[Federal Register Volume 70, Number 225 (Wednesday, November 23, 2005)]
[Rules and Regulations]
[Pages 70720-70730]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 05-23120]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 312

[Docket No. 2000N-1663]
RIN 0910-AA61


Investigational New Drugs: Export Requirements for Unapproved New 
Drug Products

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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

DATES: This rule is effective December 23, 2005.

FOR FURTHER INFORMATION CONTACT: Philip L. Chao, Office of Policy and 
Planning (HF-23), Food and Drug Administration, 5600 Fishers Lane, 
Rockville, MD 20857, 301-827-0587.

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of June 19, 2002 (67 FR 41642), we (FDA) 
published a proposed rule to describe various options for exporting an 
investigational new drug, including a biological product. We issued the 
proposed rule to implement statutory changes resulting from the FDA 
Export Reform and Enhancement Act of 1996 (Pub. L. 104-134, as amended 
by Pub. L. 104-180) and to modify a pre-existing regulatory program for 
exporting investigational new drugs.
    Under current Sec.  312.110(b) (21 CFR 312.110(b)), any person who 
intends to export an unapproved new drug product for use in a clinical 
investigation must have either an investigational new drug application 
(IND) or submit a written request to us (FDA). The written request must 
provide sufficient information about the drug to satisfy us 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 (id.). If we authorize exportation of 
the drug, we notify the government of the importing country (id.). 
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

[[Page 70721]]

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, we received nearly 1,800 export requests under the 312 
program. We found that very few requests (less than 1 percent) 
presented any public health concerns.
    In 1996, the FDA Export Reform and Enhancement Act of 1996 became 
law. The FDA Export Reform and Enhancement Act created, among other 
things, two new provisions that affect the exportation of 
investigational drug products, including biological 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, Cyprus, the Czech Republic, Denmark, Estonia, 
Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, 
Lithuania, Luxembourg, Malta, the Netherlands, Poland, Portugal, 
Slovakia, Slovenia, 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 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)).
    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:
     Is not manufactured, processed, packaged, and held in 
substantial conformity with current good manufacturing practice (CGMP) 
requirements;
     Is adulterated under certain provisions of section 501 of 
the act (21 U.S.C. 351);
     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;
     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;
     Presents an imminent hazard to the public health of the 
foreign country;
     Fails to comply with labeling requirements in the country 
receiving the exported drug; or
     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. In the Federal Register of December 19, 2001 (66 FR 65429), we 
issued a final rule on these recordkeeping and notification 
requirements, and the rule is codified at Sec.  1.101 (21 CFR 1.101).
    The new export provisions in section 802 of the act significantly 
reduced the number of requests under the 312 program from an annual 
average of 570 requests to 200 requests. This final rule amends Sec.  
312.110 to conform to the FDA Export Reform and Enhancement Act of 1996 
and to modify the 312 program.

II. Comments on the Proposed Rule

A. What Did the Proposed Rule Cover? How Many Comments Did FDA Receive?

    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 modify the export 
requirements for the 312 program. The proposed rule would not contain 
any new recordkeeping requirements because such records are already 
required under Sec.  312.57 (if the foreign clinical trial is under an 
IND) or Sec.  1.101.
    We received eight comments on the proposed rule. The comments came 
from seven sources: A pharmaceutical trade association, four 
pharmaceutical companies, one consulting firm, and one university 
student. In general, six comments strongly supported the rule with few 
or no modifications. One comment opposed exports of investigational new 
drugs generally, and another comment sought clarification of one 
statutory provision and did not address the rule itself. We address 
most comments in greater detail below. (We do not discuss the comment 
seeking a clarification of the statute because it was not directly 
related to the rule.) To make it easier to identify comments and our 
responses, the word ``Comment,'' in parenthesis, will appear before the 
comment's description, and the word ``Response,'' in parenthesis, will 
appear before our response. We have also numbered each comment to 
identify them more easily. The number assigned to each comment is 
purely for organizational purposes and does not signify the comment's 
value or importance or the order in which it was received.

