Federal Register / Vol. 63, No. 109 / Monday, June 8, 1998 / Proposed Rules 31143

individual flap transmission shafts. The

FAA does not consider it practicable for

U.S. operators to accomplish an

inspection program that necessitates

tracking the landings accumulated on

individual flap transmission shaft

components due to the difficulty of such

tracking.

Operators should further note that,

unlike the procedures described in the

maintenance instructions, this proposed

AD would not permit further flight if

cracks are detected in the flap

transmission shaft. The FAA has

determined that, because of the safety

implications and consequences

associated with such cracking, any

subject flap transmission shaft that is

found to be cracked must be repaired or

modified prior to further flight.

Cost Impact

The FAA estimates that 2 airplanes of

U.S. registry would be affected by this

proposed AD, and that it would take

approximately 30 work hours per

airplane to accomplish the proposed

inspection and functional test, at an

average labor rate of $60 per work hour.

Based on these figures, the cost impact

proposed by this AD on U.S. operators

is estimated to be $3,600, or $1,800 per

airplane, per cycle.

The cost impact figure discussed

above is based on assumptions that no

operator has yet accomplished any of

the proposed requirements of this AD

action, and that no operator would

accomplish those actions in the future if

this AD were not adopted.

Regulatory Impact

The regulations proposed herein

would not have substantial direct effects

on the States, on the relationship

between the national government and

the States, or on the distribution of

power and responsibilities among the

various levels of government. Therefore,

in accordance with Executive Order

12612, it is determined that this

proposal would not have sufficient

federalism implications to warrant the

preparation of a Federalism Assessment.

For the reasons discussed above, I

certify that this proposed regulation (1)

is not a ‘significant regulatory action’

under Executive Order 12866; (2) is not

a ‘significant rule’ under the DOT

Regulatory Policies and Procedures (44

FR 11034, February 26, 1979); and (3) if

promulgated, will not have a significant

economic impact, positive or negative,

on a substantial number of small entities

under the criteria of the Regulatory

Flexibility Act. A copy of the draft

regulatory evaluation prepared for this

action is contained in the Rules Docket.

A copy of it may be obtained by

contacting the Rules Docket at the

location provided under the caption

ADDRESSES.

List of Subjects in 14 CFR Part 39

Air transportation, Aircraft, Aviation

safety, Safety.

The Proposed Amendment

Accordingly, pursuant to the

authority delegated to me by the

Administrator, the Federal Aviation

Administration proposes to amend part

39 of the Federal Aviation Regulations

(14 CFR part 39) as follows:

PART 39—AIRWORTHINESS

DIRECTIVES

1. The authority citation for part 39

continues to read as follows:

Authority: 49 U.S.C. 106(g), 40113, 44701.

§ 39.13 [Amended]

2. Section 39.13 is amended by

adding the following new airworthiness

directive:

Construcciones Aeronauticas, S.A. (CASA):

Docket 98–NM–160–AD.

Applicability: All CASA Model CN–235

series airplanes, certificated in any category.

Note 1: This AD applies to each airplane

identified in the preceding applicability

provision, regardless of whether it has been

modified, altered, or repaired in the area

subject to the requirements of this AD. For

airplanes that have been modified, altered, or

repaired so that the performance of the

requirements of this AD is affected, the

owner/operator must request approval for an

alternative method of compliance in

accordance with paragraph (c) of this AD.

The request should include an assessment of

the effect of the modification, alteration, or

repair on the unsafe condition addressed by

this AD; and, if the unsafe condition has not

been eliminated, the request should include

specific proposed actions to address it.

Compliance: Required as indicated, unless

accomplished previously.

To detect and correct cracking in the flap

transmission shafts, and to correct a

malfunctioning flap braking sub-system,

which could result in the inability to move

the flaps, or in an asymmetric flap condition,

and consequent reduced controllability of the

airplane; accomplish the following:

(a) Prior to the accumulation of 6,000 total

landings, or within 30 days after the effective

date of this AD, whichever occurs later,

perform a high frequency eddy current

(HFEC) inspection of the flap transmission

shafts to detect cracking, in accordance with

Annex I, dated June 16, 1997, of CASA

Maintenance Instructions COM 235–113,

Revision 02, dated June 16, 1997.

(1) If no cracking is detected, repeat the

HFEC inspection thereafter at intervals not to

exceed 2,000 landings.

(2) If any cracking is detected, prior to

further flight, replace the cracked shaft with

a new or serviceable shaft, in accordance

with the maintenance instructions; and

repeat the HFEC inspection thereafter at

intervals not to exceed 2,000 landings.

(b) Prior to the accumulation of 6,000 total

landings, or within 30 days after the effective

date of this AD, whichever occurs later,

perform a functional test (check) to verify

proper operation of the flap braking subsystem, in accordance with Annex II, dated

July 1, 1997, of CASA Maintenance

Instructions COM 235–113, Revision 02,

dated June 16, 1997.

(1) If no malfunction is detected, repeat the

functional test thereafter at intervals not to

exceed 300 landings.

(2) If any malfunction is detected, prior to

further flight, replace any discrepant

component with a new or serviceable

component in accordance with the

maintenance instructions; and repeat the

functional test to verify proper operation of

the flap braking sub-system; thereafter, repeat

the functional test thereafter at intervals not

to exceed 300 landings.

(c) An alternative method of compliance or

adjustment of the compliance time that

provides an acceptable level of safety may be

used if approved by the Manager,

International Branch, ANM–116, FAA,

Transport Airplane Directorate. Operators

shall submit their request through an

appropriate FAA Principal Maintenance

Inspector, who may add comments and then

send it to the Manager, International Branch,

ANM–116.

Note 2: Information concerning the

existence of approved alternative methods of

compliance with this AD, if any, may be

obtained from the International Branch,

ANM–116.

(d) Special flight permits may be issued in

accordance with sections 21.197 and 21.199

of the Federal Aviation Regulations (14 CFR

21.197 and 21.199) to operate the airplane to

a location where the requirements of this AD

can be accomplished.

Note 3: The subject of this AD is addressed

in Spanish airworthiness directive 11/96,

Revision 1, dated June 19, 1997.

Issued in Renton, Washington, on June 2,

1998.

Darrell M. Pederson,

Acting Manager, Transport Airplane

Directorate, Aircraft Certification Service.

[FR Doc. 98–15135 Filed 6–5–98; 8:45 am]

BILLING CODE 4910–13–U

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 16 and 99

[Docket No. 98N–0222]

Dissemination of Information on

Unapproved/New Uses for Marketed

Drugs, Biologics, and Devices

AGENCY: Food and Drug Administration,

HHS.

ACTION: Proposed rule.
31144 Federal Register / Vol. 63, No. 109 / Monday, June 8, 1998 / Proposed Rules

SUMMARY: The Food and Drug

Administration (FDA) is proposing to

issue new regulations pertaining to the

dissemination of information on

unapproved uses (also referred to as

‘‘new uses’’ and ‘‘off-label uses’’) for

marketed drugs, including biologics,

and devices. The proposal, which

would implement the dissemination

provisions of the Food and Drug

Administration Modernization Act of

1997 (FDAMA), would describe the new

use information that a manufacturer

may disseminate and describe the

content of and establish procedures for

a manufacturer’s submissions to FDA

before it may begin disseminating

information on the new use. The

proposal also would describe how

manufacturers seeking to disseminate

new use information must agree to

submit a supplement for that use within

a specified period of time, unless a

supplemental application already has

been submitted or FDA has exempted

the manufacturer from the requirement

to submit a supplement. The proposal

also would provide for requests to

extend the time period for submitting a

supplement for a new use, and it would

describe how a manufacturer can seek

an exemption from the requirement to

submit a supplement. Additionally, the

proposal would discuss FDA actions in

response to manufacturers’ submissions,

corrective actions that FDA may take,

and recordkeeping and reporting

requirements.

DATES: Written comments by July 23,

1998.

ADDRESSES: Submit written comments

to the Dockets Management Branch

(HFA–305), Food and Drug

Administration, 12420 Parklawn Dr.,

rm. 1–23, Rockville, MD 20857. Submit

written comments on the information

collection requirements to the Office of

Information and Regulatory Affairs,

Office of Management and Budget

(OMB), New Executive Office Bldg., 725

17th St. NW., Washington, DC 20503,

Attn: Desk Officer for FDA.

FOR FURTHER INFORMATION CONTACT:

Regarding general questions: Margaret

M. Dotzel, Office of Policy (HF–22),

Food and Drug Administration,

5600 Fishers Lane, Rockville, MD

20857, 301–827–5321.

Regarding biological products and

devices regulated by the Center for

Biologics Evaluation and Research:

Toni M. Stifano, Center for

Biologics Evaluation and Research

(HFM–200), Food and Drug

Administration, 1401 Rockville

Pike, Rockville, MD 20852, 301–

827–3028.

Regarding human drug products:

Laurie B. Burke, Center for Drug

Evaluation and Research (HFD–40),

Food and Drug Administration,

5600 Fishers Lane, Rockville, MD

20857, 301–827–2828.

Regarding medical devices: Byron L.

Tart, Center for Devices and

Radiological Health (HFZ–302),

Food and Drug Administration,

2098 Gaither Rd., Rockville, MD

20850, 301–594–4639.

SUPPLEMENTARY INFORMATION:

I. Introduction/Summary of Legislation

On November 21, 1997, the President

signed into law FDAMA (Pub. L. 105–

115). Section 401 of FDAMA amended

the Federal Food, Drug, and Cosmetic

Act (the act) to permit drug, biologic,

and device manufacturers to

disseminate certain written information

concerning the safety, effectiveness, or

benefits of a use that is not described in

the product’s approved labeling to

health care practitioners, pharmacy

benefit managers, health insurance

issuers, group health plans, and Federal

and State government agencies,

provided that:

1. The information is about a drug or

device that is being legally marketed;

2. The information is not derived from

another manufacturer’s clinical

research, unless that other manufacturer

has given its permission for the

dissemination;

3. Sixty days prior to the

dissemination, the manufacturer

submits to FDA a copy of the

information to be disseminated and any

other clinical trial information that the

manufacturer has relating to the safety

or effectiveness of the new use, any

reports of clinical experience that

pertain to the safety of the new use, and

a summary of such information;

4. The information is not false or

misleading and does not pose a

significant risk to public health;

5. The information is in the form of

unabridged reprints or copies of peer

reviewed articles about scientifically

sound clinical investigations published

in scientific or medical journals or in

the form of unabridged reference

publications that include information

about scientifically sound clinical

investigations;

6. The manufacturer includes with

such information a prominently

displayed statement disclosing: That the

use is not approved or cleared by FDA;

if applicable, that the information is

being disseminated at the

manufacturer’s expense; if applicable,

the names of any authors of the

information who are employees of or

consultants to the manufacturer or have

received compensation or have a

significant financial interest in the

manufacturer; if applicable, a statement

that there are products or treatments

that have been approved or cleared for

the use that is the subject of the

information; and the identification of

any person that has provided funding

for the study related to the new use for

which such information is being

disseminated;

7. The manufacturer includes the

official labeling and a bibliography of

other articles from scientific reference

publications or journals relating to the

new use;

8. If FDA determines that the

information fails to provide data,

analyses, or other written matter that is

objective and balanced, the

manufacturer includes additional

objective and scientifically sound

information that pertains to the safety or

effectiveness of the new use and/or an

objective statement prepared by FDA

that bears on the safety or effectiveness

of the new use; and

9. The manufacturer has: (a)

Submitted a supplemental application

for the new use; (b) completed the

studies needed for a supplemental

application for the new use and certified

that such studies are completed and that

a supplemental application will be

submitted within 6 months of the initial

dissemination; (c) provided a proposed

protocol and schedule for conducting

the studies needed for a supplemental

application for the new use, which FDA

has found to be adequate and reasonable

(respectively) and certified that such

application will be submitted no later

than 36 months after the initial

dissemination; or (d) received an

exemption from the requirement to file

a supplemental application on the

grounds that conducting the studies

needed for a supplemental application

would be unethical or economically

prohibitive.

Under the new law, if FDA fails to act

on a request for an exemption within 60

days, the exemption is deemed

approved, and a manufacturer who

meets all other requirements may begin

to disseminate the written information.

FDA may, however, subsequently

terminate the deemed approval and

order a manufacturer to cease

dissemination. FDA can also order the

manufacturer to take corrective action if

the new use would pose a significant

risk to public health.

Manufacturers have an ongoing

responsibility to provide FDA with

additional information about the new

uses that are the subject of

dissemination under these provisions,

and, if this information indicates that

the new use may not be effective or may
Federal Register / Vol. 63, No. 109 / Monday, June 8, 1998 / Proposed Rules 31145

present a significant risk to public

health, FDA may order the cessation of

the dissemination about the new use.

FDA may also order cessation of

dissemination if the manufacturer fails

to comply with any requirement for

dissemination, including the

requirements relating to the completion

of studies and/or the submission of a

supplemental application.

Every 6 months, manufacturers that

disseminate information under these

provisions are required to prepare and

submit to FDA lists of the titles of

articles and reference publications that

have been disseminated during the

previous 6-month period and the

categories of providers who have

received the materials. In addition,

manufacturers must keep records that

can be used by the manufacturer or FDA

to take corrective action. Such records

may, at FDA’s discretion, identify either

the recipient of the information or the

categories of such recipients.

Manufacturers that have committed to

doing the studies needed for submission

of a supplement on a new use must also

submit periodic reports to FDA that

describe the status of the studies.

