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

SUMMARY: The Food and Drug Administration (FDA) is issuing final

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 final

rule describes the new use information that a manufacturer may

disseminate and describes the content of and establishes procedures for

a manufacturer's submission to FDA before it may begin disseminating

information on the new use. The final rule also describes how

manufacturers seeking to disseminate information on a new use must

agree to submit a supplemental application 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 final rule provides for

requests to extend the time period for submitting a supplemental

application for a new use and describes how a manufacturer can seek an

exemption from the requirement to submit a supplemental application for

the new use. Additionally, the final rule discusses FDA actions in

response to manufacturers' submissions, corrective actions that FDA may

take or require, and recordkeeping and reporting requirements. The

final rule implements sections 551 through 557 of the Federal Food,

Drug, and Cosmetic Act (the act) (21 U.S.C. 360aaa through 360aaa-6) as

amended by section 401 of the Food and Drug Administration

Modernization Act of 1997 (FDAMA).

DATES: The final rule is effective November 20, 1998. Written comments

on the information collection requirements should be submitted by

January 19, 1999.

ADDRESSES: Submit written comments on the information collection

requirements to the Dockets Management Branch (HFA-305), Food and Drug

Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT:

Regarding biological products and devices regulated by the Center

for Biologics Evaluation and Research: Toni M. Stifano, Center for

Biologics Evaluation and Research (HFM-602), 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

In the Federal Register of June 8, 1998 (63 FR 31143), FDA

published a proposed rule that would add to title 21 of the Code of

Federal Regulations (CFR) a new part 99 entitled, ``Dissemination of

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

Devices.''

The proposed rule was intended to implement section 401 of FDAMA.

In brief, section 401 of FDAMA amended 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 the manufacturer complies with certain statutory requirements. For

example, the information that is to be disseminated must be about a

drug or device that is being legally marketed; it must be in the form

of an unabridged reprint or copy of a peer-reviewed journal article or

reference publication; and it must not be derived from another

manufacturer's clinical research, unless that other manufacturer has

given its permission for the dissemination. The information must be

accompanied by certain information, including a prominently displayed

statement that the information discusses a use or uses that have not

been approved or cleared by FDA. Additionally, 60 days prior to the

dissemination, the manufacturer must submit 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.

A detailed description of section 401 of FDAMA appeared in the

preamble to the proposed rule (see 63 FR 31143 at 31144 and 31145).

II. Highlights of the Final Rule

Although the statute is very detailed, and the final rule closely

tracks its provisions, there are some places where the regulation fills

in the details of the statutory requirements. For example, the final

rule defines terms that were not defined in the legislation (e.g.,

``supplemental application'' and ``clinical investigation,'' and it

explains concepts that required additional explanation (e.g., what is

meant by the term ``unabridged''). The final rule also sets forth the

more detailed procedures for how to submit the required information to

FDA before disseminating any new use information (e.g., where the

information should be submitted and how many copies are required).

Finally, the final rule defines what is meant by the basic criteria

that the statute sets forth for granting an exemption from the

requirement to submit a supplement application on the basis that it

would be unethical or economically prohibitive to conduct the studies

needed to submit a supplemental application.

The final rule has been revised in response to comments received on

the proposal. For example, Sec. 99.3 was revised to add a definition

for pharmacy benefit manger, which is not included in the statute. The

definition of ``clinical investigation'' in Sec. 99.3 also was revised.

Section 99.101 was revised to reflect FDA's position that most journal

articles and reference texts (as those terms are defined in the

regulation) would be considered to be scientifically sound and to

describe specific instances (e.g., letters to the editor, Phase 1

trials in healthy individuals) when that would not be the case.

Section 99.103 revised the mandatory statement that the

disseminated information has not been approved or cleared by FDA. That

section also was revised to ensure that the financial disclosures

required under this part would be consistent with FDA's final rule on

financial disclosures by clinical investigators.

Sections 99.201(a)(4)(i)(B) and (a)(4)(ii)(B), 99.203(b), and

99.401(b) were revised to clarify that for purposes of computing time

periods that begin on the date of initial dissemination, FDA will look

to the date that dissemination can begin. This clarification was

[[Page 64557]]

necessary because FDA will not know when a manufacturer actually begins

to disseminate materials.

Sections 99.203 and 99.303 were revised to clarify that there are

two different ways that FDA can extend the time period for completing

the studies needed to submit a supplemental application for a new use:

One before any studies have begun and one after the studies have begun.

FDA also revised the standard for granting an exemption from the

requirement to submit a supplemental application on the basis that it

would be economically prohibitive. The focus is now on the revenue from

the new use rather than the revenue from the product.

In Sec. 99.301, FDA clarified when it would require a manufacturer

to keep records identifying the individual recipients of new use

information as opposed to just the categories of such recipients.

Finally, the final rule was revised to ensure that a decision on a new

use submission would be made within 60 days.

III. Responses to Comments on the Proposed Rule

FDA received over 50 written comments on the proposed rule. In

addition, on July 8, 1998, FDA held a public meeting on the proposed

rule. Thirteen speakers commented on the proposal. In general, the

comments expressed a diverse range of opinions, both favoring and

opposing the proposed rule, and were submitted by health professionals,

medical organizations, consumer groups, patient groups, a medical

journal, members of Congress, trade associations, and manufacturers.

A. General Comments

Several comments addressed the concept of disseminating information

on unapproved or new uses rather than the proposed rule itself. Other

comments sought further restrictions on the dissemination of

information on unapproved or new uses, while still other comments

sought to expand the rule to cover more products.

1. A number of comments expressed concern that the proposed rule

could result in harm to patients. One comment expressed concern over

the self-policing aspects of the rule. Another comment cited several

examples where drugs were administered for unapproved uses and proved

to be harmful. The comment stated that dissemination of information on

unapproved uses for approved drugs would further encourage the use of

``untested'' drugs and discourage clinical trials that would show

whether the drugs are safe and effective for their intended uses. The

comment asked FDA to ``revise or abandon these regulations so as to

continue to protect consumers from untested and potentially dangerous

drugs.'' One comment argued that the new rule was not ``warranted''

because the disseminated information may be inappropriate and would

pose a significant risk to public health. The comment further argued

that current practices in this area are the best way to handle

information on unapproved uses. Finally, a number of comments expressed

concern that FDA does not have sufficient resources to implement the

regulation in a manner that can adequately protect the public health.

Such comments urged FDA to direct adequate resources to implementation.

Section 401(c) of FDAMA required FDA to issue regulations to

implement sections 551 through 557 of the act by November 21, 1998. The

final rule, which closely tracks the statutory language, represents

FDA's effort to comply with that requirement. FDA is committed to

implementing this new statutory authority consistent with its

obligation to protect the public health.

2. Several comments claimed that dissemination of information on

unapproved or new uses of drugs for which pediatric labeling is not

available would be contrary to section 505A of the act (21 U.S.C. 355A)

as it pertains to pediatric studies of drugs because it would impede

the development of pediatric data. Several comments said that

dissemination of information on unapproved uses for pediatric therapy

should be limited to drugs that have ``sufficient labeling in the ages

of the children addressed by the information disseminated.'' Another

comment noted that dissemination of information for an unapproved use

of a drug in children when the drug's approved use has not been tested

for safety in pediatric patients may pose even more risk than

unapproved uses generally. Others said that for drugs without labeling

for pediatric populations or specific age populations, drug

manufacturers should not be able to disseminate unapproved use

information about pediatric populations or about specific age

populations not specified in the label, unless such information is

specifically requested by the physician.

FDA declines to amend the rule as suggested by the comments. It is

FDA's hope that the statutory scheme set forth in section 401 of FDAMA

and implemented by this part will actually stimulate research and the

development of data on new uses, including pediatric uses. Moreover,

nothing in section 401 of FDAMA or its legislative history suggests

that Congress intended to exclude pediatric uses from section 551 of

the act or to further limit how information on such uses can be

disseminated. Finally, the act does not require that the disseminated

information be specifically requested by a physician in order to be

disseminated.

Although FDA is not amending the codified language in any way, it

does recognize that the potential dangers of unapproved uses in

children may be greater than for adults because few drugs have been

tested in children. The agency will take this into account in making a

determination as to whether a proposed dissemination of information on

a new use poses a significant risk to public health such that the

dissemination under this part should not be permitted.

3. One comment would revise the rule to exclude drugs that may be

covered by orphan drug exclusivity. The comment explained that a

manufacturer may obtain orphan drug exclusivity for a particular use of

a drug, but that other manufacturers could be marketing the same drug

for non-orphan indications. The comment stated that such other

manufacturers could disseminate information on the orphan indication,

thereby undermining the value of orphan drug exclusivity.

There is no indication in section 401 of FDAMA or its legislative

history that Congress intended the dissemination of information on

unapproved uses of drugs and devices to undermine patent protection or

exclusivity granted to a product under the Orphan Drug Act, the Waxman-

Hatch Amendments, or the pediatric exclusivity provisions in section

111 of FDAMA. Therefore, an indication that is not included in a

particular sponsor's approved product labeling because the indication

is protected by patent or exclusivity is not eligible for dissemination

under part 99.

4. Several comments urged FDA to broaden the proposal to include

over-the-counter (OTC) drug products being marketed under an OTC

monograph.

Section 401 of FDAMA requires that in the case of a drug, there be

in effect for the drug an application filed under section 505(b) or (j)

of the act. OTC drugs being marketed under an OTC monograph do not have

an application filed under section 505(b) or (j) of the act in effect.

Therefore, FDA declines to revise the rule as suggested in these

comments.

5. One comment stated that companies sometimes assist physicians

and patients in obtaining reimbursement from Medicare, Medicaid, and

private insurers by furnishing copies of journal articles and reference

publications on unapproved

[[Page 64558]]

uses to the insurer or government agency when reimbursement is denied

on the ground that use of the product is experimental. The comment

concluded that this practice appeared to be legal prior to the passage

of section 401 of FDAMA and asked FDA to clarify that it did not become

illegal as a result of FDAMA.

Prior to passage of FDAMA, the practice described in this comment

was not permissible unless the unapproved use information was provided

in response to an unsolicited request for such information. FDA's

policy, which allows manufacturers to provide unapproved use

information in response to an unsolicited request, was not affected by

FDAMA (see section 557(a) of the act). Accordingly, manufacturers who

wish to furnish unapproved use information as described in the comment

may do so if it is in response to an unsolicited request. Otherwise,

they must comply with the requirements set forth in section 401 of

FDAMA and this part.

6. One comment asserted that the proposal should recognize the

specific legal authorization for manufacturers to provide off-label

information to health care practitioners in response to an unsolicited

request.

Section 401 of FDAMA added a new section 557(a) of the act, which

provides that nothing in section 551 of the act shall be construed as

prohibiting a manufacturer from disseminating information in response

to an unsolicited request from a health care practitioner. Although FDA

does not construe section 557(a) of the act as a specific legal

authorization for manufacturers to provide off-label use information to

health care practitioners in response to an unsolicited request,

Sec. 99.1(b) of the final rule recognizes this statutory provision.

7. One comment stated that FDA should exempt manufacturers from the

``pre-approval and reporting requirements'' when the primary focus of a

publication is on the approved uses of the product.

Section 401 of FDAMA and this part do not cover publications

regarding approved uses. FDA intends to permit manufacturers to

disseminate certain information that focuses primarily on approved uses

and that report the results of studies that have been relied on by FDA

in its approval or clearance of a drug or device without meeting all of

the requirements set forth in this part. (Cf. Guidance to Industry on

Dissemination of Reprints of Certain Published Original Data (61 FR

52800, October 8, 1996). The agency was enjoined from applying this

guidance document in Washington Legal Foundation v. Friedman, CA No.

1:94CV1306 (D.D.C. July 30, 1998) (hereinafter referred to as WLF v.

Friedman). FDA sought clarification on the scope of the order through a

motion to amend the judgment in that case.) FDA plans to issue guidance

on this issue at some time in the future pending clarification by the

court.

8. One comment suggested that FDA exempt manufacturers from the

requirements set forth in this part if the new use that is the subject

of the information being disseminated has been accepted as standard

medical practice (i.e., indications listed in the United States

Pharmacopoeia Drug Information for the Health Care Professional (USP

DI) or American Hospital Formulary Service, etc.).

FDA declines to create an exemption from the entire rule as

suggested by the comment. Regardless of whether the unapproved use is

listed in the USP DI or American Hospital Formulary Service, the

statutory requirements in sections 551 through 557 of the act apply to

a manufacturer who intends to disseminate information on the unapproved

use for an approved product to health care practitioners, pharmacy

benefit managers, health insurance issuers, group health plans, or

Federal or State governmental agencies. Evidence that the unapproved

use represents standard medical care may, however, enable the

manufacturer to seek an exemption from the requirement to submit a

supplemental application for the unapproved use if the manufacturer can

demonstrate that it would be unethical to conduct the studies necessary

for a supplemental application for the new use. A discussion of the

``unethical'' exemption appears later in section III of this document.

9. Some comments stated that the proposal properly reflects the

intent of Congress and achieves the important goals of assuring the

public health and encouraging the dissemination of information. Others

argued that the proposal is contrary to congressional intent,

paternalistic and cumbersome, and would restrict, rather than

facilitate, access to information about new uses.

Although FDA drafted the proposed rule to reflect congressional

intent, the agency has revised the rule in response to specific

comments. These revisions are meant to ensure that the final rule more

accurately reflects congressional intent.

B. Comments on Specific Provisions

1. Subpart A--General Information

a. Scope (Sec. 99.1). Proposed Sec. 99.1 described the scope of

part 99, explaining that the part applies to the dissemination of

information on human drugs, including biologics, and devices where the

information to be disseminated pertains to 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 and 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.

10. Several comments urged FDA to add pharmacists to the list of

recipients of information under this part.

Section 401 of FDAMA specifically lists who can receive the new use

information under this provision and proposed Sec. 99.1 tracked that

statutory provision. Therefore, FDA declines to amend the regulation as

requested. However, to the extent that pharmacists fall within the

definitions of ``health care practitioner,'' ``pharmacy benefit

manager,'' health insurance issuer,'' or ``group health plan'' (see

Sec. 99.3) they will be included as recipients of this information.

b. Definitions (Sec. 99.3). Proposed Sec. 99.3 defined various

terms, such as ``clinical investigation'' (proposed Sec. 99.3(b)),

``health care practitioner'' (proposed Sec. 99.3(d)), ``new use''

(proposed Sec. 99.3(g)), ``scientific or medical journal'' (proposed

Sec. 99.3(i)), and supplemental application (proposed Sec. 99.3(j)).

