Medical Devices; Humanitarian Use Devices

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