[Federal Register Volume 67, Number 118 (Wednesday, June 19, 2002)]
[Proposed Rules]
[Pages 41642-41648]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-15358]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 312

[Docket No. 00N-1663]
RIN 0910-AA61


Investigational New Drugs: Export Requirements for Unapproved New 
Drug Products

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend 
its regulations on the exportation of investigational new drugs, 
including biological products. The proposed rule would provide four 
different mechanisms for exporting an investigational new drug product. 
These provisions would implement changes in FDA's export authority 
resulting from the FDA Export Reform and Enhancement Act of 1996, and 
they would also simplify the existing requirements for exports of 
investigational new drugs.

DATES: Submit written or electronic comments by September 17, 2002. 
Submit written comments on the information collection requirements by 
July 19, 2002.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852. Submit electronic comments to http://www.fda.gov/dockets/ecomments. Submit written comments on the information 
collection requirements to the Office of Information and Regulatory 
Affairs, OMB, New Executive Office Bldg., 725 17th St. NW., rm. 10235, 
Washington, DC 20502, Attn: Stuart Shapiro.

FOR FURTHER INFORMATION CONTACT: Philip L. Chao, Office of Policy, 
Planning, and Legislation (HF-23), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-827-3380.

SUPPLEMENTARY INFORMATION:

I. Background

    Current FDA regulations at Sec. 312.110 (21 CFR 312.110) require 
any person who intends to export an unapproved new drug product for use 
in a clinical investigation either to have an investigational new drug 
application (IND) or to submit a written request to FDA. The written 
request must 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 (see Sec. 312.110(b)(2)(i)). The 
request must also specify the quantity of the drug to be shipped and 
the frequency of expected shipments (Sec. 312.110(b)(2)(i)). If FDA 
authorizes exportation of the drug, it notifies the government of the 
importing country (Sec. 312.110(b)(2)(i)). Similar procedures exist for 
export requests made by foreign governments (see 
Sec. 312.110(b)(2)(ii)). Section 312.110(b)(3) states that the 
requirements in paragraph (b) apply only where the drug is to be used 
for the purpose of a clinical investigation. Section 312.110(b)(4) 
states that the requirements in paragraph (b) do not apply to the 
exports of new drugs approved or authorized for export under section 
802 of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 
382) or section 351(h)(1)(A) of the Public Health Service Act.
    The program for exporting investigational new drugs is commonly 
known as the ``312 program'' because the regulation pertaining to the 
program is located in part 312 (21 CFR part 312). Between fiscal years 
1994 and 1997, FDA received nearly 1,800 export requests under the 312 
program. Very few requests (less than 1 percent) presented any safety, 
quality, or other public health concerns.
    In 1996, the President signed into law amendments to the act that 
changed the export requirements for certain drugs, biologics, and 
devices that may not be marketed or sold in the United States. These 
amendments, known as the FDA Export Reform and Enhancement Act of 1996 
(Public Law 104-134, amended by Public Law 104-180), created, among 
other things, two new provisions that affect the exportation of 
investigational drug products. One provision, now section 802(b)(1)(A) 
of the act, authorizes exportation of an unapproved new drug to any 
country if that drug has valid marketing authorization by the 
appropriate authority in Australia, Canada, Israel, Japan, New Zealand, 
Switzerland, South Africa, the European Union (EU), or a country in the 
European Economic Area (EEA) and certain other requirements are met. 
These countries are listed in section 802(b)(1)(A)(i) and (b)(1)(A)(ii) 
of the act and are sometimes referred to as the ``listed countries.'' 
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, and Iceland, Liechtenstein, and Norway. The list of 
countries in section 802(b)(1)(A)(i) of the act will expand 
automatically if any country accedes to the EU or becomes a member of 
the EEA. Exports under section 802(b)(1)(A) of the act can encompass 
exportation of an unapproved new drug product for investigational use 
in a foreign country if the exported drug product has marketing 
authorization in any listed country and the relevant statutory 
requirements are met. Exports under section 802(b)(1)(A) of the act do 
not require prior FDA authorization.
    The second provision, now section 802(c) of the act, permits 
exportation of unapproved new drugs (including biological products) 
intended for investigational use to any listed country in accordance 
with the laws of that country. Exports of drugs to the listed countries 
under section 802(c) of the act do not require prior FDA authorization 
and are exempt from regulation under section 505(i) of the act (21 
U.S.C. 355(i)).

