Federal Register / Vol. 63, No. 113 / Friday, June 12, 1998 / Notices 32219

program. For a complete description of

each, see Addendum I (included in the

application kit).

AR98–1 Human Subjects

Requirements

AR98–2 Requirements for Inclusion of

Women and Racial and Ethnic

Minorities in Research

AR98–9 Paperwork Reduction Act

Requirements

AR98–10 Smoke-Free Workplace

Requirements

AR98–11 Healthy People 2000

AR98–12 Lobbying Restrictions

AR98–13 Prohibition on Use of CDC

Funds for Certain Gun Control

Activities

I. Authority and Catalog of Federal

Domestic Assistance Number

This program announcement is

authorized under Sections 391, 392,

393, and 394 [42 U.S.C. 280b, 280b–1,

280b–1a, and 280b–2] of the Public

Service Act, as amended. The Catalog of

Federal Domestic Assistance number is

93.136.

J. Where To Obtain Additional

Information

The program announcement and

application forms may be downloaded

from the Internet: www.cdc.gov (look

under funding). You may also receive a

complete application kit by calling 1–

888–GRANTS4. You will be asked to

identify the program announcement

number and provide your name and

mailing address. A complete

announcement kit will be mailed to you.

Please refer to Program

Announcement 98070 when you request

information.

If you have questions after reviewing

the forms, for business management

technical assistance, contact: Joanne

Wojcik, Grants Management Specialist,

Grants Management Branch,

Procurement and Grants Office,

Announcement 98070, Centers for

Disease Control and Prevention (CDC),

255 East Paces Ferry Road, NE., Room

300, Mailstop E–13, Atlanta, GA 30305–

2209, telephone (404) 842–6535, E-mail

address jcw6@cdc.gov.

For program technical assistance,

contact Wendy Watkins, Division of

Violence Prevention, National Center for

Injury Prevention and Control, Centers

for Disease Control and Prevention

(CDC), 4770 Buford Highway, NE.,

Mailstop K–60, Atlanta, GA 30341–

3724, telephone (770) 488–4646, E-mail

address dmw7@cdc.gov.

Dated: June 8, 1998.

John L. Williams,

Director, Procurement and Grants Office,

Centers for Disease Control and Prevention

(CDC).

[FR Doc. 98–15686 Filed 6–11–98; 8:45 am]

BILLING CODE 4163–18–M

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

[Docket No. 98D–0307]

Draft Guidance for Industry; Exports

and Imports Under the FDA Export

Reform and Enhancement Act of 1996

AGENCY: Food and Drug Administration,

HHS.

ACTION: Notice.

SUMMARY: The Food and Drug

Administration (FDA) is announcing the

availability of a draft guidance

document entitled, ‘‘FDA Draft

Guidance for Industry on: Exports and

Imports Under the FDA Export Reform

and Enhancement Act of 1996.’’ The

draft guidance document addresses

issues pertaining to the exportation of

human drugs, animal drugs, biologics,

food additives, and devices as well as

the importation of components, parts,

accessories, or other articles for

incorporation or further processing into

articles intended for export.

DATES: Written comments on the draft

guidance document may be submitted

by August 26, 1998. General comments

on the agency’s guidance documents

may be submitted at any time.

ADDRESSES: Submit written comments

on the draft guidance document to the

Dockets Management Branch (HFA–

305), Food and Drug Administration,

12420 Parklawn Dr., rm. 1–23,

Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT:

Philip L. Chao, Office of Policy (HF–23),

Food and Drug Administration, 5600

Fishers Lane, Rockville, MD 20857,

301–827–3380.

SUPPLEMENTARY INFORMATION: FDA is

announcing the availability of a draft

guidance document entitled, ‘‘FDA Draft

Guidance for Industry on: Exports and

Imports Under the FDA Export Reform

and Enhancement Act of 1996.’’ Enacted

and later amended in 1996, the FDA

Export Reform and Enhancement Act

(Pub. L. 104–134, as amended by Pub.

L. 104–180) significantly changed the

export requirements for human drugs,

animal drugs, biologics, devices, and, to

a limited extent, food additives. For

example, before the law was enacted,

most exports of unapproved new drug

products could only be made to 21

countries identified in section 802 of the

Federal Food, Drug, and Cosmetic Act

(the act), and these exports were subject

to various restrictions. The FDA Export

Reform and Enhancement Act amended

section 802 of the act to allow, among

other things, the export of unapproved

new drugs to any country in the world

if the drug complies with the laws of the

importing country and has valid

marketing authorization from any of the

following countries: Australia, Canada,

Israel, Japan, New Zealand, Switzerland,

South Africa, and the countries in the

European Union (EU) and the European

Economic Area (EEA). (Currently, the

EU countries are Austria, Belgium,

Denmark, Germany, Greece, Finland,

France, Ireland, Italy, Luxembourg, the

Netherlands, Portugal, Spain, Sweden,

and the United Kingdom. The EEA

countries are the EU countries, Iceland,

Liechtenstein, and Norway. The list of

countries will expand automatically if

any country accedes to the EU or

becomes a member of the EEA.)

The draft guidance document

provides information on the statutory

requirements for exporting human

drugs, animal drugs, biologics, and

medical devices, general requirements

for products exported under section 801

of the act (21 U.S.C. 381), labeling

requirements for drugs and biologics

exported under section 801(e) of the act,

export requirements for unapproved

drugs, biologics, and devices under

section 802(b) of the act (21 U.S.C.

382(b)), exports of unapproved drugs

and devices for investigational use,

exports of unapproved drugs and

devices in anticipation of foreign

approval; exports of drugs and devices

for diagnosing, preventing, or treating a

tropical disease or a disease ‘‘not of

significant prevalence in the United

States,’’ export notifications to FDA, and

‘‘import for export.’’ The draft guidance document

represents the agency’s current thinking

on exports and imports-for-export under

sections 801 and 802 of the act. It does

not create or confer any rights for or on

any person and does not operate to bind

FDA or the public. An alternative

approach may be used if such approach

satisfies the requirements of the

applicable statute, regulations, or both. Interested persons may submit to the

Dockets Management Branch (address

above) written comments on the draft

guidance document. Two copies of any

comments are to be submitted, except

that individuals may submit one copy.

Comments are to be identified with the

docket number found in brackets in the

heading of this document. A copy of the

draft guidance document and received

comments may be seen in the office
32220 Federal Register / Vol. 63, No. 113 / Friday, June 12, 1998 / Notices

1This guidance document may be supplemented

by other guidance documents on specific topics.

2 If a product meets the requirements for sale in

the United States, the act has no restrictions on its

exportation.

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

Monday through Friday. The agency

invites comments on the following

issues:

• What are the draft guidance

document’s strengths and weaknesses?

For example, which topics might

require more explanation?

• Which international standards

organization(s), if any, should FDA

recognize for purposes of section

802(f)(1) of the act? Which international

standards should be used and for which

products? Under section 802(f)(1) of the

act, all drugs and devices exported

under section 802 of the act must be in

substantial conformity with current

good manufacturing practice

requirements or meet ‘‘international

standards as certified by an

international standards organization

recognized’’ by FDA.

• Section 802(e) of the act requires an

application to export a drug or device

intended to treat a tropical disease or a

disease that is not of significant

prevalence in the United States. FDA

may approve exportation if it finds that

the drug or device will not expose

patients in the foreign country to an

unreasonable risk of illness or injury

and that the probable health benefits

from using the drug or device under its

labeled conditions of use outweigh the

risk of injury or illness from its use,

‘‘taking into account the probable risks

and benefits of currently available drug

or device treatment.’’ What should the

application contain so that FDA may

make these findings? How many

applications might be submitted?

The draft guidance document, with a

table of contents and ‘‘quick locator

guide,’’ can be accessed electronically at

http://www.fda.gov/opacom/fedregister/

frexport.html. The full text of the draft

guidance document, without the table of

contents and quick locator guide (due to

reformatting and pagination changes in

the Federal Register), follows:

FDA Guidance for Industry on: Exports

and Imports Under the FDA Export

Reform and Enhancement Act of 1996

I. Introduction

This guidance document is intended

to summarize and to explain the basic

requirements and procedures for

exporting and importing human drugs,

animal drugs, biologics, devices, food

additives, color additives, and dietary

supplements that may not be sold or

distributed in the United States under

the FDA Export Reform and

Enhancement Act of 1996 (Pub. L. 104–

134, and amended by Pub. L. 104–

180). 1 This law amended sections 801

and 802 of the Federal Food, Drug, and

Cosmetic Act (the act), as well as section

351(h) of the Public Health Service Act,

simplifying the requirements for

exporting unapproved human drugs,

biologics, and devices. 2 In addition, the

FDA Export Reform and Enhancement

Act substantially reduced the

requirements for exporting unapproved

new animal drugs, provided a new

option for exporting unapproved

devices, and added a new provision, at

section 801(d)(3) of the act that permits

the import of certain components, parts,

and accessories of human drugs,

biologics, devices, food additives, color

additives, and dietary supplements for

further processing or incorporation into

products intended for export.

This guidance document does not

address export certificates and fees.

Information on these subjects can be

found in Compliance Policy Guide

7150.01, ‘‘Certification for Exports.’’

Please note that a firm or product

may be subject to additional statutory

or regulatory requirements beyond

those described in this guidance. For

example, depending on the type of

products it manufactures, a firm may be

subject to registration requirements

under section 510 of the act (21 U.S.C.

360).

This guidance document represents

the agency’s current thinking with

respect to the exportation of various

products under the FDA Export Reform

and Enhancement Act of 1996 and

replaces FDA’s previous guidance on

exports entitled, ‘‘A Review of FDA’s

Implementation of the Drug Export

Amendments of 1986.’’ It does not

create or confer any rights for or on any

person and does not operate to bind

FDA or the public. An alternative

approach may be used if such approach

satisfies the requirements of the

applicable statute, regulations, or both.

II. Terms Used in This Guidance

This guidance uses the following

terms:

‘‘act’’ means the Federal Food, Drug,

and Cosmetic Act. Citations to specific

sections of the act will use the

numerical sequence specified in the act

rather than the section numbers used in

the U.S. Code.

‘‘cGMP’’ means current good

manufacturing practice. For drugs and

biologics, cGMP regulations can be

found at parts 210 and 211 (21 CFR

parts 210 and 211). For devices, cGMP

regulations can be found at part 820 (21

CFR part 820). For blood and blood

components, additional regulations can

be found at part 606 (21 CFR part 606).

‘‘FDA’’ or ‘‘agency’’ means the Food

and Drug Administration.

‘‘IDE’’ means an investigational

device exemption application. These are

applications containing requests to use

an unapproved device in clinical tests

using human subjects. The regulations

are authorized under section 520(g) of

the act (21 U.S.C. 360(g)), and the

implementing regulations can be found

at part 812 (21 CFR part 812).

‘‘IND’’ means an investigational new

drug application. These applications are

required for persons who intend to

conduct clinical investigations

involving products subject to section

505 of the act (21 U.S.C. 355) or to the

licensure provisions of the Public

Health Service Act (42 U.S.C. 262). The

IND regulations are authorized by

section 505(i) of the act and are found

at part 312 (21 CFR part 312).

‘‘1986 Amendments’’ means the Drug

Export Amendments Act of 1986 (Pub.

L. 99–960). Most provisions in the 1986

Amendments were revised or

eliminated by the 1996 Amendments.

‘‘1996 Amendments’’ means the FDA

Export Reform and Enhancement Act of

1996 (Pub. L. 104–134 and amended by

Pub. L. 104–180).

‘‘PHS Act’’ means the Public Health

Service Act (42 U.S.C. 201 et seq.).

Citations to specific sections of the PHS

Act will use the numbers specified in

the PHS Act rather than the section

numbers used in the U.S. Code.

‘‘PMA’’ means a premarket approval

application. This is a marketing

application for certain devices under

section 515 of the act. The regulation for

PMA’s can be found at 21 CFR part 814.

‘‘312 Program’’ means the regulatory

program used by FDA for permitting the

exportation of investigational drugs or

biologics for clinical use in foreign

countries. The principal statutory

authority for the 312 Program is section

505(i) of the act, and the regulation can

be found at § 312.110.

III. Statutory Background

Some background information on the

statutory requirements that existed

before the enactment of the 1996

Amendments is helpful to understand

why the 1996 Amendments were

enacted.