11. One comment urged FDA to include a definition for ``pharmacy

benefit manager'' and to include pharmacists in that definition.

Although the statute defines the other recipients of information

under this provision (i.e., health care practitioner, health insurance

issuer, and group health plan), it does not define pharmacy benefit

manager. FDA has revised the rule to define a ``pharmacy benefit

manager'' (PBM) as ``a person or entity that has, as its principal

focus, the implementation of one or more device and/or prescription

drug benefit programs.'' PBM's, which generally include pharmacists,

typically provide claims processing services for devices and/or

prescription drugs; negotiate device and/or prescription drug prices;

negotiate volume purchase agreements with medical device and/or

pharmaceutical manufacturers, develop formularies, and institute

formulary

[[Page 64559]]

compliance programs (e.g., mandatory generic substitution programs).

The new definition is in Sec. 99.3(h) and the agency has redesignated

the remaining definitions accordingly.

12. Proposed Sec. 99.3(b) defined a ``clinical investigation'' as

an ``investigation in humans that is prospectively planned to test a

specific clinical hypothesis.'' Several comments argued that FDA should

delete the proposed definition of ``clinical investigation.'' They

argued that restricting clinical investigations to those that are

prospectively planned is not part of the statute, that it would

preclude the use of retrospective studies, modeling studies, open label

studies, metanalysis, reference articles, and consensus standards,

which these comments assert may be useful, and that Congress never

intended for the definition to be limited in this manner. One comment

argued that the prospective planning criteria should not have to meet

the criteria for investigational new drug applications (IND's).

FDA believes that many of these comments misconstrued what the

agency meant by the phrase ``prospectively planned.'' FDA does not

consider modeling studies, which are not actual studies, but rather

extrapolations of information or data that are used to predict how a

study might come out, to be clinical investigations. Moreover, FDA does

not consider consensus standards and reference articles to contain

adequate detail about ``clinical investigations'' as defined by this

rule. However, it was the agency's intent that the definition could

include historically controlled studies, retrospective analyses, open

label studies, and metanalyses if they are testing a specific clinical

hypothesis. To avoid any confusion, FDA is eliminating the phrase

``prospectively planned'' from the definition of ``clinical

investigation.'' In the final rule, FDA has defined a clinical

investigation to mean ``an investigation in humans that tests a

specific clinical hypothesis.''

13. Several comments urged FDA to revise the definition of ``health

care practitioner'' in Sec. 99.3(d) to include pharmacists.

Section 556(1) of the act (21 U.S.C. 360aaa-5(1)) defines the term

``health care practitioner'' to mean a physician, or other individual

who is a provider of health care, who is licensed under the law of a

State to prescribe drugs or devices.'' FDA's proposed regulation

tracked this statutory definition. FDA declines to revise the

definition. To the extent that pharmacists fall within this definition,

they will be eligible to receive information disseminated under this

part.

14. Proposed Sec. 99.3(g) defined ``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. The preamble to the proposed rule explained that 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.

The preamble to the proposed rule explained that ``new uses,''

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 (see 63 FR 31143 at 31145).

A number of comments supported FDA's definition of new use.

However, others disagreed with the specific examples set forth in the

preamble as too broad. Most of the latter comments objected to the

inclusion of patient subgroups and comparative claims for approved

indications. They argued that their inclusion in the definition is

inconsistent with the agency's prescription drug advertising

regulations, which permit companies to promote patient subgroups and

comparative claims if certain conditions are met. Several comments

disagreed with the inclusion of a new age group--specifically

children--in the definition of new use. One comment argued that

children should not be considered a ``use,'' but a ``user.'' One

comment stated that the definition should focus only on information

that differs from the current labeling; it should not include

information that is consistent with, but more detailed than what is

described in the approved labeling. Finally, one comment disagreed with

the agency's characterization of a different intended outcome as an

off-label use.

FDA agrees with the comments discussed previously, which note that

FDA's prescription drug advertising regulations permit companies to

make comparative claims about two approved uses, without getting the

claims on the approved label if the companies have on file, substantial

evidence or substantial clinical experience to support such claims.

(See Sec. 202.1(e) (21 CFR 202.1(e)).) FDA did not intend to change the

provision found in its prescription drug advertising regulations. In

addition, FDA agrees that as long as the comparison is between two

approved claims, there technically is not a new ``use'' involved.

Therefore, FDA is deleting comparative claims about approved uses from

its interpretation of ``new use.'' Manufacturers who want to make such

claims for a drug, must submit a labeling supplement or must meet the

requirements set forth in FDA's drug advertising regulations. (See

Sec. 202.1(e).) Manufacturers who want to make such claims for a

medical device must meet the requirements set forth in

Secs. 807.81(a)(3)(ii) or 814.39 (21 CFR 807.81(a)(3)(ii) or 814.39).

With respect to claims of efficacy in a new patient subgroup,

including a new age group, claims that are more detailed than the

approved labeling, and claims that relate to different intended

outcomes (as well as with respect to some of the other types of new use

claims listed in the preamble to the proposed rule), FDA's prescription

drug advertising regulations may permit companies to make such claims

about prescription drugs in certain circumstances, without submitting a

supplement, provided they have on file the required evidence to support

the claim. (See Sec. 202.1(e).) However, FDA does consider such claims,

including claims regarding children, to be new uses in some cases. In

cases where such claims constitute new uses, manufacturers also can use

the procedures set forth in this part to disseminate journal articles

and reference publications about those claims. For medical devices,

manufacturers can use the procedures set forth in this part to

disseminate journal articles and reference publications about these

types of claims. Otherwise, they must comply with the requirements set

forth in Secs. 807.81(a)(3)(ii) or 814.39.

15. Proposed Sec. 99.3(i) (now redesignated as Sec. 99.3(j))

defined ``scientific or medical journal,'' in part, as a journal that

is indexed in Index Medicus. It excluded scientific and medical

publications that are in the form of special supplements that have been

funded in whole or in part by one or more manufacturers. One comment

agreed that special supplements are not appropriate for dissemination

under this part. One comment, however, stated that the definition was

too narrow by requiring that the publication be listed

[[Page 64560]]

in Index Medicus and by excluding special supplements.

The definition in FDA's rule, which excludes journals not indexed

in Index Medicus and scientific and medical publications that are in

the form of special supplements that have been funded in whole or in

part by one or more manufacturers, tracks the statutory definition.

(See section 556(5) of the act.) Accordingly, no changes to the final

rule have been made.

16. Proposed Sec. 99.3(j) (now redesignated as Sec. 99.3(k))

defined ``supplemental application'' as a supplement to support a new

use to an approved new drug application (NDA) for human drugs or a

supplement to an approved license application for biologics. Several

comments argued that the definition of a supplemental application for a

drug should be expanded to include the possibility that a ``new use''

could require a new NDA rather than just a supplemental NDA. One

comment claimed that there are certain review divisions in the Center

for Drug Evaluation and Research (CDER) that require NDA's for all new

uses.

There may be times when a manufacturer would be required to submit

an NDA rather than a supplemental NDA to support a new use. In these

instances, the unapproved use would not be covered by this part.

However, it would not be appropriate to exclude new uses from this part

merely because a review division assigns a new NDA number to the

supplement for administrative convenience. In the latter instance, the

difference would be in name only. Therefore, although FDA is declining

to revise the regulation as suggested by the comments, FDA will treat

applications that have been assigned a new NDA number for

administrative convenience as a supplemental NDA for purposes of this

part.

17. One comment recommended expanding the definition of

supplemental application to cover OTC drugs that are subject to a

monograph.

As set forth previously, OTC drugs that are subject to a monograph

are not covered by this provision. Therefore, FDA declines to expand

the definition as requested.

18. For devices, proposed Sec. 99.3(j) (now redesignated as

Sec. 99.3(k)) defined ``supplemental application'' as a new 510(k)

submission, if the device that is cleared for marketing is the subject

of a 510(k) submission, or a supplement to an approved premarket

approval application (PMA), if the device that is marketed is the

subject of an approved PMA. One comment recommended expanding the

definition of supplemental application for devices to include a 510(k)

to a 510(k) exempt device.

FDA agrees that the statutory provision covers 510(k) exempt

devices and so has amended the definition of supplemental application

accordingly.

19. Several comments disagreed with FDA's definition of

supplemental application for devices because it did not include a PMA

for a new use for a device on the market under section 510(k) of the

act (21 U.S.C. 360(k)).

Because there are no supplemental applications for 510(k) devices,

FDA could have interpreted the statute to exclude all 510(k) devices

from the scope of the rule. FDA drew a distinction between those that

require a new 510(k) and those that require a PMA because the agency

determined that this was similar to the distinction between a

supplemental NDA and an NDA (i.e., a supplemental NDA and a 510(k) are

filed on products about which the agency has some accumulated knowledge

and experience such that it is not required to start its review from

scratch; an NDA and a PMA are filed for products about which the agency

has no such accumulated knowledge or experience upon which to base a

decision).

FDA disagrees with the comment that an original PMA submission

should be included in the definition of ``supplemental application''

for a device that entered the marketplace through the 510(k) process.

The 510(k) process and the PMA process are designed to provide

different ways to market regulated products, are supported by a

different extent and kind of data, and are predicated on different

concepts of how to assure consumer protection.

A product entering the market via the 510(k) process does so

because the agency agrees with the sponsor that the new device is

substantially equivalent to a device commercially distributed before

May 28, 1976, or to a newer predicate device for the same intended use.

For a 510(k) product, the consumer protection objective of the act is

met in part by the accumulated experience with the predicate devices

and the review and establishment of the device category in the

appropriate class and a modicum of device specific information.

Information on manufacturing and premarket assurance of conformance to

good manufacturing practices (GMP's) are not addressed. The agency does

not, in the case of a 510(k), make an individual product determination

of safety or effectiveness.

The act requires a PMA for a device for which there is a new

intended use with no predicate, or which raises new issues of safety

and effectiveness. Evidence required under a PMA is substantial and the

sponsor must show, through the use of well-controlled clinical trials

or, at the discretion of the agency, other valid scientific evidence,

that there is a reasonable assurance the product is safe and effective

for its intended use. As part of its review of a PMA, FDA reviews and

audits clinical trial information and the GMP's employed by the

manufacturer.

Allowing an original PMA submission to be regarded in this context

as a supplement for a device already marketed under a 510(k) would

undermine the statutory and regulatory requirements established to

ensure the safety and effectiveness of products subject to PMA's. It

would be analogous to applying the dissemination provision to new

devices that were never legally marketed. For a PMA product, a new

intended use supplement is intended to provide the agency with

additional data supporting a new use for an approved device. It relies,

in large part, on information previously reviewed regarding product

materials, biocompatibility, design, performance, and basic safety

data. For a 510(k) product, a PMA would not be providing additional

information; it would be providing all of the information.

To illustrate, a product not currently marketed, but that was

marketed as a general use tool without any known labeling or identified

product specific intended use in the 1960's preamendment period may be

re-introduced through a 510(k) for that same (implied) intended general

tool use (e.g., it ablates or thermally destroys tissue). The product

will be regarded as an unclassified preamendment product. If a

manufacturer wished to market it for a specific intended purpose where

that new purpose creates a new use with attendant questions of safety

and effectiveness of the new use, it must do so through a PMA. In a

recent instance, a company sought to market its unclassified

preamendment product, an interuterine probe for a cryosurgery machine

(using freezing to thermally destroy tissue), for ablation of the

uterine endometrium with ultrasound control of the location and extent

of tissue being frozen to control excessive menstrual bleeding. By

moving to a tissue and anatomic specific intended use and indication,

as well as by incorporation of a new (external) control procedure, the

manufacturer has created a new intended use. The product's underlying

safety and manufacture have never been evaluated. Even the presumption

that ultrasound

[[Page 64561]]

measurement of the extent of tissue being frozen accurately predicts

the extent of tissue necrosis and allows proper positioning of the

probe remains unevaluated. Nevertheless, the comments would argue that

this product could be the subject of an article or text disseminated

under section 401 of FDAMA.

In passing section 401 of FDAMA, Congress intended to provide

health care practitioners important scientific information about

unapproved uses of approved products. The risks to the public of

disseminating information in a case such as that described previously

are closer to the risks from instances where there has never been an

approved product than those for a new use of a previously approved

product. FDA believes that these risks are far greater than those

authorized by section 401 of FDAMA.

2. Subpart B--Information To Be Disseminated

a. Information that may be disseminated (Sec. 99.101). Proposed

Sec. 99.101 discussed the types of information concerning the safety,

effectiveness, or benefit of a new use that a manufacturer may

disseminate. For example, the proposal required (among other things)

that the written information to be disseminated concern a drug or

device that has been approved, licensed, or cleared for marketing by

FDA and be in the form of an unabridged reprint or copy of a peer-

reviewed scientific or medical journal article 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. Proposed Sec. 99.101 also described criteria for

determining whether the information to be disseminated is false or

misleading, whether a clinical investigation is ``scientifically

sound,'' and whether a reprint or copy of an article or reference

publication is ``unabridged.''

20. One comment urged FDA to include a 60-day window in advance of

a drug's Prescription Drug User Fee Act date during which time a

manufacturer could submit proposed material for review. In other words,

the comment urged FDA to accept dissemination materials for review

before a drug has been approved.

FDA declines to adopt this approach. The statute does not direct

FDA to accept submissions on products that have not yet been approved

or cleared. If FDA accepts submissions on products that have not yet

been approved or cleared, it may be wasting resources reviewing

submissions on products that never get approved or cleared.

21. One comment urged FDA to make clear that this part does not

permit the verbal dissemination of unapproved use information. Another

comment suggested that companies that disseminate information on a new

use should be permitted to discuss the clinical investigation that is

the subject of the disseminated materials with the recipient.

FDA agrees with the first comment that neither this part nor

section 401 of FDAMA, would permit the verbal dissemination of

information about unapproved uses. Section 551(a) of the act and

Sec. 99.101 refer clearly and specifically to ``written'' information.

