[Federal Register Volume 61, Number 124 (Wednesday, June 26, 1996)]
[Rules and Regulations]
[Pages 33232-33248]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-15993]
[[Page 33231]]
_______________________________________________________________________
Part V
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
_______________________________________________________________________
21 CFR Parts 20 and 814
Medical Devices; Humanitarian Use Devices; Final Rule
Federal Register / Vol. 61, No. 124 / Wednesday, June 26, 1996 /
Rules and Regulations
[[Page 33232]]
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 20 and 814
[Docket No. 91N-0404]
RIN 0910-AA09
Medical Devices; Humanitarian Use Devices
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is issuing a final rule
to implement the provisions of the Safe Medical Devices Act of 1990
(the SMDA) regarding humanitarian use devices (HUD's). A HUD is a
device that is intended to benefit patients by treating or diagnosing a
disease or condition that affects or is manifested in fewer than 4,000
individuals in the United States per year. This final rule prescribes
the procedures for submitting humanitarian device exemption (HDE)
applications, amendments, and supplements; procedures for obtaining an
extension of the exemption; and the criteria for FDA review and
approval of HDE's. The purpose of this HDE is, to the extent consistent
with the protection of the public health and safety and with ethical
standards, to encourage the discovery and use of devices intended to
benefit patients in the treatment or diagnosis of diseases or
conditions that affect fewer than 4,000 individuals in the United
States.
DATES: This final rule is effective October 24, 1996.
Written comments on the information collection requirements should
be submitted by August 26, 1996.
ADDRESSES: Submit written comments on the information collection
requirements to the Dockets Management Branch (HFA-305), Food and Drug
Administration, 12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857. All
comments should be identified with the docket number found in brackets
in the heading of this document.
FOR FURTHER INFORMATION CONTACT: Joanne R. Less, Office of Device
Evaluation (HFZ-403), Center for Devices and Radiological Health, Food
and Drug Administration, 9200 Corporate Blvd., Rockville, MD 20850,
301-594-1190.
SUPPLEMENTARY INFORMATION:
I. Background
On November 28, 1990, the President signed into law the SMDA (Pub.
L. 101-629). In enacting the SMDA, Congress sought to improve the
Medical Device Amendments of 1976 (the amendments). The amendments were
the first legislative effort to establish a comprehensive framework to
regulate medical devices and to ensure their safety and effectiveness.
Congress subsequently recognized that for diseases and conditions
affecting small populations, a device manufacturer's research and
development costs could exceed its market returns, thereby creating an
impediment to the development of such devices. In the SMDA, Congress
enacted an amendment to section 520(m) of the Federal Food, Drug, and
Cosmetic Act (the act) (21 U.S.C. 360j(m)) to create an incentive for
the development of devices for use in the treatment or diagnosis of
diseases or conditions affecting a small number of individuals.
Accordingly, section 520(m) of the act authorizes FDA, by
regulation, to exempt a HUD from the effectiveness requirements of
sections 514 and 515 of the act (21 U.S.C. 360d and 360e) (i.e.,
``reasonable assurance that the device is effective'') provided that:
(1) The device is to be used to treat or diagnose a disease or
condition that affects fewer than 4,000 individuals in the United
States; (2) the device would not be available to a person with such a
disease or condition unless the exemption is granted; (3) no comparable
device (other than a device that has been granted such an exemption) is
available to treat or diagnose the disease or condition; and (4) the
device will not expose patients to an unreasonable or significant risk
of illness or injury, and the probable benefit to health from using the
device outweighs the risk of injury or illness from its use, taking
into account the probable risks and benefits of currently available
devices or alternative forms of treatment.
As specified in the statute, an HDE is valid for a term of 18
months from the date of approval but can be extended at 18-month
intervals as long as certain approval criteria are met. Under section
520(m)(5) of the act, an exemption may only be initially granted in the
5-year period commencing on the effective date of this rule, although
extensions may continue to be granted after the expiration of the
initial 5-year period. Section 520(m) of the act also states that a HUD
cannot be sold for an amount that exceeds the costs of research and
development, fabrication, and distribution. In addition, such devices
may only be used in facilities that have established a local
institutional review board (IRB) to supervise clinical testing of
devices, and after an IRB has approved the use of the device to treat
or diagnose the specific rare disease (section 520(m)(3) and (m)(4) of
the act).
On December 21, 1992 (57 FR 60491), FDA published a proposed rule
on humanitarian use devices in the Federal Register. The proposed rule
would have amended the investigational device exemption (IDE)
regulations at part 812 (21 CFR part 812). At that time, FDA believed
that amending the IDE regulations would be preferable to creating a new
part to its premarket approval regulations because part 812 already
contains provisions on IRB review and approval, patient informed
consent, and limitations on charging. In the proposed rule, FDA
explicitly invited comment on ``the advantages or disadvantages of
using the IDE regulation as the means to implement section 520(m) of
the act, as well as the desirability of using other alternative methods
of implementation'' (57 FR 60491 at 60492).
FDA received 11 comments on the proposed rule. In general, most of
the comments opposed including the HDE provisions in part 812. These
comments asserted that applying the IDE regulations would make the HDE
process more burdensome, discourage HUD development, prevent firms from
promoting a HUD or distributing information about a HUD, preclude firms
from obtaining third party reimbursement for a HUD, and increase a
firm's liability insurance costs. In addition, these comments asserted
that this approach would be contrary to the intent behind section
520(m) of the act which, some comments claimed, was to facilitate
marketing of HUD's rather than clinical investigations involving HUD's.
Three comments suggested that FDA implement section 520(m) of the act
by creating special marketing procedures for HUD's under the premarket
approval regulations of part 814 (21 CFR part 814), which implement
section 515 of the act. One of these comments stated that FDA should
issue a new proposal requesting comments on this approach.
Upon further consideration, the agency agrees that placing the HDE
provisions in the IDE regulations is inappropriate because section
520(m) of the act is intended to facilitate the discovery and use of
HUD's rather than to promote their use in clinical studies.
Accordingly, the agency has chosen to create a new subpart H under part
814, specifically addressing HUD's, thereby establishing these devices
as legally marketed products under the act.
[[Page 33233]]
However, section 520(m) of the act, which provides for an exemption
from the effectiveness requirements of sections 514 and 515, also
establishes a number of specific requirements for HUD's that do not
apply to medical devices that are reviewed for both safety and
effectiveness. Therefore, while subpart H references many of the
procedures and requirements set forth elsewhere in part 814, it also
explicitly incorporates the statutory requirements of section 520(m) of
the act.
The final rule is responsive to the comments FDA received on the
proposed rule, which generally objected to the use of the IDE
regulations and supported a marketing approval procedure for HUD's. As
noted above, several comments specifically requested FDA to regulate
HUD's by amending part 814 for device premarket approval applications.
In accordance with the statute and the comments received, the general
approach of this final rule is to treat HDE's as premarket approval
applications (PMA's) that do not require evidence or review of
effectiveness. FDA has followed the statutory provisions of section
520(m) of the act closely in issuing this final rule, and the
differences between the PMA and HDE approval process reflect the
requirements established by Congress for an HDE.
The agency has determined that a reproposal is neither necessary
for reasoned decisionmaking nor desirable as a matter of policy. As
noted above, the proposed rule invited comments on alternative
approaches, including the one now adopted. The comments FDA received
contained significant and thoughtful analysis in favor of the approach
being adopted in this final rule. Accordingly, the agency has concluded
that there is no legal requirement to repropose. Moreover, the SMDA
provided that FDA should issue regulations implementing section 520(m)
of the act within 1 year of the statute's enactment. Further delay
caused by reproposal, therefore, would be inconsistent with the
legislative intent of section 520(m) of the act.
II. Summary of the Final Rule
A HUD is approved for marketing through an HDE application filed in
accordance with the requirements of this final rule. An HDE application
is a PMA application that is not required to contain clinical data
demonstrating ``effectiveness'' (defined under Sec. 860.7(e)(1) (21 CFR
860.(e)(1))) as ``reasonable assurance * * * based upon valid
scientific evidence, that in a significant portion of the target
population, the use of the device for its intended uses and conditions
of use, when accompanied by adequate directions for use and warnings
against unsafe use, will provide clinically significant results''). An
HDE application will contain all other information ordinarily required
in a PMA. In addition, an HDE application will require certain special
information to satisfy the statutory requirements established by
section 520(m) of the act.
A. HUD Designation
Under Subpart H, marketing approval for a HUD is accomplished in
two distinct steps. First, the sponsor of a HUD must submit a request
to FDA's Office of Orphan Products Development (OOPD) seeking a
determination that the disease or condition which the device is
intended to treat or diagnose affects or is manifested in fewer than
4,000 individuals in the United States per year. FDA added the
qualifying phrase ``per year'' in order to clarify this provision of
the statute. The agency believes that defining the criteria on a per
year basis is consistent with the intent of section 520(m) of the act
(i.e., to provide an incentive for the development of devices to be
used in the treatment or diagnosis of diseases or conditions affecting
small patient populations), whereas a point prevalence definition would
be considerably more restrictive and provide less of an incentive for
the development of such devices. In response to comments, FDA also has
added ``or is manifested'' to the definition of a HUD in order to
establish that HUD designation may be appropriate in cases where more
than 4,000 people have the disease but fewer than 4,000 manifest the
condition.
A request for HUD designation may be made at any time, and FDA
encourages applicants to submit the request at the earliest possible
time. In the request for designation, the applicant should include
information that addresses the following three areas. First, the
proposed indication(s) for use should be precisely defined within the
context of current medical and scientific knowledge. If the proposed
indication represents a subset of a larger, more common disease or
condition, the applicant should provide a justification for limiting
the patient population to this subset. Factors such as identification
of the basic pathologic process, chronic versus acute nature of the
disease or condition, age of the patient, compliance history, or mental
competence may also create a viable subset, but the applicant is
responsible for demonstrating that the defined population is medically
plausible. Some devices may be used to achieve similar functions across
a broad spectrum of diagnoses. For example, some apheresis devices are
approved for separation of blood components, generally, and not
approved on a disease by disease basis. In this situation, the
appropriate prevalence would be determined by the combined use of the
device for all diagnostic indications.
Second, in order to permit an understanding of the use of the
device for the proposed indication, the request for HUD designation
should also include a brief description of the device, including
illustrations, as well as a discussion of its principle of operation.
Finally, in order to demonstrate that the rare disease or condition
affects or is manifested in fewer than 4,000 people in the United
States per year, the request should include documentation, with
appended authoritative references, estimating the target population.
For diagnostic devices, the documentation should demonstrate that fewer
than 4,000 patients in the United States per year would be subjected to
diagnosis with the device. FDA recognizes that, in some cases, the
number of patient contacts with a device may exceed one per patient.
Such devices may still qualify for HUD designation as long as the total
number of patients treated or diagnosed with the device is less than
4,000 per year in the United States.