A. Exports of Drugs and Biologics That

May Not be Sold in the United States

The export provision in the act had its

origins in 1906 as part of the Federal

Food and Drugs Act (Pub. L. 59–384).
Federal Register / Vol. 63, No. 113 / Friday, June 12, 1998 / Notices 32221

3The 1986 Amendments did not alter the export

requirements for insulin and antibiotics. These

products remained subject to the basic export

requirements that are now seen in section 801(e)(1)

of the act, and so exports could occur without prior

FDA approval.

Section 2 of the 1906 Federal Food and

Drugs Act stated that:

* * * no article shall be deemed

misbranded or adulterated within the

provisions of this act when intended for

export to any foreign country and prepared

or packed according to the specifications or

directions of the foreign purchaser when no

substance is used in the preparation or

packing thereof in conflict with the laws of

the foreign country to which said article is

intended to be shipped; but if said article

shall be in fact sold or offered for sale for

domestic use or consumption, then this

proviso shall not exempt said article from the

operation of any of the other provisions of

this act.

This export provision remained

essentially unchanged in the Federal

Food, Drug, and Cosmetic Act of 1938

(Pub. L. 75–717), where it was codified

as section 801(d). Section 801(d) of the

1938 Act stated that:

A food, drug, device, or cosmetic intended

for export shall not be deemed to be

adulterated or misbranded under this Act if

it (1) accords to the specifications of the

foreign purchaser, (2) is not in conflict with

the laws of the country to which it is

intended for export, (3) is labeled on the

outside of the shipping package that it is

intended for export, and (4) is not sold or

offered for sale in domestic commerce * * *.

The 1938 act, however, also defined

the terms, ‘‘drug,’’ and ‘‘new drug,’’ and

these definitions led to the conclusion

that section 801(d)(1) of the act did not

apply to new drugs. (See, e.g., United

States v. An Article of Drug, etc. * * *

Ethionamide-INH, No. 67 C 288 (E.D.

N.Y., Aug. 19, 1967); United States v.

Yaron Laboratories, Inc., 365 F.Supp.

917, 919 (N.D. Cal. 1972); Compliance

Policy Guide 7132c.01 (Oct. 1, 1980).)

As a result, the act was interpreted as

permitting the export of approved drugs,

but not the export of unapproved new

drugs. This interpretation was viewed as

imposing hardships on the

pharmaceutical industry (by impairing

its ability to compete in international

markets) without any accompanying

public health benefits (see S. Rept. 99–

225, 99th Cong., 2d sess. 5–6 (1985)).

To remedy the situation, Congress

enacted the Drug Export Amendments

Act of 1986 (Pub. L. 99–960). Insofar as

human drug products and biologics

were concerned, the 1986 Amendments

created section 802 of the act and

established three separate ‘‘tracks’’ for

exporting unapproved drugs and

unlicensed biologics. Under ‘‘track 1,’’

FDA was authorized to approve an

application for the export of new human

and animal drugs and biologics that

were not approved in the United States,

so long as the drug contained the same

active ingredient(s) as a product for

which marketing approval in the United

States was being sought or the biological

product was one for which licensing

was actively being pursued. Exports

under ‘‘track 1’’ were confined to 21

specific countries listed in section 802

of the act. Those countries were:

Australia, Austria, Belgium, Canada,

Denmark, the Federal Republic of

Germany, Finland, France, Iceland,

Ireland, Italy, Japan, Luxembourg, the

Netherlands, New Zealand, Norway,

Portugal, Spain, Sweden, Switzerland,

and the United Kingdom.

Under ‘‘track 2,’’ FDA was authorized

to approve the export of drugs and

biologics intended for the treatment of

tropical diseases. Persons seeking to

export a drug under track 2 had to

submit an application to FDA, and FDA

had to find, based on ‘‘credible

scientific evidence,’’ that the drug

would be safe and effective in the

country to which it would be exported

in the prevention or treatment of a

tropical disease in that country.

‘‘Track 3’’ applied to partially

processed biological products and

amended section 351 of the PHS Act.

FDA was authorized to approve the

export of partially processed human

biological products intended for further

manufacture in any of the 21 listed

countries, but the final product had to

be approved or in the process of

receiving approval from the foreign

country.

Additionally, the 1986 Amendments

added a new section 801(d) of the act

(regarding importation of drugs), and

renumbered the existing section 801(d)

as a new section 801(e)(1) of the act. 3

The 1986 Amendments, however,

presented several problems and

concerns. One significant problem was

that the 1986 Amendments limited

exports of unapproved drugs and

biologics to 21 countries. Although the

1986 Amendments provided criteria for

adding more countries to the list, it did

not provide any administrative

mechanism for doing so. Consequently,

exports to countries that were not on the

list were not permitted.

The requirement that the drug contain

the same active ingredient as a drug for

which marketing approval in the United

States was being ‘‘actively pursued’’

also caused some concern in the

industry. Questions arose concerning

the degree to which the active

ingredient had to be the ‘‘same’’ or how

‘‘actively’’ the manufacturer had to be

seeking approval.

The concept in the 1986 Amendments

which required FDA approval before a

product could be exported generated

criticism and debate as well. The 1986

Amendments required a person to file

an application to export a drug at least

90 days before the date on which the

applicant proposed to export the drug;

required FDA to publish a notice in the

Federal Register identifying the

applicant, the drug to be exported, and

the country to which the drug was being

exported (for Track 1 exports only); and

established requirements for the

application as well as the agency’s

action on an application. For example,

if the agency decided to disapprove an

application, it had to provide a written

statement to the applicant describing

deficiencies that the applicant must

correct and give the applicant 60 days

to correct those deficiencies. Some firms

charged that this approval process took

too long; others questioned why the

United States should have to approve

the export of a product to a foreign

country, particularly when the foreign

country had its own public health

authorities or had approved the product

for marketing.

B. Exports of Animal Drugs That May

Not be Sold in the United States

As stated earlier, section 801(e) of the

act was construed as not applying to the

exportation of unapproved new human

drugs. This interpretation also covered

unapproved new animal drugs, and was

made explicit in 1968 as part of the

Animal Drug Amendments of 1968

(Pub. L. 90–399). Although the initial

Congressional bill would have

permitted exportation of unapproved

new animal drugs, Congress, at the

request of the then-Department of

Health, Education, and Welfare, elected

to amend section 801 of the act to

prevent the exportation of unapproved

new animal drugs and animal feed

containing unapproved new animal

drugs (see S. Rept. 1308, 90th Cong., 2d

sess., 1968 U.S. Code Cong. & Admin.

News 2160). The legislative history

explained that the amendment’s

purpose was to ‘‘preserve, essentially,

the status quo with respect to the export

exemption’’ (id.).

The Drug Export Amendments Act of

1986 altered the export requirements for

unapproved new animal drugs in the

same manner that it changed the export

requirements for unapproved new

human drugs (such as limiting exports

to 21 countries and requiring the

exporter to be pursuing product

approval in the United States as a

condition for allowing exportation).

Consequently, an unapproved new
32222 Federal Register / Vol. 63, No. 113 / Friday, June 12, 1998 / Notices

4Animal drugs cannot be exported under section

802 of the act because that section pertains to

biologics, devices, and human drugs.

animal drug could be exported under

section 802 of the act.

C. Exports of Devices That May Not be

Sold in the United States

As stated earlier, then-section 801(d)

of the Federal Food, Drug, and Cosmetic

Act of 1938 (now codified at section

801(e)) stated that a food, drug, device,

or cosmetic intended for export would

not be considered adulterated or

misbranded if the product: (1) Met the

foreign purchaser’s specifications; (2)

was not in conflict with the laws of the

country to which it was being exported;

(3) was labeled on the outside of the

shipping package that the product was

intended for export; and (4) was not

sold or offered for sale in domestic

commerce.

This authority remained unchanged

until 1976 when, as part of the Medical

Device Amendments Act of 1976 (Pub.

L. 94–295), Congress amended the

provision to state that the four criteria

did not apply to any device that did not

comply with an applicable requirement

under sections 514 (performance

standards) or 515 (premarket approval)

of the act, to devices that were exempt

from sections 514 or 515 of the act

under section 520(g) of the act (devices

subject to an IDE), and to banned

devices (under section 516 of the act)

unless, in addition to requiring

compliance with section 801(e)(1) of the

act, the agency determined that

exportation of the device would not be

contrary to the public health and safety

and the device had the approval of the

foreign country that would receive the

device. In other words, most

unapproved devices could not be

exported unless the agency determined

that exportation would not be contrary

to the public health or safety and that

the foreign country approved of the

device. This provision was, and

remains, codified at section 801(e)(2) of

the act (21 U.S.C. 381(e)(2)).

As in the case of FDA drug export

approvals, the statutory requirement

that FDA approve device exports began

to generate criticism from the device

industry. The device industry criticized

the agency for the time FDA took to

determine whether an export request

met the statutory criteria. FDA reduced

the average time for processing device

export requests from an average of 91

days in 1992 to 10 days in 1995, yet,

despite this significant reduction in

processing time, the statute’s export

approval requirements were seen as

adversely affecting the ability of U.S.

firms to enter or to compete in foreign

markets.

D. Enactment of the FDA Export Reform

and Enhancement Act of 1996

The FDA Export Reform and

Enhancement Act of 1996 (Pub. L. 104–

134, and amended by Pub. L. 104–180)

addressed industry’s problems and

concerns. For human drugs and

biologics that may not be sold in the

United States, the 1996 Amendments:

• Amended section 801(d) of the act

to allow import of components of drugs

and biologics into the United States that

do not comply with other provisions in

the act where those components are

intended for incorporation or further

processing by the initial owner or

consignee into a drug or biologic that

will be exported under section 801(e) or

section 802 of the act or section 351(h)

of the PHS Act.

• Amended section 801 of the act to

allow exports of approved drugs (except

for insulin and antibiotics) to countries

that have different or additional labeling

requirements. The new provision, at

section 801(f) of the act, requires such

drugs to be labeled in accordance with

the requirements and conditions for use

in the foreign country and to be labeled

in accordance with the act. If the drug’s

labeling includes conditions of use that

are not approved in the United States,

the labeling must state that such

conditions for use have not been

approved under the act.

• Replaced section 802 of the act in

its entirety with a new section 802 of

the act that:

• Eliminated the requirement for prior FDA

approval of exports of unapproved drugs (in

most cases),

• Significantly expanded the list of

countries to which unapproved products can

be exported without prior FDA approval (and

also provided administrative mechanisms for

the Secretary of Health and Human Services

(the Secretary) to add countries to the list and

for FDA to permit exports of specific

products to unlisted countries),

• Authorized exports of unapproved drugs

and biologics intended for use in clinical

investigations in any of 25 countries

identified in section 802(b)(1)(A) of the act,

• Authorized the export of unapproved

products to a listed country in anticipation

of marketing approval in that country,

• Created a simple notification process for

most exported products (as opposed to the

application process required under the 1986

Amendments). Notification is not required

for drugs exported for investigational use in

a listed country or drugs exported in

anticipation of marketing authorization in a

listed country, and

• Authorized FDA to permit the export of

unapproved products intended to treat

tropical or other diseases that are ‘‘not of

significant prevalence in the United States.’’

For animal drugs that may not be sold

in the United States, the 1996

Amendments:

• Again restricted the authority to

export an unapproved new animal drug

to section 801 of the act. 4 However,

unlike the situation that existed from

1968 to 1986, an unapproved new

animal drug can be exported if it is:

Intended for export; accords to the

specifications of the foreign purchaser;

is not in conflict with the laws of the

importing country; is labeled on the

outside of the shipping package that it

is intended for export; and is not sold

or offered for sale in interstate

commerce (see section 801(e)(1) of the

act).

• The only unapproved new animal

drugs that cannot be exported under

section 801 of the act are ‘‘banned’’

animal drugs (see section 801(e)(3) of

the act). Neither the statute nor the

legislative history explains what a

‘‘banned’’ animal drug is, and FDA is

working on an interpretation as to what

constitutes a ‘‘banned’’ animal drug.