The dissemination of information in

accordance with new section 551 of the

act (21 U.S.C. 360aaa) is not construed

as evidence of a new intended use of the

drug or device, and it is not considered

to be labeling, adulteration, or

misbranding. This rule of construction

applies, however, only to the

dissemination of information in

compliance with the statutory

requirements. Moreover, disseminating

information in violation of the

requirements of section 551 of the act is

prohibited.

Section 401(c) of FDAMA directs FDA

to issue regulations to implement the

new statutory provisions within 1 year

of enactment (by November 21, 1998).

Accordingly, the agency must solicit

public comment on this proposal,

consider the comments submitted, and

prepare and publish a final

implementing regulation by November

21, 1998. In light of this limited

timeframe, the Commissioner finds good

cause under 21 CFR 10.40(b)(2) for

providing a shortened comment period

of 45 days.

Section 401(d) of FDAMA provides

that the new provisions will take effect

1 year after the date of enactment

(November 21, 1998) or upon FDA’s

issuance of final regulations, whichever

is sooner. According to section 401(e) of

FDAMA, the provisions will sunset on

September 30, 2006, or 7 years after the

date on which the agency issues its

regulations, whichever is later.

II. Description of the Proposed Rule

The proposed rule would create a new

part 99 entitled ‘‘Dissemination of

Information on Unapproved/New Uses

for Marketed Drugs, Biologics, and

Devices.’’

A. Subpart A—General Information

Proposed subpart A would consist of

two provisions. Proposed § 99.1 would

describe the scope of part 99. Proposed

§ 99.1(a)(1) would explain that the part

applies to the dissemination of

information on human drugs, including

biologics, and devices where the

information to be disseminated

concerns the safety, effectiveness, or

benefit of a use that is not included in

the approved labeling for an approved

drug or device or in the statement of

intended use for a cleared device.

Proposed § 99.1(a)(2) would provide

that the information is to be

disseminated to a health care

practitioner, pharmacy benefit manager,

health insurance issuer, group health

plan, or Federal or State government

agency. This description of the rule’s

scope would be consistent with section

551(a) of the act.

Proposed § 99.3 would define various

terms, such as ‘‘group health plan’’

(proposed § 99.3(c)), ‘‘health care

practitioner’’ (proposed § 99.3(d)), ‘‘new

use’’ (proposed § 99.3(g)), and

‘‘scientific or medical journal’’

(proposed § 99.3(i)). In most cases, the

definitions paraphrase or repeat the

statutory definitions at section 556 of

the act (21 U.S.C. 360aaa–5). However,

proposed § 99.3(f) would elaborate on

the statutory definition of

‘‘manufacturer’’ to include sponsors of

marketed drugs or devices. FDA is

proposing to elaborate in this manner so

that sponsors of a drug or device who

received marketing approval for the

product, but do not actually

manufacture the product, would be able

to disseminate information under this

part.

The proposed rule would track the

statutory definition of ‘‘new use’’ to

mean a use that is not included in the

approved labeling of an approved drug

or device or a use that is not included

in the statement of intended use for a

cleared device. A new use is one that

would require approval or clearance of

a supplemental application in order for

it to be included in the product labeling.

‘‘New uses’’ that would require approval

of a supplemental application to add the

use to the labeling of an approved drug

or to the labeling of an approved or

cleared device and that, therefore,

would be covered by this part include,

but are not limited to: A completely

different indication; modification of an

existing indication to include a new

dose, a new dosing schedule, a new

route of administration, a different

duration of usage, a new age group (e.g.,

unique safety or effectiveness in the

elderly), another patient subgroup not

explicitly identified in the current

labeling, a different stage of the disease,

a different intended outcome (e.g., longterm survival benefit, improved quality

of life, disease amelioration),

effectiveness for a sign or symptom of

the disease not in the current labeling;

and comparative claims to other agents

for treatment of the same condition.

This illustrative listing is consistent

with the statutory intent that clearly

links the new use discussed in the

materials to be disseminated to the

sponsor’s submission of a supplemental

application in order to add the use to

the product labeling.

The proposed rule would also define

‘‘clinical investigation’’ and

‘‘supplemental application,’’ which are

not defined in the statute. A clinical

investigation would be defined as an

investigation in humans that is

prospectively planned to test a specific

clinical hypothesis. The conduct of a

clinical investigation according to a

preplanned protocol generally is a

fundamental aspect of hypothesis

testing.

The proposal would define a

‘‘supplemental application’’ to mean a

supplemental new drug application

(NDA) for human drugs or a supplement

to an approved license application for

biologics. A supplement to an NDA

could be a supplement to an application

submitted under section 505(b)(1) of the

act (21 U.S.C. 355(b)(1)) or section

505(b)(2) of the act. For devices,

proposed § 99.3(j)(3) would define a

‘‘supplemental application’’ as a new

510(k) submission, if the device is the

subject of a cleared 510(k) submission,

or a supplement to an approved

premarket approval application (PMA),

if the device is the subject of an

approved PMA. FDA is proposing to

include new 510(k) submissions as

‘‘supplemental applications’’ because

there are no ‘‘supplements’’ for a new

use to a 510(k) submission, instead, a

new use is the subject of a new 510(k)

submission. There are instances when a

new use for a 510(k) device would

require the submission of a PMA, but

this would not be the equivalent of a

‘‘supplement’’ and thus, has not been

included in the definition.

Manufacturers that would be required to

submit a PMA for a new use of a device

cleared under section 510(k) of the act

(21 U.S.C. 360(k)) would not be eligible
31146 Federal Register / Vol. 63, No. 109 / Monday, June 8, 1998 / Proposed Rules

to disseminate materials under the

provisions of section 551 of the act.

B. Subpart B—Information to be

Disseminated

Proposed subpart B would describe

the types of information that

manufacturers may disseminate under

part 99; the information that

manufacturers must disseminate if they

choose to disseminate written

information about the safety,

effectiveness, or benefit of new uses;

and the persons who may receive the

information about new uses.

Proposed § 99.101 would discuss the

types of information concerning the

safety, effectiveness, or benefit of a new

use that a manufacturer may

disseminate. In brief, the proposal

would require that the written

information to be disseminated:

1. Concern a drug or device that has

been approved, licensed, or cleared for

marketing by FDA;

2. Be in the form of an unabridged

copy of a peer-reviewed scientific or

medical journal article or reprint, or an

unabridged reference publication that

pertains to a clinical investigation

involving the drug or device and that is

considered scientifically sound by

experts who are qualified to evaluate the

product’s safety or effectiveness;

3. Not pose a significant risk to the

public health;

4. Not be false or misleading; and

5. Not be derived from clinical

research conducted by another

manufacturer, unless the manufacturer

disseminating the information has

permission to make the dissemination.

Under the proposal, FDA could

consider the information to be

misleading if, among other things, the

information includes only favorable

publications or excludes articles,

reference publications, or other

information concerning risks and

adverse effects that are or may be

associated with the new use. This

element is intended to help ensure that

manufacturers disseminate balanced

and objective information. FDA also

could consider the information to be

false or misleading if the study design,

conduct, data, or analyses do not

reasonably support the conclusion

reached by the authors. In addition, the

information would be considered

misleading if the clinical study utilized

a study endpoint that is not reasonably

well-established as indicative of clinical

benefit.

As set forth in the statute and FDA’s

proposal, the information that can be

disseminated under part 99 must be in

the form of a reprint or copy of a journal

article or a reference publication.

Although the requirements set forth in

the statute are easily applied to journal

articles, they are not as easily applied to

reference publications. For example, the

definition of a reference publication

indicates that the publication may not

focus on a particular drug or device of

the manufacturer that disseminates the

information under section 551 of the act

and may not have a primary focus on

new uses of drugs or devices that are

marketed or under investigation by a

manufacturer supporting the

dissemination of information. This is

not altogether consistent with the

purpose of section 401 of FDAMA,

which is to permit the dissemination of

information about a clinical

investigation concerning a specific new

use if certain criteria are met. In

addition, although journal articles

typically include a detailed description

and discussion of clinical

investigations, reference publications

often just refer generally to the results

of such investigations. Because the

statute requires the information being

disseminated to be about a clinical

investigation, it seems unlikely that

many reference publications will meet

the requirements for dissemination

under this provision. Finally, the statute

requires that a manufacturer submit (or

commit to submit) a supplement for

each new use discussed in the

information to be disseminated. This

could be construed to mean that a

manufacturer that disseminates a

reference publication that discusses

many new uses would be required,

under the statute, to submit (or commit

to submit) a supplement for each of the

many new uses mentioned.

Despite these issues, FDA believes

that the statutory provisions can be

interpreted and applied to conform with

the text and spirit of the legislation.

Although the statute does not allow a

reference publication, as a whole, to

focus on the disseminating

manufacturer’s products or new uses, it

does not prohibit a manufacturer from

citing a particular use or uses in a

publication that does not have such a

focus if the manufacturer complies with

the requirements set forth in section 401

of FDAMA. This will, therefore, allow

manufacturers to use reference

publications in the same manner as they

would use journal articles, i.e., to

disseminate information about a specific

new use. Although a manufacturer must

submit (or commit to submit) a

supplemental application for the new

use that it has cited in the reference

publication, the manufacturer would

not have to submit (or commit to

submit) a supplement for each new use

mentioned in the publication.

Nevertheless, because reference

publications rarely include detailed

discussions of clinical investigations,

FDA recognizes that the majority of

such publications would probably not

meet the requirements of section 401 of

FDAMA and this proposed

implementing regulation. FDA,

therefore, plans to develop draft

guidance and solicit public comment on

reference publications that do not fall

within the scope of part 99.

Proposed § 99.101 would also explain

that the determination of whether a

clinical investigation is considered to be

scientifically sound rests on whether the

design, conduct, data, and analysis of

the investigation described or discussed

in a reprint or copy of an article or in

a reference publication reasonably

support the conclusions reached by the

authors. A clinical investigation

described or discussed in an article or

reference publication must include a

description of the study design and

conduct, data presentation and analysis,

summary of results, and conclusions

pertaining to the new use. In order to

provide a basis for determining whether

the conclusions are reasonably

supported and the findings represent

evidence of safety and effectiveness of

the new use, the article or reference

publication should provide, where

applicable, evidence that the

investigation:

1. Was prospectively planned. Types

of prospectively planned investigations

include: A clinical trial in which

subjects are enrolled and assigned to

treatment according to a protocol; a

meta-analysis of published clinical

investigations in which there is a

planned strategy for the inclusion of

published articles and for the integrated

analysis of their results; or a welldocumented prospective case series that

utilizes a predetermined strategy for the

inclusion of cases. Ordinarily, such a

case series would be considered to be a

scientifically sound clinical

investigation for the purposes of

dissemination only in those

circumstances where the disease under

study had high and predictable

mortality and/or morbidity and was not

expected to improve spontaneously;

2. Enrolled an appropriately defined

and diagnosed patient population for

the specific clinical condition of

interest;

3. Accounted for all patients enrolled,

including all patients who discontinued

therapy prematurely. An analysis that is

based on only a portion of all study

subjects enrolled should provide

information on how this population was

derived;
Federal Register / Vol. 63, No. 109 / Monday, June 8, 1998 / Proposed Rules 31147

4. Utilized clinically meaningful

endpoints or utilized surrogate

endpoints that are reasonably likely to

predict safety and effectiveness. These

endpoints should have been assessed

using well-established instruments, and

using appropriate measurement

frequencies;

5. Used a well-described treatment

regimen with a clear description of

dose, schedule, duration, and route of

administration;

6. Used an appropriate control group

or made reference to an appropriate

historical control;

7. Collected and reported adequate

information on adverse experiences, and

the need for dose reductions and

treatment interruptions due to toxicity;

and

8. Was analyzed in a scientifically

appropriate manner. In circumstances

where response to therapy is expected

to differ between patient subgroups,

results should be reported accordingly.

A clinical investigation presented in a

format that does not represent a

reasonably comprehensive presentation

of the study design, conduct, data,

analyses, and conclusions, for example,

letters to the editor, review abstracts,

abstracts of a publication, or other

incomplete reports, would not qualify

for dissemination under this provision.

Such reports do not provide sufficient

information to determine the adequacy

of the study design and cannot be

critically judged by the reader.

Proposed § 99.101 would further

explain what is meant by the term

‘‘unabridged,’’ i.e., the reprint, article, or

reference text must retain the same

appearance, form, format, content, or

configuration as the original article or

publication. It cannot be accompanied

by information that is promotional in

nature. Because a reference text might

include a discussion of many new uses

and a manufacturer might want to

disseminate it under part 99 for the

purpose of providing information on

one particular discussion in the book,

proposed § 99.101(b)(2) would permit

the manufacturer to cite a particular

discussion about a new use in a

reference publication in the information

that is required to be attached to the

reference publication under proposed

§ 99.103.

Proposed § 99.103(a) would,

consistent with section 551(b) and (c) of

the act, describe the information that

must accompany the journal article or

reference publication. Specifically it

would require:

1.A prominently displayed statement

that discloses that the information being

disseminated is about a use that has not

been approved or cleared by FDA and

is being disseminated under section 551

et seq. of the act; if applicable, that the

manufacturer is disseminating such

information at its own expense, the

names of authors who are employees or

consultants to, or have received

compensation from the manufacturer or

who have a significant financial interest

in the manufacturer, and a statement

that there are products or treatments

approved/cleared for the new use; and

the identification of any person that has

provided funding for the study that is

the basis of the information for which

such information is being disseminated;

2. The official labeling for the

product;

3. A bibliography of other articles

(that concern reports of clinical

investigations) both supporting and not

supporting the new use;

4. Any additional information

required by FDA, including objective

and scientifically sound information

pertaining to the safety or effectiveness

of the new use that FDA determines is

necessary to provide objectivity and

balance, including information that the

manufacturer has submitted to FDA or,

where appropriate, a summary of such

information, and any other information

that can be made publicly available; and

an objective statement prepared by FDA,

based on data or other scientifically

sound information bearing on the safety

or effectiveness of the new use of the

product.