Within 45 days of receiving a request for HUD designation, OOPD
will issue its determination based upon the information submitted by
the sponsor as well as OOPD's own research and consultation. In some
cases, OOPD may consult with the Center for Devices and Radiological
Health (CDRH) regarding the proposed patient population to be treated
or diagnosed with the device. In response to the designation request,
OOPD will either approve the request, return it pending submission of
additional information, or disapprove the request. If the request for
designation does not contain all of the information required under
Sec. 814.102(a), it will be returned to the applicant with a
description of the deficiencies. If the applicant chooses to address
the deficiencies and resubmit the request for HUD designation, OOPD
will reevaluate the application. The request for HUD designation may be
disapproved if: (1) There is insufficient evidence to support the
estimate that the disease or condition which the device is designed to
treat or diagnose affects or is manifested in fewer than 4,000 people
in the United States per year; (2) FDA determines that, for a
diagnostic device, 4,000 or more patients in the United States would be
[[Page 33234]]
subjected to diagnosis using the device per year; or (3) FDA determines
that the patient population defined in the request is not a medically
plausible subset of a larger population. If FDA disapproves the request
for HUD designation, the applicant may address the reasons for
disapproval and resubmit the request.
B. HDE Application
If OOPD determines that a device is eligible for designation as a
HUD, this determination must be included or referenced in the HDE
application that is subsequently submitted to the Office of Device
Evaluation (ODE), CDRH, FDA. The agency believes that this two-step
process will make optimal use of its own time and resources as well as
that of HDE applicants by ensuring that HDE's are only prepared and
reviewed for devices genuinely eligible for HUD status.
The HDE application, which should be submitted to ODE, is similar
in both form and content to a PMA application submitted under
Sec. 814.20. For example, the HDE application must contain a summary of
the indications for use of the device, significant physical and
performance characteristics of the device, and any clinical and
nonclinical data that are relevant to evaluating the safety and
probable benefit of the device. The application must contain sufficient
information for FDA to determine, as required by the statute, that the
device does not pose an unreasonable risk of illness or injury to
patients and that the probable benefit outweighs the risk of injury or
illness from its use, taking into account the probable risks and
benefits of currently available devices or alternative forms of
treatment. FDA believes that such a determination cannot be made in the
absence of most of the information required to be filed under a full
PMA submitted in accordance with Sec. 814.20.
However, the HDE is not required to contain the results of
scientifically valid clinical investigations demonstrating that the
device is effective for its intended purpose. While in some instances
there may be little or no clinical experience with the device, an
applicant is required to include such information in the HDE whenever
it is available. Depending upon the nature of the device and its
associated risks, FDA may require that clinical data regarding the
safety of the device be collected in support of an HDE. Clinical
investigations of a HUD are subject to the requirements of part 812,
which may require the submission of an IDE to FDA if the device study
poses a ``significant risk'' (Sec. 812.3(m)).
An HDE application must also contain information that will allow
FDA to make the other determinations required by section 520(m) of the
act. Specifically, the HDE must contain information to enable FDA to
determine that: (1) The device would not otherwise be available unless
an HDE were granted, and (2) no comparable device (other than another
HUD approved under this subpart or a device being studied under an
approved IDE) is available to treat or diagnose the disease or
condition. In order to address why the device would not otherwise be
available unless an exemption is granted, the applicant should estimate
the number of patients who would be required to generate data to
support a full PMA and explain why such a study is not feasible or why
the cost of conducting such a study could not reasonably be expected to
be recovered. (See S. Rept. 513, 101st Cong., 2d sess. 41 (1990).)
C. Charging for the Device
Section 520(m) of the act does not permit devices marketed under
the HDE provision to be sold for a price that exceeds the costs of
research and development, fabrication, and distribution of the device.
Therefore, the final rule requires that an HDE application include a
report by an independent certified public accountant verifying that the
amount to be charged does not exceed the costs of research and
development, fabrication, and distribution for the device. FDA also
expects research and development costs to be treated (i.e., capitalized
or expensed) in accordance with guidelines or requirements of the
Financial Accounting Standards Board.
D. FDA Action
As with a PMA application, FDA will notify the submitter of an
original HDE or an HDE supplement, within 45 days, whether the
submission is sufficiently complete to permit substantive review. FDA
may refuse to file an HDE or HDE supplement if: (1) The application is
incomplete; (2) FDA determines that there is a comparable device
available, other than under this exemption or an approved IDE, to treat
or diagnose the disease or condition for which approval of the HUD is
being sought; or (3) the application contains a false statement of
material fact.
If the HDE is filed, the agency will act upon the application
within 180 days from the time such application is received by the
agency. FDA believes that this timeframe will generally be required to
perform a thorough evaluation of a HUD's safety, probable benefit,
proposed labeling, and any appropriate conditions of approval. If the
HDE applicant believes that the HUD may meet the agency's criteria for
expedited review (i.e., the device is for a life-threatening or
irreversibly debilitating condition, provides a clear, clinically
meaningful advantage over existing technology, or meets a specific
public health need, as determined by FDA), the applicant is encouraged
to raise this issue when submitting the application. In reviewing an
HDE, the same options available to FDA under the PMA regulations
(namely, issuing an approval order, an approvable letter, a not
approvable letter, or a denial of approval order) are available,
although the criteria for each action are different in some important
respects from Secs. 814.44 and 814.45 of the PMA regulations. For
example, as specified by the statute, one of the criteria for approval
of an HDE is that the device would not otherwise be available unless
this exemption were granted. Therefore, if an HDE applicant has
established that the affected patient population is fewer than 4,000
per year but each patient may require numerous devices, the agency may
determine that the device would be commercially viable and thus not
meet this statutory requirement for the exemption. (See H. Conf. Rept.
959, 101st Cong., 2d sess. 28 (1990).)
Approval of an HDE is valid for a period of 18 months. After that
time, the device may continue to be marketed only if the HDE holder has
sought and obtained an extension of the exemption as provided for in
Sec. 814.120. During the period of marketing approval, HDE holders are
strongly encouraged to collect data that may later be submitted in
support of a full PMA.
E. Labeling for a HUD-
Because labeling for a humanitarian use device is not addressed in
section 520(m) of the act, the labeling requirements for a HUD reflect
the comments received on this issue and the agency's desire to disclose
pertinent information regarding HUD's to health care practitioners.
Therefore, under the final rule, the labeling for a HUD will state that
the device is a humanitarian device, that use of the device to treat or
diagnose a specific disease or condition is authorized by Federal law,
and that the effectiveness of the device for the specific use has not
yet been demonstrated.
F. Postapproval Requirements
During the period of marketing approval, the HDE holder is subject
to the requirements of the good manufacturing practice (GMP)
[[Page 33235]]
regulations unless an exemption is sought by the applicant and granted
by FDA. Devices approved under subpart H are also subject to the
postapproval requirements and reports set forth under subpart E of part
814, including medical device reporting requirements (part 803 (21 CFR
part 803)) and labeling requirements (21 CFR parts 801 and 809). In
addition, a holder of an approved HDE is required to notify FDA of the
withdrawal of approval for the use of a HUD by a reviewing IRB within 5
working days after being notified of the action.
G. Extension Requests -
As stated previously, approval of an HDE differs in several
important respects from the approval of a PMA submitted under
Sec. 814.20. By statute, approval of an HDE is valid for a period of 18
months, after which the device may no longer be marketed unless the HDE
holder has sought and obtained an extension as provided for in
Sec. 814.120 of subpart H. The request must be submitted prior to
expiration of marketing approval. FDA will review extension requests
within 90 days; therefore, in order to avoid the risk of a lapse in
approval, the request must be submitted at least 90 days prior to the
expiration. The request for extension shall be clearly marked as such,
and should be submitted to ODE.
The request should also include an update of the information that
was originally submitted in the HDE application, as well as a
separately bound volume which addresses the device's continuing
qualification for HUD designation. (ODE will submit this volume to OOPD
for review.) The request should include an update of the information
originally required (Sec. 814.104(c)(2), (c)(3), and (c)(5)) as well as
information describing the applicant's experience with the device since
the HDE was initially approved (Sec. 814.120(b)(4)). This shall include
any new safety information that is known or reasonably should be known
to the applicant, medical device reports made pursuant to part 803, any
data generated from postmarketing studies, and any published or
unpublished information that is known or reasonably should be known
that may affect an evaluation of the safety of the device or that may
affect the statement of contraindications, warnings, precautions, and
adverse reactions in the labeling. In order to allow the applicant
adequate time to prepare the request for extension, FDA would expect
the request for extension to include the applicant's experience with
the device based on the first 12-month period following the most recent
approval of the HDE. The request shall also include a summary of any
changes to the device (as permitted under Sec. 814.108 of the final
rule).
The HDE holder must also include data demonstrating that the number
of devices shipped or sold is consistent with the earlier determination
by OOPD that the device is for a disease or condition affecting or
manifested in fewer than 4,000 patients per year. If the number of
devices shipped or sold during the previous 12 months of marketing
approval exceeds 4,000, the HDE holder should include an explanation
and estimate of the number of devices used per patient. If a single
device is used on multiple patients, the applicant shall submit an
estimate of the number of patients treated or diagnosed using the
device together with an explanation of the basis for the estimate. If
experience during the period of marketing approval so indicates, the
agency may determine that the device no longer meets the statutory
requirements for HDE's.
Under the final rule, FDA will respond to extension requests within
90 days of receipt of such a request, or the request shall be deemed
approved. Requests for extension may be granted more than once and may
be granted even after the expiration of the initial 5-year period. In
the event that the HDE holder does not wish to extend the HDE, a final
report is required to be submitted no later than 90 days following the
expiration of the period of marketing approval (Sec. 814.126(b)(i)).
H. IRB Approval -
Section 520(m)(4) of the act states that a HUD may only be used in
facilities that have established, in accordance with FDA regulations,
``a local institutional review committee [commonly known as an
institutional review board or IRB] to supervise clinical testing of
devices in the facilities.'' The statute also requires an IRB to
approve the use of the HUD before the device is administered to humans.
In accordance with this statutory requirement, FDA has specified in
subpart H of part 814 that the HDE holder must ensure that the HUD is
administered only to patients at health care facilities having an IRB.
IRB's which oversee the use of a HUD should be constituted and act
in accordance with the agency's regulations governing IRB's (21 CFR
part 56), including responsibility for continuing review of use of the
device. FDA has codified this requirement in Sec. 814.124. The agency
does not believe the statute intends to require IRB review and approval
for each individual use of the HUD. FDA has interpreted the statute to
permit the IRB to approve the use of the device in general, use of the
device for groups of patients meeting certain criteria, or use of the
device under a treatment protocol. If it so wishes, an IRB may specify
limitations on the use of the device based upon one or more measures of
disease progression, prior use and failure of any alternative treatment
modalities, reporting requirements to the IRB or IRB chair, appropriate
followup precautions and evaluations, or any other criteria it
determines to be appropriate.
It should be emphasized that under the final rule (Sec. 814.124),
it is the HDE holder who is responsible for ensuring that the HUD is
not administered to or implanted in a patient prior to obtaining IRB
approval at the health care facility. An HDE holder may wish to enforce
this requirement by not shipping the HUD to the health care facility
until it has received confirmation of IRB approval. In order to provide
flexibility to the approval requirement, FDA has included a provision
that permits an IRB located at a treatment facility to defer (in
writing) to another similarly constituted IRB that has agreed to assume
responsibility for initial and continuing review of the use of the
device.
I. Informed Consent-
Section 520(m) of the act does not require that informed consent be
obtained before a HUD is used. Therefore, subpart H of the final rule
does not include a provision requiring compliance with the informed
consent regulations (part 50 (21 CFR part 50)). FDA has decided that a
humanitarian device exemption, which provides for temporary marketing
approval, does not constitute ``research'' or an ``investigation,''
which would normally require informed consent. A HUD is intended to
benefit patients who have a rare disease or condition rather than to
generate data to support a finding of effectiveness. FDA believes,
therefore, that waiving compliance with the informed consent
regulations is consistent with section 520(m) of the act because the
statute expressly uses the phrase ``to the extent consistent with the
protection of the public health and safety and with ethical standards''
rather than requiring informed consent from each patient.