For devices that may not be sold in

the United States, the 1996

Amendments:

• Amended section 801(d) of the act

to permit the import of component

parts, accessories, or other articles of a

device that do not comply with other

provisions in the act, if those

component parts, accessories, or other

articles are intended for incorporation

or further processing by the initial

owner or consignee into a device that

will be exported under section 801(e) or

section 802 of the act or section 351(h)

of the PHS Act;

• Amended section 801 of the act to

permit exportation of devices under

section 801(e) of the act or under section

802 of the act;

• Replaced section 802 of the act in

its entirety with a new section 802 of

the act that:

• Eliminated the requirement for prior FDA

approval for exports (for devices approved in

a listed country or destined for clinical

investigations in a listed country),

• Created administrative mechanisms for

the Secretary to add countries to the list and

for FDA to approve exports of specific

products to unlisted countries,

• Authorized exports of unapproved

devices intended for use in clinical

investigations in any of 25 countries

identified in section 802 of the act,

• Authorized the export of unapproved

devices to a listed country in anticipation of

marketing approval in that country,

• Created a simple notification process for

exported devices (as opposed to the

application process under section 801(e)(2) of

the act). Notification is not required for

devices exported for investigational use to a

listed country or devices exported in
Federal Register / Vol. 63, No. 113 / Friday, June 12, 1998 / Notices 32223

5The requirements in section 801(e)(1) of the act

apply to all products exported under section 802 of

the act due to section 802(f)(3) of the act. That

section prohibits exportation of a product under

section 802 of the act if the requirements in section

801(e)(1)(A) through (e)(1)(D) of the act are not met.

The requirements in section 801(e)(1) of the act also

apply to partially processed biologics exported

under section 351(h) of the PHS Act.

anticipation of marketing authorization in the

listed country, and

• Authorized FDA to permit the export of

unapproved devices intended to treat tropical

diseases or other diseases that are ‘‘not of

significant prevalence in the United States.’’

Additionally, the 1996 Amendments

permit importation of food additives,

color additives, and dietary

supplements into the United States if

those articles are intended for

incorporation or further processing by

the initial owner or consignee into a

drug, biologic, device, food, food

additive, color additive, or dietary

supplement that will be exported.

This document describes the

requirements for drugs (both human and

animal), biologics, and devices under

sections 801 and 802 of the act and

section 351(h) of the PHS Act, as

amended by the 1996 Amendments. It

begins with a discussion of the principal

export requirements under sections 801

and 802 of the act and section 351(h) of

the PHS Act, followed by a discussion

of the ‘‘import-for-export’’ requirements

under section 801 of the act.

IV. General Requirements for Products

Exported Under Section 801(e)(1) of the

Act

Section 801(e)(1) of the act contains

general requirements for any food, drug,

device, or cosmetic that may not be sold

in the United States and is intended for

export. These requirements apply

regardless of whether the product is

exported under section 801(e) or section

802 of the act or section 351(h) of the

PHS Act. 5 (Additional requirements

apply to products exported under

section 802 of the act and to devices

exported under section 801(e)(2) of the

act; those requirements are described

later in this document).

Section 801(e)(1) of the act states that

a food, drug, device, or cosmetic

intended for export shall not be deemed

to be adulterated or misbranded if the

product: Accords to the specifications of

the foreign purchaser; is not in conflict

with the laws of the country to which

it is intended for export; is labeled on

the outside of the shipping package that

it is intended for export; and is not sold

or offered for sale in domestic

commerce.

During routine inspections, FDA will

evaluate whether a firm has complied

with section 801(e)(1) of the act.

Consequently, records are very

important for demonstrating compliance

with each element of section 801(e)(1) of

the act.

To demonstrate that the product

meets the foreign purchaser’s

specifications, FDA recommends that

the firm exporting the product maintain

records describing or listing the product

specifications requested by the foreign

purchaser. This would include details

about the product (e.g., dosage strength,

dosage form, purity, quality, operating

parameters, composition, etc.) and any

details concerning the product’s

manufacture (e.g., type of sterilization

process to be used, compliance with a

particular manufacturing standard, etc.)

as requested by the foreign purchaser.

FDA recommends that the firm have an

English-language translation of the

specifications document or be prepared

to translate the document into English at

the time of any FDA inspection.

To demonstrate that the product does

not conflict with the laws of the

importing country, FDA recommends

that the firm obtain a letter from the

foreign government agency, department,

or other body stating that the product

has marketing approval from the foreign

government or does not conflict with

that country’s laws. Letters should not

be from nongovernmental bodies or

persons (such as company officials or

attorneys in the foreign country).

Additionally, if the letter from the

foreign government is not in English,

FDA recommends that the firm have an

English-language translation of that

document or be prepared to translate the

document into English at the time of

any FDA inspection. Such translations

are essential because they will enable

the firm to show, and for FDA to verify,

that the product does not conflict with

the laws of the importing country.

To demonstrate that the product is

labeled on the outside of the shipping

package that it is intended for export,

FDA recommends that the firm place a

statement on the shipping packages

themselves. A statement such as ‘‘For

export only’’ may be sufficient.

To demonstrate that the product is not

sold or offered for sale in the United

States, FDA recommends that the firm

maintain records concerning the

product, its labeling, and similar

products sold or offered for sale in the

United States. The labeling can simply

state that the product is ‘‘Not for sale in

the United States,’’ or bear a similar

statement. As for the product itself, FDA

examines whether the product (as

opposed to batches, lots, or production

runs of a product) is sold or offered for

sale in the United States. For example,

if company A makes five batches of a

particular unapproved drug and intends

to export two batches (and sell the

remaining three batches in the United

States), the fact that company A intends

to export the two batches does not mean

that the product is ‘‘not sold or offered

for sale in the United States.’’ Instead,

FDA considers the unapproved drug to

be sold in the United States because

other batches of the same product are

sold in the United States.

The requirements in section 801(e)(1)

of the act apply to foods, drugs (both

human and animal (except for ‘‘banned’’

animal drugs, which may not be

exported)), biologics, devices, and

cosmetics intended for export, whether

they are exported under section 801 or

section 802 of the act or section 351(h)

of the PHS Act. Furthermore, depending

on the type of product being exported

and the legal authority supporting the

product’s exportation, additional

requirements may apply.

A. Special Requirements for Certain

Devices

Some devices face additional

statutory requirements before they can

be exported under section 801(e)(1) of

the act. Under section 801(e)(2) of the

act, if an unapproved device does not

comply with an applicable requirement

under sections 514 (performance

standards) or 515 (premarket approval)

of the act, is exempt from either such

section under section 520(g) of the act,

or is a banned device under section 516

of the act, the device may be deemed to

be adulterated or misbranded unless, in

addition to the requirements in section

801(e)(1) of the act, FDA has determined

that exportation of the device is not

contrary to the public health and safety

and has the approval of the country to

which it is intended for export.

The act provides that any device

introduced into interstate commerce

after May 28, 1976, is automatically

considered to be a ‘‘class III’’ device

requiring premarket approval under

section 515 of the act. Such devices may

not be legally marketed, unless and

until FDA: (1) Classifies the device into

class I or II; (2) grants marketing

clearance by issuing an order under

section 513(i) of the act, in response to

a report submitted by the sponsor under

section 510(k) of the act, determining

that the device is substantially

equivalent to a predicate device that

does not require premarket approval

(hereinafter referred to as 510(k)

marketing clearance); or (3) issues an

order under section 515(d)(1)(A) of the

act approving an application for

premarket approval.

Although the act prohibits exportation

of class III devices requiring premarket
32224 Federal Register / Vol. 63, No. 113 / Friday, June 12, 1998 / Notices

6Such devices may be eligible for export under

section 802 of the act. (A discussion of section 802

of the act appears in section VI.B of this document.)

7For in vitro diagnostic devices, where the device

is to be the sole determinate of whether a particular

course of treatment will be initiated for a lifethreatening disease, the agency recommends that

the manufacturer provide a statement indicating

whether an alternative test will be available to

confirm the test results.

8A device may be considered to have an approved

IDE if an institutional review board determines that

the device is a nonsignificant risk device, and

provided the device has met the requirements for

nonsignificant risk devices under § 812.2(b).

9Unlicensed biologics that fail to qualify for

export under section 351(h) of the PHS Act may

qualify for export under section 802 of the act.

approval unless the criteria under

section 801(e)(2) of the act are met, 6

FDA, in exercising its enforcement

discretion, has not taken enforcement

action against those manufacturers who

have not complied with the export

criteria in section 801(e)(2) of the act,

provided that the manufacturers have

reasonably concluded that, if a report

under section 510(k) of the act had been

submitted to FDA, FDA would have

granted 510(k) marketing clearance.

FDA intends to continue exercising its

enforcement discretion in this manner,

with respect to the requirements in

section 801(e)(2) of the act. FDA

emphasizes, however, that it does not

intend to exercise enforcement

discretion with respect to the

requirements in section 801(e)(1) of the

act for manufacturers who reasonably

believe that their devices would receive

a 510(k) marketing clearance.

To help FDA determine whether

exportation of the device is not contrary

to the public health and safety, FDA

recommends that manufacturers provide

basic safety data for the device. Such

data often consists of a statement

certifying that a search of medical

databases has not identified any adverse

safety data for similar devices or the

materials used in the device, or

summaries of any adverse safety data,

including a discussion as to why the

adverse effects should not be considered

applicable to the device that is to be

exported. Brief summaries of available

animal safety studies conducted with

the device and safety data from human

clinical studies are also helpful. 7 FDA

ordinarily does not need safety data if

the device is the subject of an approved

IDE or is considered to have an

approved IDE and will be marketed or

used in the importing country for the

same intended use. 8

To help FDA determine whether

exportation of the device has the

approval of the country to which it is

intended for export, FDA recommends

that the manufacturer obtain a letter

from the foreign country approving of

the device’s importation. If the

manufacturer is exporting the device to

a country in the European Economic

Area and the device has received a CE

mark, documentation of the CE mark

will ordinarily be sufficient.

Additional information regarding

device exports under section 801(e)(2)

of the act can be found in the guidance

document entitled, ‘‘Procedures for

Obtaining FDA Approval to Export

Unapproved Medical Devices.’’ (See

‘‘For Further Information Contact’’ in

section XII of this document.)

B. Special Requirements for Partially

Processed Biologics

The 1996 Amendments also changed

the export requirements for partially

processed biological products. Under

section 351(h) of the PHS Act, a

partially processed biological product

may be exported if it is: ‘‘not in a form

applicable to the prevention, treatment,

or cure of diseases or injuries of man;’’

not intended for sale in the United

States; and intended for further

manufacture into final dosage forms

outside the United States.

Exports of such products must

comply with section 801(e)(1) of the act

and with cGMP’s or international

manufacturing standards as certified by

an international standards organization

recognized by the agency.

1. What Constitutes a Partially

Processed Biological Product?

FDA interprets the term ‘‘partially

processed biological products’’ as

meaning biological products requiring

purification, inactivation, fractionation,

or significant chemical modification

(such as the formation or breakage of

covalent bonds and the incorporation of

peptides into a diagnostic test kit) before

being used in the formulation of a final

product. Thus, a finished bulk product

that could be formulated into a finished

dosage form through manufacturing

steps other than purification,

inactivation, fractionation, or significant

chemical modification would not

constitute a partially processed

biological product that could be

exported under section 351(h) of the

PHS Act. Certain other products, such

as source plasma and source leukocytes,

also would not be partially processed

biological products because they are

finished products (notwithstanding the

possibility that their intended use may

be as a source material for further

manufacturing into another product),

and FDA requires such products to be

licensed. 9

Products that do qualify as partially

processed biological products include

intermediate biological products that a

manufacturer has partially processed

and that would be subject to licensure

as final products after the completion of

additional manufacturing steps. For

example, synthetic peptides that are a

component of an in vitro diagnostic test

kit would be partially processed

biological products.

FDA encourages persons who may be

uncertain as to whether their products

are partially processed biological

products to contact the Import/Export

Team in the Center for Biologics

Evaluation and Research (see the ‘‘For

Further Information Contact’’ in section

XII of this document for the address and

phone number).

2. cGMP Requirements

Section 351(h) of the PHS Act also

requires partially processed biological

products to be ‘‘manufactured,

processed, packaged, and held in

conformity with current good

manufacturing practice requirements’’

or international manufacturing

standards recognized by the agency.

FDA will inspect manufacturers to

ensure that they are in compliance with

cGMP’s.

FDA acknowledges that section 351(h)

of the PHS Act also refers to

‘‘international manufacturing standards

as certified by an international

standards organization’’ recognized by

FDA. At this time, FDA has not

recognized any such international

standards or organizations for purposes

of section 351(h) of the PHS Act, but is

examining this issue closely.