[[Page 41643]]

    All drug products exported under section 802 of the act are, 
however, subject to certain general requirements. Section 802(f) of the 
act prohibits export if the unapproved new drug: (1) Is not 
manufactured, processed, packaged, and held in substantial conformity 
with current good manufacturing practice requirements; (2) is 
adulterated under certain provisions of section 501 of the act (21 
U.S.C. 351); (3) does not comply with section 801(e)(1) of the act (21 
U.S.C. 381(e)(1)), which requires that the exported product be intended 
for export, meet the foreign purchaser's specifications, not be in 
conflict with the laws in the importing country, be labeled on the 
outside of the shipping package that the products are intended for 
export, and not be sold or offered for sale in the United States; (4) 
is the subject of a determination by FDA that the probability of 
reimportation of the exported drug would present an imminent hazard to 
the public health and safety of the United States; (5) presents an 
imminent hazard to the public health of the foreign country; (6) fails 
to comply with labeling requirements in the country receiving the 
exported drug; or (7) is not promoted in accordance with labeling 
requirements in the importing country and, where applicable, in the 
listed country in which the drug has valid marketing authorization. 
Section 802(g) of the act also imposes certain recordkeeping and 
notification obligations on drugs exported under section 802 of the 
act; these recordkeeping and notification obligations were the subject 
of a final rule that appeared in the Federal Register of December 19, 
2001 (66 FR 65429).
    The new export provisions in section 802 of the act have 
significantly reduced the number of requests under the 312 program from 
an annual average of 570 requests to 100 requests. This proposed rule 
would conform the present regulation to the provisions of, and would be 
consistent with, the FDA Export Reform and Enhancement Act of 1996.

II. Description of the Proposed Rule

    The proposed rule would amend Sec. 312.110 to provide four 
mechanisms for exporting investigational new drugs, eliminate 
unnecessary language in the current regulation, and streamline the 
export requirements for the ``312 program.'' The proposed rule would 
not contain any new recordkeeping requirements because such records 
would already be required under Sec. 312.57 or the final export 
notification and recordkeeping rule that appeared in the Federal 
Register of December 19, 2001 (66 FR 65429).
    Proposed Sec. 312.110(b)(1) would represent the first mechanism for 
exporting an investigational new drug and would apply if the foreign 
clinical investigation is to be done under an IND. Exports under 
proposed Sec. 312.110(b)(1) could be made to any foreign country. 
Proposed Sec. 312.110(b)(1) would provide that an investigational new 
drug may be exported from the United States if an IND is in effect for 
the drug under Sec. 312.40, the drug complies with the laws of the 
country to which it is being exported, and each person who receives the 
drug is an investigator in a study submitted to and allowed to proceed 
under the IND. This is similar to current Sec. 312.110(b) although it 
would expressly, rather than implicitly, require the exported drug to 
comply with the laws of the foreign country.
    Drugs that are the subject of an IND may be exported to any country 
in the world if the export is for the purpose of conducting an 
investigation in the importing foreign country. The agency reiterates 
that the requirements in proposed Sec. 312.110(b)(1) would apply only 
if the foreign clinical investigation is to be done under an IND.
    Proposed Sec. 312.110(b)(2) would represent the second mechanism 
for investigational new drug exports and would implement section 
802(b)(1) of the act with respect to exports of unapproved new drugs 
for investigational use. Under the proposal, if a drug product that is 
not approved for use in the United States has valid marketing 
authorization in Australia, Canada, Israel, Japan, New Zealand, 
Switzerland, South Africa, or in any country in the EU or the EEA, the 
drug may be exported for any use, including investigational use, to any 
country, provided that the export complies with all applicable 
requirements pertaining to exports. Prior FDA approval to export the 
drug would not be required. The proposal also would not require the 
drug to be the subject of an IND, but would not preclude the exporter 
from obtaining an IND if it chose to submit an IND to the agency. The 
exporter and the exported products, however, would have to comply with 
the foreign country's laws and with requirements in section 802(f) and 
(g) of the act. Recordkeeping requirements are the subject of 
Sec. 1.101, which was published in the Federal Register of December 19, 
2001.
    Proposed Sec. 312.110(b)(3), the third mechanism for 
investigational new drug exports, would implement section 802(c) of the 
act with respect to exports of unapproved new drugs for investigational 
use. In brief, if an unapproved drug is to be exported for 
investigational use to any listed country in accordance with the laws 
of that country, then no prior FDA authorization would be required. 
Export of a drug for investigational use under proposed 
Sec. 312.110(b)(3) would have to comply with the foreign country's laws 
and the applicable provisions in section 802(c), (f), and (g) of the 
act. Recordkeeping requirements, as stated earlier, were the subject of 
Sec. 1.101 which was published in the Federal Register of December 19, 
2001.
    FDA anticipates that most investigational new drugs would be 
exported under proposed Sec. 312.110(b)(3), because the agency's 
experience indicates that most investigational new drugs are exported 
to the listed countries.
    FDA interprets section 802(c) of the act, and proposed 
Sec. 312.110(b)(3), to permit exportation of investigational new drugs 
to the listed countries, but not to permit the transshipment of 
investigational new drugs to nonlisted countries. (``Transshipment'' 
refers to the practice of shipping a product to a country from which it 
will later be shipped to another country.) The agency is aware that 
some firms have interpreted section 802(c) of the act as permitting 
transshipment to unlisted countries; section 802(c) of the act is 
silent with respect to transshipment, however, and a more reasonable 
interpretation is that the provision does not allow transshipments. 
Interpreting section 802(c) of the act to allow transshipment would be 
inconsistent with FDA's traditional practice under Sec. 312.110; would 
presume, in the absence of any supporting language in the statute or 
its legislative history, that the listed countries may serve as mere 
transfer points or conduits for investigational new drugs and devices 
destined for unlisted countries; and would make the limitation to the 
listed countries in section 802(c) of the act virtually meaningless.
    FDA, however, interprets section 802(c) of the act as permitting 
investigational new drugs to be sent to principal investigators in a 
listed country who use the investigational new drug in an unlisted 
country if the principal investigator conducts the clinical 
investigations in accordance with the requirements of both the listed 
country and the unlisted country where the investigation is conducted. 
For example, if firm A exported an investigational new drug to 
principal investigator X in Norway (a listed country), section 802(c) 
of the act would