Notwithstanding the above, FDA does not intend to preempt any
applicable requirement for informed consent that may be imposed as a
matter of State law or institutional policy.
As a point of clarification, however, if a HUD is the subject of a
clinical
[[Page 33236]]
investigation, informed consent from the patients involved in the study
would be required. Thus, if a holder of an approved HDE wishes to
collect safety and effectiveness data in support of a PMA, compliance
with part 50 would be required at those institutions participating in
the investigation.
III. Response to Comments
The proposed rule consisted of 10 provisions. Nine provisions
proposed amending the existing IDE regulations to establish content
requirements for HDE applications and supplements, as well as FDA
action on such applications; the tenth provision proposed a
certification statement for HDE applications. FDA received 11 comments
on the proposed rule. As discussed earlier, most of the comments
generally disagreed with the proposed amendments to the IDE regulations
or sought changes to the proposed HDE provisions. One comment supported
the proposed rule without any changes. A summary of the comments and
the agency's response to them is provided below.
A. General Comments
1. Several comments asserted that the proposed rule would require
too much data and information from HUD sponsors.
FDA disagrees with these comments. In granting an HDE, the agency
must have sufficient information to enable it to make the
determinations required by section 520(m) of the act, including the
pivotal determinations that the device will not expose patients to an
unreasonable or significant risk of illness or injury and that the
probable benefit to health from use of the device outweighs the risk of
injury or illness, taking into account the probable risks and benefits
of currently available devices or alternative forms of treatment. The
agency can only make these determinations if the sponsor provides FDA
with sufficient data, including information about device design,
materials, laboratory and animal studies, as well as any available
clinical experience with the device.
2. One comment claimed that the proposal had little value because
long PMA review times would mean that few HUD's could be approved for
use before section 520(m) of the act expired (since the HDE authority
expires 5 years from the date this final rule takes effect).
FDA disagrees with this comment. Average FDA review times for
original PMA's have been decreasing. In addition, there is not
necessarily a correlation between PMA review times and review times for
HDE's. FDA believes that it will be able to meet the 180-day review
time set forth in subpart H. Moreover, although an HDE is initially
approved for only 18 months, extensions of the exemption period may
continue to be granted after the end of the 5-year period. -
3. One comment recommended amending the PMA regulations instead of
the IDE regulations and also relieving HUD's from certain IDE
requirements. The comment would amend Sec. 812.2(b) so that a HUD would
be considered to have an approved IDE and be subject only to the
``abbreviated requirements'' of the IDE regulations.
As recommended in the comment, FDA has chosen to amend the PMA
regulations rather than the IDE regulations as a means of implementing
section 520(m) of the act. The agency declines, however, to adopt the
recommended change to Sec. 812.2(b). Section 812.2(b) states, in
essence, that an investigation involving a nonsignificant risk device
shall be considered as having an approved IDE as long as certain
regulatory requirements are met. Although section 520(m) of the act
only permits approval of HDE's if the device ``will not expose patients
to an unreasonable or significant risk,'' it is possible that a HUD
could be tested in an investigation involving procedures that present a
serious risk to a subject's health or safety (i.e., a ``significant
risk'' study that requires an FDA-approved IDE). Furthermore, rare
diseases for which HUD's are developed may be serious conditions
requiring an intervention that poses some risk of harm. Consequently,
it would be inappropriate to presume, or to infer that Congress
intended, that all HUD's qualify as ``nonsignificant risk'' devices, as
proposed in the comment.
4. The same comment, as part of its recommendation to place the HUD
requirements in part 814, suggested conforming changes to the
``Purpose'' and ``Definitions'' sections at Secs. 814.2 and 814.3,
respectively, to account for HUD's. The comment would create a new
subpart F in part 814, entitled ``Humanitarian Device Applications,''
that would contain a general statement on HUD's, prescribe labeling
requirements (including a required statement showing that the device is
a humanitarian device whose use is limited to a specific treatment or
diagnosis of a disease or condition and has not been shown to be
effective), and prohibit commercialization (although it would permit
``incidental'' profits which exceed ``good faith estimates of costs'').
The comment patterned its suggested HDE application requirements after
the PMA application requirements in Sec. 814.20, recommending that an
HDE application include, among other things, information on the
device's indications for use, a description of the device (including an
explanation of how the device functions, the basic scientific concepts
forming the basis for the device, and the device's significant physical
and performance characteristics), a description of the device's
marketing history in the United States and in foreign countries, a
summary of safety studies or other information, and conclusions drawn
from safety studies or other information. The comment further suggested
that the application contain a complete description of the device, its
functional components or ingredients, the device's properties relevant
to the diagnosis, treatment, prevention, cure, or mitigation of a
disease or condition, its operating principles, a discussion of current
good manufacturing practices applied to the device, references to any
performance standard under section 514 of the act or the Radiation
Control for Health and Safety Act of 1968 or any voluntary standard
relevant to any aspect of the device's safety ``that is known to or
that should reasonably be known to the applicant,'' including
information demonstrating how the device meets or deviates from a
performance standard or deviates from a voluntary standard.
The comment further suggested that FDA create a new provision on
labels and that the labels provide the manufacturer, packager, or
distributor's name and place of business, the quantity of contents (if
appropriate), and a ``Caution'' statement declaring:
CAUTION--Humanitarian Device. Limited by Federal (or United
States) law to use in the treatment or diagnosis of [specify disease
or condition]. The effectiveness of this device in treating or
diagnosing [specify disease or condition] had not been demonstrated.
The label would also describe ``all relevant contraindications,
hazards, adverse effects, interfering substances or devices, warnings,
and precautions'' and not represent that the device is effective for
the humanitarian use.
Additionally, the comment would have the application contain
information showing why any amount to be charged does not constitute
commercialization of the device, an environmental assessment or request
for categorical exclusion under part 25, and ``such other information
as FDA may request.'' The comment would also authorize FDA to refer to
information in a master file or to other information submitted to FDA
by a person other than the applicant, but only if the applicant had
written authorization to
[[Page 33237]]
refer to such information. The comment would have FDA return a master
file to the person who filed it if no one referenced that master file
within 5 years after it was submitted to FDA.
The agency agrees, in part, with the comment and has revised the
final rule to amend the PMA regulations by adding a new subpart
concerning premarket approval for HUD's. The agency elected to adopt
this approach because it was persuaded by the comments that section
520(m) of the act was intended to encourage marketing rather than
investigational use of humanitarian use devices. While it exempts a HUD
from demonstrating effectiveness, section 520(m) of the act establishes
some requirements for approval of HUD's that are similar to the IDE
requirements under section 520(g). For example, section 520(m) of the
act states that the HUD provisions should function to the extent
``consistent with the protection of the public health and safety and
with ethical standards'' and require IRB approval before the use of the
device.
Thus, FDA used the PMA provisions suggested by the comments as a
template for the format and content of an HDE and issued different or
additional provisions when such changes were required by the statute.
Accordingly, Sec. 814.104(c)(4) requires the application to contain
most of the information required under Sec. 814.20(b), with the
exception of clinical data demonstrating the effectiveness of the
device. In lieu of such evidence, the HDE must nevertheless contain
``summaries, conclusions, and results of all clinical experience or
investigations (whether adverse or supportive) reasonably obtainable by
the applicant which are relevant to an assessment of the risks and
probable benefits of the device.'' FDA emphasizes that data or
information, whether derived from clinical or nonclinical studies or
laboratory experience, relating to the device's use in humans may be
critical in determining whether the risk of illness or injury outweighs
the probable benefit from using the device, taking into account the
probable risks and benefits of currently available devices or
alternative forms of treatment. While an HDE applicant will not be
required to generate data from clinical investigations to demonstrate
the device's effectiveness, clinical data may sometimes be necessary in
order to demonstrate this risk/benefit relationship.
FDA agrees, in part, with the comment's suggested format and
content for the labeling of a HUD. FDA believes that the label should
disclose that the effectiveness of the device has not yet been
demonstrated. The agency does not, however, believe that the HUD label
needs to contain the word ``Caution,'' because that term may imply that
the device exposes the patient to dangers not ordinarily associated
with lawfully marketed products. Also, in view of the safety analysis
that FDA will perform in reviewing HDE's, as well as the requirement of
IRB approval, the agency does not believe that the word ``Caution'' is
necessary.
In response to the comment suggesting that FDA return a master file
to the person who submitted it in the event that the file is not
referenced within 5 years after its submission to FDA, the agency notes
that such a requirement already exists in part 814 (Sec. 814.20(c)) and
that it is therefore applicable to applications submitted under subpart
H.
5. As part of its recommendation to amend the PMA regulations to
include HDE's, one comment would create a new reporting provision to
require applicants to update safety information ``that may reasonably
affect the evaluation of the safety of the device or that may
reasonably affect the statement of contraindications, warnings,
precautions, and adverse reactions'' in the labeling. The comment would
require compliance with the medical device reporting requirements in
part 803 and would require the submission of reports at 6-month
intervals after approval of the HDE application. These reports would
identify changes affecting the device and contain a summary and
bibliography of unpublished reports involving the device or related
devices that are known to or should reasonably be known by the
applicant as well as reports in the scientific literature. The comment
would not require the applicant to provide copies of reports in the
scientific literature unless FDA notified the applicant that it should
submit those reports. The comment's suggested provision would be
similar to the existing reporting requirements for PMA's at
Sec. 814.84.
The agency agrees, in part, with the comment. Under Sec. 814.126,
an HDE approved under subpart H is subject to the postapproval
requirements and reports as required for PMA's (subpart E of part 814).
In addition, HDE holders must provide the IRB of record with a copy of
any report submitted in compliance with the requirements of part 803.
Also, under Sec. 814.126(b)(1), if a request for extension of the
exemption is not submitted, a final report must be submitted to the
agency no later than 90 days after the expiration of the marketing
approval. This final report should contain an estimate of the number of
devices shipped or sold and the number of patients treated or
diagnosed, information regarding the retrieval or disabling of unused
devices, a summary of results or conclusions with regard to the
clinical use of the device, and a summary of the medical device reports
submitted under part 803. The final report should also contain a
summary and bibliography of published and unpublished data, reports,
and studies involving the device that are known to or should reasonably
be known by the applicant and were not previously submitted to the
agency.
In addition to the above reports, Sec. 814.124(b) requires the
holder of an approved HDE to notify FDA within 5 working days of any
withdrawal of approval for use of a HUD by a reviewing IRB. Finally,
Sec. 814.126(b)(2) instructs applicants to maintain records of the
names and addresses of the facilities to which the HUD's have been
shipped, correspondence with reviewing IRB's, and any other information
requested by a reviewing IRB or FDA. All such records should be
maintained for the duration of the period that a HUD is approved for
marketing.
The agency declined to accept the comment's suggestion for the
submission of periodic reports (at 6-month intervals) because FDA
believes it is unlikely that many changes or significant new
information ordinarily would be generated for a HUD in such a short
period of time.
6. As part of its suggestion that FDA amend the PMA regulations
rather than the IDE regulations, one comment proposed a new provision
describing where an HDE application should be sent.