3. Additional Requirements Under

Section 351(h) of the PHS Act

All exports of FDA-regulated products

that may not be sold or marketed in the

United States, including partially

processed biological products exported

under section 351(h) of the PHS Act,

must conform to the standard export

requirements of section 801(e)(1) of the

act. Thus, a product intended for export

under section 351(h) of the PHS Act

must: Accord with specifications of the

foreign purchaser; not be in conflict

with the laws of the country to which

it is intended for export; be labeled on

the outside of the shipping package that

as intended for export; and not be sold

or offered for sale in domestic

commerce. Consistent with section

801(e)(1) of the act, section 351(h)(2) of

the PHS Act further requires that the

product may not be intended for sale in

the United States.

Records are important in FDA’s

evaluation of compliance with section
Federal Register / Vol. 63, No. 113 / Friday, June 12, 1998 / Notices 32225

10 Insulin and antibiotics were excluded from

section 801(f) of the act because they have

historically been subject only to the export

requirements now seen in section 801(e)(1) of the

act. In 1997, the Food and Drug Administration

Modernization Act (Pub. L. 105–115) expressly

stated that insulin and antibiotics may be exported

without regard to the requirements in section 802

of the act so long as they meet the requirements in

section 801(e)(1) of the act.

11While section 802(b) of the act refers to drugs

requiring approval under section 505 of the act, it

does not apply to insulin, antibiotics, or over-thecounter drug products that do not require approval

under section 505 of the act. In 1997, the Food and

Drug Administration Modernization Act amended

section 802 of the act so that exports of insulin and

antibiotics are subject to the export requirements in

section 801(e)(1) of the act.

351(h) of the PHS Act, including the

requirements section 801(e)(1) of the

act. FDA recommends that the firm or

manufacturer maintain the following

records for possible review during a

routine annual or biennial FDA

inspection. Depending on the particular

circumstances of export, different or

additional records may also be relevant.

• Evidence that product for export

qualifies as a partially processed

biological product;

• Evidence that the partially

processed biological product complies

with the laws of the country to which

it is being exported and accords to the

specifications of the foreign purchaser,

in accordance with section 801(e)(1) of

the act, and is intended for further

manufacture into final dosage form

outside the United States, in accordance

with section 351(h)(3) of the PHS Act.

Such evidence may consist of a valid

marketing authorization for the partially

processed biological product or the final

product from the foreign ministry of

health, contractual agreement, and

purchase orders that may include

foreign specifications;

• Records, such as manufacturing

records, that trace the partially

processed biological product through

the assignment of a batch or lot

numbering system at the U.S. exporting

firm. The agency suggests that these

records also include temperature

stability data for product during the

conditions of transit (export) and

periodic checks of the capacity of the

shipping containers;

• Distribution records of exported

partially processed biological products;

• Copies of all labeling that

accompanies the partially processed

biological product for export (i.e.,

container label or any package insert).

FDA recommends that the partially

processed biological product’s container

label state, ‘‘Caution: For Further

Manufacturing Use Only;’’ and

• Evidence that the product is not

intended for sale in the United States

and has not been sold or offered for sale

in the United States. This may consist

of purchase orders from the foreign

purchaser and distribution records and

records of the product’s labeling and

similar products sold in the United

States. FDA examines whether the

product itself (as opposed to batches or

lots) is sold or offered for sale in the

United States. For example, if a

company produces five batches of a

partially processed biological product

and intends to export two batches and

sell the remaining three in the United

States, the product is deemed ‘‘sold or

offered for sale in the United States’’

and ‘‘intended for sale in the United

States’’ within the meaning of section

351(h) of the PHS Act.

Additionally, firms that manufacture,

prepare, or process partially processed

biologics for export must register with

FDA and list their products under

section 510 of the act and parts 207 and

607 (21 CFR parts 207 and 607).

V. Labeling Requirements for Drugs and

Biologics Exported Under Section

801(e)(1) of the Act—Section 801(f) of

the Act

The 1996 Amendments contained a

new provision that permits the export of

drugs (other than insulin, antibiotics,

animal drugs, or drugs exported under

section 802 of the act) 10 that may be

sold in the United States. For these

drugs, section 801(f) of the act imposes

certain labeling requirements. If the

drug that is approved in the United

States is being exported to a country

that has different or additional labeling

requirements or conditions for use

(compared to those on the FDAapproved labeling), and the foreign

country requires the drug to be labeled

in accordance with those requirements

or uses, section 801(f)(1) of the act

specifies that the drug may be labeled in

accordance with the foreign

requirements and conditions for use so

long as the drug is also labeled in

accordance with the act.

For those conditions of use that are

not approved in the United States,

section 801(f)(2) of the act requires the

labeling to state that those uses are not

approved under the act. The act defines

‘‘labeling’’ as ‘‘all labels and other

written, printed, or graphic matter (1)

upon any article or any of its containers

or wrappers, or (2) accompanying such

article.’’ Thus, to comply with section

801(f)(2) of the act, FDA suggests that a

firm place a statement on the labeling

regarding the uses that are not approved

in the United States wherever an

unapproved use appears. For example,

if an unapproved use is on the

immediate label and on the product’s

container, a statement identifying the

uses that are not approved in the United

States would appear on the immediate

label and on the product’s container.

FDA has received questions whether

the statement identifying the uses that

are not approved in the United States

should be in the language used in the

foreign country. Although section 801(f)

of the act is silent on this point, the

agency suggests that the statement be in

the foreign language because the

requirement would be meaningless if

foreign consumers could not read the

statement and would have no value for

U.S. consumers who, because section

801(e)(1)(D) of the act prohibits the

exported product from being sold or

offered for sale in domestic commerce,

would not have access to the product

when labeled for the unapproved use(s).

In some instances, products that may

be exported in compliance with the

labeling requirements in section 801(f)

of the act may also qualify for export

under section 802(b)(1)(A) of the act

(discussed later in section VII.D of this

document). In such cases, a firm may

elect to export a product under either

section 801(e) or section 802(b) of the

act so long as the product meets the

statutory requirements for export. As

discussed in section VII of this

document, a drug exported under

section 802 of the act is not subject to

the labeling requirements in section

801(f) of the act.

VI. Exports of Unapproved Drugs,

Biologics, and Devices Under Section

802(b) of the act

A. Drugs and Biologics

As stated earlier, courts and FDA have

interpreted section 801(e) of the act as

being inapplicable to unapproved new

drugs and biologics. As a result, the

1986 Amendments amended the act so

that the export of unapproved new

drugs and biologics was regulated under

section 802 of the act.

The 1996 Amendments, insofar as

human drugs and biologics are

concerned, modified the scope of

section 802 of the act to state that the

provision applies to drugs and biologics

that: Require approval under section

505 of the act or, for biologics, require

licensing under section 351 of the PHS

Act; do not have such approval or

license; and are not exempt from section

505 of the act or section 351 of the PHS

Act.

Thus, section 802 of the act applies to

unapproved new human drugs and

biologics and to approved human drugs

and biologics being exported for

unapproved uses. 11 If FDA declines to

approve or license a drug or biologic or
32226 Federal Register / Vol. 63, No. 113 / Friday, June 12, 1998 / Notices

12The agency has not recognized an international

standards organization or standard for any FDAregulated product for purposes of section 802(f) of

the act, but is examining this issue closely.

13A statement on the outside of the shipping

package, such as, ‘‘For export only’’ or similar

language, may be sufficient.

14As stated in section IV of this document, FDA

advises firms to maintain records concerning the

product, its labeling, and similar products sold in

the United States. The product’s labeling can state

that the product is ‘‘Not for sale in the U.S.’’ or use

similar language.

15The listed countries, under section 802(b) of

the act, are: Australia, Canada, Israel, Japan, New

Zealand, Switzerland, South Africa, and the

member nations of the European Union and the

European Economic Area. As of January 1, 1998, the

EU countries are Austria, Belgium, Denmark,

Germany, Greece, Finland, France, Ireland, Italy,

Luxembourg, the Netherlands, Portugal, Spain,

Sweden, and the United Kingdom. The EEA

countries are the EU countries, Iceland,

Liechtenstein, and Norway. The number of listed

countries expands automatically as countries

become members of the EU or the EEA.

decides to withdraw approval or revoke

licensure for a drug or biologic and that

product has been exported to one or

more foreign countries, section 802(a) of

the act requires FDA to notify the

appropriate foreign public health

official in those countries of its

decision.

Section 802 of the act also contains

special provisions for drugs intended for

investigational use in a listed country,

drugs intended for further processing or

labeling to fill the pipeline in

anticipation of marketing authorization

in a listed country, and drugs intended

to treat a tropical disease or disease that

is ‘‘not of significant prevalence in the

United States.’’ These provisions are

discussed in greater detail in sections

VII through IX of this document.

B. Devices

Section 802(b) of the act, like section

801(e)(2) of the act, applies to devices

that: Do not comply with an applicable

requirement under section 514 or 515 of

the act; are subject to an IDE; or are

banned devices.

This means that devices that have

premarket approval are not subject to

section 802 of the act, nor are devices

that are the subject of a marketing

clearance under the premarket

notification provision under section

510(k) of the act.

C. Basic Requirements for All Products

Exported Under Section 802 of the Act

Under section 802(f) of the act, the

basic requirements for all drugs,

biologics, and devices exported under

section 802 of the act are as follows:

• The product must be manufactured,

processed, packaged, and held in

‘‘substantial conformity’’ with cGMP’s

or meet international standards as

certified by an international standards

organization recognized by FDA. 12

Neither the 1996 Amendments nor its

legislative history explains what

constitutes ‘‘substantial conformity’’

with cGMP’s, but the legislative history

for the Generic Drug Enforcement Act of

1992 may be instructive. In discussing

the terms ‘‘substantial compliance’’ with

cGMP’s and good laboratory practices,

the House Committee on Energy and

Commerce suggested that ‘‘substantial

compliance’’ could not mean full

compliance with GMP’s because FDA

‘‘lacks the continuing presence that

would be necessary to conclude that a

firm is in full compliance with GMPs

and GLPs’’ (see H. Rept. 102–272, 102d

Cong., 2d sess. 20 (1992)). The term

does mean that the firm must have

passed its most recent GMP inspection

(or that GMP violations have been

rectified, and the firm has credible

systems and personnel in place to

prevent a recurrence of the violation(s)).

FDA interprets the term ‘‘substantial

conformity’’ under section 802(f)(1) of

the act in a similar manner.

• The product must not consist in

whole or in part of any filthy, putrid, or

decomposed substance and must not

have been prepared, packed, or held

under insanitary conditions where it

may have been contaminated or made

injurious to health;

• The container for the product must

not be composed, in whole or in part,

of any poisonous or deleterious

substance which may render the

contents injurious to health;

• The product must have the strength,

purity, or quality that it is represented

to possess;

• For drugs, no substance may be

mixed or packed with the drug that

would reduce the drug’s quality or

strength or may substitute in whole or

in part for another substance in the

drug;

• The product must comply with the

requirements in section 801(e)(1) of the

act. As stated earlier, section 801(e)(1) of

the Act requires that the drug or device

to be exported: (1) Accords to the

specifications of the foreign purchaser;

(2) not conflict with the laws of the

country to which it is intended for

export; (3) be labeled on the outside of

the shipping package that it is intended

for export; 13 and (4) not be sold or

offered for sale in domestic

commerce. 14 (A discussion of the

requirements in section 801(e)(1) of the

act appears earlier in this guidance.)

• The product cannot be the subject of

a notice by FDA or the U.S. Department

of Agriculture determining that the

probability of reimportation of the

exported product would present an

imminent hazard to the public health

and safety of the United States, such

that exportation must be prohibited;

• The product cannot present an

imminent hazard to the public health of

the country to which it would be

exported; and

• The product must be labeled in

accordance with the requirements and

conditions of use in the listed country 15

which authorized it for marketing and

the country to which it is being

exported, and must be labeled in the

language and units of measurement

used in or designated by the country to

which the drug or device is being

exported. Additionally, a drug or device

may not be exported if the drug or

device is not promoted in accordance

with these labeling requirements.

If the above requirements are not met,

section 802(f) of the act states that a

drug or device may not be exported.

Furthermore, in determining whether a

drug or device may present an imminent

hazard to the public health of the

foreign country or is improperly labeled

or promoted, section 802(f) of the act

requires FDA to consult with the

‘‘appropriate public health official in

the affected country.’’