Proposed § 99.103(c) would describe

what is meant by a ‘‘prominently

displayed’’ statement by setting forth

criteria that are consistent with the

agency’s regulations on prescription

drug advertising (21 CFR

202.1(e)(7)(viii)) and labeling (21 CFR

201.10(g)(2)). Factors to be considered

in determining whether a statement is

prominently displayed may include, but

are not limited to, type size, font, layout,

contrast, graphic design, headlines,

spacing, and any other technique to

achieve emphasis or notice. In addition,

proposed § 99.103(c) would require

such statements to be outlined, boxed,

highlighted, or otherwise graphically

designed and presented on the front of

the disseminated information in a

manner that achieves emphasis or

notice and is distinct from the other

information being disseminated.

For purposes of proposed

§ 99.103(a)(1)(iii), an author would have

a significant financial interest in a

manufacturer when there is a

relationship that may give rise to actual

or perceived conflicts of interest. The

concept of relationships that may give

rise to conflicts of interest has specific

and well understood application to

medical and scientific discourse (e.g., in

the publication and peer review

process). When there is a question as to

whether a relationship is significant, it

should be disclosed. For further

guidance and direction on the

disclosure of significant financial

interests, manufacturers should refer to

FDA’s final rule on Financial Disclosure

by Clinical Investigators (63 FR 5233,

February 2, 1998).

The official labeling that would be

required by proposed § 99.103(a)(2)

would for drugs constitute the current

package insert. Because devices do not

always include a package insert in the

same form and manner as drugs, the

agency would expect device

manufacturers to provide the same

information that is generally found in

package inserts, namely: (1) The name

of the device, including its trade or

proprietary name; (2) the manufacturer’s

name, address, and telephone number;

(3) a statement of intended use,

including a general description of the

diseases or conditions that the device is

intended to diagnose, treat, cure, or

mitigate; (4) a description of the patient

population for which the device is

intended; (5) a description of

indications that have been approved or

cleared by FDA; (6) a description of any

limitations or conditions that have been

placed on the sale, distribution, or use

of the device; and (7) all warnings,

contraindications, side effects, and

precautions associated with the use of

the device. The agency expects that this

information will be found in the

information that manufacturers

distribute with their legally marketed

devices.

The bibliography that would be

required by proposed § 99.103(a)(3)

should appear in the same format used

by Index Medicus and should include

all authors, the full title of the article,

and complete source information.

Proposed § 99.103(a)(1)(i) would

require the statement that the use has

not been approved or cleared by FDA

and is being disseminated under section

551 et seq. of the act to be permanently

attached to the front of each reprint or

copy of an article or reference

publication. Proposed § 99.103(a)(4)

would require any additional

information required by FDA also to be

attached to the front of the disseminated

information. Under proposed

§ 99.103(b), all other statements or

information would have to be attached

to the article or reference publication.

Proposed § 99.105 would identify

who may receive information

disseminated under this part. Possible

recipients would include health care

practitioners, pharmacy benefit

managers, health insurance issuers,
31148 Federal Register / Vol. 63, No. 109 / Monday, June 8, 1998 / Proposed Rules

group health plans, or Federal or State

government agencies. This is consistent

with section 551(a) of the act and is

important because it is essential that

this information be provided only to

persons who have the education,

training, and experience to interpret its

meaning and relevance.

C. Subpart C—Manufacturer’s

Submissions, Requests, and

Applications

Proposed subpart C would describe

what must be included in the different

types of submissions that manufacturers

would send to FDA in order to be able

to disseminate information under part

99.

Proposed § 99.201 would provide that

60 days before disseminating

information on a new use, a

manufacturer must submit to FDA:

1. A copy of all the information to be

disseminated (i.e., including all

attachments) in the form in which the

manufacturer plans to disseminate it.

This will enable FDA to see how the

information will be presented to its

intended audience and to determine

whether the information is objective and

balanced, and meets all of the

requirements of this part;

2. All other clinical trial information

that the manufacturer has relating to the

safety or effectiveness of the new use,

any reports of clinical experience

pertinent to the safety of the new use,

and a summary of such information. For

purposes of this section, clinical trial

information would include, but would

not be limited to, published papers and

abstracts, even if not intended for

dissemination, and unpublished

manuscripts, abstracts, and data

analyses from completed or ongoing

investigations. The information and

reports required under this paragraph

would include case studies,

retrospective reviews, epidemiological

studies, adverse event reports, and any

other material concerning adverse

effects or risks reported for or associated

with the new use. If the manufacturer

has no knowledge of or has no such

information, it would include a

statement to that effect;

3. An explanation of the search

strategy for the bibliography that must

be included with the disseminated

information. The search strategy must

include the data bases and criteria used

to generate the bibliography and the

time period covered by the

bibliography; and

4. If a supplement for the new use has

not been submitted, a certification that

the manufacturer will submit a

supplement or an application for an

exemption from the requirement to

submit a supplement. If a supplement

for the new use has been submitted, the

manufacturer would include a crossreference to that supplemental

application.

When the certification provides that

the studies have been completed, the

submission would include the protocols

for the studies or would cross reference

and provide the relevant information on

any protocols that are already in FDA’s

files as part of an investigational new

drug application (IND) or an

investigational device exemption (IDE).

The certification would state that the

manufacturer will submit a

supplemental application within 6

months from the date of initial

dissemination of information.

When the certification is that studies

will be conducted, proposed protocols

and a schedule must be submitted. The

proposal would require that the

protocols submitted comply with all

applicable requirements in 21 CFR parts

312 and 812, which relate to

investigational new drug applications

and investigational device exemptions.

This means that the protocols must be

sent to the appropriate review divisions

within the Center for Drug Evaluation

and Research, the Center for Biologics

Evaluation and Research, or the Center

for Devices and Radiological Health.

The protocols will be reviewed as an

original IND or IDE or an amendment to

an existing IND or IDE. The schedule

would include the expected dates for

principal study events (e.g., initiation

and completion of patient enrollment,

completion of data collection,

completion of data analysis, and

submission of a supplemental

application). The certification would

state that the manufacturer will exercise

due diligence to complete the clinical

studies needed to submit a

supplemental application for the new

use and will submit such application to

FDA no later than 36 months after the

date of the initial dissemination of

information.

Proposed § 99.201(b) would describe

who should sign a submission and

certification statement or application for

an exemption. In general, an authorized

official would sign the submission and

certification statement or application for

an exemption. For foreign

manufacturers, proposed § 99.201(b)

would require the signature, name, and

address of an authorized official

residing or maintaining a place of

business in the United States.

Proposed § 99.201(c) would provide

that manufacturers must submit three

copies of the submission (including the

certification statement or application for

an exemption) to FDA and would

provide the appropriate addresses for

such submissions. The outside of the

shipping container of the submission

would identify the documents as

‘‘Submission for the Dissemination of

Information on an Unapproved/New

Use.’’

Proposed § 99.201(d) would provide

that the 60-day period begins to run

when FDA receives a complete

submission. The submission would be

considered complete if FDA determines

that it is sufficiently complete to permit

a substantive review.

Section 554 of the act (21 U.S.C.

360aaa–3) anticipates that there will be

times when the 36-month period for

filing a supplemental application for a

new use based on new studies will not

be enough time. It provides, therefore,

that FDA may, on its own initiative at

the time of initial dissemination, give

the manufacturer more than 36 months,

or that FDA may, upon a manufacturer’s

request after such studies have begun,

extend the 36-month period by up to 24

months. Proposed § 99.203 would set

forth the procedures that a manufacturer

must follow to request an extension of

time for submitting a supplemental

application. In its request, the

manufacturer would: (1) Identify the

product and new use; (2) describe the

study or studies that cannot be

completed on time; (3) explain why the

study or studies cannot be completed;

(4) describe the current status of the

incomplete study or studies; (5)

summarize the work conducted,

including the dates on which principal

events concerning the study or studies

occurred; and (6) estimate the additional

time needed to complete the study or

studies and submit a supplemental

application. The manufacturer would

submit three copies of the request to the

same address identified for the initial

submission.

When Congress passed these

provisions of the act, it recognized that

there may be rare circumstances in

which it would be appropriate to

exempt a manufacturer that seeks to

disseminate information about a new

use from the requirement to submit a

supplement for that new use. The act

sets forth two very narrow exemptions:

(1) When, for reasons defined by the

agency, it would be economically

prohibitive to incur the costs necessary

for the submission of a supplement, and

(2) when, for reasons defined by the

agency, it would be unethical to

conduct the studies necessary for the

supplemental application.

In making a determination that it

would be economically prohibitive to

conduct the needed studies, section 554

of the act directs FDA to consider (in
Federal Register / Vol. 63, No. 109 / Monday, June 8, 1998 / Proposed Rules 31149

addition to any other considerations the

agency finds appropriate): (1) The lack

of the availability under law of any

period during which the manufacturer

would have exclusive marketing rights

with respect to the new use, and (2) the

size of the population expected to

benefit from approval of the

supplemental application. In making a

determination that it would be unethical

to conduct the needed studies, the act

directs FDA to consider (in addition to

any other considerations the agency

finds appropriate) whether the new use

involved is the standard of medical care

for a health condition.

Proposed § 99.205 would set forth

what a manufacturer must submit when

seeking an exemption from the

requirement to file a supplemental

application relating to a new use. It

would require the manufacturer to

include an explanation as to why an

exemption is sought and include

materials demonstrating that it would be

economically prohibitive or unethical to

conduct the studies needed to submit a

supplemental application.

To obtain either exemption, a

manufacturer must first explain why

existing data, including data from the

scientifically sound study described in

the information to be disseminated, are

not adequate to support approval of the

new use. This is a critical element of the

request because submitting the existing

data in a supplement, which may

require some attempt to retrieve old

records, is almost never unethical and

would almost never be economically

prohibitive. The manufacturer should

make every effort, therefore, to

determine whether existing data would

be adequate, and should include

reference to discussions with the agency

concerning the adequacy of existing

data.

If the manufacturer is seeking an

exemption on the grounds that it would

be economically prohibitive to conduct

the study or studies needed for approval

of the use, it must also show, at a

minimum, that the estimated cost of the

necessary studies would exceed the

estimated total revenue from the

product minus the cost of goods sold

and marketing and administrative

expenses attributable to the product,

and that there are not less expensive

ways to obtain the needed information.

Proposed § 99.205(b)(1) would set

forth the type of evidence that the

manufacturer must include to meet the

requirements for an economically

prohibitive exemption. These would

include:

1. A description of the current and

projected U.S. patient population for the

product and an estimate of the current

and projected economic benefit to the

manufacturer from the use of the drug

or device in this population. The

estimate would assume that the total

potential market for the drug or device

is equal to the prevalence of all of the

diseases or conditions that the drug or

device will be used to treat and involve

the following considerations:

(a) The estimated market share for the

drug or device during any exclusive

market period, a summary of the

exclusive market period for the product,

and an explanation of the basis for the

estimate;

(b) a projection of and justification for

the price at which the drug or device

will be sold; and

(c) comparisons with sales of

similarly situated drugs or devices,

where available.

2. A description of the additional

studies that the manufacturer believes

are necessary to support the submission

of a supplemental application for the

new use and an estimate of the

projected costs for such studies; and

3. An attestation by a responsible

individual of the manufacturer verifying

that the estimates included with the

submission are accurate and were

prepared in accordance with generally

accepted accounting procedures. The

data underlying and supporting the

estimates shall be made available to

FDA upon request.

FDA considered requiring a report of

an independent certified public

accountant made in accordance with the

Statement on Standards for Attestation

established by the American Institute of

Certified Public Accountants with

respect to the estimates submitted under

this section. FDA is soliciting comment

on whether such a report should be

required in lieu of or as an alternative

to the attestation that would be required

by the proposal.

Although Congress made it very clear

that exemptions from the requirement to

submit a supplement are to be rare, it

left it up to the agency to determine

when it would grant these exemptions.

This was a particularly difficult task for

the ‘‘economically prohibitive’’

exemption because it is difficult to

assess cost and income projections. The

agency is proposing to compare the cost

of the studies needed for a supplement

with the total revenue of the product

minus the cost of goods sold, and

marketing and administrative expenses

attributable to the product. FDA is not

focusing only on sales from the new use

because the agency does not believe that

it would be ‘‘prohibitive’’ if the sales

from the new use did not cover the cost

of the studies. In such a situation, it

might not be economically wise to

conduct the studies, but it would not

rise to the level of being prohibitive.

The agency considered whether it

should also require that the cost of

conducting the studies needed for the

supplement substantially exceed

revenues and be unusually great

compared to the typical costs of

developing products for similar uses.

Given the uncertainty about cost and

revenue streams, it is possible that these

measures would better define what is

economically prohibitive. Although

FDA decided not to include these

requirements in the proposal, they are

still under consideration and, therefore,

the agency invites comment on whether

they are useful in the determination of

what is economically prohibitive. FDA

also is seeking comment on other

possible ways to define economically

prohibitive.