The agency agrees that such a provision is necessary and has
specified in Sec. 814.104(e) that HDE applications, amendments,
supplements, requests for extension, and related correspondence
(excluding reports submitted under part 803) should be sent or
delivered to the Document Mail Center (HFZ-401), Office of Device
Evaluation, Center for Devices and Radiological Health, Food and Drug
Administration, 9200 Corporate Blvd., Rockville, MD 20850.
B. Specific Provisions and Comments
Proposed Sec. 812.1(b) Scope-
7. Proposed Sec. 812.1(b) would have added HDE provisions to the
IDE regulations. Because the agency has elected to create a new subpart
H under part 814, the agency has renumbered this provision as
Sec. 814.100 and
[[Page 33238]]
redesignated it as ``Purpose and Scope.'' Under this section, FDA has
also modified the reference to uses other than humanitarian uses. The
proposed rule stated that the HDE provisions applied only to
humanitarian uses; FDA has modified this statement to note that persons
seeking approval of non-HUD uses must comply with the premarket
approval or premarket notification provisions of the regulations, as
appropriate.
Proposed Sec. 812.3(d) Humanitarian Use Device (HUD)
8. Proposed Sec. 812.3(d) defined a HUD as ``a device that is
intended for use in the treatment or diagnosis of a disease or
condition that affects fewer than 4,000 individuals in the United
States and that otherwise meets the requirements in 21 U.S.C.
360j(m)(2).''
Three comments recommended revising the definition of a HUD. The
comments would revise the definition to include manifestations of a
disease so that, even if the total number of patients who had a disease
or condition exceeded 4,000, one could obtain an HDE if the patient
population that manifested the disease was less than 4,000.
FDA agrees with the comments and has modified the definition of a
HUD to state that the device must be intended for use in the treatment
or diagnosis of a disease or condition that ``affects or is manifested
in fewer than 4,000 individuals in the United States per year.'' This
definition has been added to the existing definition section of part
814. The agency has also modified the definition to clarify that the
number of affected patients is determined at the time the request for
HUD designation is submitted under Sec. 814.102, and again each time a
request for extension is submitted under Sec. 814.120. Regarding this
prevalence determination, FDA would not withdraw approval of an HDE
solely because it is subsequently determined that the disease or
condition for which the HUD is intended affects or is manifested in
more than 4,000 people in the United States per year. However, this
fact may serve as a basis for disapproving an extension request.
9. One comment suggested revising the definition of a HUD by
paraphrasing section 520(m)(2)(A) through (m)(2)(C) of the act.
FDA declines to amend the definition as suggested by the comment.
The final rule's definition of a HUD incorporates language from section
520(m)(2)(A) of the act and conveys that, based solely on the estimated
prevalence or manifestation of a rare disease or condition, a
particular device has been found eligible for review under subpart H.
This eligibility will be determined by the division within OOPD with
the most expertise in these matters. The statutory provisions which the
comment suggests for inclusion in the definition of a HUD are
requirements for approval of the HDE application (i.e., the device
would not otherwise be available, there is no comparable device, the
device would not expose patients to an unreasonable or significant risk
of illness or injury, and the benefits of using the device outweigh the
risks). Review of the HDE application and these approval decisions will
be made by ODE, which is the group within CDRH that reviews PMA's.
Furthermore, FDA believes that it is useful to have a term that
describes those devices that are eligible for an HDE, i.e., qualify as
a humanitarian use device, but have not yet been granted marketing
approval under subpart H.
10. One comment suggested defining ``HDA'' as ``any humanitarian
device application, including all information submitted with or
incorporated by reference therein.'' The comment also suggested
defining ``safe'' or ``safety,'' for HUD purposes, as meaning that the
device ``will not expose patients to an unreasonable or significant
risk of illness or injury and the device's probable benefit outweighs
the risk of injury or illness associated with its use.''
FDA declines to adopt this suggestion. Section 520(m) of the act is
titled ``Humanitarian Device Exemption'' and authorizes the agency to
grant an exemption from the effectiveness requirements of sections 514
and 515 of the act. Therefore, the agency will refer to an application
submitted pursuant to section 520(m) of the act as a ``humanitarian
device exemption application'' or ``HDE.'' This represents a more
accurate description of the application itself.
Regarding the comment's suggested definition of ``safe'' or
``safety,'' FDA notes that this definition is similar to the statutory
requirement that a HUD ``not expose patients to an unreasonable or
significant risk of illness or injury, and the probable benefit to
health from using the device outweighs the risk of injury or illness
from its use, taking into account the probable risks and benefits of
currently available devices or alternative forms of treatment.''
Because Sec. 814.118 of the final rule includes failure to meet this
criterion as a basis for denying or withdrawing approval of an HDE, FDA
believes that repeating the risk-benefit concept in the definition
section is unnecessary.-
Proposed Sec. 812.10 Waivers
FDA received four comments on the proposed waivers from the IDE
requirements. Although the final rule does not waive any sections of
the IDE regulations, the agency believes that some of the issues raised
in the comments merit discussion or clarification.
11. One comment questioned whether clinical data generated under an
HDE application would still qualify as ``valid scientific evidence''
under Sec. 860.7. The comment asserted that, if clinical data generated
under an HDE application is not ``valid scientific evidence'' within
Sec. 860.7, then there would be little incentive to submit an HDE
application.
Although the final rule for HDE's provides for marketing approval
under subpart H of part 814, rather than investigation under part 812,
this comment does raise the issue of whether the HDE application, which
is a marketing application under part 814, must contain ``valid
scientific evidence'' as defined in Sec. 860.7. FDA recognizes that
there are a limited number of patients for whom a HUD may have been
prescribed and that the device was likely to have been used in a
treatment rather than research context. FDA, therefore, intends to
exercise its discretion in applying Sec. 860.7 to the data submitted in
support of an original HDE or HDE extension request and not require the
HDE to contain the same valid scientific evidence as other premarket
approval applications. However, FDA urges HDE applicants, whenever
possible, to try to ensure that clinical information submitted in
support of an original HDE or an HDE extension request does constitute
``valid scientific evidence.''
12. One comment questioned the applicability of GMP regulations to
HDE applicants, particularly where the applicant is a university or
hospital.
The quality systems for FDA regulated products (food, drugs,
biologics, and devices) are known as the good manufacturing practice
regulations or GMP's. GMP requirements for devices (part 820 (21 CFR
part 820)) were first authorized by section 520(f) of the act which was
among the authorities added to the act by the 1976 Amendments (Pub. L.
94-295). GMP's are intended to ensure that the methods, facilities, and
controls used for manufacturing, packing, storing, and installing a
finished device are appropriate and will ensure that the device is safe
for use.
The SMDA amended section 520(f) of the act, providing FDA with the
explicit authority to add preproduction design validation controls to
the GMP
[[Page 33239]]
regulation. FDA expects to publish a final rule revising the GMP
regulations in the near future.
Under the final rule, HUD's will be subject to the GMP regulations,
as are other legally marketed devices. The agency may require as a
condition of approval that the HDE applicant demonstrate compliance
with these regulations (e.g., through an inspection). However,
consistent with the regulatory flexibility which FDA believes Congress
intended in enacting the HUD exemption, the agency intends to focus
primarily on those manufacturing practices that the agency deems most
relevant to the safety of the device. An HDE applicant or holder who
believes that he/she cannot comply or should not be held to GMP
standards may request an exemption from such requirements
(Sec. 820.1(d)). In evaluating such exemption requests, FDA will give
overriding consideration to the risks posed by the device, the
potential risks that a manufacturing defect might pose to patients, and
the public health need for the device.
13. One comment suggested adding Sec. 812.35(a) and (b) to the list
of IDE requirements that would be waived for a HUD. Currently,
Sec. 812.35(a) requires a supplemental IDE if a sponsor or investigator
proposes a change in the investigational plan that may affect the
plan's scientific soundness or the subjects' rights, safety, or
welfare. Section 812.35(b) requires sponsors to submit to FDA a
certification of any IRB approval of an investigation or part of an
investigation that is not included in an IDE. The comment asserted that
these supplemental IDE requirements are time-consuming and deprive
patients from receiving a device.
Because the agency has elected to create a new subpart H that
provides for marketing approval for HUD's rather than amending the IDE
regulations, the issue raised by the first part of this comment is
moot. In reference to the suggestion that sponsors should not be
required to submit supplemental applications to FDA when IRB approval
is obtained, the agency agrees, and the final rule does not require FDA
to be notified of such approval.
14. One comment asserted that the waivers in proposed Sec. 812.10
would not adequately reduce the cost of preparing IDE's and PMA's.
Although proposed Sec. 812.10 is not a part of the final rule, the
agency notes that section 520(m) of the act is intended to encourage
the discovery and use of devices intended to benefit patients in the
treatment or diagnosis of diseases or conditions that affect small
populations by granting an exemption from the effectiveness
requirements of sections 514 and 515 of the act. Such an exemption from
the effectiveness requirements should significantly lower the cost of
preparing a marketing application. -
Proposed Sec. 812.20(e)(2) Information Required for HUD's
15. Proposed Sec. 812.20(e)(2) would have required the agency to
determine that the device would not be available to a person with a
rare disease or condition without an exemption and that ``there is no
comparable device, other than under this exemption, available to treat
or diagnose such disease or condition.'' One comment would modify the
reference to ``no comparable devices'' so that other investigational
devices in addition to HDE-devices would not be considered as
``comparable devices.''
FDA agrees with the comment and has modified the provision, which
is now codified at Sec. 814.104(c)(2), to include devices under an
approved IDE. FDA wishes to emphasize that a ``comparable'' device need
not be identical to the device that is the subject of the HDE
application in order for the agency to determine that the applicant's
device does not qualify for the statutory exemption. In determining
whether a ``comparable device'' exists, FDA will consider the device's
intended use and technological characteristics and make a judgment
regarding the degree to which it is similar to any lawfully distributed
device (other than another HUD or a device under an approved IDE). The
agency will use the information provided by the applicant as well as
any other information at its disposal to determine whether a comparable
device exists.
Sec. 812.27 Report of Prior Investigations
16. Although FDA did not propose any amendments to Sec. 812.27, one
comment suggested adding a new paragraph to Sec. 812.27(a) to state:
When long-term testing is required to justify the proposed
investigation, the application must include: (i) A description of
the long-term tests; (ii) a description of the test protocol and
number of samples in the test; (iii) the rationale for the test and
protocol; and (iv) a timetable for completing the tests.
Although the comment is no longer literally applicable because the
final rule amends part 814 rather than part 812, the agency agrees in
part with the comment. The HDE application, which is now part of the
PMA regulations, must provide sufficient information about the device
to permit the agency to determine that its use will not unduly put
patients at risk and that there is some probable benefit to using the
device. This determination requires the submission of preclinical
testing, and in some cases clinical testing, to support such a finding.
However, because section 520(m) of the act provides for initial
humanitarian use exemptions only for 5 years from the effective date of
the final rule, and because the term of an exemption or renewal is 18
months, the agency does not anticipate that many long-term tests will
be performed in support of an original HDE application. When
appropriate, FDA could provide for such testing as a condition of
approval under Sec. 814.116(c).
Proposed Sec. 812.35(c) Request for Extension of a HUD Investigation
FDA received three comments pertaining to proposed Sec. 812.35(c),
which would have established certain requirements for requesting an
extension of a HUD investigation.