[[Page 41644]]

permit exportation to proceed without prior FDA authorization so long 
as firm A and the exported drug met all other statutory conditions 
pertaining to the exportation. Principal investigator X could then 
administer the investigational new drug in an unlisted country so long 
as principal investigator X conducts the clinical investigation in 
accordance with Norwegian requirements and any requirements in the 
unlisted country where the investigational new drug is administered.
    If the drug presents an imminent hazard to the public health or 
safety of the foreign country, fails to comply with labeling 
requirements, or is not promoted in accordance with labeling 
requirements, section 802(f) of the act requires the agency to consult 
with the appropriate public health official in the foreign country. 
Section 802(g) of the act requires exporters to maintain records of all 
drugs exported under section 802 of the act. This provision of the act 
allows enforcement of section 802 of the act because it provides FDA 
with a means to determine what drugs have been exported under section 
802 of the act and where the drugs were sent. Consequently, although 
proposed Sec. 312.110(b)(3) would not require firms to submit reports 
to the agency concerning exported drugs, it would, consistent with 
section 802 of the act, require firms to maintain records documenting 
their compliance with section 802(c) and (f) of the act. In the Federal 
Register of December 19, 2001 (66 FR 65429), FDA published a final rule 
concerning the recordkeeping and notification requirements for products 
exported under sections 801(e) and 802 of the act and section 351(h) of 
the Public Health Service Act; the recordkeeping and notification 
requirements will be codified in a new Sec. 1.101.
    Additionally, proposed Sec. 312.110(b)(3) would provide that 
exports of drugs that are not under an IND to the listed countries for 
investigational use under section 802(c) of the act do not have to 
comply with the labeling requirement in Sec. 312.6(a). Section 312.6(a) 
requires that the immediate package for an investigational new drug 
bear the following statement: ``Caution: New Drug-Limited by Federal 
(or United States) law to investigational use.'' In response to 
industry concerns, FDA is proposing to exempt unapproved new drugs 
exported under section 802(c) of the act and that are not under an IND 
from the label statement requirement in Sec. 312.6(a). The industry 
expressed concerns in response to a preliminary, informal FDA 
interpretation shortly after enactment of the FDA Export Reform and 
Enhancement Act of 1996 indicating that all unapproved new drugs 
exported for investigational use under section 802(c) of the act should 
carry the label statement provided in Sec. 312.6(a). After careful 
consideration, FDA has decided that drugs exported under section 802(c) 
of the act that are not under an IND should be exempted from the label 
statement in Sec. 312.6(a). FDA is proposing the exemption because the 
principal authority for Sec. 312.6 is section 505(i) of the act, but 
section 802 of the act expressly declares that exports under 
section 802 of the act are not subject to the requirements 
in section 505(i) of the act. An investigational new drug exported 
under an IND, however, would continue to be subject to the label 
requirement as the investigational new drug remains subject to section 
505(i) of the act by virtue of the IND.
    Proposed Sec. 312.110(b)(4) would represent the fourth mechanism 
for exporting an investigational new drug and would pertain to 
unapproved new drugs exported to any country for investigational use 
without an IND, although the agency anticipates that the provision 
would be used by persons who intend to export a drug for 
investigational use to countries that are not listed in section 802 of 
the act and proposed Sec. 312.110(b)(2). Proposed Sec. 312.110(b)(4) 
would streamline the requirements for the 312 program by eliminating 
the requirement of prior FDA authorization. Instead, the proposal would 
require a person seeking to export an unapproved new drug for 