If the manufacturer is seeking an

exemption on the grounds that it would

be unethical to conduct a needed study

or studies, proposed § 99.205(b)(2)

would require the manufacturer also to

show that, notwithstanding the

insufficiency of existing data to support

the submission of a supplemental

application for the new use, the data are

persuasive to the extent that

withholding the drug in the course of

conducting a controlled study would

pose an unreasonable risk of harm to

human subjects. For purposes of

determining what is unethical under

this part, an unreasonable risk of harm

would ordinarily arise only in situations

in which the intended use of the drug

or device appears to affect mortality or

irreversible morbidity. Evidence

suggesting that the drug or device is the

standard of care for the intended use

can add weight to an argument that

conduct of a needed study or studies

would be unethical. To support its

conclusion that the conduct of a needed

study or studies would be unethical, the

manufacturer would need to provide

evidence that it had explored various

alternative study designs (e.g., active

control studies, studies in different

populations, studies where the product

is added to existing treatment),

discussed these alternatives with the

agency, and determined that there were

no options that were both ethical and

capable of generating data adequate to

support approval. Specifically, the

proposal would require the

manufacturer to provide:

1. An explanation of why,

notwithstanding the insufficiency of

available data to support the submission

of a supplemental application for the

new use, the data are persuasive to the

extent that withholding the drug or

device in a controlled study (e.g., by
31150 Federal Register / Vol. 63, No. 109 / Monday, June 8, 1998 / Proposed Rules

providing no therapy, a placebo, an

alternative therapy, or an alternative

dose) would pose an unreasonable risk

of harm to human subjects. For

purposes of determining what is

unethical under this part, an

unreasonable risk of harm would

ordinarily arise only when the new use

appears to affect mortality or

irreversible morbidity; and

2. A discussion of the possibility of

conducting studies in different

populations or of modified design (e.g.,

adding the new therapy to existing

treatments or using an alternative dose

if monotherapy studies could not be

conducted).

In assessing the appropriateness of

conducting studies to support the new

use, the manufacturer may provide

evidence that the new use represents

standard medical treatment or therapy.

Evidence that the new use represents

standard medical therapy can be one

element of an argument that studies

cannot ethically be conducted, but the

persuasiveness of available data is

equally important. Evidence that the

new use represents standard medical

therapy might be obtained from a

number of different sources. Some

possible considerations might include:

(1) Whether the new use meets the

requirements of section 1861(t)(2)(B) of

the Social Security Act, which defines

‘‘medically accepted indications’’ with

respect to the use of a drug;

(2) whether a medical specialty

society that is represented in or

recognized by the Council of Medical

Specialty Societies (or is a subspecialty

of such society) or is recognized by the

American Osteopathic Association has

found that the new use is consistent

with sound medical practice;

(3) whether the new use is described

in a recommendation or medical

practice guideline of a Federal health

agency, including the National Institutes

of Health, the Agency for Health Care

Policy and Research, and the Centers for

Disease Control and Prevention of the

Department of Health and Human

Services; and

(4) whether the new use is described

in a current compendia such as the

United States Pharmacopoeia

Dispensing Information, the American

Medical Association Drug Evaluations,

or the American Hospital Formulary

Service.

While these sources would not be

definitive evidence of standard medical

treatment or therapy, they may provide

evidence of it in certain circumstances.

FDA has struggled to develop an

approach to these exemptions that

strikes the proper balance. It should be

emphasized that Congressional intent

was clear in expecting exemptions to be

rare. Congress emphasized the

importance of having safe and effective

uses of drugs and devices reflected in

labeling. The agency believes that it has

struck the proper balance, but it invites

comment on the exemption criteria it

has developed.

D. Subpart D—FDA Action on

Submissions, Requests, and

Applications

Proposed subpart D would describe

FDA’s actions in response to a

submission, a request for an extension

of the time period to conduct studies,

and an application for an exemption

from the requirement to conduct clinical

studies and to submit a supplemental

application.

Proposed § 99.301(a) would provide

that within 60 days of receiving a

submission, FDA may:

1. Determine that the manufacturer

does not comply with the requirements

under this part (e.g., the new use poses

a significant risk to public health or the

clinical investigation described in the

publication is not scientifically sound)

and thus, cannot disseminate

information about the new use;

2. Request additional information or

documents to assist in determining

whether the information to be

disseminated complies with the

requirements under this part;

3. Determine that the information fails

to provide data, analyses, or other

written matter that is objective and

balanced. In this case, FDA would

provide the manufacturer notice and an

opportunity for a meeting, may require

the manufacturer to disseminate

additional information that is objective

and scientifically sound, pertains to the

safety or effectiveness of the new use,

and is necessary to provide objectivity

and balance, and may require the

manufacturer to disseminate an

objective statement prepared by FDA

that is based on data or other

scientifically sound information

available to the agency; and

4. Require a manufacturer to maintain

records that will identify individual

recipients of the information that is to

be disseminated.

This last provision is tied to the

statutory requirement that

manufacturers keep records of the

recipients of the disseminated materials

so that the manufacturer or FDA can

take appropriate corrective action, e.g.,

so that the manufacturer or FDA can

notify recipients if it is later determined

that the new use that is the subject of

the dissemination may not be effective

or may present a significant risk to

public health. Section 553 of the act (21

U.S.C. 360aaa–2) provides that such

records, at the agency’s discretion, may

identify recipients of the information or

the categories of such recipients.

Although keeping records that identify

the individual recipients of the

information might best ensure that the

people who have seen and relied on the

information will learn of problems or

risks associated with the use, FDA

recognizes that it may not be necessary

to keep such specific records if the

manufacturer is willing to take steps to

ensure that the individual recipients

will see any materials that might correct

any misperceptions. Under proposed

§ 99.501, FDA would generally permit

the manufacturer to decide whether to

keep individual records or to keep more

general records and take more

conspicuous corrective action. However,

there may be instances when it would

be in the best interest of public health

if the manufacturer kept the names of

the individual recipients. In these cases,

proposed § 99.301(a)(4) would provide

that FDA will generally notify the

manufacturer in advance, i.e., within

the 60-day period for review of the

submission, that such records must be

kept.

Proposed § 99.301(b) would set forth

FDA actions in response to a

manufacturer’s submission when the

manufacturer is committing to submit a

supplement for completed studies or is

agreeing to conduct the necessary

studies and then submit a supplement.

If the manufacturer has planned studies

and submits proposed protocols (either

as a new IND or IDE or as an

amendment to an existing IND or IDE)

and a schedule for completing such

studies, FDA will, within 60 days,

review the manufacturer’s proposed

protocol and schedule for completing

such studies to determine whether the

protocols are adequate and the schedule

for completing the studies is reasonable

for purposes of disseminating the new

use information. The manufacturer

cannot disseminate the new use

information until FDA determines that

the proposed protocol is adequate and

the proposed schedule is reasonable. If

the manufacturer has completed studies

that it believes would be an adequate

basis for the submission of a

supplemental application for the new

use, FDA will, under the proposal,

conduct a preliminary review of the

study reports to determine whether the

studies are potentially adequate to

support the filing of a supplemental

application for the new use. If FDA

determines that they are inadequate to

support the filing of a supplemental

application for the new use or are not
Federal Register / Vol. 63, No. 109 / Monday, June 8, 1998 / Proposed Rules 31151

complete, FDA will notify the

manufacturer and the manufacturer

shall not disseminate the new use

information under this subpart.

Proposed § 99.303 would describe

FDA’s ability to allow a manufacturer

more than 36 months to submit a

supplemental application on its own

initiative, based on the review of the

protocols(s) and planned schedule, or to

grant a manufacturer’s request to extend

the 36-month period (for up to 24

months). Proposed § 99.303(a) would

describe FDA’s ability to determine, on

its own initiative, that a manufacturer

needs more than 36 months to complete

the studies needed for submission of a

supplemental application and to submit

such application. Proposed § 99.303(b)

and (c) would describe FDA’s ability,

after such studies have begun, to grant

an extension of the time to submit a

supplement by up to 24 months. FDA

can grant such an extension if the

manufacturer makes a request for an

extension in writing and FDA

determines that the manufacturer has

acted with due diligence to conduct the

studies needed for the submission of a

supplemental application for a new use

and to submit such a supplemental

application, but still needs more time.

In this context, ‘‘due diligence’’ refers to

a manufacturer’s good faith effort to

develop the data necessary to support a

supplemental application for the new

use and to pursue approval of an

application based on those data in a

timely manner. In its consideration of a

request to extend the time for

completing studies, the agency will look

at all relevant factors and will focus on

the manufacturer’s efforts to meet the

milestones identified in the schedule

submitted with the manufacturer’s

certification to complete required

studies (i.e., completion of patient

enrollment in clinical studies,

completion of data collection,

completion of data analysis, and

submission of a supplemental

application). If a manufacturer has

failed to meet identified milestones

despite reasonable efforts to do so and,

in the agency’s judgment, an extension

of time to complete the studies will

enable a manufacturer to complete

development of the necessary data and

submit a supplemental application, the

agency may grant an extension of the

time to complete studies and submit the

supplemental application.

If FDA extends the time period for

completing the studies and submitting a

supplemental application or grants a

manufacturer’s request for an extension,

the manufacturer shall submit a new

certification under § 99.201(a)(4)(ii)(B)

that sets forth the timeframe within

which clinical studies will be

completed and a supplemental

application will be submitted to FDA.

Proposed § 99.305 would describe

FDA action on an application for an

exemption from the requirement to

submit a supplemental application. FDA

may grant an application for an

exemption if it determines that it would

be economically prohibitive for the

manufacturer to conduct the studies

needed for a supplemental application

or it would be unethical to conduct

clinical studies needed to approve the

new use.

FDA may find that it would be

economically prohibitive if, at a

minimum, existing data characterizing

the product’s safety and effectiveness,

including data from the study described

in the information to be disseminated,

are not adequate to support the

submission of a supplemental

application for the new use and the

estimated cost of the studies needed to

support the submission of a

supplemental application for the new

use would exceed the estimated total

revenue from the product minus the

cost of goods sold and the marketing

and administrative expenses attributable

to the product and that there are not less

expensive ways to obtain the needed

information. FDA may find that it

would be unethical to conduct the

clinical studies needed to support the

submission of a supplemental

application for the new use when

existing data characterizing the

product’s safety and effectiveness,

including data from the study described

in the information to be disseminated,

are not adequate to support the

submission of a supplemental

application for the new use and there is

sufficiently persuasive evidence that

withholding the drug or device in a

controlled study would pose an

unreasonable risk of harm to human

subjects and no studies in different

populations or of modified design can

be utilized. In determining whether it

would be unethical to conduct clinical

studies, the agency will consider, in

addition to the persuasiveness of

available evidence, whether the new use

of the drug or device is broadly accepted

as current standard medical treatment or

therapy.

The evidence and factors that FDA

will consider in granting an exemption

were discussed previously. The agency

reiterates, however, that these

exemptions cannot and will not be

liberally granted. Congress was trying to

balance the need to get potentially

important information on new uses to

physicians with the need to get these

new uses studied, approved, and in the

labeling. If FDA were to liberally grant

exemptions from the requirement to

submit a supplemental application, the

exemptions would undermine

Congress’s intent to ensure, through the

review and approval of supplemental

applications, that the drug or device is

safe and effective for the new use.

Proposed § 99.305(a)(1) would

acknowledge that FDA must act on an

application for an exemption within 60

days of receipt or it will be deemed

approved. However, under proposed

§ 99.305(a)(2), FDA may, at any time,

terminate such deemed approval if it

determines that the requirements for

granting an exemption have not been

met.

E. Subpart E—Corrective Actions and

Cessation of Dissemination

Proposed subpart E would discuss

various actions FDA could take or

require a manufacturer to take after a

manufacturer has begun disseminating

information on a new use.

Proposed § 99.401 would pertain to

corrective actions and orders to cease

dissemination of information. These

corrective actions and orders to cease

dissemination of information could

apply under three different situations,

which are set forth in paragraphs (a), (b),

and (c). Under proposed § 99.401(a), if

FDA receives data after a manufacturer

has begun disseminating information on

a new use and the agency determines

that the new use may not be effective or

may present a significant risk to public

health, FDA would consult the

manufacturer and, after such

consultation, take appropriate action to

protect the public health. These actions

might include ordering the

manufacturer to cease disseminating

information on the new use and to take

appropriate corrective action.

Appropriate corrective action might

include, among other things, issuing

‘‘Dear Doctor’’ letters, publishing

corrective advertising, including

warning labels on the product, or

including warnings or otherwise

revising the product labeling.

Proposed § 99.401(b) would address

FDA actions in response to information

disseminated by a manufacturer. If the

agency determined that the

disseminated information did not

comply with the regulations, proposed

§ 99.401(b) would give FDA two

options: (1) If the manufacturer’s

noncompliance constituted a minor

violation, provide the manufacturer an

opportunity to bring itself into

compliance; or (2) if the manufacturer’s

noncompliance does not constitute a

minor violation, order the manufacturer

to cease dissemination and to take
31152 Federal Register / Vol. 63, No. 109 / Monday, June 8, 1998 / Proposed Rules

corrective action, such as issuing ‘‘Dear

Doctor’’ letters, publishing corrective

advertising, including warning labels on

the product, or including warnings or

otherwise revising the product labeling.

These orders would be issued only after

FDA provided notice of its intent to

issue an order to cease dissemination

and provided an opportunity for a

meeting to the manufacturer. However,

an opportunity for a meeting would not

be required if the manufacturer’s

noncompliance was failure to submit a

supplemental application within 6

months as certified in the initial

submission.

Proposed § 99.401(c) would describe

when FDA may order a manufacturer to

cease disseminating information and/or

take corrective action based on the

manufacturer’s supplemental

application for the new use. These

orders would be issued when: (1) FDA

determines that a supplemental

application for a new use does not

contain adequate information for

approval of the new use; (2) the

manufacturer has certified that it will

submit a supplemental application

within 6 months or within 36 months

and has not done so; (3) the

manufacturer has certified that it will

submit a supplemental application

within 36 months and FDA, after an

informal hearing, determines that the

manufacturer is not acting with due

diligence to initiate or complete the

studies needed to support the

submission of the supplemental

application; or (4) the manufacturer has

certified that it will submit a

supplemental application within 36

months and it has discontinued or

terminated the studies needed to

support such supplemental application.