17. One comment asserted that clinical investigations may prompt a
sponsor to change a device's design or performance characteristics, but
that submitting a supplemental application (to reflect the changes in
the device) would be time consuming and would deny patients access to
the modified device. The comment suggested adding a new provision
stating that supplemental HDE applications are not required to be
submitted to FDA if an IRB reviewed the device modification together
with other relevant data and determined that the modification will not
expose patients to additional risk. Additionally, the comment would
require the sponsor to maintain a description of each device
modification, a summary of all tests, a rationale for why the
modification does not expose patients to additional risk, a
modification to any long-term clinical investigation plans, and a copy
of a letter from the IRB that reviewed the modification.
The agency declines to amend the rule as suggested by the comment.
While section 520(m)(4)(B) of the act requires IRB approval for the use
of a HUD, it is FDA that is required to determine the relative safety
and potential benefit of the device for the intended patient
population. Additionally, the agency notes that IRB's may not possess
the technical or scientific expertise that may be required to review a
supplemental application for device modifications. FDA regulations
require IRB's to have members who ``shall be sufficiently qualified
through the experience and expertise of its members * * * to promote
respect for its advice and counsel in safeguarding the
[[Page 33240]]
rights and welfare of human subjects'' (21 CFR 56.107(a)). Thus, IRB
members focus on ethical concerns rather than on the scientific and
technological issues that supplemental applications usually address.
Finally, the requirement for agency review of device modifications for
HUD's is consistent with the procedures required for other types of
marketing applications (PMA's and premarket notifications (510(k)'s)).
18. One comment addressed the preamble discussion for proposed
Sec. 812.35. The comment claimed that the preamble to the proposed rule
erred in describing extensions of an HDE. The preamble to the proposed
rule stated that, ``[a] request for an exemption extension which would
allow the continuation of the investigation would have to contain any
relevant new information as to the safety and effectiveness of the HUD
or the prevalence of the disease or condition for which the exemption
was first approved * * *'' (57 FR 60491 at 60493). The comment said
that FDA should delete the word ``effectiveness'' because the HDE
eliminates the need to comply with the effectiveness requirements in
the act.
FDA agrees that an approved HDE relieves a party from the
effectiveness requirements of sections 514 and 515 of the act.
Accordingly, Sec. 814.120 of the final rule, which provides for
extensions of the exemption, does not require that effectiveness
information be included with the request. The agency wishes to note,
however, that clinical experience gathered under an HDE may provide
information regarding a device's effectiveness that would be relevant
to FDA's making the statutorily-mandated determination that ``the
probable benefit to health * * * outweighs the risk of injury or
illness * * *.'' In addition, Sec. 814.118(a)(2) of the final rule
states that a determination by FDA that the ``device is ineffective
under the conditions of use prescribed, recommended, or suggested in
the labeling thereof'' is sufficient grounds for denial of approval of
an HDE or of a request for an extension. FDA believes that no device
that is demonstrably ineffective can pass the ``probable benefit''
test. Therefore, while effectiveness data is not required for an
extension of the exemption, if any such information is available, it
should be submitted to aid the agency in making its benefit/risk
determination. As the Conference Report states, ``this inquiry requires
the Secretary to consider the efficacy and potential benefits of the
device * * *'' (H. Conf. Rept. at 28).
19. One comment suggested a new provision on supplemental
applications, specifying the types of supplements that would or would
not require FDA approval. The changes suggested by the comment would
mirror the requirements of the PMA regulations. The comment also
suggested that supplements follow format and content requirements
similar to those for original HDE applications (which, under the
comment, would be similar to PMA requirements) and be subject to the
same time periods for review as original HDE applications.
The agency agrees, in part, with the comment. Under the final rule
(Secs. 814.106 and 814.108), HDE amendments and supplements (with one
exception) are subject to the same regulations and time periods as
those for PMA's. The single exception under the final rule is that a
request for a new indication for use of a HUD may not be submitted as a
supplement, but instead shall be treated as a new application,
requiring redesignation of HUD status and an original HDE (see
Sec. 814.110). As with PMA's, a major amendment to an original HDE or
HDE supplement may extend the review period for 180 days, and failure
to respond in writing to an agency request for an amendment within 180
days will result in the pending HDE or supplement being deemed
voluntarily withdrawn by the applicant (see Sec. 814.37).
20. One comment would amend the rule to add a new provision
describing an applicant's obligations when requesting an extension of
an HDE. Section 520(m)(5) of the act states that the agency may extend
an exemption for an additional 18 months if the agency is able to make
the same findings that were necessary to grant the initial request for
an HDE exemption. The statute also requires applicants to supply
information showing that the applicant is not selling the device for an
amount that exceeds the cost of research and development, fabrication,
and distribution. The comment would require applicants to provide such
information, and require FDA to grant an extension if the request for
an extension ``confirms the FDA's original findings'' and demonstrates
compliance with the statutory prohibition against commercialization.
The comment would also permit applicants to request, and FDA to
approve, more than one extension.
The agency agrees with the comment. Section 814.120 of the final
rule states that FDA may, in response to a request by the holder of an
HDE, extend the HDE for an additional 18-month term. The contents of
the extension request and the approval criteria parallel the statutory
requirements and are set forth under Sec. 814.120(b) and (c),
respectively. The agency also agrees that extending an exemption more
than once is consistent with section 520(m)(5) of the act.
Institutional Review Board Review
21. One comment would add a new provision describing an IRB's role,
including requiring IRB's to presume that FDA approval of an HDE
application establishes that a device is designed to treat or diagnose
a disease or condition that affects fewer than 4,000 individuals in the
United States. The comment would also confine the IRB's review to ``the
patient's need for the device and the likelihood that the device is
appropriate for the patient's condition or disease state.'' The comment
would further state that an IRB may deny approval of the use of the
device ``if it finds that the device has no potential to benefit the
patient'' and require semiannual submissions to the holder of the
approved HDE of ``all records of approvals for use of the humanitarian
device.''
FDA agrees, in part, with the comment. Section 814.124(a) states
that, before administering a humanitarian use device to humans, the
applicant must obtain review and approval by an IRB that is established
at the facility or site where the device is to be used or the local IRB
must defer, in writing, to a similarly constituted IRB that has agreed
to oversee such use. Absent IRB approval, the device cannot be
administered to humans. The agency declines to limit the IRB's review
or its functions in the manner suggested by the comment because IRB's
have traditionally enjoyed considerable latitude in establishing their
own operational procedures and reviews. FDA believes that the approval
criteria set forth in the IRB regulations (21 CFR 56.111) can and
should be interpreted to include consideration of the patient's need
for the HUD and the likelihood that the device is appropriate for the
patient's condition or disease state. For example, the regulations
require that the IRB determine that the ``risks to subjects are
reasonable in relation to anticipated benefits.'' Such a determination
would necessarily require a balancing of patient need together with the
probability of clinical benefit against the possible risks of using the
device. In contrast, an IRB evaluating a HUD retains the discretion to
minimize or ignore approval criteria that may be inappropriate in the
treatment context (e.g., ``the importance of the knowledge that may be
expected to result'').
FDA declines to adopt the suggestion that the IRB make semiannual
[[Page 33241]]
submissions to the holder of the HDE of ``all records of approvals for
use of the humanitarian device.'' Section 814.124(a) requires the IRB
to comply with the regulations in part 56 (21 CFR part 56), including
provisions concerning continuing review and recordkeeping. Insofar as
the holder of the approved HDE retains control over the shipment of the
device, it has the discretion to require any reports from the IRB or
the treating physician as a condition of the initial shipment of the
device or future shipments.-
Proposed Sec. 812.30(d) and (e) FDA Action on Applications and
Revocation of an Application for a HUD
Proposed Sec. 812.30(d) and (e) described FDA action on HDE
applications, and the agency received two comments on these sections.
22. One comment suggested amending the requirement that an
application list the name, address, and chairperson of each IRB that
has been or will be asked to review the investigation and a
certification of the action taken by the IRB's. The comment asserted
that requiring individual approval of each location where a clinical
investigation would be conducted would deny timely access to HUD's.
Alternatively, the comment suggested that FDA only approve the study
protocol and a sample consent form, and that IRB's rather than FDA
approve participation of each location. The sponsor would send
information regarding additional study locations and IRB's to FDA every
18 months.
Because FDA has elected not to regulate HUD's as investigational
devices subject to the requirements of part 812, the final regulation
does not include any provision requiring the applicant to submit the
name or address of any reviewing IRB. Nor will FDA review sample
consent forms since informed consent is not being required by FDA. As
discussed elsewhere in this notice, the HDE applicant is responsible
for ensuring that the HUD is not used in the treatment or diagnosis of
a patient prior to obtaining IRB approval from either the IRB at the
health care facility or another IRB who has assumed that responsibility
for the facility. Although IRB's are required to comply with the
regulations in part 56, FDA will not require any reports from IRB's or
HDE applicants other than those specified in part 56 and Secs. 814.124
and 814.126.
23. The second comment suggested a new provision establishing
strict timeframes for FDA review, criteria for approving, not
approving, and withdrawing approval of an HDE application, and the
factors and evidence FDA would consider in deciding whether the device
would expose patients to an unreasonable or significant risk of illness
or injury. For example, the comment would require FDA to notify
applicants, in writing, when the agency receives an HDE application and
would require FDA to approve the HDE application within 30 days of
receipt or, if the agency did not approve the HDE application within 30
days, the application would be considered to be approved unless FDA
requested additional information from the HDE applicant or denied
approval within 30 days. The comment's suggested criteria for approving
an HDE application paraphrased the statutory requirements at section
520(m)(2) of the act. The criteria the comment suggested for denying
approval included the applicant's failure to comply with application or
labeling requirements or, if nonclinical laboratory studies were
involved, failure to comply with good laboratory practice requirements,
a false statement of material fact, and the applicant's refusal to
permit an authorized FDA employee to conduct an inspection. The comment
would also create an administrative appeals mechanism to the ODE and
later to the Office of the Center Director, CDRH for a decision not to
approve an HDE application.
FDA agrees, in part, with the comment and has established specific
timeframes for processing requests for HUD designation as well as for
filing and reviewing HDE applications. Under Sec. 814.102 of the final
rule, a request for HUD designation will be reviewed within 45 days of
receipt by OOPD. If the request for HUD designation is approved, this
designation may be submitted or referenced in the HDE application
(Sec. 814.104) which is submitted to ODE.
ODE will notify the applicant within 45 days of receiving an
original HDE application or HDE supplement whether the application has
been accepted for filing (see Sec. 814.112). The criteria and
procedures for filing an HDE are similar to those for PMA's. After
filing an HDE or HDE supplement, Sec. 814.114(a) requires that FDA take
action on the application within 180 days from the date of receipt.
(This time period includes the 45 days allotted to FDA under
Sec. 814.112 for making the filing decision.)
Although these time periods are longer than the 30 day IDE review
period suggested by the comment, FDA believes that they are warranted.
While HDE applications will not contain data intended to establish
effectiveness, they will contain other information that is not included
in PMA's under part 814. As discussed previously, therefore, the agency
believes that 180 days will generally be required in order to review
the information submitted in the HDE application and to make the
determinations required by the statute (section 520(m)(2)(A) through
(m)(2)(C)). By establishing intermediate steps in the submission and
review process, the agency has attempted to ensure expeditious review
of an HDE application, because only those applications that contain (or
reference) a HUD designation and are complete enough to be filed will
enter the review queue. In addition, FDA notes that there is nothing in
the legislative history of section 520(m) of the act to suggest that
Congress expected FDA to review marketing applications for HUD's within
accelerated timeframes which would detract resources from reviews of
other devices that may benefit larger populations. Furthermore, as
discussed earlier, humanitarian use devices may meet the criteria for
expedited review. In such cases, the agency will review these
applications as quickly as possible.