Therefore, a manufacturer (or its representatives or agents) is not

permitted to discuss with a recipient the clinical investigation that

is the subject of the written materials disseminated under this part.

22. Several comments asked whether Internet or electronic

dissemination would be permitted under this part.

Although, as set forth previously, FDA agrees that the provision

was not meant to cover verbal dissemination, it could cover electronic

dissemination. However, a manufacturer seeking to disseminate

information electronically would have to ensure that all of the

requirements under this part could be met for electronic dissemination.

For example, the manufacturer would have to ensure that the recipients

of the information are appropriately limited and that all of the

required information and disclosures can be attached in accordance with

this part. FDA may, in the future, issue guidance on this subject.

23. One comment noted the importance of requiring manufacturers to

disseminate unabridged journal articles so that information from a

clinical study is not pulled out of context or released without all

relevant data.

FDA agrees with this comment. Both the statute and the regulation

require that a journal article or reference publication disseminated

under this part be unabridged.

24. Several comments objected to the requirement that a reprint or

copy of an article be published prior to submission for FDA for review.

These comments argued that manufacturers should be allowed to send FDA

final manuscripts. Another comment opposed allowing submissions to

include manuscripts or preprints of articles that have been accepted

for publication. This comment stated that it could take months for

these manuscripts to be published and that they might be submitted

before the peer-review process is complete.

FDA understands manufacturers' desire to disseminate new use

information as quickly as possible. However, section 552 of the act (21

U.S.C. 360aaa-1) requires that the peer-reviewed journal articles

disseminated under this part be published. If FDA were to accept

manuscripts before publication, it could not be sure that what gets

published, and then disseminated, is exactly what it was given to

review. The agency might not even be sure that the peer-review process

has been completed. FDA does not have the resources to verify this

information or to conduct duplicative reviews. Therefore, FDA is not

revising the rule to permit submission of unpublished manuscripts.

25. Several comments took issue with the statement in the proposal

that information can be false or misleading if it includes only

favorable publications. These comments argued that dissemination should

not be prohibited if the only information that has been published is

favorable and the research is scientifically rigorous. These comments

noted that FDA should make clear that a single favorable publication

can be disseminated if it is objective, balanced, and discusses

appropriate safety information. One comment noted that a more

appropriate manner in which to state the issue would be to cite the

exclusion of an unfavorable publication as the example.

FDA agrees that new use information is not necessarily without

balance or misleading just because there is no unfavorable information

disseminated with it and FDA did not intend to suggest the contrary.

FDA agrees that it would be inappropriate to find a favorable article

misleading just because it is disseminated without an unfavorable

publication when no unfavorable publication exists. What FDA will be

looking for is whether the manufacturer has failed to include

unfavorable information that exists and that is necessary to provide

balance. FDA has revised the rule to clarify this point.

26. One comment said that proposed Sec. 99.101(a)(4) was unclear on

what ``other information concerning risks and adverse effects that are

or may be associated with the new use'' a company would have to include

to ensure that the disseminated information is not false or misleading.

The other information refers to the additional information that FDA

can require under Sec. 99.103(a)(4). FDA has revised the rule to

clarify this point.

[[Page 64562]]

27. Proposed Sec. 99.101(a)(5) required that the disseminated

information 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.

One comment noted that the rule should clarify that contracts or

agreements between sponsors may specify how the data are to be used by

the sponsoring companies. In other words, cosponsoring companies should

be responsible for maintaining their own agreements without FDA input.

Several other comments opined that once a peer-reviewed article is

published, it is in the public domain and a sponsor should be able to

pursue use of the data published by the original sponsor (i.e., without

first obtaining permission) as long as proper credit is given. One

comment asked FDA to clarify the rule to show that research conducted

by an independent academic or similar organization can be disseminated

if the information meets the standards for dissemination and is legally

available for such use.

Section 551(b)(3) of the act prohibits the dissemination of

information derived from research conducted by another manufacturer

without that other manufacturer's permission. The fact that an article

has been published does not eliminate the need to get permission from

the researching company. If it did, this requirement in the statute

would be meaningless because all information disseminated under this

part must be published. Therefore, FDA declines to revise the rule to

permit the dissemination of all published articles reporting on

research conducted by another manufacturer without that manufacturer's

permission. However, FDA agrees that cosponsoring companies can make

agreements without FDA's input and that research conducted by

independent parties does not, by the terms of the statute, require that

party's permission.

28. One comment noted that reference publications will include many

unapproved use discussions that reflect research conducted by other

manufacturers and that proposed Sec. 99.101(a)(5) would appear to make

the disseminating company get permission from every one of those

manufacturers.

As set forth in the proposal, FDA expects that manufacturers that

disseminate reference publications under this part will flag the

section of the text that describes the clinical investigation of a

specific unapproved use (otherwise, they would have to commit to study

all of the unapproved uses discussed in the reference publication).

Therefore, FDA would expect that a manufacturer would be required only

to seek the permission of another manufacturer if that other

manufacturer conducted the study for that specific discussion of an

unapproved use.

29. Proposed Sec. 99.101(b)(1) provided that 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. It further provided that 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. The proposal also stated that 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, abstracts of a publication) would not qualify for

dissemination under this provision.

The preamble to the proposal provided that 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; (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; (4) utilized clinically meaningful

endpoints or utilized surrogate endpoints that are reasonably likely to

predict safety and effectiveness; (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. (See 63 FR 31143

at 31146 and 31147.)

Some comments supported FDA's interpretation and applauded the

agency's efforts to ensure that journal articles and reference

publications are scientifically sound. These comments noted that FDA's

interpretation reflected what is required by most peer-reviewed

journals.

In contrast, a number of comments objected to FDA's approach. Some

of these comments objected to FDA making any determination that an

article or reference publication is scientifically sound. They stated

that it was not Congress' intent to have FDA ``do its own peer

review.'' Others criticized the criteria set forth in the proposed

codified language and/or the eight criteria in the preamble to the

proposal. They argued that FDA would be requiring more detail than is

ever found in articles or reference publications and/or that FDA's

standard is akin to that for a supplemental application. One comment

said that FDA should require only enough detail to determine if the

article or publication is scientifically sound. One comment urged FDA

to adopt a broader definition of scientifically sound by removing the

specific requirements, i.e., prospectively planned, and recognizing the

value of scientifically sound studies as long as any limitations (e.g.,

epidemiological data) are fully disclosed. One comment said that FDA

should require the journal article to include the ``typical level of

detail'' and, if it does not, then the company should be able to attach

it to the article. Several comments opposed the specific exclusion of

abstracts. Finally, a number of comments specifically criticized the

requirement that the clinical investigation be prospectively planned.

FDA has a role to play with respect to whether an article or

reference publication is scientifically sound. The statute includes a

requirement that the disseminated article or reference publication

pertain to a clinical investigation that would be considered to be

scientifically sound by experts qualified by scientific training or

experience to evaluate the safety or effectiveness of the drug or

device involved. FDA believes that this provision indicates that

Congress meant for FDA to look at whether experts would find that the

article or publication is about an investigation that experts would

consider to be scientifically sound. However, FDA also believes that

its role in determining whether an article or publication is

scientifically sound is limited. This approach is consistent with the

proposed rule and FDA fully expected that most journal articles about a

clinical investigation from reputable peer-reviewed journals would meet

the definition of scientifically sound set

[[Page 64563]]

forth in its proposal. Nevertheless, to ensure that the provision will

be implemented consistent with congressional intent, FDA is revising

Sec. 99.101(b)(1) to provide that FDA will find that all journal

articles and reference publications (as those terms are defined in

Sec. 99.3) are scientifically sound except: (1) Letters to the editor;

(2) abstracts of a publication; (3) those regarding Phase 1 trials in

healthy people; (4) flagged reference publications that contain little

or no substantive discussion of the relevant clinical investigation;

and (5) those regarding observations in four or fewer people that do

not reflect any systematic attempt to collect data, unless the

manufacturer demonstrates to FDA that such reports could help guide a

physician in his/her medical practice.

Section 552(a)(2) of the act prohibits the dissemination of

information that is false or misleading. That provision prohibits the

dissemination of journal articles and reference publications that

contain conclusions that are not supported by the study results. FDA

has revised Sec. 99.101(a)(4) accordingly.

30. One comment asked what FDA would do if an article discussed

multiple unapproved uses, but the manufacturer wanted to focus on just

one unapproved use.

FDA expects that there may be articles that discuss multiple

unapproved uses and that such articles may be disseminated only if the

requirements are met for each of those uses. There also may be

instances when an article discusses multiple unapproved use(s), but

there is one (or more) predominant unapproved use(s) discussed in the

article. Under certain circumstances, it may make sense for the

manufacturer to have to meet the requirements set forth in this part

only for the predominant use(s). However, FDA will have to make this

determination on a case-by-case basis.

31. One comment argued that dissemination of reference publications

is not consistent with the purpose of section 401 of FDAMA because, by

their very nature, reference publications are considerably out of date

at the time of their publication. The comment further opined that

because the authors do not report the methods used to assess the

current scientific literature, reference publications should be

considered the authors' opinion and thus, not scientifically sound.

FDA agrees that many reference publications may not be up to date.

However, Congress did include reference publications within the scope

of section 401 of FDAMA. There is no basis to presume that all

reference publications are not scientifically sound.

32. Several comments opposed the requirement that disseminated

information in the form of a reference publication ``pertain to a

clinical investigation regarding the drug or device.'' Instead, they

argued, the reference publication should ``include information about''

such a study. Some comments interpreted this to mean that the study

should meet all of the criteria to establish scientific soundness, but

the information about such a study should not be required. One comment

said that the language means that the information needs to be based on

a scientifically sound clinical investigation, it need not be about or

describe such clinical investigation.

Both the act and this part provide that reference publications must

``include information about a clinical investigation.'' However, this

does not mean that the information about that clinical investigation

should be any less complete than the information included in a journal

article. It means only that the text may have a lot of additional

information that is not about the clinical investigation. The idea

behind the dissemination provision is that physicians and other

recipients be in a position to make treatment decisions based on

published reports of clinical trials. If the information that is

disseminated gives them little or no information about the actual

trial, then it would be difficult to argue that they have a reasonable

basis upon which to make such treatment decisions.

33. A number of comments argued that the proposal has written

reference publications out of the statute by requiring the same level

of detail as would appear in journal articles. One comment said that

FDA should accept the dissemination of peer-reviewed reference

publications. Some comments argued that the proposal would make text

book dissemination more difficult than it was prior to passage of FDAMA

and that FDA should adopt a final rule that is consistent with its

existing reference text guidance or it should leave that guidance in

place. One comment argued that the statute makes it clear that FDA must

allow the dissemination of reference publications that meet the

requirements of the statute and that the agency's decision to issue a

guidance document on this issue is not an option.

As set forth previously, FDA does not believe that Congress meant

that reference publications disseminated under this part could have

less detail about clinical investigations than journal articles. In

addition, reference publications are not subject to classic peer-

review. Therefore, FDA rejects the comment that FDA accept all peer-

reviewed reference publications. As discussed in the preamble to the

proposal, however, FDA recognizes that it will be difficult for many

reference publications to meet the statutory criteria. Moreover, as set

forth in many of the comments, the new statutory scheme in most

respects makes it more difficult to disseminate reference publications

than was possible before FDAMA. Thus, FDA plans to permit companies to

distribute unabridged reference publications (as defined in the statute

and Sec. 99.3(i)) without meeting all of the requirements set forth in

this part if the company does not focus on or point to a specific

unapproved use in the publication and it includes a disclaimer that the

publication includes information about unapproved uses. (Cf. Guidance

for Industry Funded Dissemination of Reference Texts (61 FR 52900,

October 8, 1996). The agency was enjoined from applying this guidance

document in WLF v. Friedman. FDA sought clarification on the scope of

the order in that case through a motion to amend the judgment.) FDA

plans to issue guidance on this issue at some time in the future

following clarification by the court. Of course, manufacturers that

want to focus or point to a specific unapproved use will have the

option of doing so by meeting the requirements set forth in this part.

34. One comment argued that Congress intended for manufacturers to

be able to disseminate reference publication chapters.

Section 552(a)(1) of the act clearly requires that the reference

publication be unabridged. A chapter from a textbook does not meet this

requirement.

35. Proposed Sec. 99.101(b)(2) provided that journal articles and

reference publications disseminated under part 99 cannot be

disseminated with any information that is promotional in nature. One

comment strongly agreed with the concept of prohibiting promotional

material to be distributed with scientific information on a new use.

One comment opposed the concept, stating that there is no policy or

legal rationale for prohibiting companies from distributing information

on approved uses with these reprints. A number of comments requested

clarification of this statement. These comments were concerned that it

could preclude a sponsor from delivering a promotional piece on a

labeled use during the same office visit or detail. These comments

suggested that FDA

[[Page 64564]]

clarify that so long as the promotional material concerns an approved

use and is kept physically distinct from the unapproved use

information, FDA would not consider the two to be distributed together.

FDA did not intend to prohibit a sponsor from delivering

promotional pieces on an approved or cleared use during an office visit

or detail in which it has delivered information on an unapproved use.

Any unapproved use information, however, must be kept physically

distinct from the promotional materials, and the sponsor may not

verbally promote the unapproved use or include materials about the

unapproved use, beyond those permitted or required under this part.

b. Mandatory statements and information (Sec. 99.103). Proposed

Sec. 99.103 described the information that must accompany the journal

article or reference publication. For example, it required a

prominently displayed statement disclosing (among other things) 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 and, 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 dissemination. It also required the official

labeling and a bibliography of other articles to accompany the

disseminated information. In addition, the proposal described what is

meant by a ``prominently displayed'' statement by setting forth

criteria that are consistent with the agency's regulations on

prescription drug advertising (Sec. 202.1(e)(7)(viii)) and labeling (21

CFR 201.10(g)(2)). Proposed Sec. 99.103 required the statement that the

use has not been approved and the additional information required by

FDA to be attached to the front of the disseminated materials and that

all other mandatory information be attached to the disseminated

information.