The latter provision is intended to deter

a manufacturer from certifying that it

will complete the studies needed to

submit a supplement so that it can begin

disseminating information even though

it has no intention of completing such

studies and submitting a supplement.

The agency’s determination of what

corrective action would be appropriate

will be based on a number of factors,

including the seriousness of any

violation of this part, whether there is

evidence of abuse of this part, and the

potential risk to the public health. For

example, consistent with past agency

practice, FDA generally would require

warnings on the product or in the

approved product labeling only when

there are serious public health concerns.

Proposed § 99.401(e) provides that a

manufacturer must immediately (on its

own) cease disseminating information

under this part if it falls out of

compliance with the requirements set

forth in this part.

As set forth in proposed § 99.305, if

FDA fails to act within 60 days on an

application for an exemption from the

requirement to file a supplemental

application, such request shall be

deemed approved. Proposed § 99.403

would provide, however, that FDA may,

at any time, terminate the deemed

approval of an application for an

exemption if FDA determines that the

manufacturer has failed to meet the

requirements for granting an exemption,

i.e., the manufacturer has failed to show

that it would be economically

prohibitive or unethical to conduct the

studies needed to submit a

supplemental application. If FDA

terminates such approval, it may order

the manufacturer, within 60 days, to

cease disseminating the information

about the new use and, if the new use

would pose a significant risk to public

health, FDA could order the

manufacturer to take corrective action.

FDA must notify a manufacturer if it

terminates a deemed approval of an

application for an exemption.

Under proposed § 99.403(d), FDA

may, at any time, terminate the approval

of an application for an exemption from

the requirement to file a supplemental

application for a new use if, after

consulting with the manufacturer that

was granted such exemption, FDA

determines that the manufacturer no

longer meets the requirements for an

exemption on the basis that it is

economically prohibitive or unethical to

conduct the studies needed to submit a

supplemental application for the new

use. If FDA terminates an approval of an

application for an exemption under

§ 99.403(d), proposed § 99.403(e) would

require such manufacturer within 60

days of being notified by FDA that its

exemption approval has been

terminated, to file a supplemental

application for the new use that is the

subject of the information being

disseminated under the exemption,

certify, under § 99.201(a)(4)(i) or

(a)(4)(ii) that it will file a supplemental

application for the new use, or cease

disseminating information on the new

use. FDA may require a manufacturer

that ceases the dissemination of

information on the new use to

undertake corrective action.

Proposed § 99.405 would provide that

the dissemination of information about

a new use could constitute labeling,

evidence of a new intended use,

adulteration or misbranding of the

product if such dissemination fails to

comply with the requirements in section

551 of the act and the requirements of

this part. A manufacturer who fails to

act with due diligence to submit a

supplement or to begin or complete the

clinical studies needed to submit a

supplement would be deemed to be not

in compliance with the requirements of

this part.

F. Subpart F—Recordkeeping and

Reports

Subpart F would describe the

recordkeeping and reporting

requirements of a manufacturer that

disseminates information under this

part.

Proposed § 99.501(a) would require a

manufacturer that disseminates

information under this part to maintain

records sufficient to allow it to take

corrective action that is required by

FDA. Under the proposal, such records

must either identify, by name, those

persons receiving the disseminated

information or identify, by category, the

recipients of the disseminated

information. However, manufacturers

who choose to identify the recipient by

category must be willing to ensure that

any corrective action FDA requires will

be sufficiently conspicuous so as to

reach the individuals who have received

the information about the new use.

Moreover, if FDA determines that,

because of the nature of the information

being disseminated or the seriousness of

the new use, it is essential to keep

records that identify the name of the

persons receiving the disseminated

information, it can require a

manufacturer to keep such records.

Proposed § 99.501(a) would also

require manufacturers that disseminate

information under this part to maintain

an identical copy of any information

disseminated under this part and, upon

submission of a supplemental

application to FDA, to notify the

appropriate office, identified in

proposed § 99.201, which is responsible

for overseeing the implementation of

this part.

Proposed § 99.501(b) would require

manufacturers that disseminate

information under this part to, on a

semiannual basis, provide FDA:

1. A list of articles and reference

publications disseminated under this

part during the 6-month period

preceding the date on which the list is

provided;

2. A list identifying the categories of

health care practitioners, pharmacy

benefit managers, health insurance

issuers, group health plans, or Federal

of State government agencies that

received the articles and reference

publications in the 6-month period

described above; such list must identify

which category received a particular

article or reference publication;
Federal Register / Vol. 63, No. 109 / Monday, June 8, 1998 / Proposed Rules 31153

3. A notice and summary of any

additional clinical research or other data

relating to the safety or effectiveness of

the new use, and if the manufacturer

possesses such clinical research or data,

a copy of the research or data. Such

other data may include, but is not

limited to, new articles, reference

publications, and summaries of adverse

events that are or may be associated

with the new use; and

4. If the manufacturer is conducting

studies needed for submission of a

supplemental application, reports that

describe the studies’ current status (i.e.,

progress on patient enrollment, any

significant problems that could affect

the manufacturer’s ability to complete

the studies, and expected completion

dates). If the manufacturer discontinues

or terminates a study before completing

it, it would, as part of this semiannual

report, notify FDA of the

discontinuation or termination of the

study and state the reasons for such

discontinuation or termination.

Proposed § 99.501(c) would require

manufacturers to maintain a copy of all

information, lists, records, and reports

required or disseminated under this part

for a period of 3 years after it has ceased

dissemination of the new use

information that triggered such

requirements and make such documents

available to FDA for inspection and

copying.

G. Conforming Amendments

The proposal would make a

conforming amendment to part 16. Part

16 describes the procedures for

regulatory hearings before FDA. Section

16.1 lists the statutory and regulatory

actions that may be the subject of a part

16 hearing. The proposal would amend

§ 16.1(a)(2) to add the due diligence

determinations under proposed

§ 99.401(c) to the list of regulatory

actions that may be the subject of a part

16 hearing.

III. Analysis of Impacts

FDA has examined the impacts of the

proposed rule under Executive Order

12866 and the Regulatory Flexibility Act

(5 U.S.C. 601–612). 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). Under the

Regulatory Flexibility Act, unless an

agency certifies that a rule will not have

a significant impact on small entities,

the agency must analyze regulatory

options that would minimize the impact

of the rule on small entities. Title II of

the Unfunded Mandates Reform Act

(Pub. L. 104–114) (in section 202)

requires that agencies prepare an

assessment of anticipated costs and

benefits before proposing any rule that

may result in an expenditure in any 1

year by State, local, and tribal

governments, in the aggregate, or by the

private sector, of $100 million or more

(adjusted annually for inflation).

The agency has reviewed this

proposed rule and has determined that

it is consistent with the regulatory

philosophy and principles identified in

Executive Order 12866, and these two

statutes. Although this proposal is not

an economically significant regulatory

action, it is still a significant regulatory

action as defined by the Executive Order

due to the novel policy issues it raises.

With respect to the Regulatory

Flexibility Act, the agency certifies that

the rule will not have a significant effect

on a substantial number of small

entities. Because the proposed rule does

not impose any mandates on State,

local, or tribal governments, or the

private sector that will result in a 1-year

expenditure of $100 million or more,

FDA is not required to perform a costbenefit analysis under the Unfunded

Mandates Reform Act.

The proposed rule implements

section 401 of FDAMA by describing the

new use information that a

manufacturer may disseminate and

setting forth the procedures that

manufacturers must follow before

disseminating information on the new

use. FDA has long recognized that in

certain circumstances, new (off-label)

uses of approved products are

appropriate, rational, and accepted

medical practice. There are important

off-label uses of approved products. The

benefits of the rule will derive from the

public health gains associated with the

earlier dissemination of objective,

balanced, accurate information about

such important new uses. In addition,

the proposed rule may actually

stimulate new studies or the collection

of evidence about these new uses.

The costs of the rule are modest.

Firms typically conduct clinical studies

in support of supplemental applications

for new uses only where the firm

believes that the added revenues

associated with the new use would

exceed the cost of the supporting

studies. Because this rule will accelerate

the receipt of these revenues, it is

possible that some new use

supplemental applications that would

not have been economically justified in

the absence of this rule will now be

submitted. FDA cannot estimate the

number or cost of the additional clinical

studies that would accompany these

applications, but emphasizes that they

would be undertaken voluntarily by the

affected firms in the expectation that

they would raise company profitability.

Manufacturers that choose not to

disseminate new use information will

incur no costs. Firms choosing to

disseminate new use information will

experience added paperwork costs for

each submission to the agency, but gain

sales revenues from the information

dissemination. FDA cannot make a

precise estimate of the number of

submissions that will be filed each year,

but as explained in section IV of this

document, the agency preliminarily

forecasts that it will receive

approximately 300 submissions from

manufacturers for disseminating new

use information. FDA also estimates that

the paperwork associated with these

submissions might total over 33,000

hours, at an average labor cost of $35

per hour. Thus, the total cost of the

added paperwork is estimated to cost

industry approximately $1.2 million per

year.

The proposed rule, however, will not

have an adverse impact on any

manufacturer. Firms will compare the

expected sales revenue from the new

dissemination activity to the associated

paperwork cost and disseminate the

new information only if it increases

their profitability. As noted previously,

firms choosing not to disseminate the

new use information will face no

increased costs due to this rule. Firms

choosing to disseminate the new use

information will do so only if the

expected increased sales revenues

exceed the associated regulatory costs.

Because no firm will experience a

reduced net income, the proposed rule

will not have a significant adverse effect

on a substantial number of small entities

and no further analysis is required

under the Regulatory Flexibility Act.

IV. Paperwork Reduction Act of 1995

This proposed rule contains

information collection requirements that

are subject to public comment and

review by the Office of Management and

Budget (OMB) under the Paperwork

Reduction Act of 1995 (44 U.S.C. 3501–

3520). A description of these provisions

is given below in this section of the

document with an estimate of the

annual reporting and recordkeeping

burden. Included in the estimate is the

time for reviewing instructions,

searching existing data sources,

gathering and maintaining the data

needed, and completing and reviewing

each collection of information.

FDA invites comments on: (1)

Whether the proposed collection of
31154 Federal Register / Vol. 63, No. 109 / Monday, June 8, 1998 / Proposed Rules

information is necessary for the proper

performance of FDA’s functions,

including whether the information will

have practical utility; (2) the accuracy of

FDA’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 respondents, including through the

use of automated collection techniques,

when appropriate, and other forms of

information technology.

Title: Dissemination of Treatment

Information on Unapproved Uses for

Marketed Drugs, Biologics, and Devices.

Description: The proposed rule

implements sections 551 through 557 of

the act (21 U.S.C. 360aaa-360aaa-6) as

amended by FDAMA, which requires a

manufacturer that intends to

disseminate certain treatment

information on unapproved uses for a

marketed drug, biologic, or device to

submit that information to FDA. The

proposed rule sets forth the criteria and

procedures for making such

submissions. Under the proposed rule, a

submission would include a

certification that the manufacturer has

completed clinical studies necessary to

submit a supplemental application to

FDA for the new use and will submit

the supplemental application within 6

months after its initial dissemination of

information. If the manufacturer has

planned, but not completed, such

studies, the submission would include

proposed protocols and a schedule for

conducting the studies, as well as a

certification that the manufacturer will

complete the clinical studies and submit

a supplemental application no later than

36 months after its initial dissemination

of information. The proposal would also

permit manufacturers to request

extensions of the time period for

completing a study and submitting a

supplemental application and to request

an exemption from the requirement to

submit a supplemental application. The

proposal would prescribe the timeframe

within which the manufacturer shall

maintain records that would enable it to

take corrective action. The proposal

would require the manufacturer to

submit lists pertaining to the

disseminated articles and reference

publications and the categories of

persons (or individuals) receiving the

information and to submit a notice and

summary of any additional research or

data (and a copy of the data) relating to

the product’s safety or effectiveness for

the new use. The proposal would

require the manufacturer to maintain a

copy of the information, lists, records,

and reports for 3 years after it has

ceased dissemination of the information

and to make the documents available to

FDA for inspection and copying.

Description of Respondents: All

manufacturers (persons and businesses,

including small businesses) of drugs,

biologics, and device products.

The estimated burden associated with

the information collection requirements

for this proposed rule is 2,907 hours.

FDA estimates the burden of this

collection of information as follows:

TABLE 1.—ESTIMATED ANNUAL REPORTING BURDEN1

21 CFR Section No. of

Respondents

Number of

Responses per

Respondent

Total Annual

Responses

Hours per

Response Total Hours

99.201(a)93) 172 1.7 297 1 297

99.201(a)(4)(i)(A) 57 1.7 98 1 98

99.201(a)(4)(ii)(a) 57 1.7 98 10 980

99.201(a)(5) 57 1.7 98 1 98

99.20(c) 172 1.7 297 0.5 148.5

99.203(b) 1 1.7 1 10 10

99.203(c) 1 1.7 1 0.5 0.5

99.205(b) 2 1.7 3 125 375

99.301(a)(2) 2 1.7 3 1 3

99.501(b)(2) 172 3.4 594 1 594

99.501(b)(4) 2 1.7 3 2 6

Total 2,610

1There are no capital costs or operating and maintenance costs associated with this collection of information.

