual reporting for treatment IDE's is consistent 
with the reporting requirements for IDE's in general and does not 
conflict with the Paperwork Reduction Act.
     Finally, FDA agrees that the adverse event reporting requirements 
for IDE's in general should provide adequate patient protection for 
treatment IDE's. (See Sec. 812.150(b)(1).) Under final Sec. 812.36(f), 
semi-annual progress reports for treatment IDE's are no longer required 
to include a summary of anticipated and unanticipated adverse device 
effects because this information will be captured in the annual 
progress reports of Sec. 812.150(b)(5) and by the 10-day reporting 
requirements of Sec. 812.150(b)(1).

IV. Environmental Impact

    The agency has determined under 21 CFR 25.24(a)(8) that this final 
rule 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.

V. Analysis of Impacts

    FDA has examined the impacts of the final rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C.601-612) (as 
amended by subtitle D of the Small Business Regulatory Fairness Act of 
1996 (Pub. L. 104-121), and the Unfunded Mandates Reform Act of 1995 
(Pub. L. 104-4). Executive Order 12866 directs agencies to assess all 
costs 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 final rule is consistent with 
the regulatory philosophy and principles identified in the Executive 
Order. In addition, the final rule is not a significant regulatory 
action as defined by the Executive Order and so is not subject to 
review under the Executive Order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Because relevant information should already 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 additional 
burden that could result if sponsors were required to submit new 
applications. As a result, this final rule will not impose significant 
economic impact on any small entities. The Commissioner, therefore, 
certifies that the final rule will not have a significant economic 
impact on a substantial number of small entities. In addition, this 
final rule will not impose costs of $100 million or more on either the 
private sector or State, local, and tribal governments in the 
aggregate, and therefore a summary statement of analysis pursuant to 
section 202(a) of the Unfunded Mandates Reform Act of 1995 is not 
required.

VI. Paperwork Reduction Act of 1995

    This final rule contains information collections requirements that 
are subject to review by the OMB under the Paperwork Reduction Act of 
1995 (44 U.S.C. 3501-3520). The title, description, and respondent 
description of the information collection requirements are shown below 
with an estimate of the annual reporting and recordkeeping 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 the collection of information.
    Title: Investigational Device Exemptions; Treatment Use.
    Description: This regulation establishes the procedures for the 
treatment use of investigational devices. The purpose of this 
regulation is to permit broader availability of investigational devices 
to treat serious or immediately life-threatening diseases or conditions 
for which there are no satisfactory alternative treatments. Under the 
final 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 
for the same use 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 burdens connected with the requirements for applications for 
treatment use are limited, but consistent with protecting patient 
safety and monitoring 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

[[Page 48947]]

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 semi-
annual progress reports until a marketing application is filed, and 
annual reports thereafter.
    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(c)                               6               2              12              20             240       
Total                                                                                                 960       
----------------------------------------------------------------------------------------------------------------
There are no operating and maintenance costs or capital costs associated with this information collection.      

    Based on its experience with the treatment use of drugs and FDA's 
knowledge of the types of devices that may meet the treatment use 
criteria, FDA estimates that an average of six applications will be 
submitted each year. Based upon FDA's knowledge of the preparation of 
IDE's, FDA estimates that it will take approximately 120 hours to 
prepare a treatment use IDE. Thus, the total annual burden for 
preparing applications will be 720 hours.
    Prior to the effective date of this final rule, FDA will publish a 
notice in the Federal Register announcing OMB's decision to approve, 
modify, or disapprove the information collection requirements 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: Secs. 301, 501, 502, 503, 505, 506, 507, 510, 513-
516, 518-520, 701, 702, 704, 721, 801, 802, 803 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, 382, 383); 
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 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 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 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

[[Page 48948]]

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 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 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 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. 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 Sec. 812.150(b)(5). The sponsor 
of a treatment IDE is responsible for submitting all other reports 
required under Sec. 812.150.
    3. Section 812.150 is amended by revising paragraph (b)(5) to read 
as follows:

Sec.  812.150  Reports.

* * * * *
    (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. A sponsor of a treatment IDE shall submit semi-annual 
progress reports to all reviewing IRB's and FDA in accordance with 
Sec. 812.36(f) and annual reports in accordance with this section.
* * * * *

    Dated: August 20, 1997.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 97-24735 Filed 9-17-97; 8:45 am]
BILLING CODE 4160-01-F