The agency agrees with the comment's suggestion that criteria for
the various actions FDA may take on an application should be
incorporated into the final rule. Section 814.116 specifies the
criteria for issuing an approval order, an approvable letter, or a not
approvable letter, while Sec. 814.118 specifies the criteria for
issuing a denial or withdrawal of approval. These criteria are largely
similar to the criteria for FDA action on a PMA and, thus, are
consistent with those suggested by the comment.
The agency agrees with the comment that administrative appeal
mechanisms should be provided. Thus, subpart H provides for such
mechanisms by referencing Sec. 814.42(d) for filing decisions and
Sec. 814.44 for not approvable letters.
Proposed Sec. 812.38(e) Availability of Data and Information
24. Proposed Sec. 812.38(e) would have maintained the
confidentiality of data and information in an HDE application until
final approval of the IDE application for the HUD. At that time, FDA
would make publicly available information such as the identity of the
device, the disease or condition to be treated, patient exclusion
criteria, and the name, address, and phone number of a contact person
for the sponsor. One comment suggested a new confidentiality provision
that would be similar, but not identical, to the confidentiality
provision for PMA's at
[[Page 33242]]
Sec. 814.9. The comment would essentially permit disclosure of
information in an HDE application in accordance with the agency's
regulations governing disclosure of information in a PMA application.
The comment would permit disclosure of the existence of an application
only if the application had been publicly disclosed or acknowledged,
and, if the HDE application's existence had been publicly disclosed or
acknowledged, restrict disclosures to summaries of portions of the
safety data. If FDA approved the HDE application, the comment suggested
that FDA could disclose the HDE application's existence and a detailed
summary of the safety information, including any adverse event reports
or consumer complaints, assay or analytical methods (unless otherwise
protected as confidential or trade secret information), and all
correspondence and written summaries of oral discussions. The comment
would also permit disclosure of a summary of portions of the safety
data before FDA approved the HDE application ``if disclosure is
relevant to public consideration of a specific pending issue.''
Because the agency has moved the HDE provisions from the IDE
regulations to the PMA regulations, FDA has created Sec. 814.122 to
address the confidentiality of data and information in an HDE
application. Under Sec. 814.122(a), the HDE application file consists
of all data and information submitted with or incorporated by reference
in the HDE application, any IDE incorporated into the HDE application,
or any other related submission. Disclosure of any record contained in
an HDE application file will be in accordance with part 20 (21 CFR part
20) and Sec. 814.122. (In this final rule, the agency is amending part
20 to include a reference to HDE's.)
Section 814.122(b) states that HDE's shall be subject to the same
restrictions and conditions regarding disclosure as are applied to
PMA's under the provisions of Sec. 814.9(b) through (h), as applicable.
FDA has included ``as applicable'' in this provision, as in other
provisions in subpart H, to signify that certain portions of the PMA
regulations, namely those relating to the submission, review, or
disclosure of effectiveness data, may not be applicable to HDE's. In
accordance with Sec. 814.9, the existence of an HDE file or data and
information in the file may not be disclosed by FDA unless the
existence of the file has been publicly disclosed or acknowledged.
Also, if the existence of the HDE file has been publicly disclosed or
acknowledged before an order approving or denying approval issued, data
and information in the file are not available for disclosure. Once FDA
has issued an approval order or an order denying approval of an
application, FDA will make available to the public the fact of the
existence of the HDE and a detailed summary of information submitted to
FDA respecting the safety of the device and the basis for the order.
Information such as safety data, test or study protocols, adverse event
reports, product experience reports, consumer complaints or similar
information, lists of components previously disclosed to the public,
assay methods or analytical methods, and all correspondence and written
summaries of oral discussions related to the HDE file, in accordance
with the provisions of Sec. 814.9(e) also become available for public
disclosure. Finally, FDA may disclose a summary of portions of the
safety data before an approval order or an order denying approval of
the HDE issues, if disclosure is relevant to public consideration of a
pending issue and, in accordance with Sec. 814.9(g), other information
contained in an HDE becomes available under the particular
circumstances set forth in that provision.
Proposed Sec. 812.39 Certification
25. Proposed Sec. 812.39 would have required sponsors to certify
that the data and information submitted to the agency are true and
accurate.
FDA received no comments on this provision but has reconsidered the
need for it. As provided for in Secs. 814.42 and 814.45 for PMA's,
subpart H includes provisions that would permit FDA to not file, deny
approval, or withdraw approval of an HDE application if the agency
determines that the application contained a false statement of material
fact. Therefore, the agency has concluded that a certification as to
the truthfulness and accuracy of the information submitted in an
application is not needed. -
Limitations on Charging
26. One comment suggested that, because the original proposed rule
included a prohibition against commercialization, a provision should be
added to insulate HDE holders from charges of commercialization in the
event that they earned ``incidental profits which exceed its good faith
estimates of costs.''
To address the cost issue, the final rule requires a report by an
independent certified public accountant, made in accordance with the
Statement on Standards for Attestation established by the American
Institute of Certified Public Accountants, verifying that the amount
charged will not exceed the costs of the device's research,
development, fabrication, and distribution. The statute does not create
an exemption for ``incidental profits.'' FDA believes that a report
made in accordance with the requirements stated above should provide
adequate assurance to both the HDE holder and the agency that the
amount being charged does not violate section 520(m)(3) of the act.
This requirement is also consistent with the cost verification
procedures required for orphan drugs under 21 CFR 316.21(c)(8).
However, as suggested by the Conference Report on the SMDA, an
applicant will not be considered in violation of this provision if it
receives incidental profits which exceed its good faith estimates of
costs (H. Conf. Rept. at 28).--
IV. Analysis of Impacts
FDA has examined the impacts of the final rule under Executive
Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354).
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 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 the final rule reduces the requirements
imposed on firms conducting research and development activities on
devices intended for use in diagnosing or treating small populations,
the agency certifies that the final rule will not have a significant
economic impact on a substantial number of small entities. Therefore,
under the Regulatory Flexibility Act, no further analysis is required.
V. Environmental Impact
The agency has determined under 21 CFR 25.24(a)(8) that this action
is of a type that does not individually or cumulatively have a
significant effect on the human environment. Therefore, neither an
environmental assessment nor an environmental impact statement is
required.
[[Page 33243]]
VI. Paperwork Reduction Act of 1995
This final rule contains information collections which are subject
to review by OMB under the Paperwork Reduction Act of 1995 (Pub. L.
104-13). The title, description, and respondent description of the
information collections are shown below with an estimate of the annual
recordkeeping and periodic reporting 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: Medical Devices; Humanitarian Use Devices.
Description: This regulation implements the provision of the SMDA
regarding HUD's. A HUD is exempt from the effectiveness requirements of
sections 514 and 515 of the act. In order to implement this exemption,
FDA is amending the premarket approval regulations in part 814 by
creating new subpart H. This final regulation prescribes the procedures
for submitting HDE applications, amendments, and supplements;
procedures for obtaining an extension of the exemption; and the
criteria for FDA review and approval of HDE's. This final rule will
create a needed incentive for the development of devices for use in the
treatment or diagnosis of diseases or conditions affecting a small
number of individuals.
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
----------------------------------------------------------------------------------------------------------------
814.102 20 1 20 40 800
814.104 15 1 15 320 4,800
814.106 10 1 10 120 1,200
814.108 12 1 12 80 960
814.110(a) 1 1 1 80 80
814.112(b) 1 1 1 8 8
814.116(b) 12 1 12 8 96
814.118(d) 1 1 1 8 8
814.120(b) 10 1 10 200 2,000
814.124(b) 2 1 2 2 4
814.126(b)(i) 2 1 2 120 240
TOTAL 10,196
----------------------------------------------------------------------------------------------------------------
ESTIMATED ANNUAL RECORDKEEPING BURDEN
----------------------------------------------------------------------------------------------------------------
Annual
21 CFR Section No. of Frequency per Total Annual Hours per Total Hours
Recordkeepers Recordkeeping Records Recordkeeper
----------------------------------------------------------------------------------------------------------------
814.126(b)(ii) 12 1 12 2 24
Total 24
----------------------------------------------------------------------------------------------------------------
There are no operating and maintenance costs or capitol costs associated with this information collection.
Although the December 21, 1992, proposed rule provided a 60-day
comment period under the Paperwork Reduction Act of 1980, and this
final rule is based on the comments received, as required by 44 U.S.C.
section 3507(d), FDA is providing additional opportunities for public
comment under the Paperwork Reduction Act of 1995, which applies to
this final rule and was enacted after the expiration of the comment
period. Organizations and individuals wishing to submit comments
regarding these burden estimates or any aspect of these information
collection requirements should do so by August 26, 1996. These comments
should be directed to FDA's Dockets Management Branch (address above).
FDA particularly invites comments on: (1) Whether the proposed
collection of information is necessary for the proper performance of
the functions of the agency, including whether the information will
have practical utility; (2) the accuracy of the agency's estimate of
the burden of the proposed collection of information, including the
validity of the methodology and assumptions used; (3) ways to enhance
the quality, utility, and clarity of the information to be collected;
and (4) ways to minimize the burden of the collection of information on
those who are to respond, including through the use of automated
collection techniques, when appropriate, and other forms of information
technology.
At the close of the 60-day comment period, FDA will review the
comments received, make revisions as necessary to the information
collection requirements, and submit the requirements to OMB for review
and approval. Additional time will be allotted for public comment to
OMB on the requirements and OMB review. Prior to the effective date of
this final rule, FDA will publish a notice in the Federal Register of
OMB's decision to approve, modify, or disapprove the information
collection requirements. 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
21 CFR Part 20
Confidential business information, Courts, Freedom of information,
Government employees.
21 CFR Part 814
Administrative practice and procedure, Confidential business
information, 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 parts
20 and 814 are amended as follows:
[[Page 33244]]
PART 20--PUBLIC INFORMATION
1. The authority citation for 21 CFR part 20 continues to read as
follows:
Authority: Secs. 201-903 of the Federal Food, Drug, and Cosmetic
Act (21 U.S.C. 321-393); secs. 301, 302, 303, 307, 310, 311, 351,
352, 354-360F, 361, 362, 1701-1706, 2101 of the Public Health
Service Act (42 U.S.C. 241, 242, 242a, 242l, 242n, 243, 262, 263,
263b-263n, 264, 265, 300u-300u-5, 300aa-1); 5 U.S.C. 552; 18 U.S.C.
1905; 19 U.S.C. 2531-2582; 21 U.S.C. 1401-1403.
2. Section 20.100 is amended by adding new paragraph (c)(41) to
read as follows:
Sec. 20.100 Applicability; cross-reference to other regulations.
* * * * *
(c) * * *
(41) Humanitarian device exemption application, in Sec. 814.122 of
this chapter.-
PART 814--PREMARKET APPROVAL OF MEDICAL DEVICES
3. The authority citation for 21 CFR part 814 continues to read as
follows:
Authority: Secs. 501, 502, 503, 510, 513-520, 701, 702, 703,
704, 705, 708, 721, 801 of the Federal Food, Drug, and Cosmetic Act
(21 U.S.C. 351, 352, 353, 360, 360c-360j, 371, 372, 373, 374, 375,
379, 379e, 381).