TABLE 2.—ESTIMATED ANNUAL RECORDKEEPING BURDEN1

21 CFR Section No. of

Recordkeepers

Annual

Frequency per

Recordkeeping

Total Annual

Records

Hours per

Recordkeeper Total Hours

99.501(a)(2) 172 1.7 297 1 297

1There are no capital costs or operating and maintenance costs associated with this collection of information.

The above estimates reflect the

reporting or recordkeeping burden that

would be attributable solely to the rule.

FDA derived these estimates from

existing data on submissions made

under supplemental applications and

other submissions to the agency, as well

as information from industry sources

regarding similar or related reporting

and recordkeeping burdens.

The agency has submitted the

information collection requirements of

this proposed rule to OMB for review.

Interested persons are requested to send

comments regarding information

collection by July 8, 1998, to the Office

of Information and Regulatory Affairs,

OMB (address above).

V. Environmental Impact

The agency has determined, under 21

CFR 25.30(h) 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. 63, No. 109 / Monday, June 8, 1998 / Proposed Rules 31155

VI. Request for Comments

Interested persons may, on or before

July 23, 1998, submit to the Dockets

Management Branch (address above)

written comments regarding this

proposal. Two copies of any comments

are to be submitted, except that

individuals may submit one copy.

Comments are to be identified with the

docket number found in brackets in the

heading of this document. Received

comments may be seen in the office

above between 9 a.m. and 4 p.m.,

Monday through Friday.

List of Subjects

21 CFR Part 16

Administrative practice and

procedure.

21 CFR Part 99

Administrative practice and

procedure, Biologics, Devices, Drugs,

Reporting and recordkeeping

requirements.

Therefore, under the Federal Food,

Drug, and Cosmetic Act and under

authority delegated to the Commissioner

of Food and Drugs, it is proposed that

21 CFR chapter I be amended to read as

follows:

PART 16—REGULATORY HEARING

BEFORE THE FOOD AND DRUG

ADMINISTRATION

1. The authority citation for 21 CFR

part 16 is revised to read as follows:

Authority: 21 U.S.C. 141–149, 321–394,

467f, 679, 821, 1034; 42 U.S.C. 201–262,

263b, 364; 15 U.S.C. 1451–1461; 28 U.S.C.

2112.

2. Section 16.1 is amended in

paragraph (b)(2) by numerically adding

an entry for § 99.401(c) to read as

follows:

§ 16.1 Scope.

* * * * *

(b) * * *

(2) Regulatory provisions:

* * * * *

§ 99.401(c), relating to a due diligence

determination concerning the conduct of

studies necessary for a supplemental

application for a new use of a drug or device.

* * * * *

3. Part 99 is added to read as follows:

PART 99—DISSEMINATION OF

INFORMATION ON UNAPPROVED/

NEW USES FOR MARKETED DRUGS,

BIOLOGICS, AND DEVICES

Subpart A—General Information

Sec.

99.1 Scope.

99.3 Definitions.

Subpart B—Information To Be

Disseminated

99.101 Information that may be

disseminated.

99.103 Mandatory statements and

information.

99.105 Recipients of information.

Subpart C—Manufacturer’s Submissions,

Requests, and Applications

99.201 Manufacturer’s submission to the

agency.

99.203 Request to extend the time for

completing planned studies.

99.205 Application for exemption from the

requirement to file a supplemental

application.

Subpart D—FDA Action on Submissions,

Requests, and Applications

99.301 Agency action on a submission.

99.303 Extension of time for completing

planned studies.

99.305 Exemption from the requirement to

file a supplemental application.

Subpart E—Corrective Actions and

Cessation of Dissemination

99.401 Corrective actions and cessation of

dissemination of information.

99.403 Termination of approvals of

applications for exemption.

99.405 Applicability of labeling, adulteration,

and misbranding authority.

Subpart F—Recordkeeping and Reports

99.501 Recordkeeping and reports.

Authority: 21 U.S.C. 321, 331, 351, 352,

355, 360, 360c, 360e, 360aa–360aaa-6, 371,

and 374; 42 U.S.C. 262.

Subpart A—General Information

§ 99.1 Scope.

(a) This part applies to the

dissemination of information on human

drugs, including biologics, and devices

where the information to be

disseminated:

(1) Concerns the safety, effectiveness,

or benefit of a use that is not included

in the approved labeling for a drug or

device approved by the Food and Drug

Administration for marketing or in the

statement of intended use for a device

cleared by the Food and Drug

Administration for marketing; and

(2) Will be disseminated to a health

care practitioner, pharmacy benefit

manager, health insurance issuer, group

health plan, or Federal or State

government agency.

(b) This part does not apply to a

manufacturer’s dissemination of

information that responds to a health

care practitioner’s unsolicited request.

§ 99.3 Definitions.

(a) Agency or FDA means the Food

and Drug Administration.

(b) For purposes of this part, a clinical

investigation is an investigation in

humans that is prospectively planned to

test a specific clinical hypothesis.

(c) Group health plan means an

employee welfare benefit plan (as

defined in section 3(1) of the Employee

Retirement Income Security Act of 1974

(29 U.S.C. 1002(1))) to the extent that

the plan provides medical care (as

defined in paragraphs (c)(1) through

(c)(3) of this section and including items

and services paid for as medical care) to

employees or their dependents (as

defined under the terms of the plan)

directly or through insurance,

reimbursement, or otherwise. For

purposes of this part, the term medical

care means:

(1) Amounts paid for the diagnosis,

cure, mitigation, treatment, or

prevention of disease, or amounts paid

for the purpose of affecting any

structure or function of the body;

(2) Amounts paid for transportation

primarily for and essential to medical

care referred to in paragraph (c)(1) of

this section; and

(3) Amounts paid for insurance

covering medical care referred to in

paragraphs (c)(1) and (c)(2) of this

section.

(d) Health care practitioner means a

physician or other individual who is a

health care provider and licensed under

State law to prescribe drugs or devices.

(e) Health insurance issuer means an

insurance company, insurance service,

or insurance organization (including a

health maintenance organization, as

defined in paragraph (e)(2) of this

section) which is licensed to engage in

the business of insurance in a State and

which is subject to State law which

regulates insurance (within the meaning

of section 514(b)(2) of the Employee

Retirement Income Security Act of 1974

(29 U.S.C. 1144(b)(2))).

(1) Such term does not include a

group health plan.

(2) For purposes of this part, the term

health maintenance organization

means:

(i) A Federally qualified health

maintenance organization (as defined in

section 1301(a) of the Public Health

Service Act (42 U.S.C. 300e(a)));

(ii) An organization recognized under

State law as a health maintenance

organization; or

(iii) A similar organization regulated

under State law for solvency in the same

manner and to the same extent as such

a health maintenance organization.

(f) Manufacturer means a person who

manufactures a drug or device or who

is licensed by such person to distribute

or market the drug or device. For

purposes of this part, the term may also

include the sponsor of the approved,

licensed, or cleared drug or device.

(g) New use means a use that is not

included in the approved labeling of an
31156 Federal Register / Vol. 63, No. 109 / Monday, June 8, 1998 / Proposed Rules

approved drug or device, or a use that

is not included in the statement of

intended use for a cleared device.

(h) A reference publication is a

publication that:

(1) Has not been written, edited,

excerpted, or published specifically for,

or at the request of, a drug or device

manufacturer;

(2) Has not been edited or

significantly influenced by such a

manufacturer;

(3) Is not solely distributed through

such a manufacturer, but is generally

available in bookstores or other

distribution channels where medical

textbooks are sold;

(4) Does not focus on any particular

drug or device of a manufacturer that

disseminates information under this

part and does not have a primary focus

on new uses of drugs or devices that are

marketed or are under investigation by

a manufacturer supporting the

dissemination of information; and

(5) Does not present materials that are

false or misleading.

(i) Scientific or medical journal means

a scientific or medical publication:

(1) That is published by an

organization that has an editorial board,

that uses experts who have

demonstrated expertise in the subject of

an article under review by the

organization and who are independent

of the organization, to review and

objectively select, reject, or provide

comments about proposed articles, and

that has a publicly stated policy, to

which the organization adheres, of full

disclosure of any conflict of interest or

biases for all authors or contributors

involved with the journal or

organization;

(2) Whose articles are peer-reviewed

and published in accordance with the

regular peer-review procedures of the

organization;

(3) That is generally recognized to be

of national scope and reputation;

(4) That is indexed in the Index

Medicus of the National Library of

Medicine of the National Institutes of

Health; and

(5) That is not in the form of a special

supplement that has been funded in

whole or in part by one or more

manufacturers.

(j) Supplemental application means:

(1) For drugs, a supplement to support

a new use to an approved new drug

application;

(2) For biologics, a supplement to an

approved license application;

(3) For devices that are the subject of

a cleared 510(k) submission, a new

510(k) submission to support a new use

or, for devices that are the subject of an

approved premarket approval

application, a supplement to support a

new use to an approved premarket

approval application.

Subpart B—Information To Be

Disseminated

§ 99.101 Information that may be

disseminated.

(a) A manufacturer may disseminate

written information concerning the

safety, effectiveness, or benefit of a use

not described in the approved labeling

for an approved drug or device or in the

statement of intended use for a cleared

device, provided that the manufacturer

complies with all other relevant

requirements under this part. Such

information shall:

(1) Be about a drug or device that has

been approved, licensed, or cleared for

marketing by FDA;

(2) Be in the form of:

(i) An unabridged reprint or copy of

an article, peer-reviewed by experts

qualified by scientific training or

experience to evaluate the safety or

effectiveness of the drug or device

involved, which was published in a

scientific or medical journal. In

addition, the article must be about a

clinical investigation with respect to the

drug or device and must be considered

to be scientifically sound by the experts

described above; or

(ii) An unabridged reference

publication that includes information

about a clinical investigation with

respect to the drug or device, which

experts qualified by scientific training

or experience to evaluate the safety or

effectiveness of the drug or device that

is the subject of the clinical

investigation would consider to be

scientifically sound;

(3) Not pose a significant risk to the

public health;

(4) Not be false or misleading. FDA

may consider information disseminated

under this part to be false or misleading

if, among other things, the information

includes only favorable publications or

excludes articles, reference

publications, or other information

concerning risks and adverse effects that

are or may be associated with the new

use; and

(5) Not be derived from clinical

research conducted by another

manufacturer unless the manufacturer

disseminating the information has the

permission of such other manufacturer

to make the dissemination.

(b) For purposes of this part:

(1) The determination of whether a

clinical investigation is considered to be

‘‘scientifically sound’’ will rest on

whether the design, conduct, data, and

analysis of the investigation described

or discussed in a reprint or copy of an

article or in a reference publication

reasonably support the conclusions

reached by the authors. Accordingly, a

clinical investigation described or

discussed in a reprint or copy of an

article or in a reference publication

must include a description of the study

design and conduct, data presentation

and analysis, summary of results, and

conclusions pertaining to the new use.

A clinical investigation presented in a

format that does not represent a

reasonably comprehensive presentation

of the study design, conduct, data,

analyses, and conclusions (e.g., letters to

the editor, review abstracts, or abstracts

of publications) does not qualify for

dissemination under this part; and

(2) A reprint or copy of an article or

reference publication is ‘‘unabridged’

only if it retains the same appearance,

form, format, content or configuration as

the original article or publication. Such

reprint, copy of an article, or reference

publication shall not be disseminated

with any information that is

promotional in nature. A manufacturer

may cite a particular discussion about a

new use in a reference publication in

the explanatory or other information

attached to or otherwise accompanying

the reference publication under

§ 99.103.

§ 99.103 Mandatory statements and

information.

(a) Any information disseminated

under this part shall include:

(1) A prominently displayed

statement disclosing:

(i) For a drug, ‘‘This information

concerns a use that has not been

approved by the Food and Drug

Administration and is being

disseminated under section 551 et seq.

of the Federal Food, Drug, and Cosmetic

Act.’’ For devices, the statement shall

read, ‘‘This information concerns a use

that has not been approved or cleared by

the Food and Drug Administration and

is being disseminated under section 551

et seq. of the Federal Food, Drug, and

Cosmetic Act.’’ If the information to be

disseminated includes both approved

and unapproved uses or cleared and

uncleared uses, the manufacturer shall

modify the statement to identify the

unapproved or uncleared new use. The

manufacturer shall permanently affix

the statement to the front of each reprint

or copy of an article from a scientific or

medical journal and to the front of each

reference publication disseminated

under this part;

(ii) If applicable, the information is

being disseminated at the expense of the

manufacturer;

(iii) If applicable, the names of any

authors of the information who are
Federal Register / Vol. 63, No. 109 / Monday, June 8, 1998 / Proposed Rules 31157

employees of, or consultants to, or have

received compensation from the

manufacturer, or who have a significant

financial interest in the manufacturer;

(iv) If applicable, a statement that

there are products or treatments that

have been approved or cleared for the

use that is the subject of the information

being disseminated; and

(v) The identification of any person

that has provided funding for the

conduct of a study relating to the new

use of a drug or device for which such

information is being disseminated; and

(2) The official labeling for the drug

or device;

(3) A bibliography of other articles

(that concern reports of clinical

investigations both supporting and not

supporting the new use) from a

scientific reference publication or

scientific or medical journal that have

been previously published about the

new use of the drug or device covered

by the information that is being

disseminated, unless the disseminated

information already includes such a

bibliography; and

(4) Any additional information

required by FDA. Such information,

which shall be attached to the front of

the disseminated information, may

consist of:

(i) Objective and scientifically sound

information pertaining to the safety or

effectiveness of the new use of the drug

or device and which FDA determines is

necessary to provide objectivity and

balance. This may include information

that the manufacturer has submitted to

FDA or, where appropriate, a summary

of such information and any other

information that can be made publicly

available; and

(ii) An objective statement prepared

by FDA, based on data or other

scientifically sound information,

bearing on the safety or effectiveness of

the new use of the drug or device.