investigational use without an IND to send a written certification to 
FDA. The certification would be submitted at the time the drug is first 
exported and would describe the drug being exported (i.e., trade name 
(if any), generic name, and dosage form), identify the country or 
countries to which it is being exported, and affirm that:
     The drug is intended for export;\1\
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    \1\This requirement would be consistent with a decision by the 
United States Court of Appeals for the Fourth Circuit in United 
States v.Kanasco, Ltd., 123 F.3d 209 (4th Cir. 1997), in which a 
firm sought to claim that drugs that were not manufactured in 
accordance with good manufacturing practices (GMPs) were 
nevertheless exempt from the GMP requirements because they were 
intended for export. However, the firm did not have a foreign 
purchaser for the drug and could not identify a specific foreign 
country to which the drug would be exported; instead, it argued that 
it could find a foreign purchaser at a future date and that the 
drugs met the requirements of unnamed and unspecified foreign 
countries. The Court of Appeals rejected the arguments that the drug 
was intended for export, stating that the firm's argument ``would 
create an unwarranted escape hatch for violators of the Act'' (id. 
at page 212).
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     The drug is intended for investigational use in a foreign 
country;
     The drug meets the foreign purchaser's or consignee's 
specifications;
     The drug is not in conflict with the importing country's 
laws;
     The outer shipping package is labeled to show that the 
package is intended for export from the United States;
     The drug is not sold or offered for sale in the United 
States;
     The clinical investigation will be conducted in accordance 
with Sec. 312.120;
     The drug is manufactured, processed, packaged, and held in 
substantial conformity with current good manufacturing practices;
     The drug is not adulterated within the meaning of section 
501(a)(1), (a)(2)(A), (a)(3), (c), or (d) of the act;\2\
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    \2\In brief, these sections of the act state that a drug shall 
be deemed to be adulterated if it consists in whole or in part of 
any filthy, putrid, or decomposed substance; if it has been 
prepared, packed, or held under insanitary conditions whereby it may 
have been contaminated with filth, or whereby it may have been 
rendered injurious to health; if its container is composed in whole 
or in part of any poisonous or deleterious substance which may 
render the contents injurious to health; if the drug's strength 
differs from or its purity or quality falls below that which it 
purports or is represented to possess; or if any substance has been 
mixed or packed with the drug so as to reduce the drug's quality or 
strength or any substance has been substituted in whole or in part 
for the drug.
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     The drug does not present an imminent hazard to public 
health, either in the United States if the drug were to be reimported 
or in the foreign country;
     The drug is labeled in accordance with the foreign 
country's laws; and
     The drug is promoted in accordance with its labeling.
    In short, the certification in proposed Sec. 312.110(b)(4) would 
combine the statutory requirements at sections 801(e)(1) and 802(f) of 
the act with the requirements of informed consent and the use of 
qualified clinical investigators at section 505(i) of the act. This 
approach is intended to accomplish several goals.
    First, because the agency's experience with the 312 program 
indicates that very few investigational new drug exports under the 
existing program raise any safety, quality, or other public health 
concerns, the certification would eliminate the requirement of prior 
FDA authorization of a request to export a drug for investigational 
use. Instead, a certification would be sent to FDA's Office of 
International Programs (formerly the Office of International Affairs) 
when the drug is exported.