36. Although some comments supported FDA's position on mandatory

statements, there were others that thought the proposal was unduly

restrictive. For example, although some comments supported the

requirement for a uniform statement disclosing that the new use has not

been approved by FDA, there were a number of comments that thought

manufacturers should be allowed to use alternative language to convey

this message. One comment specifically objected to the phrase ``and is

being disseminated under section 551 of the Federal Food, Drug, and

Cosmetic Act.'' This comment said that the phrase was unnecessary and

could be confusing.

FDA continues to believe that it is important to have a uniform

disclosure stating that the new use has not been approved by FDA.

Different statements can be confusing and recipients of the information

may believe that they have different meanings. FDA agrees, however,

that the phrase: ``and is being disseminated under section 551 et seq.

of the Federal Food, Drug, and Cosmetic Act'' is unnecessary and has

therefore dropped it from the final rule.

37. One comment stated that clarification is needed regarding

articles that discuss more than one use because, as written,

Sec. 99.103(a)(1)(i) uses singular and plural forms in a way that is

confusing.

FDA agrees that clarification was needed and has revised the final

rule accordingly.

38. Proposed Sec. 99.103(a)(1)(iii) required a statement disclosing

any authors who have a significant financial interest in the

manufacturer. One comment noted that, although the disclosure is

appropriate, the final rule should make clear that such disclosure be

in line with the level required by the rule on financial disclosure and

should apply only to the financial interests at the time the study was

conducted and not the author's current interest.

In the preamble to the proposed rule, FDA stated that 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 and that when there is a question as to whether a

relationship is significant, it should be disclosed (see 63 FR 31143 at

31147). Manufacturers may consult the final rule on financial

disclosure by clinical investigators (codified at 21 CFR part 54) to

learn the types of financial interests of greatest concern to the

agency. However, because the purposes and terminology of this final

rule and the final rule on financial disclosure by clinical

investigators are different, manufacturers should consult the

provisions of this final rule for the requirements that apply to

disclosures regarding authors. FDA agrees that the financial disclosure

should not necessarily apply to the author's current financial

interest. FDA believes, however, that it should apply to the author's

financial interests during the time the study was conducted up through

1 year after the time the journal article or reference publication was

written and published. FDA has revised the final rule to reflect this

time limitation. FDA's revision is consistent with part 54.

39. One comment urged FDA to require that the statement that there

are products or treatments that have been approved or cleared for the

use that is the subject of the dissemination list the names of other

drugs that have been approved by FDA. Another comment asked whether

such statement should address adjuvant or supporting therapies.

FDA's regulation tracks the statute, which does not require a

manufacturer to identify the specific products that have been approved

or cleared for the new use or the adjuvant or supporting therapy for

the new use. (See section 551(b)(6)(A)(v) of the act.) Although FDA can

see the benefit of having those specific product names listed, it would

be difficult to develop a complete and accurate list. Moreover, the

information could be misleading if the manufacturer merely provided a

list of names. FDA also does not believe that the statement should

address adjuvant or supporting therapies. The idea behind the

disclosure is to let health care practitioners and other recipients

know that approved/cleared alternatives exist. Therefore, FDA is

retaining the requirement that the manufacturer only disclose that such

approved/cleared products exist.

40. Proposed Sec. 99.103(a)(2) provided that the manufacturer must

attach the official labeling of the product to the unapproved use

information. In the preamble to the proposed rule (63 FR 31143 at

31147), FDA noted that devices, unlike drugs, do not always include a

package insert in the same form and manner as drugs. Therefore, the

agency would expect device manufacturers to provide the same

information that is generally found in package inserts, namely: (1) The

name of the device, including its trade or proprietary name; (2) the

manufacturer's name, address, and telephone number; (3) a statement of

intended use, including a general description of the diseases or

conditions that the device is intended to diagnose, treat, cure, or

mitigate; (4) a description of the patient population for which the

device is intended; (5) a description of indications that have been

approved or cleared by FDA; (6) a description of any limitations or

conditions that have been placed on the sale, distribution, or use of

the device; and (7) all warnings, contraindications, side effects, and

precautions associated with the use of the device.

One comment suggested that a device's official labeling be

interpreted as: (1) The package insert for the device; (2) the

accompanying documents that a manufacturer distributes with its legally

[[Page 64565]]

marketed device to comply with the requirements of 21 CFR 801 or 809.10

for in vitro diagnostic products; or (3) the new labeling vehicle

created by a manufacturer that contains the listed items from the

preamble.

FDA agrees that this interpretation of official labeling for

devices is appropriate provided the third option is used only when the

first two options are not available or not feasible and provided the

third option includes only the information listed in the preamble

(i.e., no promotional statements or representations are included).

41. Proposed Sec. 99.103(a)(3) required the manufacturer to attach

a bibliography of other articles (that concern reports of clinical

investigations both supporting and not supporting the new use). One

comment noted that a bibliography is not required every time--only when

one is not present in the disseminated information. Another comment

stated that the bibliography requirement is vague regarding what needs

to be included and under what circumstances a bibliography included in

the publication is sufficient.

FDA's proposal provided that the manufacturer need not include a

separate bibliography if the disseminated information already includes

a bibliography that meets the requirements set forth in

Sec. 99.103(a)(3). The bibliography requirement would be met by a list

of all other published articles from scientific reference publications

or scientific or medical journals that discuss clinical investigations

and are specific to the new use discussed in the disseminated

information. The bibliography must include articles about clinical

investigations that both support and do not support the new use and it

must identify which articles relate to the new use. A bibliography

already included with the disseminated information would meet this

requirement only if it includes all other such published articles. The

manufacturer would still have to include its search strategy to show

that it took reasonable steps to ensure that the bibliography includes

all relevant published articles as described in Sec. 99.103(a)(3).

42. Proposed Sec. 99.103(a)(4) required a manufacturer to include

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.

Several comments noted that this provision should specify that FDA

must provide the manufacturer notice and an opportunity to meet before

requiring such information.

FDA agrees that a manufacturer must be provided notice and an

opportunity to meet before being required to include this additional

information. Redesignated Sec. 99.301(a)(2) provides this opportunity

and FDA has revised the final rule at Sec. 99.103(a)(4) to include a

reference to Sec. 99.301(a)(2).

43. Several comments opposed the requirement that the statement

that the use has not been approved and the additional information

required by FDA be attached to the front of the disseminated materials

and that all other mandatory information be attached to the

disseminated information. One comment suggested that the FDA-required

information be attached to the back, and that FDA permit the use of a

sticker on the front of the disseminated material stating that the FDA-

required information is attached to the back.

FDA believes that it is important to permanently affix the

statement indicating that the disseminated information is about an

unapproved use to the front of the materials. The recipients of such

materials should know, in advance, that they are reading information

about an unapproved use. However, FDA agrees that it could be

appropriate to attach the additional information required by FDA to the

back of the materials, provided there is a sticker or notation on the

front referring the recipient to that information. The agency has

amended Sec. 99.103(a)(4) accordingly.

FDA also believes it is important to attach the remaining

information to the disseminated materials. Congress included this

mandatory information because it determined that it was important for

the recipient to receive it. If such information is not attached, it

can easily be separated from the disseminated material and never seen

by the recipient. This is the information that helps to ensure that the

disseminated materials are objective, balanced, and not misleading.

44. Although some comments stated that the criteria in proposed

Sec. 99.103(c) for determining whether the mandatory information is

prominently displayed are appropriate, others opposed the factors that

FDA will consider in determining whether the mandatory information is

prominently displayed. The latter comments argued that manufacturers

should retain some flexibility and discretion in this area.

FDA's approach is flexible. Section 99.103(c) sets forth the

factors that FDA will consider and provides that the required

statements shall be outlined, boxed, highlighted, or otherwise

graphically designed and presented in a matter that achieves emphasis

or notice and is distinct from the other information being disseminated

(emphasis added). Such an approach is not as proscriptive as the

comments imply. FDA has retained this approach in the final rule.

45. One comment suggested that FDA permit manufacturers to post

information, such as balancing articles required by FDA, on the

Internet so long as the Internet address is prominently displayed on

the information that was disseminated. The comment said that this would

reduce paperwork burdens and provide a continuous source of current

information.

FDA does not think that it would be appropriate for manufacturers

to use the Internet to balance a published reprint disseminated in hard

copy format or to provide recipients of unapproved use information with

only part of the information required by the statute and regulations.

The idea behind the provision was that physicians would receive, at one

time, a balanced package. Such balance would not be achieved if a

manufacturer could hand a physician an article and then advise the

physician that he/she has to take steps on his/her own to retrieve the

balancing information.

46. Several comments urged FDA to require manufacturers to provide

patient labeling for drugs that are the subject of the disseminated

information. The comments noted that such labeling should identify the

drug by name, notify consumers that the drug has been promoted for an

unapproved use, and indicate FDA-approved uses for the drug. They

further argued that the patient labeling must include information about

the potential risks of the drug and meet the quality and content

standards of FDA's 1995 proposed Medication Guide rule. This comment

said that FDA-approved patient labeling must be in commercial

distribution at the level of the pharmacy before dissemination under

this part can begin. One comment stated that the labeling should state

that these products are not tested in certain populations and should

say ``use at your own risk.''

[[Page 64566]]

FDA recognizes the importance of providing consumers access to

information about the products they use. Since 1968, FDA has

occasionally required and often encouraged manufacturers to produce

patient labeling for certain prescription drugs. However, the comments'

request for additional patient labeling on drugs that are the subject

of information disseminated under part 99 is outside the scope of

section 401 of FDAMA.

47. Several comments argued that the lack of availability of

pediatric studies on a particular use should be clearly and prominently

stated in the information being disseminated to health professionals.

These comments also urged FDA to require an additional statement for

drugs that have not undergone pediatric testing: ``Safety and

effectiveness in pediatric populations have not been established for

this product for the use that has been approved by FDA or for the use

suggested by this information.''

The suggestion that for drugs and devices that have not undergone

pediatric testing, the disseminated information should include a

statement to that effect is beyond the scope of this rule. However, for

unapproved pediatric uses that are the subject of the information being

disseminated, there will be a statement that the use has not been

approved or cleared by FDA.

c. Recipients of information (Sec. 99.105). Proposed Sec. 99.105

identified who may receive information disseminated under this part.

Specifically, a health care practitioner, pharmacy benefit manager,

health insurance issuer, group health plan, or Federal or State

Government agency could receive information disseminated under part 99.

48. Several comments urged FDA to add pharmacists to the list of

recipients of information under this part.

As previously discussed, section 401 of FDAMA specifically lists

who can receive the unapproved use information under this provision. To

the extent that pharmacists are included in the definitions of ``health

care practitioner,'' ``pharmacy benefit manager,'' ``health insurance

issuer,'' or ``group health plan'' (see Sec. 99.3), they will be

included as recipients of this information.

3. Subpart C--Manufacturer's Submissions, Requests, and Applications

a. Manufacturer's submission to the agency (Sec. 99.201). Proposed

Sec. 99.201 described the contents of a manufacturer's submission to

FDA. This submission would be made 60 days before disseminating

information on an unapproved or new use and would include items such as

a copy of all of the information to be disseminated, 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, 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. The proposal also discussed what

types of information must be submitted when the certification provides

that the studies have been completed or that studies will be conducted

as well as the contents of the certification. Proposed Sec. 99.201 also

provided that the 60-day period begins to run when FDA receives a

complete submission.

49. One comment agreed that manufacturers should have to submit any

clinical trial information that they have relating to the safety and

effectiveness of the new use. However, another comment argued that the

requirement for any clinical trial information is far more exhaustive

than that required by the statute.

Section 551(b)(4)(B) of the act requires manufacturers to submit

``any clinical trial information 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.'' Proposed Sec. 99.201(a)(2) tracked this requirement

and described what it included. In the final rule, FDA is making clear

that, for effectiveness information, the requirements are limited to

information on clinical investigations of the new use; safety

information is broader and must include all relevant new data from

human experience.

50. One comment urged FDA to require manufacturers to report only

those adverse experiences that they have received directly because

companies do not have access to the details of cases submitted to other

manufacturers and thus, are unable to evaluate the reports. That same

comment stated that FDA should permit adverse experience reports to be

submitted in summary or tabular form rather than as individual case

reports. Several other comments requested the ability to reference

files that FDA already has about adverse experiences. Finally, one

comment noted that the search requirements for adverse reports should

be more clearly delineated.

Under the statute and these regulations, manufacturers would have

to submit only those adverse experience reports that they have. This

would include reports originally made to other manufacturers. If the

reports were originally submitted to other manufacturers and the

disseminating manufacturer does not know whether to attribute the

adverse experience to the new use, it should submit the information to

FDA. Manufacturers can submit adverse experience reports in summary or

tabular form if FDA already has the individual case reports. With

respect to search requirements for postmarket adverse event reports,

FDA does not think that it is necessary to be any more specific.

Manufacturers gather this information on a regular basis.

51. One comment said that the literature search requirements in

Sec. 99.201(a)(3) should be more clearly delineated. Several comments

stated that the requirement for the submission of a search strategy is

not required by statute and should be eliminated because it is

unnecessary and burdensome and could delay the process.

FDA believes that it is necessary to include the search strategy.

This is how FDA will be able to determine whether the bibliography

meets the statutory criteria. FDA has revised Sec. 99.201(a)(3),

however, to clarify the bibliography search strategy requirements.

52. FDA, on its own initiative, revised Sec. 99.201(a)(4)(i)(B) and

(a)(4)(ii)(B) to clarify that, for purposes of computing time periods

that begin on the date of initial dissemination, FDA will look to the

date on which dissemination can begin. This clarification was necessary

because FDA will not know when a manufacturer actually begins to

disseminate materials. The same revision was made to Secs. 99.203(b)

and 99.401(b).

53. Proposed Sec. 99.201(a)(4)(ii) required a manufacturer that has

planned studies that will be needed for a supplement to submit the

proposed protocols and schedule for conducting such studies. The

protocols must comply with FDA's IND or investigational device

exemption (IDE) regulations. One comment asked FDA to clarify whether a

manufacturer who has planned studies and wishes to disseminate

information must submit a complete IND or IDE in addition to the

information required in a submission under this rule. One comment

stated that if the protocols are to be treated as IND's, IDE's, or

amendments thereto, the manufacturer should be able to commence the

studies within 30 days unless the agency places the study on clinical

hold. The same comment said that if the agency does not place a

[[Page 64567]]

clinical hold on the protocol within 30 days, the agency should not be

able to determine that the protocols are inadequate on day 60 and if

the protocol is put on clinical hold within 30 days, it should not be

dispositive of the decision. The comment further stated that if the

agency decides that the protocols are adequate, it should be bound by

this decision and the final rule should reflect this. Finally, several

comments urged FDA to permit manufacturers to cross reference IND's and

IDE's rather than resubmitting such information.