(b) Except as provided in paragraphs

(a)(1)(i) and (a)(4) of this section, the

statements, bibliography, and other

information required by this section

shall be attached to such disseminated

information.

(c) For purposes of this section,

factors to be considered in determining

whether a statement is ‘‘prominently

displayed’’ may include, but are not

limited to, type size, font, layout,

contrast, graphic design, headlines,

spacing, and any other technique to

achieve emphasis or notice. The

required statements shall be outlined,

boxed, highlighted, or otherwise

graphically designed and presented in a

manner that achieves emphasis or

notice and is distinct from the other

information being disseminated.

§ 99.105 Recipients of information.

A manufacturer disseminating

information on a new use under this

part may only disseminate that

information to a health care practitioner;

a pharmacy benefit manager; a health

insurance issuer; a group health plan; or

a Federal or State government agency.

Subpart C—Manufacturer’s Submissions,

Requests, and Applications

§ 99.201 Manufacturer’s submission to the

agency.

(a) Sixty days before disseminating

any written information concerning the

safety, effectiveness, or benefit of a new

use for a drug or device, a manufacturer

shall submit to the agency:

(1) An identical copy of the

information to be disseminated,

including any information (e.g., the

bibliography) and statements required

under § 99.103;

(2) Any other clinical trial

information which the manufacturer has

relating to the safety or effectiveness of

the new use, any reports of clinical

experience pertinent to the safety of the

new use, and a summary of such

information. For purposes of this part,

clinical trial information includes, but is

not limited to, published papers and

abstracts, even if not intended for

dissemination, and unpublished

manuscripts, abstracts, and data

analyses from completed or ongoing

investigations. The information and

reports required under this paragraph

shall include case studies, retrospective

reviews, epidemiological studies,

adverse event reports, and any other

material concerning adverse effects or

risks reported for or associated with the

new use. If the manufacturer has no

knowledge of clinical trial information

relating to the safety or effectiveness of

the new use or reports of clinical

experience pertaining to the safety of

the new use, the manufacturer shall

provide a statement to that effect;

(3) An explanation of the

manufacturer’s search strategy in

selecting the articles for the

bibliography (e.g., the databases and

criteria used to generate the

bibliography and the time period

covered by the bibliography); and

(4) If the manufacturer has not

submitted a supplemental application

for the new use, one of the following:

(i) If the manufacturer has completed

studies needed for the submission of a

supplemental application for the new

use:

(A) A copy of the protocol for each

completed study or, if such protocol

was submitted to an investigational new

drug application or an investigational

device exemption, the number(s) for the

investigational new drug application or

investigational device exemption

covering the new use, the date of

submission of the protocol(s), the

protocol number(s), and the date of any

amendments to the protocol(s); and

(B) A certification stating that, ‘‘On

behalf of [insert manufacturer’s name], I

certify that [insert manufacturer’s name]

has completed the studies needed for

the submission of a supplemental

application for [insert new use] and will

submit a supplemental application for

such new use to the Food and Drug

Administration no later than [insert date

no later than 6 months from date of the

initial dissemination of information

under this part];’’ or

(ii) If the manufacturer has planned

studies that will be needed for the

submission of a supplemental

application for the new use:

(A) The proposed protocols and

schedule for conducting the studies

needed for the submission of a

supplemental application for the new

use. The protocols shall comply with all

applicable requirements in parts 312 of

this chapter (investigational new drug

applications) and 812 of this chapter

(investigational device exemptions). The

schedule shall include the projected

dates on which the manufacturer

expects the principal study events to

occur (e.g., initiation and completion of

patient enrollment, completion of data

collection, completion of data analysis,

and submission of the supplemental

application); and

(B) A certification stating that, ‘‘On

behalf of [insert manufacturer’s name], I

certify that [insert manufacturer’s name]

will exercise due diligence to complete

the clinical studies necessary to submit

a supplemental application for [insert

new use] and will submit a

supplemental application for such new

use to the Food and Drug

Administration no later than [insert date

no later than 36 months from date of the

initial dissemination of information

under this part];’’ or

(iii) An application for exemption

from the requirement of a supplemental

application; or

(5) If the manufacturer has submitted

a supplemental application for the new

use, a cross-reference to that

supplemental application.

(b) The manufacturer’s attorney,

agent, or other authorized official shall

sign the submission and certification

statement or application for exemption.

If the manufacturer does not have a

place of business in the United States,

the submission and certification

statement or application for exemption

shall contain the signature, name, and

address of the manufacturer’s attorney,
31158 Federal Register / Vol. 63, No. 109 / Monday, June 8, 1998 / Proposed Rules

agent, or other authorized official who

resides or maintains a place of business

in the United States.

(c) The manufacturer shall send three

copies of the submission and

certification statement or application for

exemption to FDA. The outside of the

shipping container shall be marked as

‘‘Submission for the Dissemination of

Information on an Unapproved/New

Use.’’ The manufacturer shall send the

submission and certification statement

or application for exemption to the

appropriate FDA component listed

below:

(1) For biological products and

devices regulated by the Center for

Biologics Evaluation and Research, the

Advertising and Promotional Labeling

Staff (HFM–202), Center for Biologics

Evaluation and Research, Food and

Drug Administration, 1401 Rockville

Pike, Rockville, MD 20852;

(2) For human drug products, the

Division of Drug Marketing,

Advertising, and Communications

(HFD–40), Center for Drug Evaluation

and Research, Food and Drug

Administration, 5600 Fishers Lane,

Rockville, MD 20857; or

(3) For medical devices, the

Promotion and Advertising Policy Staff

(HFZ–302), Office of Compliance,

Center for Devices and Radiological

Health, Food and Drug Administration,

2098 Gaither Rd., Rockville, MD 20850.

(d) The 60-day period shall begin

when FDA receives a complete

submission, including, where

applicable, a certification statement or

application for exemption. For purposes

of this part, a submission shall be

considered to be complete if FDA

determines that it is sufficiently

complete to permit a substantive review.

§ 99.203 Request to extend the time for

completing planned studies.

(a) A manufacturer who has certified

that it will complete the studies

necessary to submit a supplemental

application for a new use within 36

months from the date of initial

dissemination of information under this

part, but later finds that it will be unable

to complete such studies and submit a

supplemental application within that

time period may request an extension of

time from FDA.

(b) The manufacturer, in its request

for extension, shall identify the product,

the new use, and shall:

(1) Describe the study or studies that

cannot be completed on time and

explain why the study or studies cannot

be completed on time;

(2) Describe the current status of the

incomplete study or studies and

summarize the work conducted,

including the dates on which principal

events concerning the study or studies

occurred; and

(3) Estimate the additional time

needed to complete the studies and

submit a supplemental application. The

requested extension shall not exceed an

additional 24 months.

(c) The manufacturer shall send three

copies of the request for extension to the

same FDA office that received the

manufacturer’s initial submission and

certification statement. The outside of

the envelope shall be marked as

‘‘Request for Time Extension—

Dissemination of Information on an

Unapproved Use.’’

§ 99.205 Application for exemption from

the requirement to file a supplemental

application.

(a) In certain circumstances, described

in paragraph (b) of this section, a

manufacturer may submit an

application for an exemption from the

requirement to submit a supplemental

application for a new use for purposes

of disseminating information on that

use.

(b) The manufacturer’s application for

an exemption shall identify the basis for

the proposed exemption and shall

include materials demonstrating that it

would be economically prohibitive or

that it would be unethical to conduct

the studies necessary to submit a

supplemental application for the new

use.

(1) If the basis for the manufacturer’s

application for exemption is that it

would be economically prohibitive to

incur the costs necessary to submit a

supplemental application for a new use,

the manufacturer shall, at a minimum,

provide evidence:

(i) Explaining why existing data

characterizing the safety and

effectiveness of the drug or device,

including data from the study described

in the information to be disseminated,

are not adequate to support the

submission of a supplemental

application for the new use. Such

evidence shall include an analysis of all

data relevant to the safety and

effectiveness of the use, a summary of

those data, and any documentation

resulting from prior discussions with

the agency concerning the adequacy of

the existing data; and

(ii) Demonstrating that the estimated

cost of the studies needed for the

approval of the new use would exceed

the estimated total revenue from the

drug or device less the cost of goods

sold, and marketing, and administrative

expenses attributable to the product and

that there are not less expensive ways to

obtain the needed information. Such

evidence shall include:

(A) A description of the current and

projected U.S. patient population for the

product and an estimate of the current

and projected economic benefit to the

manufacturer from its use. Such

estimate shall assume that the total

potential market for the drug or device

is equal to the prevalence of the

disease(s) or condition(s) that the drug

or device will be used to treat and

involve the following considerations:

(1) The estimated market share for the

drug or device during any exclusive

market period, a summary of any

exclusive market period for the product,

and an explanation of the basis for the

estimate;

(2) A projection of and justification

for the price at which the drug or device

will be sold; and

(3) Comparisons with sales of

similarly situated drugs or devices,

where available.

(B) A description of the additional

studies that the manufacturer believes

are necessary to support the submission

of a supplemental application for the

new use, including documentation from

prior discussions, if any, with the

agency concerning the studies that

would be needed, and an estimate of the

projected costs for such studies;

(C) An attestation by a responsible

individual of the manufacturer verifying

that the estimates included with the

submission are accurate and were

prepared in accordance with generally

accepted accounting procedures. The

data underlying and supporting the

estimates shall be made available to

FDA upon request.

(2) If the basis for the manufacturer’s

application for exemption is that it

would be unethical to conduct the

studies necessary for the supplemental

application for a new use, the

manufacturer shall provide evidence:

(i) Explaining why existing data

characterizing the safety and

effectiveness of the drug or device,

including data from the study described

in the information to be disseminated,

are not adequate to support the

submission of a supplemental

application for the new use. Such

evidence shall include an analysis of all

data relevant to the safety and

effectiveness of the new use, a summary

of those data, and any documentation

resulting from prior discussions with

the agency concerning the adequacy of

the existing data; and

(ii) Explaining why it would be

unethical to conduct the further studies

that would be necessary for the approval

of the new use. Such evidence shall

establish that, notwithstanding the
Federal Register / Vol. 63, No. 109 / Monday, June 8, 1998 / Proposed Rules 31159

insufficiency of available data to

support the submission of a

supplemental application for the new

use, the data are persuasive to the extent

that withholding the drug or device in

a controlled study (e.g., by providing no

therapy, a placebo, an alternative

therapy, or an alternative dose) would

pose an unreasonable risk of harm to

human subjects. For purposes of

determining what is unethical under

this part an unreasonable risk of harm

would ordinarily arise only when the

new use appears to affect mortality or

irreversible morbidity. In assessing the

appropriateness of conducting studies to

support the new use, the manufacturer

may provide evidence showing that the

new use is broadly accepted as current

standard medical treatment or therapy.

The manufacturer shall also address the

possibility of conducting studies in

different populations or of modified

design (e.g., adding the new therapy to

existing treatments or using an

alternative dose if monotherapy studies

could not be conducted).

Subpart D—FDA Action on Submissions,

Requests, and Applications

§ 99.301 Agency action on a submission.

(a) Submissions. Within 60 days after

receiving a submission under this part,

FDA may:

(1) Determine that the manufacturer

does not comply with the requirements

under this part and that, as a result, the

manufacturer shall not disseminate any

information under this part;

(2) Request additional information or

documents to assist the agency in

determining whether the information to

be disseminated complies with the

requirements under this part. This may

include, but is not limited to, copies of

articles listed by the manufacturer in its

bibliography;

(3) Determine that the information

submitted regarding a new use fails to

provide data, analyses, or other written

matter that is objective and balanced. If

FDA makes such a determination, the

agency:

(i) Shall provide to the manufacturer

notice and an opportunity for a meeting

regarding the agency’s determination;

(ii) May require the manufacturer to

disseminate additional information,

including information which the

manufacturer has submitted to FDA or,

where appropriate, a summary of such

information or any other information

that can be made publicly available,

which, in the agency’s opinion:

(A) Is objective and scientifically

sound;

(B) Pertains to the safety or

effectiveness of the new use; and

(C) Is necessary to provide objectivity

and balance; and

(iii) May require the manufacturer to

disseminate an objective statement

prepared by FDA that is based on data

or other scientifically sound information

available to the agency and bears on the

safety or effectiveness of the drug or

device for the new use; and

(4) Require the manufacturer to

maintain records that will identify

individual recipients of the information

that is to be disseminated.

(b) Protocols/Studies. Within 60 days

after receiving a submission under this

part, FDA shall:

(1) If the manufacturer has planned

studies that will be needed for the

submission of a supplemental

application for the new use, review the

manufacturer’s proposed protocols and

schedule for completing such studies

and determine whether the proposed

protocols are adequate and whether the

proposed schedule for completing the

studies is reasonable. FDA shall notify

the manufacturer if it determines that

the proposed protocols are adequate and

the proposed schedule for completing

the studies is reasonable. Until such

notification, the manufacturer shall not

disseminate any information under this

part; or

(2) If the manufacturer has completed

studies that the manufacturer believes

would be an adequate basis for the

submission of a supplemental

application for the new use, conduct a

preliminary review of the completed

study reports to determine whether they

are potentially adequate to support the

filing of a supplemental application for

the new use. FDA shall notify the

manufacturer if it determines that the

completed studies are inadequate, based

on a preliminary review, to support the

filing of a supplemental application for

the new use or are not complete. Upon

such notification, the manufacturer

shall not disseminate any information

under this part.

§ 99.303 Extension of time for completing

planned studies.