[[Page 41645]]

    Second, by requiring exports under the 312 program to comply with 
requirements that are similar to those under sections 801(e)(1) and 
802(f) of the act, exports under the 312 program would be subject to 
the same minimum export requirements as other exports of unapproved new 
drugs for investigational use.
    Third, by conditioning exports to unlisted countries under the 312 
program on the conduct of clinical investigations in accordance with 
Sec. 312.120, the use of investigational new drugs under the 312 
program would be clearly subject to internationally recognized 
requirments for clinical investigations. This aspect of the proposed 
rule also reflects the fact that section 505(i) of the act, which 
authorizes FDA to issue regulations pertaining to investigational new 
drugs, is the authority for the 312 program. (In contrast, unapproved 
new drugs exported for investigational use to listed countries under 
section 802(c) of the act are not subject to the requirements in 
section 505(i) of the act.)
    Thus, the proposed rule would streamline the 312 program by 
eliminating, in all cases, the requirement of prior FDA authorization 
of exports. At the same time, the proposal would increase the 
safeguards for exports under the 312 program through the 
responsibilities placed on the sponsor as a result of the required 
certification.
    Persons exporting investigational new drugs under an IND or under 
the 312 program should note that section 402(j) of the Public Health 
Service Act (42 U.S.C. 282(j)) directs the Secretary of Health and 
Human Services to establish, maintain, and operate a data bank of 
information on clinical trials for drugs for serious or life-
threatening diseases and conditions. FDA invites comment on whether the 
agency should make available information on clinical trials involving 
investigational new drugs exported under the 312 program.
    Proposed Sec. 312.110(b)(4) would also require the person exporting 
the investigational new drug to retain records showing its compliance 
with the provision's requirements.
    Proposed Sec. 312.110 would prohibit exports under 
certain conditions. For example, for drugs under an IND that are 
exported under proposed Sec. 312.110(b)(1), exportation would not be 
allowed if the IND were terminated. For drugs exported under proposed 
Sec. 312.110(b)(2), (b)(3), or (b)(4), exportation would not be allowed 
if the requisite conditions underlying or authorizing the exportation 
are no longer met. For all investigational new drugs exported under 
Sec. 312.110, exportation would not be allowed if the drug no longer 
complied with the laws of the importing country.
    Currently, Sec. 312.110(b)(4) states that the requirements in 
Sec. 312.110(b) do not apply to the export of new drugs (including 
biological products, antibiotic drugs, and insulin) approved or 
authorized for export under section 802 of the act or section 
351(h)(1)(A) of the Public Health Service Act. The proposal would 
redesignate Sec. 312.110(b)(4) as new Sec. 312.110(d) and revise the 
text to state that the export requirements in Sec. 312.110 do not apply 
to insulin or to antibiotic drug products exported for investigational 
use. This provision would reflect section 802(i) of the act which 
provides that insulin and antibiotics may be exported in accordance 
with the export requirements in section 801(e)(1) of the act without 
complying with section 802 of the act. The proposed change would also 
eliminate a potentially confusing and incorrect reference to new drugs 
``approved or authorized for export under section 802 of the act * * * 
or section 351(h)(1)(A) of the Public Health Service Act'' because the 
proposal does, indeed, address exports of unapproved new drugs for 
investigational use under section 802(b)(1) and (c) of the act. Also, 
Sec. 312.110, and the regulations in part 312 generally, apply only to 
exports of investigational new drugs, so there is no need for 
Sec. 312.110 to expressly exclude exports of unapproved new drugs for 
other, noninvestigational uses. For example, exports of unapproved new 
drugs for marketing purposes or exports in anticipation of market 
authorization occur under the authority in section 802 of the act, and 
obviously are not investigational uses. As for section 351(h) of the 
Public Health Service Act, it pertains to exports of partially 
processed biological products that are: (1) Not in a form applicable to 
the prevention, treatment, or cure of diseases or injuries of man; (2) 
not intended for sale in the United States; and (3) intended for 
further manufacture into final dosage form outside the United States. 
Thus, partially processed biological products exported under section 
351(h) of the Public Health Service Act are not exported for 
investigational use, so they do not have to be mentioned in 
Sec. 312.110. (FDA also notes that the FDA Export Reform and 
Enhancement Act of 1996 revised and renumbered section 351(h) of the 
Public Health Service Act, and so the revised section no longer 
contains a paragraph (h)(1)(A).)
    FDA is also proposing to amend the authority citation for part 312 
to reflect additional statutory provisions, such as sections 801, 802, 
803, and 903 of the act (21 U.S.C. 381, 382, 383, and 393), that affect 
investigational new drug exports, FDA's international activities, and 
rulemaking. In addition, the proposal would remove the existing text at 
Sec. 312.110(b)(3); the existing text states that the export 
requirements in Sec. 312.110(b) apply only where the drug is to be used 
for the purpose of a clinical investigation. FDA is proposing to delete 
this language because the proposed rule expressly refers to exports of 
investigational new drugs for use in clinical investigations.
    Firms evaluating whether to export a drug under these provisions 
should carefully consider the consequences of any decision. FDA notes 
that exports under section 802(b)(1)(A) and (c) of the act do not 
require the exporter to be a sponsor of an IND. However, the existing 
patent term restoration provision in 35 U.S.C. 156 defines the 
``regulatory review period'' for drugs and biologics as starting on the 
date on which an IND becomes effective.\3\ Thus, if the drug product is 
ultimately approved or licensed for marketing and the patent is 
otherwise eligible for patent term extension under 35 U.S.C. 156, firms 
that conducted clinical investigations without an IND may have 
relinquished the opportunity to extend a patent term to compensate for 
any patent life lost during the ``testing phase'' for their drugs 
(although they may still be able to receive an extended patent term 
based on the ``approval phase'' for their products). Therefore, as a 
general matter, firms may find it in their interests to obtain an IND 
regardless of where the clinical investigations will occur.
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    \3\For drugs, the ``regulatory review period'' consists of two 
parts, a ``testing phase''--the time between the effective date of 
an IND and the submission of a marketing application (a new drug 
application or a product license application) to FDA--and an 
``approval phase''--the time between submission and approval of the 
marketing application. The regulatory review period calculation 
forms the basis for the extended patent term.
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III. Legal Authority

    Section 505(i) of the act authorizes the agency to issue 
regulations pertaining to drugs intended solely for investigational use 
by experts qualified by scientific training and experience to 
investigate the safety and effectiveness of drugs. Under this 
authority, FDA has, for many years, approved the export of certain 
unapproved new drugs for investigational use in one or more foreign 
countries. Additionally, FDA can, under its general authority over

[[Page 41646]]