4. Section 814.3 is amended by adding new paragraphs (m) and (n) to
read as follows:
Sec. 814.3 Definitions.
* * * * *
(m) HDE means a premarket approval application submitted pursuant
to this subpart seeking a humanitarian device exemption from the
effectiveness requirements of sections 514 and 515 of the act as
authorized by section 520(m)(2) of the act.
(n) HUD (humanitarian use device) means a medical device intended
to benefit patients in the treatment or diagnosis of a disease or
condition that affects or is manifested in fewer than 4,000 individuals
in the United States per year.
5. New subparts F and G are added and reserved and subpart H,
consisting of Secs. 814.100 through 814.126, is added to read as
follows:
Subpart H--Humanitarian Use Devices
Sec.
814.100 Purpose and scope.
814.102 Designation of HUD status.
814.104 Original applications.
814.106 HDE amendments and resubmitted HDE's.
814.108 Supplemental applications.
814.110 New indications for use.
814.112 Filing an HDE.
814.114 Timeframes for reviewing an HDE.
814.116 Procedures for review of an HDE.
814.118 Denial of approval or withdrawal of approval of an HDE.
814.120 Requests for extension.
814.122 Confidentiality of data and information.
814.124 Institutional Review Board requirements.
814.126 Postapproval requirements and reports.
Subpart H--Humanitarian Use Devices
Sec. 814.100 Purpose and scope.
(a) This subpart H implements section 520(m) of the act. The
purpose of section 520(m) is, to the extent consistent with the
protection of the public health and safety and with ethical standards,
to encourage the discovery and use of devices intended to benefit
patients in the treatment or diagnosis of diseases or conditions that
affect or are manifested in fewer than 4,000 individuals in the United
States per year. This subpart provides procedures for obtaining:
(1) HUD designation of a medical device; and
(2) Temporary marketing approval for the HUD notwithstanding the
absence of reasonable assurance of effectiveness that would otherwise
be required under sections 514 and 515 of the act.
(b) Although a HUD may also have uses that differ from the
humanitarian use, applicants seeking approval of any non-HUD use shall
submit a PMA as required under Sec. 814.20, or a premarket notification
as required under part 807 of this chapter.
(c) Obtaining marketing approval for a HUD involves two steps:
(1) Obtaining designation of the device as a HUD from FDA's Office
of Orphan Products Development, and
(2) Submitting an HDE to the Office of Device Evaluation (ODE),
Center for Devices and Radiological Health (CDRH).
(d) The approval by ODE of an HDE under this subpart H shall be
effective for a period of 18 months from the date of the approval
letter, and shall permit the applicant to market the HUD in the United
States in accordance with the restrictions described in this subpart H.
Extensions of the approval may be granted in accordance with this
subpart H.
Sec. 814.102 Designation of HUD status.
(a) Request for designation. Prior to submitting an HDE
application, the applicant shall submit a request for HUD designation
to FDA's Office of Orphan Products Development. The request shall
contain the following:
(1) A statement that the applicant requests HUD designation for a
rare disease or condition or a valid subset of a disease or condition
which shall be identified with specificity;
(2) The name and address of the applicant, the name of the
applicant's primary contact person and/or resident agent, including
title, address, and telephone number;
(3) A description of the rare disease or condition for which the
device is to be used, the proposed indication or indications for use of
the device, and the reasons why such therapy is needed. If the device
is proposed for an indication that represents a subset of a common
disease or condition, a demonstration that the subset is medically
plausible should be included;
(4) A description of the device and a discussion of the scientific
rationale for the use of the device for the rare disease or condition;
and
(5) Documentation, with appended authoritative references, to
demonstrate that the device is designed to treat or diagnose a disease
or condition that affects or is manifested in fewer than 4,000 people
in the United States per year. If the device is for diagnostic
purposes, the documentation must demonstrate that fewer than 4,000
patients per year would be subjected to diagnosis by the device in the
United States. Authoritative references include literature citations in
specialized medical journals, textbooks, specialized medical society
proceedings, or governmental statistics publications. When no such
studies or literature citations exist, the applicant may be able to
demonstrate the prevalence of the disease or condition in the United
States by providing credible conclusions from appropriate research or
surveys.
(b) FDA action. Within 45 days of receipt of a request for HUD
designation, FDA will take one of the following actions:
(1) Approve the request and notify the applicant that the device
has been designated as a HUD based on the information submitted;
(2) Return the request to the applicant pending further review upon
submission of additional information. This action will ensue if the
request is incomplete because it does not on its face contain all of
the information required under Sec. 814.102(a). Upon receipt of this
additional information, the review period may be extended up to 45
days; or
(3) Disapprove the request for HUD designation based on a
substantive review of the information submitted. FDA may disapprove a
request for HUD designation if:
(i) There is insufficient evidence to support the estimate that the
disease or condition for which the device is
[[Page 33245]]
designed to treat or diagnose affects or is manifested in fewer than
4,000 people in the United States per year;
(ii) FDA determines that, for a diagnostic device, 4,000 or more
patients in the United States would be subjected to diagnosis using the
device per year; or
(iii) FDA determines that the patient population defined in the
request is not a medically plausible subset of a larger population.
(c) Revocation of designation. FDA may revoke a HUD designation if
the agency finds that:
(1) The request for designation contained an untrue statement of
material fact or omitted material information; or
(2) Based on the evidence available, the device is not eligible for
HUD designation.
(d) Submission. The applicant shall submit two copies of a
completed, dated, and signed request for HUD designation to: Office of
Orphan Products Development (HF-35), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857.
Sec. 814.104 Original applications.
(a) United States applicant or representative. The applicant or an
authorized representative shall sign the HDE. If the applicant does not
reside or have a place of business within the United States, the HDE
shall be countersigned by an authorized representative residing or
maintaining a place of business in the United States and shall identify
the representative's name and address.
(b) Time for submission. An original HDE may only be submitted to
the agency between October 24, 1996, and April 27, 2001, unless
otherwise permitted by statute.
(c) Contents. Unless the applicant justifies an omission in
accordance with paragraph (d) of this section, an HDE shall include:
(1) A copy of or reference to the determination made by FDA's
Office of Orphan Products Development (in accordance with Sec. 814.102)
that the device qualifies as a HUD;
(2) An explanation of why the device would not be available unless
an HDE were granted and a statement that no comparable device (other
than another HUD approved under this subpart or a device under an
approved IDE) is available to treat or diagnose the disease or
condition. The application also shall contain a discussion of the risks
and benefits of currently available devices or alternative forms of
treatment in the United States;
(3) An explanation of why the probable benefit to health from the
use of the device outweighs the risk of injury or illness from its use,
taking into account the probable risks and benefits of currently
available devices or alternative forms of treatment. Such explanation
shall include a description, explanation, or theory of the underlying
disease process or condition, and known or postulated mechanism(s) of
action of the device in relation to the disease process or condition;-
(4) All of the information required to be submitted under
Sec. 814.20(b), except that:-
(i) In lieu of the summaries, conclusions, and results from
clinical investigations required under Secs. 814.20(b)(3)(v)(B),
(b)(3)(vi), and (b)(6)(ii), the applicant shall include the summaries,
conclusions, and results of all clinical experience or investigations
(whether adverse or supportive) reasonably obtainable by the applicant
that are relevant to an assessment of the risks and probable benefits
of the device; and-
(ii) In addition to the proposed labeling requirement set forth in
Sec. 814.20(b)(10), the labeling shall bear the following statement:
Humanitarian Device. Authorized by Federal law for use in the
[treatment or diagnosis] of [specify disease or condition]. The
effectiveness of this device for this use has not been demonstrated;
and
(5) The amount to be charged for the device and a report by an
independent certified public accountant, made in accordance with the
Statement on Standards for Attestation established by the American
Institute of Certified Public Accountants, verifying that the amount
charged does not exceed the costs of the device's research,
development, fabrication, and distribution.
(d) Omission of information. If the applicant believes that certain
information required under paragraph (c) of this section is not
applicable to the device that is the subject of the HDE, and omits any
such information from its HDE, the applicant shall submit a statement
that identifies and justifies the omission. The statement shall be
submitted as a separate section in the HDE and identified in the table
of contents. If the justification for the omission is not accepted by
the agency, FDA will so notify the applicant.
(e) Address for submissions and correspondence. Copies of all
original HDE's, amendments, supplements, and requests for extension, as
well as any correspondence relating to an HDE, shall be sent or
delivered to the Document Mail Center (HFZ-401), Office of Device
Evaluation, Center for Devices and Radiological Health, Food and Drug
Administration, 9200 Corporate Blvd., Rockville, MD 20850.
Sec. 814.106 HDE amendments and resubmitted HDE's.
An HDE or HDE supplement may be amended or resubmitted upon an
applicant's own initiative, or at the request of FDA, for the same
reasons and in the same manner as prescribed for PMA's in Sec. 814.37.
The timeframes and extension of review times set forth in Sec. 814.37
for PMA's shall also be applicable to HDE's.
Sec. 814.108 Supplemental applications.
After FDA approval of an original HDE, an applicant shall submit
supplements in accordance with the requirements for PMA's under
Sec. 814.39, except that a request for a new indication for use of a
HUD shall comply with the requirements set forth in Sec. 814.110.
Sec. 814.110 New indications for use.
(a) An applicant seeking a new indication for use of a HUD approved
under this subpart H shall obtain a new designation of HUD status in
accordance with Sec. 814.102 and shall submit an original HDE in
accordance with Sec. 814.104.
(b) An application for a new indication for use made under
Sec. 814.104 may incorporate by reference any information or data
previously submitted to the agency under an HDE.
Sec. 814.112 Filing an HDE.
(a) The filing of an HDE means that FDA has made a threshold
determination that the application is sufficiently complete to permit
substantive review. Within 45 days from the date an HDE is received by
FDA, the agency will notify the applicant whether the application has
been filed. FDA may refuse to file an HDE if any of the following
applies:
(1) The application is incomplete because it does not on its face
contain all the information required under Sec. 814.104(c);
(2) FDA determines that there is a comparable device available
(other than another HUD approved under this subpart or a device under
an approved IDE) to treat or diagnose the disease or condition for
which approval of the HUD is being sought; or
(3) The application contains an untrue statement of material fact
or omits material information.
(b) The provisions contained in Sec. 814.42(b), (c), and (d)
regarding notification of filing decisions, filing dates, the start of
the 180-day review
[[Page 33246]]
period, and applicant's options in response to FDA refuse to file
decisions shall apply to HDE's submitted under this subpart as well as
to PMA's submitted under Sec. 814.20.
Sec. 814.114 Timeframes for reviewing an HDE.
Within 180 days after receipt of an HDE that is accepted for filing
and to which the applicant does not submit a major amendment, FDA will
send the applicant an approval order, an approvable letter, or a not
approvable letter (under Sec. 814.116), or an order denying approval
(under Sec. 814.118).
Sec. 814.116 Procedures for review of an HDE.
(a) Substantive review. FDA will begin substantive review of an HDE
after the HDE is accepted for filing under Sec. 814.112. FDA may refer
an original HDE application to a panel on its own initiative, and shall
do so upon the request of an applicant, unless FDA determines that the
application substantially duplicates information previously reviewed by
a panel. If the HDE is referred to a panel, the agency shall follow the
procedures set forth under Sec. 814.44.
