[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]
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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.
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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