Exporters are primarily responsible

for determining whether export is

permitted under the act and whether

their exports meet the requirements in

section 802(f) of the act. During an

inspection, FDA will evaluate

compliance with the relevant export

provisions as appropriate. As discussed

below, section 802(g) of the act requires

persons exporting drugs and devices

under section 802(b)(1) of the act to

maintain records of such exported

products and the countries to which

they were exported and to provide a

simple notification to the agency

regarding such exports.

D. Exports of Unapproved New Drugs,

Biologics, and Devices to a Listed

Country—Section 802(b)(1)(A) of the Act

The principal provision authorizing

the exportation of unapproved new

drugs, biologics, and devices is section

802(b)(1)(A) of the act. Section

802(b)(1)(A) of the act states that a drug

or device ‘‘may be exported to any

country, if the drug or device complies

with the laws of that country and has

valid marketing authorization by the

appropriate authority’’ in Australia,

Canada, Israel, Japan, New Zealand,

Switzerland, South Africa, or any

member nation in the European Union

or the European Economic Area.
Federal Register / Vol. 63, No. 113 / Friday, June 12, 1998 / Notices 32227

16Additionally, under the 1986 Amendments,

FDA approved exports of drugs that varied, in

limited respects, from drugs that were the subject

of an IND or a marketing application. The 1986

Amendments required firms to be actively pursuing

market approval of the drug in the United States as

a condition for exportation; this condition no longer

exists in the act.

17The requirements in sections 802(b)(2) and

(b)(3) of the act do not apply to devices. Congress

omitted devices from these provisions to the act

because it found FDA’s practice of permitting

(under section 801(e)(2) of the act) exports of

devices that had approved IDE’s to provide an

acceptable alternative.

This means that a firm whose drug or

device has received marketing

authorization in any of the countries

listed above can export that drug or

device to any country in the world as

long as the drug or device meets

applicable requirements of the act,

without submitting an export request to

FDA or receiving FDA approval to

export the drug or device. Moreover, in

a change from the 1986 Amendments,

firms do not have to seek U.S. approval

of the product as a condition of

exportation.

FDA interprets the terms ‘‘marketing

authorization’’ as meaning an

affirmative decision by the appropriate

public health authority in a foreign

country to permit the drug, biologic, or

device to be sold in that country. For

example, if country D approves a drug

for investigational use, the approval

would not constitute ‘‘marketing

authorization’’ because country D’s

decision did not extend to commercial

marketing. Likewise, a decision by

country D to permit sales to another

country would not represent ‘‘marketing

authorization’’ because it does not

permit sales within country D.

Some countries, however, have

regulatory systems that permit

marketing without an affirmative act or

decision by the government. In such

cases, FDA would consider a drug,

biologic, or device to have ‘‘marketing

authorization’’ if the listed country does

not object to the product’s marketing,

and FDA recommends that the firm

obtain a document from the relevant

authority in the listed country

indicating that it does not object to the

product’s marketing.

As for the word ‘‘drug,’’ the drug to

be exported under section 802(b)(1)(A)

of the act should be the same product

as the drug that received marketing

authorization in the listed foreign

country. Thus, the issue of whether the

drug to be exported must be exactly

identical to the drug authorized in the

listed country may depend on the

conditions surrounding market

authorization in the foreign country. For

example, if country E’s marketing

authorization applies only to a drug

product with a specific composition,

rather than to drugs that have a

particular active ingredient or general

composition, then the drug that is to be

exported from the United States must

have the same composition as the drug

that received marketing authorization in

country E. If, however, country E

approves a drug product and, as a result

of that approval, permits marketing of

other drugs using the same active

ingredient, then the ‘‘drug’’ that could

be exported under section 802(b)(1)(A)

of the act could be any drug that has the

same active ingredient. 16

A similar concept applies to devices.

Devices that are exported under section

802(b)(1)(A) of the act should be similar

(to the degree that any variation could

not affect the safety or effectiveness of

the product) or identical to the devices

that receive marketing authorization in

a listed country, depending on the

requirements of that listed country.

E. Expanding the List of Countries in

Section 802(b)(1)(A) of the Act

The list of countries in section

802(b)(1)(A) of the act is not closed. The

1996 Amendments contain a

mechanism whereby the Secretary may

add other countries to the list, provided

that the country meets certain criteria.

These criteria include: (1) Statutory or

regulatory requirements which require

the review of drugs and devices for

safety and effectiveness by a

government entity in that country and

which authorizes marketing approval of

drugs and devices that trained and

qualified experts acting on behalf of the

government have determined to be safe

and effective, (2) statutory or regulatory

requirements pertaining to cGMP’s, (3)

statutory or regulatory requirements for

reporting adverse events and for

removing unsafe or ineffective drugs

and devices from the market, (4)

statutory or regulatory requirements that

a product’s labeling and promotion be

in accordance with the product’s

approval, and (5) equivalence of the

country’s marketing authorization

system with that in the listed countries.

The authority to add countries to the

list, by law, cannot be delegated below

the Office of the Secretary. Thus, FDA

has no authority to add countries to the

list.

F. Exports of Unapproved New Drugs

and Biologics to an Unlisted Country—

Section 802(b)(2) and (b)(3) of the Act

If a firm intends to export an

unapproved new drug (including

biologics) to a foreign country, but none

of the listed countries has approved the

drug for marketing, it has two other

options for exporting the product. 17

One option is in section 802(b)(2) of

the act. This section permits a firm to

export an unapproved drug directly to

an unlisted country if:

• The drug complies with the laws of

the foreign country and has valid

marketing authorization by the

‘‘responsible authority’’ in that country,

and

• The agency determines that the

foreign country has statutory or

regulatory requirements:

• Which require the review of drugs for

safety and effectiveness by a government

entity in that country and which authorizes

marketing approval of drugs which trained

and experienced experts have determined to

be safe and effective. The experts must be

employed by or acting on behalf of the

foreign government entity and base their

determination on adequate and wellcontrolled investigations (including clinical

investigations);

• Pertaining to cGMP’s;

• For reporting adverse events and for

removing unsafe or ineffective drugs from the

market; and

• Which require that the labeling and

promotion be in accordance with the

product’s approval.

FDA recommends that firms

intending to export drugs under section

802(b)(2) of the act provide

documentation showing that the drug

complies with the foreign country’s

laws and has valid marketing

authorization. (If the country has a

regulatory system that allows marketing

without an affirmative decision by the

government, FDA recommends that the

firm obtain a document indicating that

the authorities in the listed country do

not object to the product’s marketing.)

The agency also suggests that firms

provide documentation so FDA can

make its determination on the foreign

country’s statutory and/or regulatory

requirements. Copies of the foreign

country’s laws and regulations (in

English) may be helpful, but are not

required; firms may also provide a

description of the foreign country’s laws

and regulations with citations that

identify the precise law or regulation. If

FDA cannot make the necessary

determinations concerning the foreign

country’s statutory and regulatory

requirements, the firm cannot export the

drug under section 802(b)(2) of the act.

The second option is in section

802(b)(3) of the act. This section permits

a firm to petition the agency to approve

exportation to an unlisted country if the

conditions for export under section

802(b)(1) and 802(b)(2) of the act cannot

be met. Under section 802(b)(3) of the

act, FDA must allow exportation of the

drug if:

• The person exporting the drug: (1)

Certifies that the drug would not meet
32228 Federal Register / Vol. 63, No. 113 / Friday, June 12, 1998 / Notices

the conditions for approval under the

act or the conditions for approval in a

listed country; and (2) provides

‘‘credible scientific evidence’’ that is

acceptable to FDA to show that the drug

would be safe and effective under the

conditions of use in the country to

which it is being exported. The statute

does not specify what constitutes

‘‘credible scientific evidence,’’ but an

adequate and well-controlled study or

studies, animal and in vitro

pharmacology and toxicology studies,

microbiology studies (for biologics), and

statistical analyses of data should be

helpful; and

• The appropriate health authority in

the foreign country that is to receive the

drug: (1) Requests approval of the drug’s

exportation, (2) certifies that the health

authority understands that the drug is

not approved under the act or by any

listed country, and (3) concurs that the

scientific evidence provided to FDA is

credible scientific evidence that the

drug would be reasonably safe and

effective in the foreign country. A letter

from the relevant foreign government

entity addressing each item in this

paragraph should be acceptable.

As a reminder, any person who

exports a drug under section 802 of the

act also must comply with the basic

export requirements set forth in section

802(f) of the act.

Persons who wish to export a drug

under sections 802(b)(2) or 802(b)(3) of

the act should send their documentation

or requests to:

(For Biologics), Division of Case

Management (HFM–610), Center for

Biologics Evaluation and Research,

Food and Drug Administration,

1401 Rockville Pike, rm. 200N,

Rockville, MD 20852–1448.

(For Drug Products), Executive

Secretariat Team (HFD–6), Center

for Drug Evaluation and Research,

1451 Rockville Pike, Rockville, MD

20852–1420.

FDA has 60 days to act on a request

to export a drug under section 802(b)(3)

of the act. The agency will begin the 60

day period on the date that it receives

a complete petition containing the

certification and evidence required by

the act.

VII. Exports of Unapproved Drugs and

Devices for Investigational Use to Listed

Countries Under Section 802(c) of the

Act

A. Background

The 1986 Amendments did not

impose any special requirements for

drugs or devices exported for

investigational use. Moreover, FDA did

not apply section 801(e) of the act to

investigational drugs because section

801 of the act was interpreted as not

applying to ‘‘new drugs.’’ Instead, FDA

regulated the exportation of unapproved

new drugs (including biologics) for

investigational use under its authority

over investigational drugs at section

505(i) of the act.

FDA issued regulations governing the

exportation of unapproved new drugs

for investigational use on January 18,

1984 (49 FR 2095), with minor

modifications since then. These

regulations were codified at § 312.110

(the part of the Code of Federal

Regulations pertaining to investigational

drugs), and so the program became

known as the ‘‘312 program.’’ The

regulations required any person who

intends to export an unapproved new

drug product for use in a clinical

investigation either to have an IND or to

submit a written request to FDA. The

regulations required the written request

to provide sufficient information about

the drug to satisfy FDA that the drug is

appropriate for investigational use in

humans, that the drug will be used for

investigational purposes only, and that

the drug may be legally used by the

consignee in the importing country for

the proposed investigational use. The

regulations further stated that the

request must specify the quantity of the

drug to be shipped and the frequency of

expected shipments. If FDA authorized

exportation of the drug, it would notify

the government of the importing

country. The regulations, however, did

not apply to drugs approved for export

under section 802 of the act or section

351(h)(1)(A) of the PHS Act.

In contrast, the agency did apply

section 801(e) of the act to

investigational devices. This was partly

because, unlike the situation for drugs,

the act contains only one definition for

‘‘device.’’ The agency issued a

regulation on device exports on January

18, 1980 (45 FR 3732 at 3751). The

provision, codified at § 812.18(b),

simply stated that a person who intends

to export an unapproved device must

obtain FDA approval (under what is

now part of section 801(e)(2) of the act)

before exporting the device.

B. Impact of the 1996 Amendments on

Drug Exports for Investigational Use

The 1996 Amendments changed the

312 program significantly by creating a

new section 802(c) of the act. In brief,

section 802(c) of the act permits a firm

to export an unapproved drug for

investigational use in any of the listed

countries, without prior FDA approval

or even an IND. The only requirements

are that the drug be exported in

accordance with the laws of the foreign

country, and comply with the basic

export requirements in section 802(f) of

the act. The exporter, under section

802(g) of the act, must also maintain

records of all drugs exported and the

countries to which they were exported.

It is important to note that FDA

interprets section 802(c) of the act as

applying only to investigational drugs

and devices exported to the listed

countries. The agency is aware that

some firms have interpreted this

provision as permitting transshipment

to unlisted countries, but section 802(c)

of the act is silent with respect to

transshipment, and a more reasonable

interpretation would be that

transshipments are not allowed under

section 802(c) of the act. Interpreting

section 802(c) of the act to allow

transshipment would presume that the

listed countries may serve as mere

transfer points or conduits for

investigational drugs and devices

destined for unlisted countries (when

neither the statute nor its legislative

history support such a presumption)

and would make the limitation to the

listed countries in section 802(c) of the

act virtually meaningless.