(a) Upon review of a drug or device

manufacturer’s proposed protocol and

schedule for conducting studies needed

for the submission of a supplemental

application for a new use, FDA may

determine that such studies cannot be

completed and submitted within 36

months. The agency may exercise its

discretion in extending the time period

for completing the studies and

submitting a supplemental application.

(b) The manufacturer may, in writing,

request that FDA extend the time period

for conducting studies needed for the

submission of a supplemental

application for a new use and

submitting a supplemental application

to FDA. FDA may grant or deny the

request or, after consulting the

manufacturer, grant an extension

different from that requested by the

manufacturer. Extensions under this

paragraph shall not exceed 24 months.

(c) FDA may grant a manufacturer’s

request for an extension if FDA

determines that the manufacturer has

acted with due diligence to conduct the

studies needed for the submission of a

supplemental application for a new use

and to submit such a supplemental

application to FDA in a timely manner

and that, despite such actions, the

manufacturer needs additional time to

complete the studies and submit the

supplemental application.

(d) If FDA extends the time period for

completing the studies and submitting a

supplemental application under

paragraph (a) of this section or grants a

manufacturer’s request for an extension

under paragraph (c) of this section, the

manufacturer shall submit a new

certification under § 99.201(a)(4)(ii)(B)

that sets forth the timeframe within

which clinical studies will be

completed and a supplemental

application will be submitted to FDA.

§ 99.305 Exemption from the requirement

to file a supplemental application.

(a) Within 60 days after receipt of an

application for an exemption from the

requirement of a supplemental

application, FDA shall approve or deny

the application.

(1) If FDA does not act on the

application for an exemption within the

60-day period, the application for an

exemption shall be deemed to be

approved.

(2) If an application for an exemption

is deemed to be approved, FDA may, at

any time, terminate such approval if it

determines that the requirements for

granting an exemption have not been

met. FDA shall notify the manufacturer

if the approval is terminated.

(b) In reviewing an application for an

exemption, FDA shall consider the

materials submitted by the manufacturer

and may consider any other appropriate

information, including, but not limited

to, any pending or previously approved

applications for exemption submitted by

the manufacturer.

(c) FDA may grant an application for

an exemption if FDA determines that:

(1) It would be economically

prohibitive for the manufacturer to

incur the costs necessary to submit a

supplemental application for a new use,

which at a minimum requires:

(i) That existing data characterizing

the safety and effectiveness of the drug
31160 Federal Register / Vol. 63, No. 109 / Monday, June 8, 1998 / Proposed Rules

or device, including data from the study

described in the information to be

disseminated are not adequate to

support the submission of a

supplemental application for the new

use; and

(ii) That the estimated cost of the

studies needed to support the

submission of a supplemental

application for the new use exceed the

estimated total revenue from the drug or

device less the cost of goods sold and

marketing and administrative expenses

attributable to the product and there are

not less expensive ways to obtain the

needed information; or

(2) It would be unethical to conduct

clinical studies needed to support the

submission of a supplemental

application for the new use because:

(i) Existing data characterizing the

safety and effectiveness of the drug or

device, including data from the study

described in the information to be

disseminated are not adequate to

support the submission of a

supplemental application for the new

use; and

(ii) Although available evidence

would not support the submission of a

supplemental application for the new

use, the data are persuasive to the extent

that withholding the drug or device in

a controlled study would pose an

unreasonable risk of harm to human

subjects and no studies in different

populations or of modified design can

be utilized. In determining whether it

would be unethical to conduct clinical

studies, the agency shall consider, in

addition to the persuasiveness of

available evidence of effectiveness,

whether the new use of the drug or

device is broadly accepted as current

standard medical treatment or therapy.

Subpart E—Corrective Actions and

Cessation of Dissemination

§ 99.401 Corrective actions and cessation

of dissemination of information.

(a) FDA actions based on post

dissemination data. If FDA receives data

after a manufacturer has begun

disseminating information on a new use

and, based on that data, determines that

the new use that is the subject of

information disseminated under this

part may not be effective or may present

a significant risk to public health, FDA

shall consult the manufacturer and, after

such consultation, take appropriate

action to protect the public health. Such

action may include ordering the

manufacturer to cease disseminating

information on the new use and to take

appropriate corrective action.

(b) FDA actions based on information

disseminated by a manufacturer. If FDA

determines that a manufacturer is

disseminating information that does not

comply with the requirements under

this part, FDA may:

(1) Provide to the manufacturer an

opportunity to bring itself into

compliance with the requirements

under this part if the manufacturer’s

noncompliance constitutes a minor

violation of these requirements; or

(2) Order the manufacturer to cease

dissemination of information and to

take corrective action. FDA shall issue

such an order only after it has:

(i) Provided notice to the

manufacturer regarding FDA’s intent to

issue an order to cease dissemination;

and

(ii) Provided to the manufacturer an

opportunity for a meeting. FDA shall

not provide an opportunity for a

meeting if the manufacturer certified

that it will submit a supplemental

application for the new use within 6

months of initial dissemination and the

noncompliance involves a failure to

submit such supplemental application.

(c) FDA actions based on a

manufacturer’s supplemental

application. FDA may order a

manufacturer to cease disseminating

information under this part and to take

corrective action if:

(1) In the case of a manufacturer that

has submitted a supplemental

application for the new use, FDA

determines that the supplemental

application does not contain adequate

information for approval of the new use;

(2) In the case of a manufacturer that

has certified that it will submit a

supplemental application for the new

use within 6 months, the manufacturer

has not, within the 6-month period,

submitted a supplemental application

for the new use;

(3) In the case of a manufacturer that

has certified that it will submit a

supplemental application for the new

use within 36 months or within such

time as FDA has determined to be

appropriate under § 99.303(a) or (c),

such manufacturer has not submitted

the supplemental application within the

certified time or, FDA, after an informal

hearing, has determined that the

manufacturer is not acting with due

diligence to initiate or complete the

studies necessary to support a

supplemental application for the new

use; or

(4) In the case of a manufacturer that

has certified that it will submit a

supplemental application for the new

use within 36 months or within such

time as FDA has determined to be

appropriate under § 99.303(a) or (c), the

manufacturer has discontinued or

terminated the clinical studies that

would be necessary to support a

supplemental application for a new use.

(d) Effective date of orders to cease

dissemination. An order to cease

dissemination of information shall be

effective upon date of issuance by FDA,

unless otherwise stated in such order.

(e) Cessation of dissemination by a

noncomplying manufacturer. A

manufacturer that begins to disseminate

information in compliance with this

part, but subsequently fails to comply

with this part, shall immediately cease

disseminating information under this

part. A manufacturer that discontinues,

terminates, or fails to conduct with due

diligence clinical studies that it certified

it would complete under

§ 99.201(a)(4)(ii) shall be deemed not in

compliance with this part. A

manufacturer shall notify FDA if it

ceases dissemination under this

paragraph.

§ 99.403 Termination of approvals of

applications for exemption.

(a) FDA may, at any time, terminate

the approval of an application for an

exemption from the requirement to file

a supplemental application if:

(1) The application for an exemption

had been deemed to be approved

because the agency had not acted on the

application within 60 days after its

receipt by FDA;

(2) The manufacturer is disseminating

written information on the new use; and

(3) FDA determines that it would be

economically or ethically possible for

the manufacturer to conduct the clinical

studies needed to submit a

supplemental application for the new

use.

(b) If FDA terminates a deemed

approval of an application for an

exemption under paragraph (a) of this

section, FDA also may:

(1) Order the manufacturer to cease

disseminating information; and

(2) Order the manufacturer to take

action to correct the information that

has been disseminated if FDA

determines that the new use described

in the disseminated information would

pose a significant risk to public health.

(c) FDA shall notify the manufacturer

if it terminates the deemed approval of

an application for an exemption under

paragraph (a) of this section. If FDA also

issues an order to cease dissemination

of information, the manufacturer shall

comply with the order no later than 60

days after its receipt.

(d) FDA may, at any time, terminate

the approval of an application for an

exemption from the requirement to file

a supplemental application for a new

use if, after consulting with the

manufacturer that was granted such
Federal Register / Vol. 63, No. 109 / Monday, June 8, 1998 / Proposed Rules 31161

exemption, FDA determines that the

manufacturer no longer meets the

requirements for an exemption on the

basis that it is economically prohibitive

or unethical to conduct the studies

needed to submit a supplemental

application for the new use.

(e) If FDA terminates an approval of

an application for an exemption under

paragraph (d) of this section, the

manufacturer must, within 60 days of

being notified by FDA that its

exemption approval has been

terminated, file a supplemental

application for the new use that is the

subject of the information being

disseminated under the exemption,

certify, under § 99.201(a)(4)(i) or

(a)(4)(ii) that it will file a supplemental

application for the new use, or cease

disseminating information on the new

use. FDA may require a manufacturer

that ceases the dissemination of

information on the new use to

undertake corrective action.

§ 99.405 Applicability of labeling,

adulteration, and misbranding authority.

The dissemination of information

relating to a new use for a drug or

device may constitute labeling, evidence

of a new intended use, adulteration, or

misbranding of the drug or device if

such dissemination fails to comply with

section 551 of the Federal Food, Drug,

and Cosmetic Act (the act) and the

requirements of this part. A

manufacturer’s failure to exercise due

diligence in submitting the clinical

studies that are necessary for the

approval of a new use that is the subject

of information disseminated under this

part or in beginning or completing such

clinical studies shall be deemed a

failure to comply with section 551 of the

act and the requirements of this part.

Subpart F—Recordkeeping and Reports

§ 99.501 Recordkeeping and reports.

(a) A manufacturer disseminating

information under this part shall:

(1) Maintain records sufficient to

allow the manufacturer to take

corrective action as required by FDA.

The manufacturer shall make such

records available to FDA, upon request,

for inspection and copying. Such

records shall either:

(i) Identify, by name, those persons

receiving the disseminated information;

or

(ii) Identify, by category, the

recipients of the disseminated

information, unless FDA requires the

manufacturer to retain records

identifying individual recipients of the

disseminated information.

Manufacturers whose records identify

recipients by category only shall:

(A) Identify subcategories of

recipients where appropriate (e.g.,

oncologists, pediatricians, obstetricians,

etc.); and

(B) Ensure that any corrective action

to be taken will be sufficiently

conspicuous to individuals within that

category of recipients;

(2) Maintain an identical copy of the

information disseminated under this

part; and

(3) Upon the submission of a

supplemental application to FDA, notify

the appropriate office identified in

§ 99.201(c) of this part.

(b) A manufacturer disseminating

information on a new use for a drug or

device shall, on a semiannual basis,

submit to the FDA office identified in

§ 99.201(c) of this part:

(1) A list containing the titles of

articles and reference publications

relating to the new use of drugs or

devices that the manufacturer

disseminated to a health care

practitioner, pharmacy benefit manager,

health insurance issuer, group health

plan, or Federal or State government

agency. The list shall cover articles and

reference publications disseminated in

the 6-month period preceding the date

on which the manufacturer provides the

list to FDA;

(2) A list identifying the categories of

health care practitioners, pharmacy

benefit managers, health insurance

issuers, group health plans, or Federal

or State government agencies that

received the articles and reference

publications in the 6-month period

described in paragraph (b)(1) of this

section. The list shall also identify

which category of recipients received a

particular article or reference

publication;

(3) A notice and summary of any

additional clinical research or other data

relating to the safety or effectiveness of

the new use, and, if the manufacturer

possesses such clinical research or other

data, a copy of the research or data.

Such other data may include, but is not

limited to, new articles published in

scientific or medical journals, reference

publications, and summaries of adverse

effects that are or may be associated

with the new use;

(4) If the manufacturer is conducting

studies necessary for the submission of

a supplemental application, periodic

progress reports on these studies. Such

reports shall describe the studies’

current status (i.e., progress on patient

enrollment, any significant problems

that could affect the manufacturer’s

ability to complete the studies, and

expected completion dates). If the

manufacturer discontinues or terminates

a study before completing it, the

manufacturer shall, as part of the next

periodic progress report, state the

reasons for such discontinuation or

termination; and

(5) If the manufacturer was granted an

exemption from the requirement to

submit a supplemental application for

the new use, any new or additional

information that relates to whether the

manufacturer continues to meet the

requirements for such exemption. This

information may include, but is not

limited to, new or additional

information regarding revenues from the

product that is the subject of the

dissemination and new or additional

information regarding the

persuasiveness of the data on the new

use, including information regarding

whether the new use is broadly

accepted as current standard medical

treatment or therapy.

(c) A manufacturer shall maintain a

copy of all information, lists, records,

and reports required or disseminated

under this part for 3 years after it has

ceased dissemination of such

information and make such documents

available to FDA for inspection and

copying.

Dated: May 29, 1998.

Michael A. Friedman,

Lead Deputy Commissioner for the Food and

Drug Administration.

Donna E. Shalala,

Secretary of Health and Human Services.

[FR Doc. 98–14918 Filed 6–4–98; 4:30 pm]

BILLING CODE 4160–01–F

DEPARTMENT OF DEFENSE

Office of the Secretary

32 CFR Part 286

[DoD 5400.7–R]

RIN 0790–AG58

DoD Freedom of Information Act

Program Regulation

AGENCY: Office of the Secretary,

Department of Defense (DoD).

ACTION: Proposed rule.

SUMMARY: This proposed rule conforms

to the requirements of the Electronic

Freedom of Information Act

Amendments of 1996. This proposed

revision reflects substantial and

administrative changes since May 1997,

as a result of DoD reorganization. The

proposal also provides guidance to DoD

on implementation of this amended law.

DATES: Comments must be received by

August 7, 1998.