FDA intends that the protocols for planned studies under this

provision be submitted in compliance with the IND or IDE regulations.

However, a manufacturer will not be required to submit these materials

twice. If a protocol has already been submitted to an IND or IDE, the

IND or IDE can be cross referenced in the dissemination submission.

Moreover, FDA does not intend to change, in any way, the IND or IDE

regulations, including the timeframes. If an IND or IDE is submitted

and a clinical hold is not issued within 30 days, the manufacturer can

commence the study or studies. However, the fact that FDA does not

issue a clinical hold within 30 days, does not prevent FDA from

determining, within 60 days, that a protocol is inadequate. FDA can

issue a clinical hold at any time after the 30-day period if the

requirements for issuing a clinical hold are met. If the protocol is

put on clinical hold within 30 days, it may not be dispositive of the

issue because the sponsor may remedy the reason for the clinical hold

within the 60-day period. However, if the reason for issuing the

clinical hold is not resolved, it will be dispositive of the issue.

Finally, FDA is declining to revise the rule to provide that if the

agency finds that the protocols are adequate, it will be bound by this

decision. FDAMA addressed the issue of agreements regarding the

parameters of the design and size of clinical trials. (See, e.g.,

section 505(b)(4)(C) or section 520(g)(7)(A) through (g)(7)(C) of the

act (21 U.S.C. 360j(g)(7)(A) through (g)(7)(C)).) FDA will abide by

these statutory directives.

54. Proposed Sec. 99.201(a)(4)(ii) required a manufacturer that has

planned studies that will be needed for the submission of a

supplemental application for the new use to certify that it will

exercise due diligence to complete such studies and submit a supplement

within 36 months of dissemination. FDA has revised this section to

reflect the possibility that FDA may determine, before the

certification is submitted, that the studies needed to submit a

supplemental application cannot be completed and submitted within 36

months. This change is further reflected in Sec. 99.203.

55. One comment requested that the 36-month timeframe for

submitting a supplement not override the time limits created under

separate regulatory or statutory authority. This comment was concerned

that if FDA finalizes its proposed 1997 regulation on pediatric

research and it includes compliance dates for completing the pediatric

studies that are less than 36 months, the 36-month period in this part

not override that shorter timeframe.

As FDA has stated elsewhere in this document, nothing in this

regulation is meant to change or supersede other regulatory

requirements.

56. One comment asked FDA to clarify the submission requirements

and FDA action requirements with respect to nonsignificant risk

devices.

Protocols submitted for studies for devices considered to be

nonsignificant will be reviewed by FDA only to ensure that the protocol

for the study is consistent with the new use information to be

disseminated. Manufacturers must present the protocol for the

nonsignificant risk device study to an institutional review board (IRB)

for approval before starting the study. (See 21 CFR 812.1(b)(1).)

However, all reporting requirements under this part will apply to

nonsignificant risk device studies.

57. One comment requested that the agency provide the sponsor an

opportunity to meet with FDA promptly to review what changes can be

made to the protocol to ensure that it meets requisite standards.

Sections 505(b)(4)(B) and 520(g)(7)(A) and (g)(7)(C) of the act

provide sponsors with an opportunity to meet regarding their proposed

protocols. Therefore, no changes to this rule are necessary.

58. One comment recommended that all statements submitted under

this part be certified by an officer from the manufacturer's executive

committee. Another comment recommended that the language in the

certification should include ``to the best of my knowledge'' to reduce

the risk that a certifying official could be penalized for an

inadvertent mistake not within his/her knowledge.

The final rule requires that the manufacturer's attorney, agent, or

other authorized official sign the submission. Although an officer from

the manufacturer's executive committee may be an authorized official,

FDA does not think it is necessary for the submission to be signed by

such an officer. FDA also does not agree that it would be appropriate

to include the words ``to the best of my knowledge'' in the

certification. The attorney, agent, or other authorized official who

signs the submission and certification on behalf of the manufacturer,

and ultimately the manufacturer itself, is responsible for what is

submitted to the agency under this part.

59. Proposed Sec. 99.201(c) described the component in each FDA

center that will receive a submission under this part. Several comments

noted that it would be appropriate for the review divisions in the

centers to also receive copies of the information submitted under this

part.

In the final rule, FDA is retaining the requirement that the

submissions go to a single office within each center. Those offices

will forward the information to the appropriate review divisions within

the agency. The regulation need not spell out all of FDA's internal

procedures for processing these submissions.

60. One comment stated that FDA needs to clarify the required

physical organization of the documents submitted under this part.

FDA does not think it is appropriate to include that kind of detail

in this regulation. Nevertheless, FDA expects that materials in a

submission will be organized and labeled in accordance with the

submission requirements described in this part. If FDA subsequently

determines that manufacturers need more guidance in this area, it will

issue a guidance document.

61. A number of comments objected to proposed Sec. 99.201(d), which

provided that the 60-day (post submission) period shall begin to run

when FDA receives a complete submission and that a submission shall be

considered complete if FDA determines that it is sufficiently complete

to permit a substantive review. These comments argued that FDA would

use this provision to extend the 60-day time period. The concern was

that FDA would, on day 59, advise a manufacturer that their submission

was not complete and therefore the 60-day time period had not begun.

The comments said that Congress meant for FDA to give a final answer

within the 60-day time period.

As further described below, FDA is committing to give manufacturers

a final decision within 60 days. FDA has revised Sec. 99.201(d) to

provide that the 60-day period shall begin when FDA receives a

manufacturer's submission, including, where applicable, a

[[Page 64568]]

certification statement or an application for an exemption.

62. A number of comments were made regarding the appropriateness of

public disclosure of information submitted under this part. Some

comments argued that both the fact of the submission and all

information in the submission is confidential and should not be

released. Other comments argued that all of the previous information

should be public because the public, including the patient community,

wants to be involved and has a right to know about a submission, the

data in such submission, FDA action on the submission, what studies are

being conducted, and the status of those studies. Several comments

argued that upon receiving a submission, FDA should publish in the

Federal Register, the citation for the article and the bibliography,

and solicit additional published information that might be appropriate

for dissemination. One comment argued that the public should have an

opportunity to comment prior to FDA's granting approval for

dissemination of information and that FDA should hold an advisory

committee meeting and let the public participate in its decision on

whether an exemption from the requirement to submit a supplement should

be granted.

FDA declines to amend the rule to require a notice and comment

process before permitting dissemination to proceed or before granting

an exemption. However, the Freedom of Information Act (FOIA) and FDA's

regulations will dictate what information submitted under this

provision can be disclosed. Because the agency was required to issue

this regulation within such a short period of time, it has been unable

to fully examine all issues of disclosability. However, the agency will

continue to examine these issues separately.

b. Request to extend the time for completing planned studies

(Sec. 99.203). Section 554(c)(3) of the act (21 U.S.C. 360aaa-3)

describes two types of extensions of time regarding planned studies.

Section 554(c)(3)(A) of the act provides that the 36 month period for

completing planned studies and submitting a supplemental application

may be extended by the Secretary of Health and Human Services (the

Secretary) if the Secretary determines that the studies needed to

submit such application cannot be completed and submitted within 36

months. This type of extension would be granted before such studies are

begun. Section 554(c)(3)(B) of the act provides that the period for

completing planned studies and submitting a supplemental application

may be extended by the Secretary if the manufacturer submits a written

request for the extension and the Secretary determines that the

manufacturer has acted with due diligence to conduct the studies in a

timely manner. The latter extension cannot exceed 24 months. Proposed

Sec. 99.203 set forth the procedures that a manufacturer must follow

to request an extension of time for submitting a supplemental

application and the content of a request for an extension. The

provision covered only the extension in section 554(c)(3)(B) of the

act.

63. The comments to this provision indicated that there was some

confusion regarding the two different statutory procedures. Several

comments asked FDA to more clearly set out the two procedures

contemplated by the statute.

Although the statute specifically refers to a manufacturer request

in connection only with the procedure described in section 554(c)(3)(B)

of the act and FDA agrees that the agency can, under section

554(c)(3)(A), on its own initiative determine before the studies have

begun that more than 36 months is needed, FDA believes that

manufacturers will come to FDA and ask FDA to make a determination

under section 554(c)(3)(A) of the act. Therefore, FDA has revised

Sec. 99.203 to establish procedures for the two different types of

extensions. The first extension, set forth in Sec. 99.203(a), relates

to a request for an extension by the manufacturer at or before the time

it submits its dissemination package to FDA because the 36-month period

is not enough time to complete a study or studies of the new use and

submit a supplemental application. Revised Sec. 99.203(b) sets forth

the procedures that a manufacturer must follow to request an extension

of time for submitting a supplemental application after a study has

begun and the content of a request for an extension.

c. Application for exemption from the requirement to file a

supplemental application (Sec. 99.205). Proposed Sec. 99.205 set forth

what a manufacturer must submit when seeking an exemption from the

requirement to file a supplemental application for a new use for

purposes of disseminating information on that new use. It required the

manufacturer to include an explanation as to why an exemption is sought

and to include materials demonstrating that it would be economically

prohibitive or unethical to conduct the studies needed to submit a

supplemental application for the new use.

64. A number of comments supported the standards that FDA proposed

to determine whether it would be economically prohibitive or unethical

to conduct the studies needed to submit a supplemental application.

Some noted that FDA's standards are consistent with congressional

intent that exemptions be limited in scope and infrequent or rare. One

comment argued that pediatric exemptions should be extremely rare. One

comment stated that exemptions should never be granted.

FDA agrees that Congress intended that exemptions from the

requirement to file a supplemental application for a new use be granted

in limited circumstances (see H. Conf. Rept. No. 399, 105th Cong., 1st

sess. at 100 (1997); 143 Congressional Record S9,837 (daily ed. Sept.

24, 1997) (Statement of the Managers)). There is nothing in the statute

or legislative history that gives FDA authority to apply a different

standard in the case of pediatric exemptions. Moreover, the act

provides for exemptions, so FDA does not agree that such exemptions

should never be granted. In light of the comments received to the

standards set forth in its proposal (discussed in more detail below),

FDA is adopting a different standard for the economically prohibitive

exemption. Although, FDA is not changing the standard for the unethical

exemption, it has, as discussed in the following paragraphs, clarified

how it will apply that exemption.

Economically Prohibitive Exemption

Under proposed Sec. 99.205(b)(1), a manufacturer seeking an

exemption from the requirement to file a supplemental application on

the basis that it would be economically prohibitive to conduct the

needed studies would have to: (1) 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; and (2) 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) set forth the type of evidence that the

manufacturer would have to include to meet the requirements for an

economically prohibitive exemption. These included:

(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

[[Page 64569]]

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.

65. As set forth previously, some of the comments agreed with FDA's

construction of ``economically prohibitive'' These comments argued that

such exemptions should be granted rarely and that the criteria for such

an exemption should be rigorous. One comment argued that the cost for

the studies should substantially exceed revenues to qualify for the

exemption. Several comments opposed such an equation.

FDA agrees that exemptions should be granted only in limited

circumstances. As set forth below, however, FDA was convinced by the

comments that the standard set forth in its proposal was inappropriate

and has revised the standard.

66. A number of comments objected to how the agency proposed to

determine what is economically prohibitive. First, they objected to the

agency's use of the term ``rare'' in describing when such exemptions

would be granted. One comment opined that Congress meant for the

exemption to arise in a ``fair number of circumstances.'' Second, they

objected to the absence of the criteria listed in the statute and

report language from the standard set forth in the codified regulation.

Third, they claimed that the proposed rule's standard for determining

what is economically prohibitive is too high.

One comment argued that the exemption should be granted if it does

not make economic sense to pursue a supplement. Others argued that it

should be based on the revenue from the new use, not all uses of the

product. Some argued that the standard should be whether the cost of

the studies would exceed the revenues from the new use; others argued

that it should be whether the cost of the studies exceeds the new use

revenues that resulted from approval of the supplement (i.e., the

increase in revenues from the new use that result from submission of

the supplement). Several comments argued that FDA should automatically

grant an exemption if the new use is for a rare disease or condition

because for such use there is no reasonable expectation that the cost

of developing and making available a drug for such disease will be

recovered from sales in the United States of such drug. Several

comments argued that the economically prohibitive exemption should

automatically be granted if: (1) There is no market exclusivity for the

product (from patent, orphan drug status, or Waxman-Hatch); or (2) the

patient population likely to be served by the new indication will not

exceed an established number (e.g., 1,000). One comment opined that

interpreting ``prohibitive'' to mean anything other than the point at

which an economically rational company will not pursue research ignores

the needs of patients with rare disorders.

FDA agrees that Congress did not use the term ``rare'' in the

legislative history. Nevertheless, Congress did state that exemptions

to the requirement to submit a supplement would be appropriate only in

``limited circumstances,'' which in FDA's view implies fewer than in a

``fair number of circumstances.'' Moreover, Congress strongly

emphasized the critical importance of getting information about new

uses onto the label. Although FDA did not include the criteria listed

in the statute and the legislative history in the standard for

economically prohibitive, they were included as types of evidence that

would be required to support the exemption.

FDA's proposed criterion did not focus solely on sales from the new

use because the agency believed that there might be many circumstances

where the cost of the study requirements would exceed the sales from

just the new use. The agency explained that in some of these

situations, even if it were not economically ``wise'' to conduct the

studies, the cost would not rise to the level of being ``prohibitive.''

This view was judged consistent with the legislative history, which

foresaw the granting of economic exemptions only in limited

circumstances. The agency noted, however, that defining a practical

``economically prohibitive'' exemption was particularly troublesome,

because it would be so difficult for the agency to assess cost and

income projections. In view of these difficulties, FDA acknowledged

that it was not certain that the proposed approach was optimal and

sought comment on other possible ways to define economically

prohibitive.

