Dissemination of Information on Unapproved/New Uses for Marketed Drugs, Biologics, and Devices

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.

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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.

xtend 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

aurie 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

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

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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

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

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

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

o

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

Sec. 99.1 would describe the scope of part 99. Proposed Sec. 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 Sec. 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 Sec. 99.3 would define various terms, such as ``group

health plan'' (proposed Sec. 99.3(c)), ``health care practitioner''

(proposed Sec. 99.3(d)), ``new use'' (proposed Sec. 99.3(g)), and

``scientific or medical journal'' (proposed Sec. 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

Sec. 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

.S.C. 360aaa-5). However, proposed

Sec. 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., long-term 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

ess 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 Sec. 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

, 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

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 Sec. 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

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

ublications. 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

rm 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 Sec. 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

igation 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 well-documented 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;

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;

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 Sec. 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

vision. Such

reports do not provide sufficient information to determine the adequacy

of the study design and cannot be critically judged by the reader.

Proposed Sec. 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

Sec. 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 Sec. 99.103.

Proposed Sec. 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

pensation 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 Sec. 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 Sec. 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 Sec

cing,

and any other technique to achieve emphasis or notice. In addition,

proposed Sec. 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 Sec. 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

Sec. 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;

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

Sec. 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 Sec. 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 Sec. 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 Sec. 99.103(b), all other statements or

information would have to be attached to the article or reference

publication.

Proposed Sec. 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,

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

nagers, health insurance

issuers,

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 Sec. 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

ng 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 cross-reference 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

in 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 Sec. 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 Sec. 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 Sec. 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

. 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 Sec. 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 Sec. 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

Sec. 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

at 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

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 Sec

ew 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 Sec. 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 Sec

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 Sec. 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

lication 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

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

Sec. 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

ining 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

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

e 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

c 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 Sec. 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

Proposed Sec. 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

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 Sec. 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

Sec. 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 Sec. 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

ll 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 Sec. 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

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

complete, FDA will notify the manufacturer and the manufacturer shall

not disseminate the new use information under this subpart.

Proposed Sec. 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 Sec. 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 Sec. 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

tudies 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 Sec. 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 Sec. 99.305 would describe FDA action on an application

for an exemption from the requirement to submit a supplemental

application

ufacturer's

request for an extension, the manufacturer shall submit a new

certification under Sec. 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 Sec. 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

a 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 Sec. 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 Sec. 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

posed Sec. 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 Sec. 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 Sec. 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 Sec. 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 Sec. 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 Sec

, issuing ``Dear Doctor'' letters, publishing corrective

advertising, including warning labels on the product, or including

warnings or otherwise revising the product labeling.

Proposed Sec. 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 Sec. 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

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 Sec. 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

portunity 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 Sec. 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 Sec

e 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 Sec. 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 Sec. 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 Sec. 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 Sec

ication. 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 Sec. 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 Sec. 99.403(d), proposed Sec. 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 Sec. 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 Sec. 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

ses the dissemination of information on the new

use to undertake corrective action.

Proposed Sec. 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 Sec. 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 Sec

icuous 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 Sec. 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 Sec. 99.201, which is responsible for overseeing

the implementation of this part.

Proposed Sec. 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;

ich 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;

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 Sec. 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

tion

or termination.

Proposed Sec. 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 Sec. 16.1(a)(2) to add

the due diligence determinations under proposed Sec. 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)

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 cost-benefit 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

. 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

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

n 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

s 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

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

Number of

21 CFR Section No. of Responses per Total Annual Hours per Total Hours

Respondents Respondent Responses Response

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

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

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

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

information.

3(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

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

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

information.

Table 2.--Estimated Annual Recordkeeping Burden1

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

Annual

21 CFR Section No. of Frequency per Total Annual Hours per Total Hours

Recordkeepers Recordkeeping Records Recordkeeper

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

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

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

\1\ There 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.

ction 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.

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 Sec. 99.401(c) to read as follows:

Sec. 16.1 Scope.

* * * * *

G 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 Sec. 99.401(c) to read as follows:

Sec. 16.1 Scope.

* * * * *

(b) * * *

(2) Regulatory provisions:

* * * * *

Sec. 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

Sec. 99.1 Scope.

ssemination 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

Sec. 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.

Sec. 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:

ct

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.

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

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.

nels 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

Sec. 99.101 Information that may be disseminated.

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

Sec. 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;

nabridged 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

resentation 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

Sec. 99.103.

Sec. 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;

minated 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

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:

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.

Sec. 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.

er that achieves emphasis or notice and is distinct from the other

information being disseminated.

Sec. 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

Sec. 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 Sec. 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;

cal 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

rt

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.

ew 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,

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.

sion 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.

Sec. 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.

ies 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.''

Sec. 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:

d 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

ndition(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

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

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

Sec. 99.301 Agency action on a submission.

ndard 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

Sec. 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

cally 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.

Sec. 99.303 Extension of time for completing planned studies.

cation 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.

Sec. 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.

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 Sec. 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.

Sec. 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.

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

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

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

Sec. 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.

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;

(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

Sec. 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

Sec. 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.

as determined to be appropriate under

Sec. 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 Sec. 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.

Sec. 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.

es 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

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 Sec. 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.

Sec. 99.405 Applicability of labeling, adulteration, and misbranding

authority.

inated under the

exemption, certify, under Sec. 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.

Sec. 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

Sec. 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:

of this

part.

Subpart F--Recordkeeping and Reports

Sec. 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 Sec. 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 Sec. 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;

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 Fe

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