investigational new drugs, terminate an IND under certain conditions.
    The proposed rule is consistent with section 505(i) of the act 
insofar as proposed Sec. 312.110(b)(1) would pertain to drugs that are 
the subject of an IND and proposed Sec. 312.110(b)(4) would require 
clinical investigations involving an investigational new drug without 
an IND that is exported to a foreign country to be conducted in 
accordance with Sec. 312.120. Section 505(i) of the act also gives FDA 
express authority to issue regulations pertaining to investigational 
new drugs.
    The proposed rule is also authorized by sections 801(e) and 802 of 
the act. Sections 801(e) and 802 of the act both address the export of 
drug products that may not be marketed or sold in the United States, 
but in different ways. Under section 801(e)(1) of the act, a drug 
product intended for export will not be considered to be adulterated or 
misbranded 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. Section 801(e)(1) of the act 
reflects a general view that a U.S. producer should be able to make 
products intended for export that do not meet U.S. requirements 
provided that the products meet the requirements of both the purchaser 
and receiving country. Although section 801(e)(1) of the act does not 
expressly apply to unapproved new drugs, the requirements in section 
801(e)(1) of the act do apply to all drug products exported under 
section 802 of the act (see section 802(f)(3) of the act).
    Section 802 of the act applies to unapproved drug products intended 
for export. Section 802 of the act applies to exports of 
unapproved drug products intended for investigational use. As stated 
earlier, section 802 of the act permits the export of a drug 
or device intended for investigational use to Australia, Canada, 
Israel, Japan, New Zealand, Switzerland, South Africa, or any country 
in the EU or EEA in accordance with the laws of the importing country. 
No prior FDA authorization is required, and exports under section 
802 of the act are also exempt from regulation under section 
505(i) of the act. However, section 802(f) of the act prohibits export 
of a drug if certain conditions are not met (such as conformity with 
current good manufacturing practices, compliance with section 801(e)(1) 
of the act, and certain practices that would cause the drug to be 
adulterated under certain provisions of section 501 of the act).
    The proposed rule is, therefore, authorized by sections 801(e)(1) 
and 802 of the act because proposed Sec. 312.110(b)(2) would pertain to 
drugs exported under section 802(b) of the act and would require that 
such exports comply with section 802(f) of the act (which includes 
compliance with section 801(e) of the act). Proposed Sec. 312.110(b)(3) 
would pertain to exports of investigational new drugs to listed 
countries, under section 802 of the act, and would also 
require compliance with section 802(f) of the act. Authority to issue 
regulations to implement sections 801(e) and 802 of the act, and for 
the efficient enforcement of the act generally, is authorized under 
section 701(a) and (b) of the act (21 U.S.C. 371(a) and (b)). Section 
903 of the act also provides general powers for implementing policies 
respecting FDA programs and activities.
    Thus, the proposed rule implements sections 505(i), 801(e)(1), and 
802 of the act. Furthermore, it is also authorized under FDA's 
rulemaking authorities at sections 505(i) and 701(a) of the act, and 
FDA's general authority at section 903 of the act.

IV. Environmental Impact

    FDA has determined under 21 CFR 25.30(h) and (i), and 25.31(e) that 
this action is of a type that does not individually or cumulatively 
have a significant effect on the human environment. Therefore, neither 
an environmental assessment nor an environmental impact statement is 
required.

V. Paperwork Reduction Act of 1995

    This proposed rule contains information collection provisions 
requirements that are subject to review by the Office of Management and 
Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-
3520). A description of these provisions is given below with an 
estimate of the annual reporting and recordkeeping burden. Included in 
the estimate is the time for reviewing instructions, searching existing 
data sources, gathering and maintaining the data needed, and completing 
and reviewing each collection of information.
    FDA invites comments on: (1) Whether the proposed collection of 
information is necessary for the proper performance of FDA's functions, 
including whether the information will have practical utility; (2) the 
accuracy of FDA's estimate of the burden of the proposed collection of 
information, including the validity of the methodology and assumptions 
used; (3) ways to enhance the quality, utility, and clarity of the 
information to be collected; and (4) ways to minimize the burden of the 
collection of information on respondents, including through the use of 
automated collection techniques, when appropriate, and other forms of 
information technology.
    Title: Investigational New Drug Applications: Export Requirements 
for Unapproved New Drug Products.
    Description: The proposed rule would provide four different 
mechanisms for exporting an investigational new drug. First, an 
investigational new drug could be exported under an IND to any country. 
Second, an investigational new drug that has received valid marketing 
authorization from a listed country may be exported for investigational 
use in any country subject to certain conditions (such as being in 
substantial conformity with current good manufacturing practice). 
Third, an investigational new drug could be exported to any listed 
country without prior FDA authorization for use in a clinical 
investigation, but would be subject to certain conditions (such as 
being in substantial conformity with current good manufacturing 
practices). Fourth, an investigational new drug could be exported 
provided that the sponsor submits a certification that the drug meets 
certain export criteria at the time the drug is exported. The proposal 
would also require persons exporting an investigational new drug under 
either the second, third, or fourth mechanisms to maintain records 
documenting their compliance with statutory and regulatory 
requirements.
    Description of Respondents: Businesses.

                                                     Table 1.--Estimated Annual Reporting Burden\1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                        Annual Frequency per     Total Annual
                  21 CFR Section                    No. of Respondents        Response             Responses      Hours per Response      Total Hours
--------------------------------------------------------------------------------------------------------------------------------------------------------
312.110(b)(4)                                             100                    1                  100                  12               1,200
                                                                                                                                     -------------------

[[Page 41647]]

 
  Total                                                                                                                                   1,200
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.