Unfortunately, the agency has received widely conflicting public

comment on this issue and remains uncertain about the elements of a

standard that would be most appropriate and effective in achieving the

statutory goals. An approach that would grant automatic exemptions if:

(1) The new use were for a rare disease or condition; (2) there was no

market exclusivity for the product (from patent, orphan drug status, or

Waxman-Hatch); or (3) the patient population likely to be served by the

new indication would not exceed an established number (e.g., 1,000)

would be inappropriate. Neither the statute nor the legislative history

provide for automatic exemptions in these circumstances. Rather, they

direct FDA to take both market exclusivity and population size into

account. The legislative history made clear that the size of the

patient population would not necessarily justify an exemption. In fact,

the legislative history stated that an exemption based on the size of

the patient population was intended to be the exception rather than the

rule in cases of populations suffering from orphan or rare diseases or

conditions. The legislative history made clear that FDA should consider

the importance of getting products for these diseases or conditions

approved. It noted that for many years, Congress has sought to

encourage research into orphan diseases and support the approval of

innovative drugs for their treatment. Congress, therefore, has directed

FDA to recognize the vital importance of encouraging applications for

new products intended to treat rare diseases and to examine very

carefully whether an exemption from filing a supplemental application

might hinder such research (see H. Conf. Rept. No. 399, 105th Cong.,

1st sess. at 100 (1997); H. Rept. No. 310, 105th Cong. 1st. sess. at 62

(1997)).

Because the agency remains uncertain about the elements of a

standard that would be most appropriate and effective, FDA plans to

continue its search for a policy that would satisfy the congressional

expectation of approving exemptions in only limited

[[Page 64570]]

circumstances, without foreclosing the dissemination of useful

information by firms that could not otherwise conduct the needed

studies. In the meantime, FDA will implement the statute by basing its

evaluation of each exemption on a case-by-case determination of whether

the cost of the study for the new use reasonably exceeds the total

expected revenue from the new use minus the cost of goods sold and

marketing and administrative expenses attributable to the new use of

the product. This standard may not always meet a strict profitability

criterion because it considers all new use revenues, rather than just

the new use revenues that would result from approval of the supplement.

Nevertheless, it is consistent with most of the comments submitted by

the affected industry on this issue, it is consistent with the

statutory directive, and it attempts to strike a fair balance between

assuring the widest possible information dissemination while granting

economic exemptions only in ``limited circumstances.''

The final rule sets forth the statutory standard and the

information that FDA would need to make this case-by-case

determination. This will include information about: (1) The cost of the

study for the new use; (2) the expected patient population for the new

use; (3) the expected total revenue for the new use minus the cost of

goods sold and marketing and administrative expenses attributable to

the new use of the product; (4) the amount of exclusivity for the drug

or new use; and (5) other information that the manufacturer believes

demonstrates that conducting the studies on the new use would be

economically prohibitive.

As this revised criterion may significantly expand the number of

exemption applications beyond that anticipated by the Congress, the

agency is determined to review its experience with these requests as

they are submitted and, if necessary, to contract with outside economic

experts to help develop an approach that most appropriate and effective

and workable for the agency.

67. A number of comments objected to the requirement to submit

detailed financial data. These comments argued that manufacturers

should be not required to submit highly sensitive and proprietary

information. Others felt that FDA is not qualified to review and

evaluate this data.

Congress directed FDA to grant an economic exemption only upon

making a determination that conducting the studies and submitting a

supplement would be economically prohibitive. FDA cannot make this

determination without examining the relevant company data. Therefore,

the final rule retains these requirements.

68. Several comments regarding FDA's approach to economic

exemptions recommended that FDA require a manufacturer to submit a

certified public accountant's (CPA's) opinion on the economic

feasibility of filing a supplemental NDA. FDA could contest the claim

by providing a CPA's statement to the contrary.

FDA declines to adopt this approach because it removes the agency

from the statutorily-specified role of determining whether it would be

economically prohibitive to conduct the studies.

69. One comment recommended that manufacturers be given the

flexibility to present whatever information they determine is relevant

to the ``economically prohibitive'' factor, that the manufacturer be

able to use its own assumptions, and that each situation be evaluated

on a case-by-case basis.

As set forth previously, FDA is adopting a case-by-case

determination and has specified the information that is essential for

this determination. Nevertheless, manufacturers are free to provide

whatever additional information they think is relevant to the

determination. This could include information that would explain why a

study is so expensive to conduct. For example, one factor might be the

difficulty of enrolling patients in a clinical investigation if the new

use has become the standard of care.

70. Proposed Sec. 99.205(b)(1)(ii)(A) stated that the estimated

economic benefit for a drug or device shall assume that the total

potential market is equal to the prevalence of the disease(s) or

condition(s) that such product will be used to treat. Several comments

argued that this assumption should be deleted because the potential

market for the drug or device may be less than the prevalence of the

disease in question if other therapies are likely to be used in some

portion of the total patient population.

FDA agrees that this assumption should be deleted and has done so

in the final rule.

71. One comment argued that the manufacturer should not be required

to provide a ``justification'' of the price at which the drug will be

sold. According to this manufacturer, only a projection is relevant.

FDA has to be able to determine whether the manufacturer's proposed

price is reasonable. It may be that ``justification'' for the price is

not appropriate. Therefore, in Sec. 99.205(b)(ii)(C) of the final rule,

FDA will seek an explanation of the price at which the drug or device

will be sold.

72. One comment opined that permitting an exemption because of cost

is an ethical decision because it is placing a monetary value on

people's lives and safety.

FDA does not agree that an economically prohibitive exemption is

placing a monetary value on people's lives and safety. The standard in

FDA's regulation is intended to best effectuate the goals of the

statute.

73. Proposed Sec. 99.205(b)(1)(ii)(C) required a manufacturer to

provide an attestation by a responsible individual of the manufacturer

verifying that the estimates included with a submission are accurate

and were prepared in accordance with generally accepted accounting

procedures. In addition, the data underlying and supporting the

estimates would have to be made available to FDA upon request. In the

preamble to the proposed rule, FDA noted that it had considered

requiring a report of an independent CPA with respect to the estimates

and FDA solicited 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.

Some comments supported the submission of the CPA report discussed

previously, others felt that such a report should not be required.

Still other comments stated that the CPA report should be submitted in

lieu of the underlying data or that the CPA should make the

determination of economic feasibility instead of FDA.

As stated previously, FDA refuses to adopt a procedure by which it

surrenders decision making to a CPA. However, FDA is not convinced that

it is necessary to require a report of an independent CPA with respect

to the estimates. Under Sec. 99.205(b)(1)(iii), therefore, FDA will

accept either an attestation by a responsible individual of the

manufacturer or by a CPA verifying that the estimates included with a

submission are accurate and were prepared in accordance with generally

accepted accounting procedures.

Unethical Exemption

Proposed Sec. 99.205(b)(2) required a manufacturer seeking an

exemption on the basis that it would be unethical to conduct the

studies needed to submit a supplement, to: (1) 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; and (2) show that, notwithstanding the

insufficiency of existing data to support the submission of a

supplemental application for the

[[Page 64571]]

new use, the data are persuasive to the extent that withholding the

drug or device in the course of conducting a controlled study would

pose an unreasonable risk of harm to human subjects.

The proposed codified language provided that an unreasonable risk

of harm would ordinarily arise only in situations in which the new 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 new use can add weight to an argument that conduct of a

needed study or studies would be unethical.

To support its argument that the conduct of a needed study or

studies would be unethical, the proposal provided that a manufacturer

would need to 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).

The proposal further provided that 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. The

preamble to the proposal set forth the following possible

considerations: (1) Whether the new use meets the requirements of

section 1861(t)(2)(B) of the Social Security Act, which defines

``medically accepted indications'' with respect to the use of a drug;

(2) Whether a medical specialty society that is represented in or

recognized by the Council of Medical Specialty Societies (or is a

subspecialty of such society) or is recognized by the American

Osteopathic Association has found that the new use is consistent with

sound medical practice; (3) Whether the new use is described in a

recommendation or medical practice guideline of a Federal health

agency, including the National Institutes of Health, the Agency for

Health Care Policy and Research, and the Centers for Disease Control

and Prevention of the Department of Health and Human Services; and (4)

Whether the new use is described in a current compendia such as the

United States Pharmacopoeia Drug Information for the Health Care

Professional, the American Medical Association Drug Evaluations, or the

American Hospital Formulary Service (see 63 FR 31143 at 31150).

74. A number of comments objected to FDA's proposed criteria for

the unethical exemption--particularly the emphasis on the requirement

that it ordinarily would arise only in situations in which the new use

appears to affect mortality or irreversible morbidity. Some comments

believed that the criteria set forth in the legislative history (that

are discussed in the preamble) should be in the codified language.

Finally, a number of comments argued that if the new use is the

standard of medical care, FDA must automatically grant an exemption.

The act clearly does not require FDA to automatically grant an

exemption if a new use is the standard of medical care. The act says

that FDA must consider (among other considerations that the Secretary

finds appropriate) whether the new use is the standard of medical care,

and that is what FDA proposed to do. Moreover, an automatic exemption

would not be reasonable from a scientific standpoint because there are

many instances in which the results of a controlled clinical trial have

demonstrated that a drug or device is unsafe or ineffective for a new

use for which it is considered to be the standard of care.

The standard set forth in Sec. 99.205 is consistent with how FDA

determines what studies are unethical in other contexts (i.e., when a

manufacturer argues that it would be unethical to conduct a study).

Moreover, the standard is consistent with the legislative history,

which provides that such exemptions should be granted in limited

circumstances. Therefore, FDA is retaining the proposed basic standard

for the unethical exemption in the final rule (i.e., the data are

persuasive to the extent that withholding the drug or device in the

course of conducting a controlled study would pose an unreasonable risk

of harm to human subjects). FDA continues to believe an effect on

irreversible morbidity or mortality is what ordinarily would be

required to show an unreasonable risk of harm. Nevertheless, there

could be other circumstances in which the agency would find that it

would be unethical to do the study, i.e., because there would be an

unreasonable risk of harm even though the new use does not affect

irreversible morbidity or mortality. In making a determination that it

would be unethical to conduct a study, the agency must consider whether

informed consent and proper IRB review would address the concerns

raised by questions about whether it is appropriate to conduct a study.

FDA rejects the suggestion that the factors set forth in the

legislative history that FDA may consider in deciding whether to grant

an exemption be included as requirements in the codified language. FDA

has included the statutory factors in the codified language. The

legislative history provides that FDA may consider those factors among

other factors, and thus, consideration of these factors is neither

mandatory nor is it exclusive.

75. One comment argued that the standard needs to take into account

the difficulty of enrolling patients in a study in which some subjects

will receive a placebo when a patient can go to a doctor and receive a

prescription for the drug. The comment further noted that physicians

refuse to participate in placebo controlled studies of therapies they

already believe to be effective.

FDA agrees that it can be difficult to enroll patients in placebo

controlled trials and that this could be a relevant consideration.

Moreover, not all controlled studies are placebo controlled. Companies

may be able to conduct studies of a different design, depending on the

situation. For example, a company may be able to compare the new use to

another therapy that is known to work or may be able to rely on

historical controls. In some cases, the new use could be added to

existing therapy and compared with placebo added to existing therapy.

If these alternate study designs mean that the study or studies will

take longer, FDA can consider whether to extend the time to conduct the

studies and submit a supplemental application.

76. One comment suggested that FDA should grant an exemption if the

new use is listed in the USP DI or Hospital Formulary. Another comment

suggested that an unethical exemption should be granted if the

unapproved use: (1) Is accepted in a monograph of the USP; (2) is

approved by another ``first world'' country; or (3) is approved by a

state FDA. Finally, one comment suggested that FDA should automatically

grant an unethical exemption if the new use: (1) Represents the

standard of care, as represented by inclusion in specified compendia or

practice guidelines, or (2) involves a combination of products or more

than one sponsor and should grant other exemptions on a case-by-case

basis.

FDA does not agree that any of these individual factors is enough

to show that studying a new use would be unethical. Moreover, there is

nothing in the statute or legislative history to

[[Page 64572]]

suggest that any of the single factors should be sufficient to meet the

unethical exemption. FDA will, however, consider these factors in

making its determination of when it would be unethical to conduct a

study.

77. One comment noted that, although it supported the list of

sources to be used to provide evidence that a new use represents

standard medical therapy, after 1998, the American Medical

Association's (AMA's) Drug Evaluation and the USP DI may no longer be

available.

If the AMA's Drug Evaluation and/or the USP DI become unavailable,

FDA will stop using them as evidence that a new use is the standard of

care.

78. One comment noted that there are diverse opinions in the

medical community about what standard of care means. Another noted that

``consistent with sound medical practice'' is not the same as

``standard of care'' and that an unapproved treatment may be considered

to be sound medical practice but should still be studied. Several

comments noted that FDA should take care in how it interprets

``standard medical treatment or therapy.'' These comments noted that

manufacturers should not be allowed to take advantage of a situation of

their own creation. In other words, standard medical treatment should

not be interpreted as meaning treatment that is regularly used because

physicians have no other choice because to do so would eliminate the

requirements for completing any pediatric research.

FDA agrees that just because a certain treatment is consistent with

sound medical practice does not mean that it is the standard of care.

FDA has stated that 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 a new use is

consistent with sound medical practice will be considered as evidence

that it is the standard of care. Moreover, just because an unapproved

use of a drug or device is the standard of care, does not mean that it

is automatically exempt from the requirement to conduct the study

needed to submit a supplemental application.

79. Several comments noted that it is almost inconceivable that the

study of a new use for children could be viewed as unethical.

FDA will make this determination on a case-by-case basis.

80. Several comments argued for making the exemption process

public. One comment said that all information should be made public as

soon as a manufacturer requests an exemption and that if an exemption

is granted all information should remain in the public domain so that

interested parties will be able to play a role in keeping FDA informed

as to when it should be revoked. Another suggested that prior to

granting any exemption, FDA should hold a meeting of the appropriate

advisory committee so that the public has the opportunity to review and

comment upon the request.

As set forth previously, FDA declines to adopt a notice and comment

process for considering exemption requests. The information will be

made available to the public consistent with FOIA and FDA's

regulations. FDA has the option of consulting advisory committees about

exemption requests, when appropriate.

