33232 Federal Register / Vol. 61, No. 124 / Wednesday, June 26, 1996 / Rules and Regulations

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 20 and 814

[Docket No. 91N–0404]

RIN 0910–AA09

Medical Devices; Humanitarian Use

Devices

AGENCY: Food and Drug Administration,

HHS.

ACTION: Final rule.

SUMMARY: The Food and Drug

Administration (FDA) is issuing a final

rule to implement the provisions of the

Safe Medical Devices Act of 1990 (the

SMDA) regarding humanitarian use

devices (HUD’s). A HUD is a device that

is intended to benefit patients by

treating or diagnosing a disease or

condition that affects or is manifested in

fewer than 4,000 individuals in the

United States per year. This final rule

prescribes the procedures for submitting

humanitarian device exemption (HDE)

applications, amendments, and

supplements; procedures for obtaining

an extension of the exemption; and the

criteria for FDA review and approval of

HDE’s. The purpose of this HDE is, to

the extent consistent with the protection

of the public health and safety and with

ethical standards, to encourage the

discovery and use of devices intended

to benefit patients in the treatment or

diagnosis of diseases or conditions that

affect fewer than 4,000 individuals in

the United States.

DATES: This final rule is effective

October 24, 1996.

Written comments on the information

collection requirements should be

submitted by August 26, 1996.

ADDRESSES: Submit written comments

on the information collection

requirements to the Dockets

Management Branch (HFA–305), Food

and Drug Administration, 12420

Parklawn Dr., rm. 1–23, Rockville, MD

20857. All comments should be

identified with the docket number

found in brackets in the heading of this

document.

FOR FURTHER INFORMATION CONTACT:

Joanne R. Less, Office of Device

Evaluation (HFZ–403), Center for

Devices and Radiological Health, Food

and Drug Administration, 9200

Corporate Blvd., Rockville, MD 20850,

301–594–1190.

SUPPLEMENTARY INFORMATION:

I. Background

On November 28, 1990, the President

signed into law the SMDA (Pub. L. 101–

629). In enacting the SMDA, Congress

sought to improve the Medical Device

Amendments of 1976 (the amendments).

The amendments were the first

legislative effort to establish a

comprehensive framework to regulate

medical devices and to ensure their

safety and effectiveness. Congress

subsequently recognized that for

diseases and conditions affecting small

populations, a device manufacturer’s

research and development costs could

exceed its market returns, thereby

creating an impediment to the

development of such devices. In the

SMDA, Congress enacted an amendment

to section 520(m) of the Federal Food,

Drug, and Cosmetic Act (the act) (21

U.S.C. 360j(m)) to create an incentive for

the development of devices for use in

the treatment or diagnosis of diseases or

conditions affecting a small number of

individuals.

Accordingly, section 520(m) of the act

authorizes FDA, by regulation, to

exempt a HUD from the effectiveness

requirements of sections 514 and 515 of

the act (21 U.S.C. 360d and 360e) (i.e.,

‘‘reasonable assurance that the device is

effective’’) provided that: (1) The device

is to be used to treat or diagnose a

disease or condition that affects fewer

than 4,000 individuals in the United

States; (2) the device would not be

available to a person with such a disease

or condition unless the exemption is

granted; (3) no comparable device (other

than a device that has been granted such

an exemption) is available to treat or

diagnose the disease or condition; and

(4) the device will not expose patients

to an unreasonable or significant risk of

illness or injury, and the probable

benefit to health from using the device

outweighs the risk of injury or illness

from its use, taking into account the

probable risks and benefits of currently

available devices or alternative forms of

treatment.

As specified in the statute, an HDE is

valid for a term of 18 months from the

date of approval but can be extended at

18-month intervals as long as certain

approval criteria are met. Under section

520(m)(5) of the act, an exemption may

only be initially granted in the 5-year

period commencing on the effective

date of this rule, although extensions

may continue to be granted after the

expiration of the initial 5-year period.

Section 520(m) of the act also states that

a HUD cannot be sold for an amount

that exceeds the costs of research and

development, fabrication, and

distribution. In addition, such devices

may only be used in facilities that have

established a local institutional review

board (IRB) to supervise clinical testing

of devices, and after an IRB has

approved the use of the device to treat

or diagnose the specific rare disease

(section 520(m)(3) and (m)(4) of the act).

