[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]]


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Part V





Department of Health and Human Services





_______________________________________________________________________



Food and Drug Administration



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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.

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

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