4. Subpart D--FDA Action on Submissions, Requests, and Applications

a. Agency action on a submission (Sec. 99.301). Proposed

Sec. 99.301 described the range of FDA's actions when it receives a

submission. For example, under the proposal, FDA could determine that a

manufacturer's submission does not comply with the regulatory

requirements, request additional information or documents to assist the

agency in determining whether the information to be disseminated

complies with applicable requirements, or determine that the

information fails to provide data, analyses, or other written matter

that is objective and balanced. The proposal also described FDA actions

in response to a manufacturer's submission when the manufacturer is

committing to submit a supplement on completed studies or is agreeing

to conduct the necessary studies and then submit a supplement.

81. Proposed Sec. 99.301(a) provided that, within 60 days, FDA may

determine that a submission does not comply with the requirements of

the proposal or that it needs more information. A number of comments

objected to the proposal because they believed that FDA would use it to

extend the 60-day time period. The concern was that FDA would, on day

59, advise a manufacturer that their submission was not complete and

therefore the 60-day time period had not begun. The comments said that

Congress meant for FDA to give a final answer within the 60-day time

period. Some comments argued that FDA should let manufacturers know if

their submission is complete within a short period of time, e.g.,

within 15 days of receiving the submission.

In response to these comments, FDA has eliminated proposed

Sec. 99.301(a)(2) so that manufacturers will have a final decision

within 60 days. Within the 60-day period, FDA will either notify a

manufacturer that it has not met the requirements set forth in the law

or allow the dissemination to go forward. FDA is not adopting the

comment's suggestion that it advise sponsors as to whether their

submissions are complete within a certain number of days (e.g., 15).

The 60-day statutory timeframe is too short for the agency to make a

commitment to provide such advice.

82. One comment stated that FDA should be required to notify the

manufacturer promptly if it approves a submission in less than 60 days.

There is no requirement in the statute that FDA notify a

manufacturer unless it intends to stop the dissemination of information

under this part. Therefore, FDA is not revising the regulation as

suggested. The agency will, however, make an effort to notify

manufacturers promptly if it approves a submission in less than 60

days.

83. One comment requested that FDA change the ``may'' in proposed

Sec. 99.301(a) to ``shall'' and to clarify that a sponsor may begin to

disseminate material if it has not heard from FDA within 60 days.

Another comment suggested that FDA clarify Sec. 99.301 to indicate that

FDA will review an IND or IDE and will notify the manufacturer of the

IND or IDE approval and that, until such notification, the manufacturer

cannot disseminate the information.

FDA declines to change the ``may'' to ``shall'' in Sec. 99.301(a).

FDA is not required to do any of the things listed in Sec. 99.301(a),

and so use of the word ``shall'' would be inappropriate. Moreover, it

is not true that a manufacturer may, in every circumstance, begin

dissemination if it has not heard from FDA within 60 days. Under

section 554(c) of the act, a manufacturer that has certified that it

will conduct the studies needed to submit a supplement and that has

submitted a proposed protocol and schedule for conducting such studies

cannot disseminate unless the Secretary has determined that the

proposed protocol is adequate and that the schedule for completing the

studies is reasonable. Nevertheless, FDA has revised Sec. 99.301(b) to

state clearly that the agency will make a positive or negative

determination on the manufacturer's protocols (and, where appropriate,

its schedules) within 60 days after receiving a submission under part

99.

84. Proposed Sec. 99.301(a)(3) (now redesignated as

Sec. 99.301(a)(2)) provided

[[Page 64573]]

that FDA shall provide a manufacturer notice and an opportunity for a

meeting regarding the agency's determination that the information

submitted is not objective and balanced, and requires additional

information. One comment suggested that there should be a specific

timeline for when such a meeting would occur.

The statute does not require that FDA set a timeline for such a

meeting. Nevertheless, FDA will provide for such an opportunity as soon

as is mutually convenient for FDA and the manufacturer. In any event,

the meeting will take place within the 60-day period. Furthermore,

should FDA determine that additional articles are necessary to provide

objectivity and balance, the agency will apply the same standards for

scientific soundness to those additional articles.

85. Proposed Sec. 99.301(a)(4) (now redesignated as

Sec. 99.301(a)(3)) provided that within 60 days of receiving a

manufacturer's submission, FDA may require the manufacturer to maintain

records that will identify individual recipients of the information

that is to be disseminated.

Some comments supported FDA's not requiring individualized

recordkeeping in all situations. Others, however, thought it should be

invoked in all situations and still others thought that ever requiring

it was too burdensome. One comment argued that the proposed standard

for individual recordkeeping was too vague and suggested that FDA make

such a request ``only in rare circumstances, when warranted because of

special safety considerations associated with a new use.'' One comment

argued that FDA should provide notice and an opportunity to meet in the

event that it requires a company to maintain records identifying

individual recipients.

Section 553(b) of the act (21 U.S.C. 360aaa-2(b)) expressly

requires a manufacturer to keep records that the manufacturer may use

if it is required to take corrective action. Section 553(b) of the act

also states that, ``Such records, at the Secretary's discretion, may

identify the recipient of information provided * * * or the categories

of such recipients.'' FDA does not believe that it would be appropriate

to require individual recordkeeping in all circumstances. Similarly,

FDA does not believe that it would be appropriate to require

recordkeeping of categories of recipients in all circumstances. FDA

agrees, however, that it should better define the standard for

individual recordkeeping and will adopt, with slight modifications, the

standard suggested by the comments. Section 99.301(a)(3) provides for

individual recordkeeping when warranted because of special safety

considerations associated with the new use. FDA did not adopt the

``only in rare circumstances'' language because although it expects to

require this in limited circumstances, it does not yet have experience

implementing this provision and nothing in the statute or legislative

history indicates that Congress intended it to be rare.

86. One comment was concerned that because the agency has to review

all submissions within 60 days, sometimes the timeframe will expire and

allow information dissemination or exemptions to happen without agency

review and thus patients could be harmed before FDA has time to

terminate a deemed approval. This comment encouraged the agency to

provide information to health care providers on the process by which

the review will occur.

FDA recognizes that the act would allow information to be

disseminated without agency review. The agency is committed to

reviewing all of this information so that inappropriate information

does not get disseminated.

87. Proposed Sec. 99.301(b) required FDA to notify the manufacturer

if the agency determines that its protocol and schedule for conducting

studies are adequate and reasonable. Until FDA provides such

notification, dissemination cannot begin. One comment noted that it was

not the intent of Congress that the 60-day timeframe be delayed as a

result of ongoing IND/IDE negotiations.

The statute provides that a manufacturer who submits a protocol and

proposed schedule for conducting the studies needed to submit a

supplement, cannot begin to disseminate until FDA determines that they

are adequate. (See section 554(c)(1) of the act.) However, as stated

earlier, FDA has revised Sec. 99.301(b) to state that the agency will

make a positive or negative determination on the manufacturer's

protocols (and, where appropriate, its schedules) within 60 days after

receiving a submission under 21 CFR part 99.

88. Proposed Sec. 99.301(b) described FDA action on a

manufacturer's proposed protocols and schedules for completing studies.

One comment said that the rule should clarify which functional groups

within FDA will be responsible for the review of protocols and studies

and provide for a timeline for such review.

FDA has stated previously that clinical information, including

protocols, that is submitted under this part will be reviewed by the

appropriate review divisions. It is not necessary for the rule to

detail FDA's internal procedure. FDA will review such protocols and

schedules within 60 days. Section 99.301(b) includes that timeframe.

89. Under proposed Sec. 99.301(b)(2), if a manufacturer has

completed studies that it believes would be an adequate basis for the

submission of a supplemental application for the new use and has

certified that it will submit such supplement within 6 months, FDA

would 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 the

study reports 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. One comment argued that FDA should not

be allowed to take a ``sneak peek'' at preliminary clinical trial data

prior to its submission in a supplemental application.

Section 99.201(a)(4)(i) requires manufacturers that have completed

studies that they believe would be an adequate basis for the submission

of a supplemental application for the new use and have certified that

it will submit such supplement within 6 months to submit the protocols

for those studies. FDA, will, as in the case of the 36-month

certification, review those protocols to determine whether they are

adequate. The final rule has been revised to indicate that FDA will

review the protocols submitted and not the study reports. However, this

does not in any way affect the agency's ability to determine, based on

information it has, including information about clinical trials, that

the information a manufacturer seeks to disseminate is false or

misleading or would pose a significant risk to public health.

b. Extension of time for completing planned studies (Sec. 99.303).

Proposed Sec. 99.303 described FDA's ability to: (1) On its own

initiative, allow a manufacturer more than 36 months to submit a

supplemental application, based on the review of the protocols(s) and

planned schedule; or (2) grant a manufacturer's request to extend the

36-month period (for up to 24 months). Proposed Sec. 99.303(a)

described FDA's ability to determine, on its own initiative and before

any studies have begun, that a manufacturer needs more than 36 months

to complete the studies needed for submission of a

[[Page 64574]]

supplemental application and to submit such application. Proposed

Sec. 99.303(b) and (c) described FDA's ability, after such studies have

begun and the sponsor has submitted a request, to grant an extension of

the time to submit a supplement by up to 24 months. FDA would 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.

90. The comments to this provision indicated that there was some

confusion regarding these two different procedures. Several comments

asked FDA to more clearly set out the two procedures contemplated by

the statute. Several comments asked FDA to make clear that the 24-month

limitation applies only to an extension request made after a study has

begun. One comment suggested that there could be more than one 24-month

extension.

FDA has revised this section to make clear that there are two

different types of extensions. The first extension (in Sec. 99.303 (a))

relates to FDA's ability to determine, with or without a request from

the manufacturer, that 36 months is not enough time to complete a study

of the new use and submit a supplemental application. This would occur

before any studies are begun, either before the submission is made or

at the time of the submission. There is no limit on how much time FDA

may give a manufacturer under this subsection.

The second type of extension (described in revised Sec. 99.303(b))

relates to FDA's ability to grant a manufacturer's request for an

extension after a study has begun because, even though it appeared that

36 months would be sufficient and the manufacturer has acted with due

diligence, the manufacturer has run into problems and needs more time.

This type of extension is limited to 24 months and the statute does not

provide that FDA can give more than one 24-month extension.

c. Exemption from the requirement to file a supplemental

application (Sec. 99.305). Proposed Sec. 99.305 described FDA action on

a request for an exemption from the requirement to submit a

supplemental application and the criteria to be considered in deciding

whether to grant a request for an exemption, either because it would be

economically prohibitive to conduct the studies needed for a

supplemental application or it would be unethical to conduct the

clinical studies needed to approve the new use.

91. Proposed Sec. 99.305(a)(1) states 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 could,

at any time, terminate such deemed approval if it determines that the

requirements for granting an exemption have not been met. One comment

noted that FDA can terminate such deemed approval only if a

manufacturer is disseminating information under section 551 of the act.

Section 554(d)(3)(B) of the act provides that if a manufacturer

disseminates information under section 551 of the act under a deemed

approval of a request for an exemption, FDA may, at any time, terminate

a deemed approval and order the manufacturer to cease disseminating the

information under section 553(b)(3) of the act. FDA does not believe

that it has to wait for a manufacturer to actually disseminate

information in order to terminate the deemed approval.

92. A number of comments suggested that FDA provide a manufacturer

an opportunity to meet concerning: (1) FDA's determination that the

manufacturer cannot disseminate information under this part; (2) FDA's

determination that the manufacturer should maintain records of

individual recipients; (3) FDA's determination of a company's request

for an extension of time to complete the necessary studies and submit a

supplement; (4) FDA's denial of an exemption.

Section 401 of FDAMA directed FDA to provide manufacturers an

opportunity to meet regarding a determination that the information to

be disseminated is not balanced and objective and regarding the

cessation of information dissemination in certain circumstances. The

statute does not direct FDA to meet in the circumstances described

previously. Nevertheless, as always, FDA will honor requests for

meetings to the fullest extent feasible. Given the short timeframes set

forth in section 401 of FDAMA, FDA's resource constraints, and the fact

that FDA does not know how many submissions it will receive under this

part, FDA is not imposing on itself any additional requirements for

meetings by making those meetings a part of the regulation.

5. Subpart E--Corrective Actions and Cessation of Dissemination

Subpart E, as proposed, contained provisions describing the

corrective actions that FDA could take or order the manufacturer to

take, termination of approvals of applications for exemption, and the

applicability of labeling, adulteration, and misbranding authority in

the event that dissemination failed to comply with section 551 of the

act.

93. One comment claimed that proposed subpart E was ``hollow and

meaningless'' because Congress did not give FDA the authority to seek

civil money penalties against noncomplying manufacturers.

FDA disagrees with the comment's characterization of subpart E and

notes that the agency does, indeed, have the authority to seek civil

money penalties from any person who violates most requirements of the

act pertaining to devices (see section 303(f) of the act (21 U.S.C.

333(f)). Additionally, arguments regarding other civil money penalty

authority for violations of these regulations are beyond the scope of

this rulemaking.

a. Corrective actions and cessation of dissemination of information

(Sec. 99.401). Proposed Sec. 99.401 authorized FDA to take corrective

actions and to order a manufacturer to cease dissemination of

information and take corrective action. In general, the proposal would

provide for corrective action or an order to cease dissemination of

information based on post dissemination data, information disseminated

by the manufacturer, or the manufacturer's supplemental application for

the new use (or its failure to submit or to complete the studies

necessary for the supplemental application). Proposed Sec. 99.401 also

described the procedures to be observed, such as consultation with the

manufacturer, notice regarding FDA's intent to issue an order to cease

dissemination, and opportunities for a meeting, and described when a

manufacturer shall cease disseminating information in the event of its

noncompliance with the regulations.

94. Several comments would revise proposed Sec. 99.401 to give

manufacturers a mechanism for appealing the agency's decision to

require corrective action. The comments would either amend the rule to

refer to the dispute resolution provision at section 562 of the act (21

U.S.C. 360bbb-1), the regulations for internal agency review of

decisions (Sec. 10.75 (21 CFR 10.75)), or other appeals processes.