Additionally, one should note that

section 802(b)(1) of the act authorizes

exportation to unlisted countries if the

drug complies with the foreign

country’s laws and has valid marketing

authorization in a listed country.

Exports under section 802(b)(1) of the

act may be made for investigational uses

or for marketing purposes.

For exports of drugs for

investigational use in unlisted countries

where the drug product has not received

valid marketing authorization in a listed

country, the ‘‘312 program’’

requirements at § 312.110 remain

applicable. However, FDA is

considering possible revisions to the

regulations for the ‘‘312 program’’ due

to sections 802(b) and (c) of the act as

well as additional changes to the

program.

C. Impact of the 1996 Amendments on

Device Exports for Investigational Use

The 1996 Amendments also affected

device exports significantly. Section

802(c) of the act permits a firm to export

an unapproved device for

investigational use in any of the listed

countries, without prior FDA approval

or an IDE. However, as in the case for

drugs, the device must be exported in

accordance with the laws of the foreign

country.

Yet, unlike the situation for drug

exports, the 1996 Amendments give

device manufacturers the option

whether to export a device under

section 801(e)(2) of the act or under
Federal Register / Vol. 63, No. 113 / Friday, June 12, 1998 / Notices 32229

section 802 of the act. The selected

authority is important because each

section of the act carries its own

statutory requirements.

For example, if company F wants to

export an unapproved device for

investigational use to a listed country, it

could:

• Export the device under section

801(e)(2) of the act. Under this

provision, the exporter would need to

comply with section 801(e)(1) of the act

and, depending on the device, might

have to submit information that would

enable FDA to determine that

exportation is not contrary to the public

health or safety and that the foreign

country approves of the exportation, or

• Export the device under section

802(b)(1)(A) of the act if the device has

received valid marketing authorization

in any listed country. Section

802(b)(1)(A) of the act permits

exportation of an unapproved device,

for any purpose, if the device complies

with the laws of the foreign country and

has received valid marketing

authorization in a listed country.

(Exports under section 802(b)(1) of the

act may also occur to unlisted countries

so long as the device complies with the

foreign country’s laws and has valid

marketing authorization in a listed

country.) Exports under this option

must comply with the basic export

requirements at section 802(f) of the act

(such as being in ‘‘substantial

conformity’’ with cGMP’s or meeting

international standards as certified by a

recognized international standards

organization and complying with

section 801(e)(1) of the act) and the

notification and recordkeeping

requirements in section 802(g) of the

act; or

• Export the device to a listed country

under section 802(c) of the act, without

prior FDA approval or the submission of

any information to FDA. However,

under this option, compliance with the

basic export requirements in section

802(f) of the act and the recordkeeping

requirement in section 802(g) of the act

is necessary.

Consequently in the Federal Register

of May 13, 1997 (62 FR 26228), FDA

amended § 812.18 to state that a person

exporting an investigational device

subject to part 812 must obtain FDA’s

prior approval under section 801(e)(2) of

the act or comply with section 802 of

the act.

Of course, a firm always has the

additional option of conducting the

investigation under an IDE, in which

case the IDE requirements in part 812

would apply.

VIII. Exports of Unapproved Drugs and

Devices in Anticipation of Foreign

Approval—Section 802(d) of the Act

Section 802(d) of the act permits the

exportation of an unapproved drug,

biologic, or device ‘‘intended for

formulation, filling, packaging, labeling,

or further processing in anticipation of

market authorization’’ in any of the

listed countries. The only express

requirements for such exports are that

the product comply with the laws of the

foreign country and the requirements in

section 802(f) of the act. Records for

such exports must be kept in accordance

with section 802(g) of the act.

The range of activities covered under

section 802(d) of the act is very broad,

although mere storage of an unapproved

drug, biologic, or device would not

constitute ‘‘formulation, filling,

packaging, labeling, or further

processing.’’ Additionally, FDA

interprets the phrase ‘‘in anticipation of

market authorization’’ as meaning that

the manufacturer exporting the product

has filed an application or submission

to obtain final marketing authorization

in the foreign country. FDA does not

consider an intent to seek market

authorization or to file a marketing

application at some future time to

constitute ‘‘anticipation of market

authorization.’’

FDA advises firms that export a

product in anticipation of market

authorization, under section 802(d) of

the act, to notify FDA when they export

the product. The notification should

identify the drug, biologic, or device

being exported and the country

receiving the product. Notification

when a product is exported under

section 802(d) of the act is consistent

with section 802(f) of the act. As stated

earlier, section 802(f) of the act

establishes conditions for all products

exported under section 802 of the act.

For example, a product cannot be

exported under section 802 of the act if

it is not in substantial conformity with

cGMP’s. Yet, if firms do not notify FDA

about the products that have been

exported, FDA cannot determine

whether products exported under

section 802(d) of the act comply with

cGMP’s.

Additionally, notification is

consistent with a practical

interpretation of section 802(g) of the act

which requires exporters of drugs,

biologics, and devices to provide a

simple notification to the agency when

they export a product to a listed country

or to an unlisted country under section

802(b)(1) of the act. Section 802(b)(1) of

the act permits exports when the drug,

biologic, or device has received market

authorization in a listed country,

whereas section 802(d) of the act

permits exports to a listed country in

anticipation of market authorization. A

literal interpretation of section 802(g) of

the act would not require an exporter to

notify FDA when it shipped a product

to a listed country in anticipation of

market authorization, but would instead

require the exporter to notify FDA when

the exporter shipped the same product

to the same country once it received

market authorization. It would be more

practical, simple, and efficient–both for

exporters and FDA– if exporters notify

FDA when they export a product in

anticipation of market authorization,

under section 802(d) of the act, rather

than wait for market authorization in

the listed country and then notify FDA.

Details on notification under section

802(g) of the act appear later in this

guidance.

IX. Exports of Drugs and Devices for

Diagnosing, Preventing, or Treating a

Tropical Disease or a Disease ‘‘Not of

Significant Prevalence in the United

States’’—Section 802(e) of the Act

The 1986 Amendments authorized

exports of unapproved new drugs and

biologics intended to prevent or to treat

a tropical disease. Under the 1986

Amendments, the exporter had to

submit an export application to FDA.

The export application had to: (1)

Describe the drug being exported, (2) list

each country to which the drug would

be exported, (3) contain a certification

that the drug would not be exported to

a country if the agency could not find

that the drug would be safe and effective

in that country, (4) identify the

establishments where the drug is made,

and (5) show that other statutory

requirements (such as compliance with

cGMP’s) are met. FDA had to approve

the export application before

exportation could proceed.

The 1996 Amendments amended the

tropical disease provision in several

ways. The provision now covers drugs

intended to diagnose, prevent, or treat

tropical diseases, includes devices

among the products eligible for

exportation, and includes drugs,

biologics, and devices that are intended

to treat diseases that are ‘‘not of

significant prevalence’’ in the United

States. A disease that is ‘‘not of

significant prevalence’’ in the United

States can be one that is not manifested

in many Americans (either because the

pathogen is not common or because

available treatments have made the

disease rare in the United States) or is

indigenous to a particular foreign

country or to an area in another country.

For example, measles may be
32230 Federal Register / Vol. 63, No. 113 / Friday, June 12, 1998 / Notices

considered to be a disease that is not of

significant prevalence in the United

States because most children are

immunized against measles.

However, like the 1986 Amendments,

the revised provision (which is now

codified as section 802(e) of the act)

requires FDA to approve an export

application before the product can be

exported. The export application should

contain information showing that the

drug or device is intended for use in a

tropical disease or a disease that is not

of significant prevalence in the United

States. Additionally, the application

should contain information that will

enable FDA to determine whether the

drug, biologic, or device:

• Will not expose patients in the

foreign country to an unreasonable risk

of illness or injury, and

• When used under conditions

prescribed, recommended, or suggested

in the labeling or proposed labeling has

a probable benefit to health that

outweighs the risk of injury or illness

from its use, taking into account the

probable risks and benefits of currently

available drug or device treatment. By

‘‘currently available drug or device

treatment,’’ the applicant should

consider the availability of products that

are approved for the particular disease

as well as those that are commonly used

to treat the disease, even if the product

is not approved for that indication.

X. Export Notification Under Section

802(g) of the Act

Section 802(g) of the act requires

persons exporting a drug or device

under section 802(b)(1) of the act to

provide a ‘‘simple notification * * *

identifying the drug or device when the

exporter first begins to export such drug

or device’’ to any country listed in

section 802(b)(1) of the act. If the

product is to be exported to an unlisted

country, section 802(g) of the act

requires the exporter to provide a

simple notification ‘‘identifying the

drug or device and the country to which

such drug or device is being exported.’’

In all cases, section 802(g) of the act

requires the exporter to maintain

records of all drugs or devices exported

and the countries to which they were

exported.

A. The Content of the Simple

Notification

FDA suggests that, to identify a drug

or device, the exporter describe in the

notification the product’s name or type

of device, its generic name, and a

description of its strength and dosage

form (if the product is a drug) or the

product’s model number (if the product

is a device).

As for identifying the country that is

to receive the exported product, FDA

acknowledges that section 802(g) of the

act requires exporters to identify the

country that is to receive the exported

product only if the country is not a

listed country. However, FDA

encourages exporters to identify the

country that is to receive the exported

product in all cases, regardless of

whether the country is among those

listed in section 802(b)(1) of the act.

Identification of the foreign country,

regardless of whether it is listed or not,

helps FDA meet its obligations under

sections 802(a) and 802(f)(4), (f)(5), and

(f)(6) of the act which prohibit exports

under certain conditions (such as a

finding of an imminent hazard to the

public health) and/or requires FDA to

consult with the ‘‘appropriate public

health official’’ in the affected country.

B. Where to Send the Simple

Notification

Notifications may be sent to the

following addresses:

For biological drug products and

biological devices: Division of Case

Management (HFM–610), Office of

Compliance, Center for Biologics

Evaluation and Research, Food and

Drug Administration, 1401

Rockville Pike, rm. 200N, Rockville,

MD 20852–1448.

For human drug products: Division of

Labeling and Nonprescription Drug

Compliance (HFD–310), Center for

Drug Evaluation and Research,

Food and Drug Administration,

7520 Standish Pl., Rockville, MD

20855–2737.

For devices: Division of Program

Operations (HFZ–305), Center for

Devices and Radiological Health,

Food and Drug Administration,

2094 Gaither Rd., Rockville, MD

20850.

C. Recordkeeping

As stated earlier, section 802(g) of the

act requires exporters to maintain

records of all drugs and devices

exported and the countries to which the

products were exported. FDA

recommends that exporters maintain

records showing:

• The product’s name and its generic

name (if the product is a drug or a

device),

• The type of device (if the product is

a device),

• A description of its strength and

dosage form and the product’s lot or

control number (if the product is a drug)

or the product’s model number (if the

product is a device),

• The consignee’s name and address,

and

• The date and quantity of product

exported.

FDA recommends that these records

be kept at the site from which the

products were exported and be

maintained at least 5 years after the date

of exportation. The agency may request

that the records be made readily

available for review and during an

agency inspection.

Additionally, FDA reminds parties

that they may need to maintain other

records beyond those specified in

section 802(g) of the act. For example,

firms whose products must be in

substantial conformity with cGMP’s

under section 802(f)(1) of the act may be

subject to cGMP recordkeeping

requirements under the regulations that

apply to their products.

XI. ‘‘Import for Export’’—Section

801(d)(3) and (d)(4) of the Act

Before the 1996 Amendments, all

imported components of drugs,

biologics, devices, and other FDAregulated products had to comply with

the requirements of the act, even if they

were to be incorporated into products

destined solely for export.

The 1996 Amendments changed the

law by creating two subsections at

801(d)(3) and (d)(4) of the act. Under

section 801(d)(3) of the act, a

component of a drug or a biologic, a

component part, accessory, or other

article of a device, or a food additive,

color additive, or dietary supplement

that would otherwise be refused entry

into the United States, can be imported

into the United States if:

• The importer submits a statement to

the agency at the time of initial

importation declaring that the

component, part, accessory, or article is

intended to be ‘‘incorporated’’ or

‘‘further processed’’ by the initial owner

or consignee into a drug, biological

product, device, food, food additive,

color additive, or dietary supplement

that will be exported from the United

States by the initial owner or consignee

in accordance with section 801(e) or

section 802 of the act or section 351(h)

of the PHS Act (see section 801(d)(3)(A)

of the act).