On December 21, 1992 (57 FR 60491),

FDA published a proposed rule on

humanitarian use devices in the Federal

Register. The proposed rule would have

amended the investigational device

exemption (IDE) regulations at part 812

(21 CFR part 812). At that time, FDA

believed that amending the IDE

regulations would be preferable to

creating a new part to its premarket

approval regulations because part 812

already contains provisions on IRB

review and approval, patient informed

consent, and limitations on charging. In

the proposed rule, FDA explicitly

invited comment on ‘‘the advantages or

disadvantages of using the IDE

regulation as the means to implement

section 520(m) of the act, as well as the

desirability of using other alternative

methods of implementation’’ (57 FR

60491 at 60492).

FDA received 11 comments on the

proposed rule. In general, most of the

comments opposed including the HDE

provisions in part 812. These comments

asserted that applying the IDE

regulations would make the HDE

process more burdensome, discourage

HUD development, prevent firms from

promoting a HUD or distributing

information about a HUD, preclude

firms from obtaining third party

reimbursement for a HUD, and increase

a firm’s liability insurance costs. In

addition, these comments asserted that

this approach would be contrary to the

intent behind section 520(m) of the act

which, some comments claimed, was to

facilitate marketing of HUD’s rather than

clinical investigations involving HUD’s.

Three comments suggested that FDA

implement section 520(m) of the act by

creating special marketing procedures

for HUD’s under the premarket approval

regulations of part 814 (21 CFR part

814), which implement section 515 of

the act. One of these comments stated

that FDA should issue a new proposal

requesting comments on this approach.

Upon further consideration, the

agency agrees that placing the HDE

provisions in the IDE regulations is

inappropriate because section 520(m) of

the act is intended to facilitate the

discovery and use of HUD’s rather than

to promote their use in clinical studies.

Accordingly, the agency has chosen to

create a new subpart H under part 814,

specifically addressing HUD’s, thereby

establishing these devices as legally

marketed products under the act.
Federal Register / Vol. 61, No. 124 / Wednesday, June 26, 1996 / Rules and Regulations 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

§ 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 § 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
33234 Federal Register / Vol. 61, No. 124 / Wednesday, June 26, 1996 / Rules and Regulations

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 twostep 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 § 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 § 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’’ (§ 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

§§ 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 § 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)
Federal Register / Vol. 61, No. 124 / Wednesday, June 26, 1996 / Rules and Regulations 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 § 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 § 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

(§ 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

(§ 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

§ 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 (§ 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

§ 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 (§ 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
33236 Federal Register / Vol. 61, No. 124 / Wednesday, June 26, 1996 / Rules and Regulations

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 § 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 § 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 §§ 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 § 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
Federal Register / Vol. 61, No. 124 / Wednesday, June 26, 1996 / Rules and Regulations 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, § 814.104(c)(4) requires the

application to contain most of the

information required under § 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

(§ 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 § 814.84.

The agency agrees, in part, with the

comment. Under § 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 § 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,

§ 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, § 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 § 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 § 812.1(b) Scope

7. Proposed § 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 § 814.100 and
33238 Federal Register / Vol. 61, No. 124 / Wednesday, June 26, 1996 / Rules and Regulations

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 § 812.3(d) Humanitarian Use

Device (HUD)

8. Proposed § 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 § 814.102, and again

each time a request for extension is

submitted under § 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

§ 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 § 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 § 860.7. The

comment asserted that, if clinical data

generated under an HDE application is

not ‘‘valid scientific evidence’’ within

§ 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 § 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 § 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
Federal Register / Vol. 61, No. 124 / Wednesday, June 26, 1996 / Rules and Regulations 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

(§ 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

§ 812.35(a) and (b) to the list of IDE

requirements that would be waived for

a HUD. Currently, § 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 § 812.10 would not

adequately reduce the cost of preparing

IDE’s and PMA’s.

Although proposed § 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 § 812.20(e)(2) Information

Required for HUD’s

15. Proposed § 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 § 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.

§ 812.27 Report of Prior Investigations

16. Although FDA did not propose

any amendments to § 812.27, one

comment suggested adding a new

paragraph to § 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

§ 814.116(c).