FDA declines to revise the rule to refer to statutory or regulatory

appeals mechanisms. Such appeals mechanisms are available regardless of

whether Sec. 99.401 refers to them or not, and it would be both

impractical and unnecessary to list all possible statutory and

regulatory appeals mechanisms in Sec. 99.401. Moreover, such a list

would either become obsolete or useless if any

[[Page 64575]]

statutory or regulatory citations for the appeals mechanisms changed or

would require FDA to monitor constantly all cross-references without

any appreciable benefit.

95. Several comments would amend Sec. 99.401 to permit

manufacturers to continue disseminating information pending the outcome

of any appeal except where a significant safety issue or public health

concern exists. In contrast, one comment said that a manufacturer

should cease disseminating information while it and FDA are resolving

any outstanding issues. FDA declines to revise the rule to allow

manufacturers to continue disseminating information pending the outcome

of any appeal. In general, section 555 of the act (21 U.S.C. 360aaa-4)

authorizes the agency to order a manufacturer to cease dissemination of

information on the unapproved/new use; it does not require the agency

to stay or defer the effectiveness of such an order pending any appeal

by the manufacturer. This outcome is consistent with the appeals or

dispute resolution provisions cited by the comments (section 562 of the

act and Sec. 10.75), as well as other regulatory mechanisms for

requesting reconsideration (see, e.g., 21 CFR 10.33 (administrative

reconsideration of action) and 21 CFR 10.35 (administrative stay of

action)); none of these mechanisms results in an automatic stay of

agency action while the agency reconsiders its decision or considers an

appeal.

96. One comment suggested that FDA define ``appropriate corrective

action.'' The comment would amend the rule to give examples of

corrective action and to describe the circumstances under which

specific corrective actions might apply.

By using the term ``appropriate corrective action,'' FDA meant to

give itself the flexibility to fashion the corrective action to remedy

the underlying problem or deficiency. As stated in the preamble to the

proposed rule, these actions include, but are not limited to, ordering

the manufacturer to send ``Dear Doctor'' letters, to publish corrective

advertising, to include warning labels on the product, or to include

warnings or otherwise revise the product labeling (63 FR 31143 at

31151). FDA declines to define ``appropriate corrective action'' or to

give examples and to specify when it might order a manufacturer to take

a particular corrective action. The agency's regulatory experience

indicates that regulations containing lists or examples often are

misconstrued as providing an exclusive list (thereby resulting in

unnecessary disputes as to whether a particular corrective action is

within the regulation or whether the manufacturer's action is even

capable of being addressed by the agency) and that regulations that

describe specific responses to specific situations can deprive the

agency of the flexibility to tailor a corrective action to fit a

particular situation. Nevertheless, FDA would note that it expects that

``Dear Doctor'' letters and/or corrective advertising would be used

much more often than the addition of warning statements or product

labeling, which are likely to be used in the more extreme cases.

97. Proposed Sec. 99.401(a) permitted FDA to take appropriate

action to protect the public health, including ordering a manufacturer

to cease dissemination and take corrective action, if FDA determines,

based on data received after the dissemination has begun, that the new

use that is the subject of the disseminated information may not be

effective or may pose a significant risk to public health. The

provision required FDA to consult with the manufacturer before taking

any such action.

One comment disagreed that FDA should have any obligation to

consult a manufacturer before ordering the manufacturer to cease

disseminating information on an unapproved/new use.

Section 555(a)(1) of the act, regarding corrective actions

following the receipt of data after a manufacturer has begun

disseminating information, expressly states that the agency, ``after

consultation with the manufacturer,'' shall take ``such action

regarding the dissemination of the information as [the agency]

determines to be appropriate for the protection of the public health,

which may include ordering that the manufacturer to cease dissemination

of the information.'' Thus, with respect to corrective actions based on

post-dissemination data, the act requires FDA to consult the

manufacturer before taking any action, and Sec. 99.401(a) correctly

reflects this statutory requirement.

98. FDA revised Sec. 99.401(c)(3) and (c)(4), by changing the

references to Sec. 99.303 from paragraphs (a) or (c) to paragraphs (a)

or (b). This change was needed to correct an error and to reflect the

changes made to Sec. 99.303, which were previously discussed.

99. Proposed Sec. 99.401(b) discussed FDA's ability to order

cessation of dissemination or corrective action because the information

being disseminated by a manufacturer does not comply with part 99.

Proposed Sec. 99.401(b)(1) directed FDA to give a manufacturer the

opportunity to bring itself into compliance if the manufacturer's

noncompliance constituted a minor violation. Proposed Sec. 99.401(b)(2)

permitted FDA to order the manufacturer to cease dissemination of

information after providing notice to the manufacturer and an

opportunity for a meeting.

One comment would revise Sec. 99.401(b)(2) to specify a timeframe

for a meeting, but did not explain why such specificity would be

beneficial.

FDA declines to revise the rule as suggested by the comment.

Because FDA cannot require a manufacturer to cease dissemination until

it has provided an opportunity for a meeting, it has an incentive to

schedule such meetings at the earliest possible time, particularly when

the new use at issue raises significant safety concerns. By not

specifying a timeframe for a meeting, the regulation provides the

appropriate flexibility to schedule meetings.

100. One comment said that FDA should afford manufacturers an

opportunity to resolve outstanding issues before taking any corrective

action to avoid burdensome and erroneous corrective action.

Section 555(b)(1) of the act requires FDA to delay issuing an order

to provide a manufacturer an opportunity to correct a minor violation

before ordering such manufacturer to cease dissemination. Section

99.401(b) provides that opportunity. Moreover, FDA will always consider

whether and when corrective action is appropriate.

101. Proposed Sec. 99.401(c) described FDA actions based on a

manufacturer's supplemental application. For example, under proposed

Sec. 99.401(c)(1), FDA could order a manufacturer to cease

dissemination and to take corrective action if the agency determined

that the supplemental application does not contain adequate information

for approval of the new use.

One comment said that FDA should not automatically require a

manufacturer to cease dissemination if FDA does not approve a

supplemental application for the unapproved/new use because it fails to

establish effectiveness. The comment said corrective action should be

reserved for situations in which ``some significant public health

concern is identified that would be materially addressed by such

corrective action.''

FDA declines to revise Sec. 99.401(c) to limit corrective actions

as suggested by the comment. If FDA, based on the supplemental

application submitted by the manufacturer, determines that the drug or

device is not effective for that use, it could be contrary to the

interests

[[Page 64576]]

of public health to allow the manufacturer to continue disseminating

information on that use. Section 555(b)(2) of the act contemplates such

a result by stating that the agency may order a manufacturer to cease

dissemination if the agency determines that the supplemental

application does not contain adequate information for approval of the

new use.

Furthermore, one should note that both section 555(b)(2) of the act

and Sec. 99.401(c) give FDA discretion in issuing an order to cease

dissemination of information on the unapproved/new use if FDA does not

approve the supplemental application. Thus, contrary to the comment's

assertion, an order to cease dissemination under such circumstances is

not ``automatic.''

102. One comment said that if FDA does not approve a supplemental

application because the studies failed to demonstrate efficacy, the

manufacturer should advise health care practitioners who previously

received information on the unapproved/new use.

Requiring a manufacturer to notify recipients or categories of

recipients that a drug or device is not effective for the unapproved/

new use would be within the range of corrective actions that FDA may

take. Section 553(b) of the act contemplates such a result by requiring

manufacturers to keep records of categories of recipients or individual

recipients of the disseminated information and to use such records if

the manufacturer is required to take corrective action. Thus,

corrective actions, in Sec. 99.401, are not confined to orders to cease

dissemination of information on an unapproved/new use.

103. One comment sought clarification as to when FDA may determine

that a supplemental application does not contain adequate information

for approval of the new use. The comment suggested that proposed

Sec. 99.401(c)(1) could be interpreted as applying even if FDA

requested additional information or clarification of a supplemental

application. The comment stated that dissemination of information on an

unapproved/new use should cease only when FDA determines that the

supplemental application is not approvable.

Section 555(b)(2) of the act permits FDA to order a manufacturer to

cease dissemination if FDA determines that a supplemental application

submitted by such manufacturer (for the new use) does not contain

adequate information for approval of the new use. Section 99.401(c)(1)

tracks this language. FDA agrees that a decision to seek additional

data or clarification regarding a supplemental application would

generally not constitute a determination that the supplement does not

contain adequate information for approval of the new use. However,

there may be circumstances in which it is appropriate for the agency to

order a manufacturer to cease dissemination of information when

additional data is required. Accordingly, FDA will make these

determinations on a case-by-case basis.

104. Proposed Sec. 99.401(c)(2) permitted FDA to order a

manufacturer to cease dissemination if the manufacturer had certified

that it would submit a supplemental application within 6 months, and

the manufacturer failed to submit a supplemental application within 6

months.

One comment said FDA should not seek corrective action for a

manufacturer's failure to submit a supplemental application within 6

months if there is ``good cause'' for the delay. The comment said that

FDA should meet with a manufacturer to determine if there is good cause

for the delay before automatically requiring corrective action and that

manufacturers should notify FDA as soon as possible if they will not

meet any deadline.

FDA declines to revise the rule as requested by the comment.

Section 99.401(c)(2) does not require any specific corrective action in

the event that the manufacturer fails to submit a supplemental

application on time. Instead, it gives FDA the discretion to order the

manufacturer to cease dissemination of information and to take

corrective action. FDA will consider, among other things, the reasons

for a manufacturer's inability to submit a supplemental application on

time when deciding what type of corrective action to take or whether

any corrective action is needed.

Thus, while FDA would appreciate any advance notice from

manufacturers who believe that they will be unable to submit a

supplemental application on time and will meet with manufacturers as

time and resources permit, given the agency's discretion regarding

corrective actions in Sec. 99.401(c)(2), revising the rule to require

such meetings is unnecessary.

105. Proposed Sec. 99.401(d) considered an order to cease

dissemination of information to be effective upon the date of issuance

unless otherwise stated by FDA.

One comment said it would be more efficient if an order to cease

dissemination of information were effective upon date of receipt by the

manufacturer. The comment explained that a manufacturer may be unaware

when FDA issues an order to cease dissemination of information, so the

order should be effective when the manufacturer receives it. The

comment also stated that it would be unlikely that a manufacturer could

stop dissemination of information throughout the United States on the

same day it receives an order to cease dissemination. Consequently, the

comment would revise the rule to give manufacturers some time (the

comment suggested 60 days) in which to comply with the order.

FDA agrees, in part, with the comment and has revised

Sec. 99.401(d) to make an order to cease dissemination of information

effective upon receipt by the manufacturer, unless otherwise indicated

in the order. The agency does not agree that manufacturers should have

a specified amount of time after receipt to comply with an order. A

manufacturer is expected to comply immediately. If the manufacturer is

unable to comply immediately, it should notify FDA, and FDA will

evaluate the situation on a case-by-case basis.

106. Proposed Sec. 99.401(e) required a manufacturer to cease

dissemination if it fails to comply with the regulations pertaining to

dissemination of information on unapproved/new uses. This would include

discontinuation, termination, and a failure to conduct with due

diligence clinical studies. The proposal also required the manufacturer

to notify FDA if it ceases dissemination under Sec. 99.401(e).

One comment would revise the rule to require a manufacturer to

notify FDA of any failure to comply as soon as the manufacturer

realizes the failure and ceases dissemination. The comment also would

require the manufacturer to notify FDA immediately if the manufacturer

ceases dissemination. Section 99.401(e) already requires a manufacturer

to notify FDA if it ceases dissemination.

FDA agrees that the agency should be notified immediately and has

revised Sec. 99.401(e) accordingly.

b. Termination of approvals of applications for exemption

(Sec. 99.403). Under the act, if FDA fails to act within 60 days on an

application for an exemption from the requirement to file a

supplemental application, the application is deemed approved. Proposed

Sec. 99.403 allowed FDA to 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. In

addition, the agency may order the manufacturer to cease disseminating

information about the new use and, if appropriate, to take corrective

action.

[[Page 64577]]

107. One comment would revise Sec. 99.403(a)(3) to apply if FDA

determines that it would be economically and ethically possible to

conduct the studies needed for a supplement rather than economically or

ethically possible to conduct such studies.

FDA agrees and has revised the rule accordingly.

108. One comment requested that FDA provide notice and an

opportunity to meet when FDA terminates approval of an application for

an exemption.

Section 99.403(c), (d), and (e) provide for notice to the

manufacturer, and Sec. 99.403(d) also mentions consultation between FDA

and the manufacturer if 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

support a supplemental application for the new use. Thus, no further

change to the rule is necessary.

c. Applicability of labeling, adulteration, and misbranding

authority (Sec. 99.405). Proposed Sec. 99.405 provided 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 it fails to comply with the requirements in section 551 of

the act and the requirements of this part.

109. One comment claimed that proposed Sec. 99.405 was too broad

and exceeded the statute by considering a failure to comply with part

99 to constitute labeling, evidence of a new intended use,

adulteration, or misbranding of a drug or device. The comment

acknowledged that labeling that is false or misleading renders a drug

misbranded and that each introduction of the drug into interstate

commerce constitutes a separate prohibited act under section 301 of the

act (21 U.S.C. 331). The comment further acknowledged that FDA can

pursue various enforcement actions, such as seizures, injunctions, and

criminal penalties, for each prohibited act. However, the comment

argued that a failure to comply with part 99 should be a single

violation rather than a violation for each product sold and that if a

manufacturer tries to follow part 99, the act prescribes specific

enforcement consequences, such as corrective action, before FDA resorts

to other sanctions.

FDA disagrees with this comment. Although section 401 of FDAMA

provided FDA additional enforcement tools for violative dissemination

of off-label information, it did not in any way eliminate or limit

FDA's ability to use its already existing enforcement mechanisms.

6. Subpart F--Recordkeeping and Reports

Recordkeeping and reports (Sec. 99.501). Proposed Sec. 99.501

required a manufacturer that disseminates information under part 99 to

maintain records sufficient to allow it to take corrective action that

is required by FDA and described some of the records to be kept. The

proposal gave manufacturers the option of maintaining records that

identify recipients of the disseminated information by name or by

category, but would require manufacturers who choose to identify

recipients by category 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. The

proposal also permitted FDA to require manufacturers to keep records

identifying recipients by name and required a manufacturer to keep

records

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