                                                   Table 2.--Estimated Annual Recordkeeping Burden\1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                  Annual Frequency
               21 CFR Section                      Statute           No. of              per          Total Annual        Hours per        Total Hours
                                                                  Recordkeepers     Recordkeeping        Records        Recordkeeper
--------------------------------------------------------------------------------------------------------------------------------------------------------
312.100(b)(2) and (b)(3)                           Sec. 382          470                 1               470                 3             1,410
312.110(b)(4)                                                        100                 1               100                 1               100
                                                                                                                                       -----------------
  Total                                                                                                                                    1,510
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.

    The estimates are based on average export submissions in previous 
years and on information supplied by industry sources. For the 
recordkeeping requirement in proposed Sec. 312.110(b)(2) and (b)(3), 
FDA used the average annual number of export requests in previous years 
before enactment of the FDA Export Reform and Enhancement Act 
(approximately 570) and subtracted the number of export requests that 
it currently receives under the 312 program (100) to obtain an 
estimated 470 recordkeepers. These records, in general, would be 
subject to Sec. 1.101 (66 FR 65429), and the estimated burden hours for 
the relevant parts of Sec. 1.101 total 3 hours. Thus, the total record 
burden hours for Sec. 312.110(b)(2) and (b)(3) would be 1,410 hours 
(470 records multiplied by 3 hours per record).
    For proposed Sec. 312.110(b)(4), industry sources indicated that 
most firms already maintain records to demonstrate their compliance 
with export requirements, so the agency assigned a value of 1 hour for 
each response. The total recordkeeping burden for proposed 
Sec. 312.110(b)(4), therefore, is 100 hours (100 records multiplied by 
1 hour per record).
    Thus, the total recordkeeping burden would be 1,510 hours (1,410 + 
100 = 1,510). Of this recordkeeping burden, 1,410 hours would be a 
statutory burden (because section 802(g) of the act requires persons 
exporting drugs under section 802 of the act to maintain records of all 
drugs exported and the countries to which they were exported).
    For the reporting requirement in proposed Sec. 312.110(b)(4), FDA's 
experience under the 312 program suggests that extremely few reports 
would be submitted. Assuming that 100 requests are received (the 
current number of requests under the 312 program) and that the 
reporting burden remains constant at approximately 12 hours per 
response, the total burden under proposed Sec. 312.110(b)(4) would be 
1,200 hours. The reporting burden would be a regulatory (rather than 
statutory) burden.
    There are no capital or startup costs or service costs projected 
for this rule due to the minimal nature of the recordkeeping and 
reporting requirements. Consultations with industry sources estimate 
that the average costs of maintaining records would be $100 per record 
(for a total annual cost of $151,000 (1,510 total records per year x 
$100 per record)).
    The annual reporting cost is estimated to be $36,000. This estimate 
is based on the estimated total burden hours for the certification 
(1,200) multiplied by a wage of $30 per hour (1,200 hours x $30 per 
hour =$36,000).
    Thus, the total industry cost would be $187,000 ($151,000 + $36,000 
= $187,000).
    In compliance with the Paperwork Reduction Act of 1995 (44 U.S.C. 
3507(d)), the agency has submitted the information collection 
provisions of this proposed rule to OMB for review. Interested persons 
are requested to send comments regarding information collection to the 
Office of Information and Regulatory Affairs, OMB (address above) by 
July 19, 2002.

VI. Analysis of Impacts

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612 (as 
amended by subtitle D of the Small Business Regulatory Fairness Act of 
1996 (Public Law 104-121))), and the Unfunded Mandates Reform Act of 
1995 (Public Law 104-4). Executive Order 12866 directs agencies to 
assess all costs and benefits of available regulatory alternatives and, 
when regulation is necessary, to select regulatory approaches that 
maximize net benefits (including potential economic, environmental, 
public health and safety, and other advantages; distributive impacts; 
and equity). Under the Regulatory Flexibility Act, unless an agency 
certifies that a rule will not have a significant impact on small 
entities, the agency must analyze regulatory options that would 
minimize the impact of the rule on small entities.
    The Unfunded Mandates Reform Act of 1995 requires that agencies 
prepare an assessment of anticipated costs and benefits before 
proposing any rule that may result in an expenditure by State, local, 
and tribal governments, in the aggregate, or by the private sector, of 
$100 million or more (adjusted annually for inflation) in any one year.
    The agency has reviewed this proposed rule and determined that it 
is consistent with the regulatory philosophy and the principles 
identified in the Executive Order 12866 and these two statutes, as it 
will not result in an expenditure of $100 million or more in any one 
year. Because the rule raises novel policy issues, OMB has determined 
that this proposed rule is a significant regulatory action as defined 
under paragraph 4 of section 3(f) of Executive Order 12866.
    The proposed rule would facilitate exports of unapproved new drug 
products for use in clinical investigations in foreign countries by 
eliminating the need to submit requests for permission to export the 
drugs and to receive FDA authorization. This change would reduce the 
cost to the affected small firms. Thus, the agency certifies that this 
proposed rule will not have a significant economic impact on