• The initial owner or consignee

responsible for the imported article

maintains records that identify the use

of the imported component, part,

accessory, or article. Upon request from

the agency, the initial owner or

consignee must submit a report that

accounts for the exportation or the

disposition of the imported component,

part, accessory, or article (including

quantities that were destroyed),

including the manner in which the

initial owner or consignee complied
Federal Register / Vol. 63, No. 113 / Friday, June 12, 1998 / Notices 32231

with the requirements in section 801(d)

of the act (see section 801(d)(3)(B) of the

act).

• Any imported component, part,

accessory, or article that is not

incorporated into a product must be

destroyed or exported by the owner or

consignee (see section 801(d)(3)(C) of

the act).

This provision is commonly referred

to as the ‘‘import for export’’ provision.

A. Items Covered Under the Import for

Export Provision

1. Human Drugs

One issue under section 801(d)(3) of

the act is what constitutes a

‘‘component’’ of a drug. FDA regulations

define ‘‘component’’ as meaning ‘‘any

ingredient intended for use in the

manufacture of a drug product,

including those that may not appear in

such drug product.’’ (See § 210.3(b)(3).)

Additionally, for purposes of section

801(d) of the act, FDA interprets the

term ‘‘component’’ broadly to include a

range of items, such as the active and

inactive ingredients for a drug or

biologic, bulk drugs, and even

unapproved foreign versions of drugs

that are approved for use in the United

States. So, for example, if company X

wants to import a bulk drug from a

source that differs from the bulk drug

source it uses for products sold in the

United States, company X may import

the bulk drug from the different source

provided that company X incorporates

the bulk drug into a product for export

or further processes the bulk drug before

exporting it (or otherwise destroys the

bulk drug). The imported bulk drug

from the different source cannot be used

in the product to be sold in the United

States.

Additionally, an item can be a

‘‘component’’ if it is intended for

‘‘further processing’’ in the United

States before being exported to another

country. For example, a finished dosage

form that is sterilized in the United

States would be a ‘‘component’’ within

section 801(d)(3) of the act (because the

drug is ‘‘further processed’’ during the

sterilization process).

2. Devices

For devices, FDA regulations define a

‘‘component’’ as ‘‘any raw material,

substance, piece, part, software,

firmware, labeling, or assembly which is

intended to be included as part of the

finished, packaged, and labeled device.’’

(See § 820.3(c).) As in the case of drugs

and biologics, FDA interprets the term

‘‘component’’ in section 801(d) of the

act broadly to encompass a range of

items.

Yet, regardless of whether the

imported item is a drug or device

component, the key issue under section

801(d)(3) of the act is how the

component will be ‘‘incorporated’’ or

‘‘further processed.’’

3. Food Additives, Color Additives, and

Dietary Supplements

Section 801(d)(3) of the act refers to

food additives, color additives, and

dietary supplements. The act defines

‘‘food additive’’ at section 201(s) of the

act, ‘‘color additive’’ at section 201(t) of

the act, and ‘‘dietary supplement’’ at

section 201(ff) of the act.

B. Activities Covered Under the Concept

of ‘‘Incorporation’’ and ‘‘Further

Processing’’

Section 801(d)(3) of the act only

permits a component, part, accessory, or

article to enter the United States if it is

intended to be ‘‘incorporated’’ into a

product for export or is to be ‘‘further

processed’’ into a product that will be

exported.

In the context of section 801(d)(3) of

the act, FDA interprets the terms

‘‘incorporated’’ and ‘‘further

processing’’ to encompass a wide range

of activities. Thus, ‘‘incorporation’’ and

‘‘further processing’’ are not confined to

product manufacture. Instead, they

include related activities such as

packaging and labeling of finished

products and specialized processing

(such as sterilization) of a product.

However, FDA does not consider a

component, part, accessory, or article to

be ‘‘incorporated’’ or ‘‘further

processed’’ if it is merely stored in the

United States before being exported

elsewhere. Although FDA has exercised

enforcement discretion regarding

specific entries of violative products

that are stored in the United States, the

agency does not consider the

importation of an unapproved product

for storage purposes to fall within the

meaning of ‘‘incorporated’’ or ‘‘further

processed’’ under section 801(d)(3) of

the act.

C. Submission of Statements to FDA

Section 801(d)(3)(A) of the act

requires the importer to submit, ‘‘at the

time of initial importation,’’ a statement

to the agency indicating that the

imported component, part, accessory, or

other article is intended to be

incorporated or further processed by the

initial owner or consignee into a

product that will be exported in

compliance with section 801(e) or

section 802 of the act or section 351(h)

of the PHS Act. Firms should submit

this statement to FDA each time they

import an article under the ‘‘import for

export’’ provision in the act. The

statement (along with other import

documents) should be provided to the

FDA field office that has responsibility

over the port or site of entry into the

United States.

FDA recommends that the statement

contain the following information:

• The purpose for which the article is

being imported prior to export (how it

will be further processed or the name or

description of the product into which it

will be incorporated);

• The imported article’s name or

description (including any scientific or

technical name);

• Any product coding, batch, lot, or

other identifying numbers;

• The name and address of the

imported article’s foreign manufacturer

(if different from the name of the foreign

shipper identified in the import records

at the U.S. Customs Service); and

• The name and address of the initial

owner or consignee in the United States

and, if different, the address in the

United States where the imported article

will be further processed or

incorporated into a product for export.

For blood, blood components, source

plasma, source leukocytes, or a

component, accessory, or part that is not

licensed under section 351(a) of the PHS

Act and is to be imported under section

801(d)(4) of the act, FDA suggests that

the statement include a copy of the

determination by FDA granting

permission to import the product or

article. (The request for determination is

described in more detail later in section

XI.E.3 of this document.)

FDA emphasizes that, under section

801(d) of the act, the imported article

must ultimately be further processed or

incorporated into a product that is

exported in accordance with the act’s

export provisions from the United States

or the imported article must be

destroyed. The imported article cannot

be used in any product which is to be

introduced into U.S. commerce.

The agency intends to issue

regulations covering statements under

section 801(d) of the act.

D. Records to be Retained and Reports

to be Submitted for Exports Under

Section 801(d)(3) of the Act

Section 801(d)(3)(B) of the act

requires the initial owner or consignee

responsible for an imported article to

‘‘maintain records that identify the use

of such imported article and upon

request * * * [to] submit[ ] a report that

provides an accounting of the

exportation or disposition of the

imported article, including portions that

have been destroyed, and the manner in
32232 Federal Register / Vol. 63, No. 113 / Friday, June 12, 1998 / Notices

18A firm may also be subject to certain

recordkeeping requirements outside those described

in section 802(g) of the act. For example, because

all drugs and devices exported under section 802

of the act must be in substantial conformity with

cGMP’s or international standards recognized by

FDA, there may be cGMP recordkeeping

requirements that apply to the exported drug or

device.

19FDA interprets ‘‘blood’’ as whole blood

collected from a single donor and processed either

for transfusion or further manufacturing (see

§ 606.3(a) and the regulation for whole blood at 21

CFR 640.1).

20Under FDA regulations, a ‘‘blood component’’

is that part of a single-donor unit of blood separated

by physical or mechanical means (see § 606.3(c) and

part 640 (21 CFR part 640)).

21Under § 640.60, ‘‘source plasma’’ is the fluid

portion of human blood collected by

plasmapheresis and intended as source material for

further manufacturing use. The term does not

extend to single donor plasma products intended

for intravenous use.

22FDA interprets ‘‘source leukocytes’’ as

leukocytes collected for further manufacturing by

leukapheresis (as defined in § 606.3(g)). This is a

procedure in which blood is removed from the

donor, the leukocyte concentrate is separated, and

the remaining formed elements and residual plasma

are returned to the donor.

23A U.S. manufacturer that intends to incorporate

or further process certain imported blood products

for export, or the foreign supplier of such material,

may submit an import for export request under

section 801(d)(4) of the act. Section 801(d)(3) of the

act specifies that the importer must submit the

statement of intent to export to the Secretary, and

that the initial owner or consignee responsible for

the imported article must maintain certain records

and submit a report upon request. A U.S. firm that

intends to perform processing or manufacturing

steps involving an imported blood product under

section 801(d)(4) and (d)(3) of the act should have

sufficient information, to submit to FDA in support

of an import for export request, that allows FDA to

which such person complied with the

requirements of this paragraph * * *.’’

The statutory reference to the initial

owner or consignee indicates that,

under section 801(d)(3) of the act, the

person who imports the article for

incorporation or further processing may,

in turn, have other persons perform the

actions that lead to the incorporation or

further processing of the imported

article. For example, if company C

imports a drug into the United States for

sterilization purposes, but does not have

the technological capability to sterilize

the drug itself, company C could send

the drug to company D for sterilization

and, after receiving the sterilized drug

back from company D, export the drug

from the United States. However, under

this scenario, company C would remain

the owner of the product and would be

responsible for maintaining records and

for submitting, upon FDA’s request, a

report accounting for the exportation or

disposition of the imported article.

The agency suggests that firms

importing an article into the United

States under section 801(d)(3) of the act

retain records showing:

• The name or description of the

article (including any scientific or

technical name);

• Any product coding, lot, batch, or

other identifying numbers;

• The name and address of the foreign

manufacturer of the imported article;

• How the article will be or was

further processed, and the name and

description of any product into which it

will be or was incorporated in the

United States;

• The signature of the responsible

person at the importing firm;

• The name and address of the firm

in the United States where the article

will be or was further processed or

incorporated into another product;

• The disposition of the imported

article, i.e., manufacturing records

showing how specific articles were used

or destroyed and the dates of receipt,

use, destruction, and/or reexportation,

as that information becomes available;

• Any product coding, lot, batch, or

other identification number for the

further-processed article or product

incorporating the imported article;

• A copy of the label to be applied to

the shipping package, container, or crate

used to export the further-processed

article or product incorporating the

imported article (indicating that it

contains articles that may not be sold or

offered for sale in the United States and

are intended for export only); and

• The name and address of the foreign

purchaser of the further-processed

article or product incorporating the

imported article.

• Additionally, for blood, blood

components, source plasma, source

leukocytes, or a component, accessory,

or part thereof (including blood or

plasma derivatives or intermediates)

that is not licensed under section 351(a)

of the PHS Act and is to be imported

under section 801(d)(4) of the act, the

agency recommends that the records

also include documentation of the

agreement between the foreign material

supplier and the U.S. manufacturer. The

documentation should outline the

specific contractual relationship, the

foreign manufacturing specifications,

and the U.S. manufacturer’s plan for

auditing the foreign supplier to ensure

compliance with the terms of the

contract. FDA suggests that the initial

owner or consignee have written

standard operating procedures to ensure

that such products are not diverted to

domestic use in the United States and

are kept segregated from and not comingled with products or components

intended for use in the United States

(e.g., quarantine procedures used for

segregating imported blood, blood

components, or final products from

products intended for use in the United

States, including validation data for

procedures to clean equipment and

facilities used for manufacturing

products for use in the United States

and exported products).

FDA also encourages firms to

maintain any other records that would

assist FDA in determining whether they

comply with section 801(d)(3) or (d)(4)

of the act. 18 FDA suggests that firms

retain records relating to the

importation of an article for

incorporation or further processing in

the United States for 5 years after the

destruction or exportation of the last

imported component, part, accessory, or

article for a particular lot or batch. The

records may be maintained at the

importing firm’s site and may be subject

to inspection by FDA.

FDA intends to issue regulations to

establish recordkeeping requirements,

and persons subject to this provision

should note that the act specifically

prohibits the making of a knowingly

false statement in any record or report

required under section 801(d)(3)(A) or

(d)(3)(B) of the act as well as the failure

to submit or maintain records under

these sections of the act (see section

301(w) of the act).

E. Special Requirements for Blood,

Blood Components, Plasma, Source

Leukocytes, and Tissues—Section

801(d)(4) of the Act

1. Blood, Blood Components, Plasma,

and Source Leukocytes

The ‘‘import for export’’ requirements

for blood, 19 blood components, 20

plasma, 21 and source leukocytes 22

differ from those for drugs and other

biologics. Under section 801(d)(4) of the

act, the importation of these products,

components, accessories, or parts is not

permitted under section 801(d)(3) of the

act unless the importation complies

with section 351(a) of the PHS Act or

the agency permits the importation

‘‘under appropriate circumstances and

conditions.’’ (FDA intends to issue

regulations specifying the ‘‘appropriate

circumstances and conditions’’ that

would allow importation of unlicensed

products under the import for export

authority.)