Proposed § 812.35(c) Request for

Extension of a HUD Investigation

FDA received three comments

pertaining to proposed § 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
33240 Federal Register / Vol. 61, No. 124 / Wednesday, June 26, 1996 / Rules and Regulations

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

§ 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, § 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,

§ 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

(§§ 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 § 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 § 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 § 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
Federal Register / Vol. 61, No. 124 / Wednesday, June 26, 1996 / Rules and Regulations 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 § 812.30(d) and (e) FDA

Action on Applications and Revocation

of an Application for a HUD

Proposed § 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 §§ 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

§ 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 (§ 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 § 814.112). The criteria and

procedures for filing an HDE are similar

to those for PMA’s. After filing an HDE

or HDE supplement, § 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 § 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 § 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 § 814.42(d) for filing

decisions and § 814.44 for not

approvable letters.

Proposed § 812.38(e) Availability of

Data and Information

24. Proposed § 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
33242 Federal Register / Vol. 61, No. 124 / Wednesday, June 26, 1996 / Rules and Regulations

§ 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 § 814.122 to address the

confidentiality of data and information

in an HDE application. Under

§ 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 § 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 § 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 § 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 § 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

§ 814.9(g), other information contained

in an HDE becomes available under the

particular circumstances set forth in that

provision.

Proposed § 812.39 Certification

25. Proposed § 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 §§ 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.
Federal Register / Vol. 61, No. 124 / Wednesday, June 26, 1996 / Rules and Regulations 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

21 CFR Section No. of

Respondents

Annual

Frequency per

Response

Total Annual

Responses

Hours per

Response Total Hours

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

21 CFR Section No. of

Recordkeepers

Annual

Frequency per

Recordkeeping

Total Annual

Records

Hours per

Recordkeeper Total Hours

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:
33244 Federal Register / Vol. 61, No. 124 / Wednesday, June 26, 1996 / Rules and Regulations

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:

§ 20.100 Applicability; cross-reference to

other regulations.

* * * * *

(c) * * *

(41) Humanitarian device exemption

application, in § 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:

§ 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 §§ 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

§ 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 § 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.

§ 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 § 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
Federal Register / Vol. 61, No. 124 / Wednesday, June 26, 1996 / Rules and Regulations 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.

§ 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 § 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 § 814.20(b), except

that:

(i) In lieu of the summaries,

conclusions, and results from clinical

investigations required under

§§ 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

§ 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.

§ 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 § 814.37. The timeframes

and extension of review times set forth

in § 814.37 for PMA’s shall also be

applicable to HDE’s.

§ 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 § 814.39,

except that a request for a new

indication for use of a HUD shall

comply with the requirements set forth

in § 814.110.

§ 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 § 814.102 and shall submit an

original HDE in accordance with

§ 814.104.

(b) An application for a new

indication for use made under § 814.104

may incorporate by reference any

information or data previously

submitted to the agency under an HDE.

§ 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

§ 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

§ 814.42(b), (c), and (d) regarding

notification of filing decisions, filing

dates, the start of the 180-day review
33246 Federal Register / Vol. 61, No. 124 / Wednesday, June 26, 1996 / Rules and Regulations

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 § 814.20.

§ 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 § 814.116), or an order

denying approval (under § 814.118).

§ 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

§ 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 § 814.44.

(b) Approval order. FDA will issue to

the applicant an order approving an

HDE if none of the reasons in § 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 § 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 § 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

§ 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

§ 814.44(f).

§ 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 § 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

§ 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 § 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 § 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 § 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 § 814.46(c)

and (d), and will provide the public

with notice in accordance with

§ 814.46(e), as applicable.

(e) Unless FDA otherwise determines

that continued marketing under the
Federal Register / Vol. 61, No. 124 / Wednesday, June 26, 1996 / Rules and Regulations 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.

§ 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

(§ 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 § 814.102(a) in a

separately bound volume;

(2) An update of the information

required under §§ 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 § 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 § 814.126(b).

§ 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 § 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

§ 814.9(b) through (h), as applicable.

§ 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.

§ 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 § 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
33248 Federal Register / Vol. 61, No. 124 / Wednesday, June 26, 1996 / Rules and Regulations

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