[[Page 41648]]

a substantial number of small entities. Therefore, under the Regulatory 
Flexibility Act, no further analysis is required.
    Because the proposed rule does not impose any mandates on State, 
local, or tribal governments, or the private sector that will result in 
an expenditure of $100 million or more in any one year, FDA is not 
required to perform a cost-benefit analysis under the Unfunded Mandates 
Reform Act of 1995.
    Interested persons may submit to the Dockets Management Branch 
(address above) written or electronic comments regarding this proposal 
by September 17, 2002. Two copies of any comments are to be submitted, 
except that individuals may submit one copy. Comments are to be 
identified with the docket number found in brackets in the heading of 
this document. Received comments may be seen in the Dockets Management 
Branch between 9 a.m. and 4 p.m., Monday through Friday.

List of Subjects in 21 CFR Part 312

    Drugs, Exports, Imports, Investigations, Labeling, Medical 
research, Reporting and recordkeeping requirements, Safety.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, it is 
proposed that 21 CFR part 312 be amended as follows:

PART 312--INVESTIGATIONAL NEW DRUG APPLICATION

    1. The authority citation for 21 CFR part 312 is revised to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357, 
371, 381, 382, 383, 393; 42 U.S.C. 241, 243, 262.

    2. Section 312.110 is amended by revising paragraph (b) and by 
adding paragraphs (c) and (d) to read as follows:


Sec. 312.110  Import and export requirements.

* * * * *
    (b) Exports. An investigational new drug may be exported from the 
United States for use in a clinical investigation under any of the 
following conditions:
    (1) An IND is in effect for the drug under Sec. 312.40, the drug 
complies with the laws of the country to which it is being exported, 
and each person who receives the drug is an investigator in a study 
submitted to and allowed to proceed under the IND; or
    (2) The drug has valid marketing authorization in Australia, 
Canada, Israel, Japan, New Zealand, Switzerland, South Africa, or in 
any country in the European Union or the European Economic Area, and 
complies with the laws of the country to which it is being exported, 
section 802(b)(1)(A), (f), and (g) of the act, and Sec. 1.101 of this 
chapter; or
    (3) The drug is being exported to Australia, Canada, Israel, Japan, 
New Zealand, Switzerland, South Africa, or to any country in the 
European Union or the European Economic Area, and complies with the 
laws of the country to which it is being exported, the applicable 
provisions of section 802(c), (f), and (g) of the act, and Sec. 1.101 
of this chapter. Drugs exported under this paragraph that are not the 
subject of an IND are exempt from the label requirement in 
Sec. 312.6(a); or
    (4) The person exporting the drug sends a written certification to 
the Office of International Programs, Food and Drug Administration, 
5600 Fishers Lane, Rockville, MD 20857, at the time the drug is first 
exported and maintains records documenting compliance with this 
paragraph. The certification shall describe the drug that is to be 
exported (i.e., trade name (if any), generic name, and dosage form), 
identify the country or countries to which the drug is to be exported, 
and affirm that:
    (i) The drug is intended for export;
    (ii) The drug is intended for investigational use in a foreign 
country;
    (iii) The drug meets the foreign purchaser's or consignee's 
specifications;
    (iv) The drug is not in conflict with the importing country's laws;
    (v) The outer shipping package is labeled to show that the package 
is intended for export from the United States;
    (vi) The drug is not sold or offered for sale in the United States;
    (vii) The clinical investigation will be conducted in accordance 
with Sec. 312.120;
    (viii) The drug is manufactured, processed, packaged, and held in 
substantial conformity with current good manufacturing practices;
    (ix) The drug is not adulterated within the meaning of section 
501(a)(1), (a)(2)(A), (a)(3), (c), or (d) of the act;
    (x) The drug does not present an imminent hazard to public health, 
either in the United States, if the drug were to be reimported, or in 
the foreign country;
    (xi) The drug is labeled in accordance with the foreign country's 
laws; and
    (xii) The drug is promoted in accordance with its labeling.
    (c) Limitations. Exportation under paragraph (b) of this section 
may not occur if:
    (1) For drugs exported under paragraph (b)(1) of this section, the 
IND pertaining to the clinical investigation is no longer in effect;
    (2) For drugs exported under paragraph (b)(2) of this section, the 
requirements in section 802(b)(1), (f), or (g) of the act are no longer 
met;
    (3) For drugs exported under paragraph (b)(3) of this section, the 
requirements in section 802(c), (f), or (g) of the act are no longer 
met; or
    (4) For drugs exported under paragraph (b)(4) of this section, the 
conditions underlying the certification are no longer met.
    (5) For any investigational new drugs under this section, the drug 
no longer complies with the laws of the importing country.
    (d) Insulin and antibiotics. New insulin and antibiotic drug 
products may be exported for investigational use in accordance with 
section 801(e)(1) of the act without complying with this section.

    Dated: September 18, 2001.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 02-15358 Filed 6-18-02; 8:45 am]
BILLING CODE 4160-01-S