Under section 801(d)(4) of the act,

FDA may permit the import for export

of blood and blood components, source

plasma, source leukocytes, or a

component, accessory, or part thereof,

which may not be licensed or meet

cGMP requirements. Products imported

under section 801(d)(4) of the act must

also comply with section 801(d)(3) of

the act. 23
Federal Register / Vol. 63, No. 113 / Friday, June 12, 1998 / Notices 32233

make the determination whether appropriate

circumstances and conditions exist to permit such

importation.

Licensed blood products, such as

licensed source plasma, may be

imported if such importation complies

with section 351(a) of the PHS Act.

Other licensed blood products, such as

those having cGMP deficiencies, are not

considered to be in compliance with

section 351(a) of the PHS Act. If a

product does not have a license or is

considered to be in noncompliance with

section 351(a) of the PHS Act, the

manufacturer that wishes to import such

a blood product for incorporation or

further processing into a product for

export may seek FDA’s permission to

import the product. CBER will evaluate

such import for export requests on a

case-by-case basis.

Recovered plasma and serum are

blood products currently not subject to

licensure. Recovered plasma and serum

that are intended for further

manufacture or incorporation into

products for export must be imported in

accordance with the short supply

provisions at 21 CFR 601.22. Recovered

plasma and serum intended for further

manufacturing or incorporation into

noninjectable products not subject to

licensure may be imported without an

import for export submission if they are

manufactured in accordance with

cGMP’s and are labeled appropriately.

Labeling for such products should

include the applicable container label

requirements listed in § 606.121. A firm

may apply to import recovered plasma

and serum that do not meet cGMP’s by

submitting an import for export request.

CBER will evaluate these requests on a

case-by-case basis.

Thus, under section 801(d)(4) of the

act, no person may import blood

products that are: (1) Subject to

licensure and do not comply with

section 351(a) of the PHS Act; or (2) are

not subject to licensure and do not

comply with cGMP’s, without FDA’s

prior permission. For the latter, failure

to seek and obtain FDA’s permission,

under section 801(d)(4) of the act, prior

to importation may be a criminal

violation.

FDA further recommends that persons

who intend to import blood products

under section 801(d)(4) of the act

register and list or update their

registration and listing to include a

description of the imported material and

the final product for export that will be

manufactured from or incorporate the

imported biological material.

Registration and listing information

should not be contained in the import

for export request, but may instead be

sent to the appropriate registration

office listed in parts 207 or 607.

Additionally, the agency requests that

U.S.-licensed facilities receiving any

foreign biological components or

products, other than blood, under

section 801(d)(3) of the act which will

be used for manufacture into a product

for export report such changes in

accordance with 21 CFR 601.12.

2. Tissues

For tissues and tissue parts or

components, section 801(d)(4) of the act

prohibits importation unless the

importation complies with section 361

of the PHS Act. (Section 361 of the PHS

Act authorizes the issuance of

regulations to control communicable

diseases.) Thus, tissues and their parts

or components must comply with the

PHS Act and regulations issued under

the PHS Act in order to enter the United

States, even if the product is ultimately

destined for exportation.

Persons who intend to import tissues

and tissue parts or components

(intended for transplantation) under

section 801(d)(4) of the act should

comply with the regulations at part 1270

(21 CFR part 1270) and also comply

with the notification requirement in

section 801(d)(3)(A) of the act. Under

§ 1270.42, the importer of record must

notify the director (or his or her

designee) of the FDA district having

jurisdiction over the port of entry, and

the tissue must be held until FDA

releases it. If the human tissue that is

imported for further processing or

incorporation into a product for export

is kept in quarantine at all times, it does

not have to meet all the screening and

testing requirements in part 1270. If the

tissue is declared and identified as

being in quarantine, it must be

accompanied by records assuring

identification of the donor and

indicating that the tissue has not been

determined to be suitable for

transplantation (see § 1270.33(c)). The

owner or consignee in the United States

must prepare and follow written

procedures for designating and

identifying quarantined human tissue

and preventing infectious disease

contamination or cross-contamination

during processing (as stated in

§ 1270.31).

If an importer, consignee, or U.S.

manufacturer delivers or ships human

tissue or a component thereof before

FDA releases it or fails to quarantine

tissue that has not been determined to

be suitable for human transplantation,

such action may constitute a criminal

violation.

3. Requests to Import Blood, Blood

Components, Plasma, and Source

Leukocytes for Further Processing or

Incorporation into a Product for Export

(‘‘Requests for Determination’’)

Section 801(d)(4) of the act does not

specify how persons who wish to

import blood, blood components, source

plasma, source leukocytes, or their

components, accessories, or parts obtain

permission to import those products.

Nevertheless, to facilitate imports under

section 801(d)(4) of the act, FDA

recommends that manufacturers provide

an import for export request which

demonstrates that appropriate

circumstances or conditions warrant

CBER’s approval of importation under

section 801(d)(4) of the act. The agency

recommends that these requests, known

as a ‘‘request for determination,’’

contain the following information:

• The names and addresses of the

foreign manufacturer of the article to be

imported and the initial owner or

consignee in the United States that

would be responsible for the further

processing or incorporation of the

article into another product;

• The specific identity of the article to

be imported and details as to how the

imported article will be further

processed or incorporated into a

product for export;

• A description of the standard

operating procedures and safeguards

that the initial owner or consignee in

the United States will use or implement

to ensure that the imported articles or

products incorporating such articles are

segregated from and not comingled with

products, components, accessories, or

parts intended for use in the United

States (e.g., quarantine procedures used

for segregating imported blood, blood

components, or final products from

products intended for use in the United

States, including validation data for

procedures to clean equipment and

facilities used in manufacturing

products for use in the United States

and products for export);

• General donor screening

questionnaire or criteria, translated into

English, that will be used to screen

donors;

• A certification that the foreign

supplier will perform tests for infectious

disease on the blood, blood

components, source plasma, or source

leukocytes, or their components,

accessories, or parts (including blood or

plasma derivatives or intermediates) at

the time of donation and before

importation to the United States, and

the expected results of such tests. The

infectious disease agents that should be

tested for include, but are not limited to:
32234 Federal Register / Vol. 63, No. 113 / Friday, June 12, 1998 / Notices

HIV–1, HIV–2, hepatitis B virus,

hepatitis C virus, HTLV-I, HTLV-II, and

Treponema palladum. A request for

determination may be based upon

infectious agent tests performed using

test kits other than those licensed or

approved by FDA. In such cases, FDA

suggests that the request contain a copy

of the labeling for the test kit used,

translated into English, as part of the

submission; and

• A copy of the product’s label. FDA

recommends that the label include

information such as the product’s

descriptive name; the name(s) and

address(es) of establishments collecting,

preparing, labeling, or pooling the

source material; donor, lot, or pool

numbers relating the unit to the donor;

the recommended storage temperature

(in degrees Celsius); the product’s

quantity; statements such as ‘‘Import for

Export,’’ ‘‘Not for Use in Products

Subject to Licensure Under Section 351

of the Public Health Service Act,’’ and

‘‘For Manufacturing Use Only’’ or ‘‘For

Manufacturing into Noninjectable

Products Only;’’ statements indicating

that the product has been tested for

infectious disease agents and, if the

product has tested positive for an

infectious disease agent, the term

‘‘BIOHAZARD’’ as well as any other

appropriate warnings or special

handling instructions.

A request for determination may be

sent to the Center for Biologics

Evaluation and Research, Office of

Compliance, Division of Case

Management (HFM–610), 1401

Rockville Pike, Rockville, MD 20852–

1448. If FDA determines that the blood,

blood component, source plasma, or

source leukocyte, or a component,

accessory, or part meets the appropriate

circumstances and conditions to permit

its importation into the United States,

FDA will notify the person requesting

the determination that it has granted

permission to import the article.

XII. For Further Information Contact:

For animal drugs: Drugs Team,

Division of Compliance, Center for

Veterinary Medicine, Food and

Drug Administration, 7500 Standish

Pl., Rockville, MD 20855, 301–594–

1785.

For biologics: Division of Case

Management (HFM–610), Office of

Compliance, Center for Biologics

Evaluation and Research, Food and

Drug Administration, 1401

Rockville Pike, rm. 200N, Rockville,

MD 20852–1448, 301–827–6201.

For devices: Division of Program

Operations (HFZ–305), Center for

Devices and Radiological Health,

Food and Drug Administration,

2094 Gaither Rd., Rockville, MD

20850, 301–594–4699.

For drugs: Division of Labeling and

Nonprescription Drug Compliance

(HFD–310), Center for Drug

Evaluation and Research, Food and

Drug Administration, 7520 Standish

Pl., Rockville, MD 20855–2737,

301–594–0063.

For drugs exported for investigational

use under § 312.110: Office of

International Affairs (HFG–1), Food

and Drug Administration, 5600

Fishers Lane, Rockville, MD 20857,

301–443–4480.

For food additives, color additives,

and dietary supplements: Office of

Field Programs (HFS–602), Center

for Food Safety and Applied

Nutrition, Food and Drug

Administration, 200 C St. SW.,

Washington, DC 20204, 202–205–

4187.

These offices may have additional

guidance documents and information on

specific export topics or products.

For general policy questions: Office of

Policy (HF–23), Food and Drug

Administration, 5600 Fishers Lane,

Rockville, MD 20857, 301–827–

3344.

Dated: June 2, 1998.

William K. Hubbard,

Associate Commissioner for Policy

Coordination.

[FR Doc. 98–15696 Filed 6–11–98; 8:45 am]

BILLING CODE 4160–01–F

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Health Care Financing Administration.

[Document Identifier: HCFA–724]

Agency Information Collection

Activities: Submission for OMB

Review; Comment Request

AGENCY: Health Care Financing

Administration.

In compliance with the requirement

of section 3506(c)(2)(A) of the

Paperwork Reduction Act of 1995, the

Health Care Financing Administration

(HCFA), Department of Health and

Human Services, is publishing the

following summary of proposed

collections for public comment.

Interested persons are invited to send

comments regarding this burden

estimate or any other aspect of this

collection of information, including any

of the following subjects: (1) The

necessity and utility of the proposed

information collection for the proper

performance of the agency’s functions;

(2) the accuracy of the estimated

burden; (3) ways to enhance the quality,

utility, and clarity of the information to

be collected; and (4) the use of

automated collection techniques or

other forms of information technology to

minimize the information collection

burden.

Type of Information Collection

Request: Extension of a currently

approved collection; Title of

Information Collection: Medicare/

Medicaid Psychiatric Hospital Survey

Data and Supporting Regulations

Contained in 42 CFR 482.60, 482.61 and

482.62; Form No.: HCFA–724 (OMB#

0938–0378); Use: The information

collected on this form will assist HCFA

in maintaining an accurate data base on

providers participating in the Medicare

psychiatric hospital program. The

HCFA–724 has two parts; part one is

completed by the facility (i.e., location,

number of beds, number of admissions)

and part two is completed by the survey

team (i.e, dates of survey, type of

survey, survey team composition);

Frequency: Annually; Affected Public:

Federal government, Business or other

for-profit, Not-for-profit institutions,

and State, local or tribal government;

Number of Respondents: 350; Total

Annual Responses: 350; Total Annual

Hours: 175.

To obtain copies of the supporting

statement and any related forms for the

proposed paperwork collections

referenced above, access HCFA’s Web

Site address at http://www.hcfa.gov/

regs/prdact95.htm, or E-mail your

request, including your address, phone

number, OMB number, and HCFA

document identifier, to

Paperwork@hcfa.gov, or call the Reports

Clearance Office on (410) 786–1326.

Written comments and

recommendations for the proposed

information collections must be mailed

within 30 days of this notice directly to

the OMB desk officer: OMB Human

Resources and Housing Branch,

Attention: Allison Eydt, New Executive

Office Building, Room 10235,

Washington, D.C. 20503.

Dated: June 2, 1998.

John P. Burke III,

HCFA Reports Clearance Officer, HCFA Office

of Information Services, Information

Technology Investment Management Group,

Division of HCFA Enterprise Standards.

[FR Doc. 98–15648 Filed 6–11–98; 8:45 am]

BILLING CODE 4120–03–P