(b) Approval order. FDA will issue to the applicant an order
approving an HDE if none of the reasons in Sec. 814.118 for denying
approval of the application applies. FDA will approve an application on
the basis of draft final labeling if the only deficiencies in the
application concern editorial or similar minor deficiencies in the
draft final labeling. Such approval will be conditioned upon the
applicant incorporating the specified labeling changes exactly as
directed and upon the applicant submitting to FDA a copy of the final
printed labeling before marketing. The notice of approval of an HDE
will be published in the Federal Register in accordance with the rules
and policies applicable to PMA's submitted under Sec. 814.20. Following
the issuance of an approval order, data and information in the HDE file
will be available for public disclosure in accordance with
Sec. 814.9(b) through (h), as applicable.
(c) Approvable letter. FDA will send the applicant an approvable
letter if the application substantially meets the requirements of this
subpart and the agency believes it can approve the application if
specific additional information is submitted or specific conditions are
agreed to by the applicant. The approvable letter will describe the
information FDA requires to be provided by the applicant or the
conditions the applicant is required to meet to obtain approval. For
example, FDA may require as a condition to approval:
(1) The submission of certain information identified in the
approvable letter, e.g., final labeling;
(2) Restrictions imposed on the device under section 520(e) of the
act;
(3) Postapproval requirements as described in subpart E of this
part; and
(4) An FDA inspection that finds the manufacturing facilities,
methods, and controls in compliance with part 820 of this chapter and,
if applicable, that verifies records pertinent to the HDE.
(d) Not approvable letter. FDA will send the applicant a not
approvable letter if the agency believes that the application may not
be approved for one or more of the reasons given in Sec. 814.118. The
not approvable letter will describe the deficiencies in the application
and, where practical, will identify measures required to place the HDE
in approvable form. The applicant may respond to the not approvable
letter in the same manner as permitted for not approvable letters for
PMA's under Sec. 814.44(f).
Sec. 814.118 Denial of approval or withdrawal of approval of an HDE.
(a) FDA may deny approval or withdraw approval of an application if
the applicant fails to meet the requirements of section 520(m) of the
act or of this part, or of any condition of approval imposed by an IRB
or by FDA, or any postapproval requirements imposed under Sec. 814.126.
In addition, FDA may deny approval or withdraw approval of an
application if, upon the basis of the information submitted in the HDE
or any other information before the agency, FDA determines that:
(1) There is a lack of a showing of reasonable assurance that the
device is safe under the conditions of use prescribed, recommended, or
suggested in the labeling thereof;
(2) The device is ineffective under the conditions of use
prescribed, recommended, or suggested in the labeling thereof;
(3) The applicant has not demonstrated that there is a reasonable
basis from which to conclude that the probable benefit to health from
the use of the device outweighs the risk of injury or illness, taking
into account the probable risks and benefits of currently available
devices or alternative forms of treatment;
(4) The application or a report submitted by or on behalf of the
applicant contains an untrue statement of material fact, or omits
material information;
(5) The device's labeling does not comply with the requirements in
part 801 or part 809 of this chapter;
(6) A nonclinical laboratory study that is described in the HDE and
that is essential to show that the device is safe for use under the
conditions prescribed, recommended, or suggested in its proposed
labeling, was not conducted in compliance with the good laboratory
practice regulations in part 58 of this chapter and no reason for the
noncompliance is provided or, if it is, the differences between the
practices used in conducting the study and the good laboratory practice
regulations do not support the validity of the study;
(7) Any clinical investigation involving human subjects described
in the HDE, subject to the institutional review board regulations in
part 56 of this chapter or the informed consent regulations in part 50
of this chapter, was not conducted in compliance with those regulations
such that the rights or safety of human subjects were not adequately
protected;
(8) The applicant does not permit an authorized FDA employee an
opportunity to inspect at a reasonable time and in a reasonable manner
the facilities and controls, and to have access to and to copy and
verify all records pertinent to the application; and
(9) The device's HUD designation should be revoked in accordance
with Sec. 814.102(c).
(b) If FDA issues an order denying approval of an application, the
agency will comply with the same notice and disclosure provisions
required for PMA's under Sec. 814.45(b) and (d), as applicable.
(c) FDA will issue an order denying approval of an HDE after an
approvable or not approvable letter has been sent and the applicant:
(1) Submits a requested amendment but any ground for denying
approval of the application under Sec. 814.118(a) still applies;
(2) Notifies FDA in writing that the requested amendment will not
be submitted; or
(3) Petitions for review under section 515(d)(3) of the act by
filing a petition in the form of a petition for reconsideration under
Sec. 10.33 of this chapter.
(d) Before issuing an order withdrawing approval of an HDE, FDA
will provide the applicant with notice and an opportunity for a hearing
as required for PMA's under Sec. 814.46(c) and (d), and will provide
the public with notice in accordance with Sec. 814.46(e), as
applicable.
(e) Unless FDA otherwise determines that continued marketing under
the
[[Page 33247]]
HDE is inconsistent with the intent of section 520(m) of the act, FDA
will not withdraw approval of an HDE solely because it is subsequently
determined that the disease or condition for which the HUD is intended
affects or is manifested in more than 4,000 people in the United States
per year. However, this fact may serve as a basis for disapproving an
extension request. -
Sec. 814.120 Requests for extension.
(a) Eligibility. In response to a request by the holder of an HDE,
FDA may extend the HDE for an additional 18-month term. An exemption
may be extended more than once, and may be extended after the
expiration of the 5-year period that began on October 24, 1996, as
provided by section 520(m)(5) of the act. If the approval term for an
HDE has lapsed, the HDE is ineligible for extension under this section
and the applicant must cease marketing the device until a new HDE has
been submitted and approved in accordance with this part.
(b) Submission. In order to avoid the risk of a lapse in marketing
approval, the holder of an HDE wishing to obtain an extension shall
submit such a request to FDA at least 90 days prior to the expiration
of the HDE. A request for extension must be submitted in writing,
together with a new, separately bound, request for HUD designation. The
request for extension and the request for HUD designation shall be
submitted to the Office of Device Evaluation, CDRH at the address
specified for the submission of original HDE's (Sec. 814.104(e)), and
the outside envelope should be plainly marked: ``Request for Extension
of HDE Approval.'' The submission shall state the applicant's name and
address, the HDE number, and shall include the following information
based upon the first 12 months of experience with the device following
the most recent HDE approval or extension:
(1) An update of the information required under Sec. 814.102(a) in
a separately bound volume;
(2) An update of the information required under
Secs. 814.104(c)(2), (c)(3),and (c)(5);
(3) The number of devices that have been shipped or sold since
initial marketing approval under this subpart and, if the number
shipped or sold exceeds 4,000, an explanation and estimate of the
number of devices used per patient. If a single device is used on
multiple patients, the applicant shall submit an estimate of the number
of patients treated or diagnosed using the device together with an
explanation of the basis for the estimate;
(4) Information describing the applicant's clinical experience with
the device since the HDE was initially approved. This shall include
safety information that is known or reasonably should be known to the
applicant, medical device reports made pursuant to part 803 of this
chapter, any data generated from postmarketing studies, and information
(whether published or unpublished) that is known or reasonably expected
to be known by the applicant that may affect an evaluation of the
safety of the device or that may affect the statement of
contraindications, warnings, precautions, and adverse reactions in the
device labeling; and
(5) A summary of any changes made to the device in accordance with
supplements submitted under Sec. 814.108.
(c) Action. Within 90 days of receipt of a request for an extension
of an HDE that is submitted in accordance with this section, FDA will
send the applicant either an approval order, approvable letter, a not
approvable letter, or an order denying approval, applying the same
criteria under this subpart as are applicable to the original HUD
designation and HDE application. The effective date of an extension
shall be the day the extension was granted or the day following the
last effective day of the original HDE approval or the most recent
extension, whichever is later. An extension request not acted upon by
FDA within 90 days shall be deemed approved.
(d) Waiver of final report. An HDE holder seeking a request for
extension under this section is exempt from the requirement of
submitting a final report under Sec. 814.126(b).
Sec. 814.122 Confidentiality of data and information.
(a) Requirement for disclosure. The ``HDE file'' includes all data
and information submitted with or referenced in the HDE, any IDE
incorporated into the HDE, any HDE amendment or supplement, any report
submitted under Sec. 814.126, any master file, or any other related
submission. Any record in the HDE file will be available for public
disclosure in accordance with the provisions of this section and part
20 of this chapter.
(b) Extent of disclosure. Disclosure by FDA of the existence and
contents of an HDE file shall be subject to the same rules that pertain
to PMA's under Sec. 814.9(b) through (h), as applicable.
Sec. 814.124 Institutional Review Board requirements.
(a) IRB approval. The HDE holder is responsible for ensuring that a
HUD approved under this subpart is administered only in facilities
having an Institutional Review Board (IRB) constituted and acting
pursuant to part 56 of this chapter, including continuing review of use
of the device. In addition, a HUD may be administered only if such use
has been approved by the IRB located at the facility or by a similarly
constituted IRB that has agreed to oversee such use and to which the
local IRB has deferred in a letter to the HDE holder, signed by the IRB
chair or an authorized designee.
(b) Withdrawal of IRB approval. A holder of an approved HDE shall
notify FDA of any withdrawal of approval for the use of a HUD by a
reviewing IRB within 5 working days after being notified of the
withdrawal of approval.
Sec. 814.126 Postapproval requirements and reports.
(a) An HDE approved under this subpart H shall be subject to the
postapproval requirements and reports set forth under subpart E of this
part, as applicable. In addition, medical device reports submitted to
FDA in compliance with the requirements of part 803 of this chapter
shall also be submitted to the IRB of record.
(b) In addition to the reports required under subpart E of this
part, the holder of an approved HDE shall prepare and submit the
following complete, accurate, and timely reports:
(1) Final report. Unless a request for extension is submitted in
accordance with Sec. 814.120, a final report shall be submitted no
later than 90 days following the expiration of the period of marketing
approval. The final report shall include: An estimate of the number of
patients who were treated or diagnosed with the device and the number
of devices shipped or sold since initial marketing approval under this
subpart H. (If the number of devices shipped or sold exceeds 4,000 per
year, an explanation and estimate of the number of devices used per
patient shall be included. Similarly, if a single device is used on
multiple patients, the applicant shall submit an estimate of the number
of patients treated or diagnosed using the device together with an
explanation of the basis for the estimate.) The holder of the HDE shall
also report information regarding retrieval or disabling of unused
devices, a summary of results and conclusions with regard to clinical
use of the device, and a summary of the medical device reports
submitted under part 803 of this chapter. The report shall also contain
a summary and bibliography of published and unpublished data, reports,
and studies involving the device that are
[[Page 33248]]
known to or that reasonably should be known to the applicant and were
not previously submitted to FDA. If, after reviewing the summary and
bibliography, FDA concludes that FDA needs a copy of the unpublished or
published information, FDA will notify the applicant that copies shall
be submitted.
(2) Other. An HDE holder shall, for the duration of the period that
a HUD is approved for marketing, maintain records of the names and
addresses of the facilities to which the HUD has been shipped,
correspondence with reviewing IRB's, as well as any other information
requested by a reviewing IRB or FDA.
Dated: June 14, 1996.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 96-15993 Filed 6-25-96; 8:45 am]
BILLING CODE 4160-01-F