B. Can Investigational New Drugs Be Exported Under an IND?

    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. 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 who will use the drug in a study submitted to and allowed 
to proceed under the IND. Because this provision is not limited to 
particular countries, a drug that is the subject of an IND could be 
exported under the act to any country in the world if the export is for 
the purpose of conducting a clinical investigation in the importing 
foreign country. Exporters should be aware, however, that this 
provision, like all provisions in proposed Sec.  312.110, pertain only 
to the requirements of the act. Other Federal laws, such as those 
relating to customs or controlled substances or barring

[[Page 70722]]

exports to specific countries, may restrict or prohibit an export even 
if it would be permitted under this rule.
    We received no comments on this provision and have finalized it 
without change.

C. Can Investigational New Drugs Be Exported If They Have Marketing 
Authorization? Which Countries Must Provide That Marketing 
Authorization?

    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 (although section 802(b)(1) of the act has been 
in effect since April 1996). 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, nor would proposed Sec.  312.110(b)(2) 
require the drug to be the subject of an IND. 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. The proposal would also require compliance with the export 
notification and recordkeeping requirements Sec.  1.101.
    We received no comments on this provision and have finalized it 
without change.
    However, regarding the export notification and recordkeeping 
requirements at Sec.  1.101, we note that we received a petition for 
reconsideration that challenges, among other things, the recordkeeping 
requirement at Sec.  1.101(b)(2). Section 1.101(b)(2) describes the 
records that may be kept to show that an export does not conflict with 
a foreign country's laws, as required by section 801(e)(1)(B) of the 
act. Section 1.101(b)(2) states that the records may consist of a 
letter from an appropriate foreign government agency stating that the 
product has marketing approval from the foreign government or does not 
conflict with the foreign country's laws or a notarized certification 
by a responsible company official in the United States that the product 
does not conflict with the foreign country's laws. In a letter dated 
July 22, 2002, we informed the petitioner that we would exercise 
enforcement discretion regarding the letter and certification described 
in Sec.  1.101(b)(2), that parties must still comply with the statutory 
requirement in section 801(e)(1)(B) of the act, and that we would be 
evaluating whether to issue an advance notice of proposed rulemaking 
regarding the petitioner's issues (see Letter from Margaret M. Dotzel, 
Associate Commissioner for Policy, to Peter Barton Hutt, Covington & 
Burling, dated July 22, 2002; this letter can be found in FDA Docket 
No. 1998N-0583). We subsequently issued an advance notice of proposed 
rulemaking regarding the issues raised by the petitioner (see 69 FR 
30842, June 1, 2004) and are continuing to evaluate the comments. We 
are continuing to exercise enforcement discretion regarding Sec.  
1.101(b)(2), but we remind would-be exporters that they must continue 
to comply with the statutory requirement in section 801(e)(1)(B) of the 
act and the remaining provisions in Sec.  1.101.

D. Can Investigational New Drugs Be Exported Directly to Certain 
Countries Without FDA Approval?

    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 (although section 802(c) of the act has been in effect since April 
1996). In brief, under proposed Sec.  312.110(b)(3), 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. Exports 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 statutory requirements in 
section 802(c), (f), and (g) of the act. Proposed Sec.  312.110(b)(3) 
would also require compliance with the relevant recordkeeping 
requirements at Sec.  1.101.
    Proposed Sec.  312.110(b)(3) would add that investigational new 
drugs that are not under an IND and are exported under section 802(c) 
of the act do not have to bear a label stating, ``Caution: New Drug-
Limited by Federal (or United States) law to investigational use.'' 
This proposed requirement reflected the fact that the label statement 
is required under section 505(i) of the act, and that, absent an IND, 
drugs exported under section 802(c) of the act are not subject to 
section 505(i) of the act.
    The preamble to the proposed rule discussed our interpretation of 
section 802(c) of the act and the issue of ``transshipment.'' 
``Transshipment'' refers to the practice of shipping a product to a 
country from which it will later be shipped to another country. We 
stated that we were aware that some firms have interpreted section 
802(c) of the act as permitting transshipment to unlisted countries as 
long as the shipment went through a listed country (see 67 FR 41642 at 
41643). (We knew about the firms' position on transshipment from 
comments we had received on a draft export guidance document that 
appeared in the Federal Register of June 12, 1998 (63 FR 32219).) We 
noted that section 802(c) of the act is silent with respect to 
transshipment, and a more reasonable interpretation is that the 
provision does not allow transshipments. We added that interpreting 
section 802(c) of the act to allow transshipment would be inconsistent 
with our traditional practice under Sec.  312.110 and 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 (67 FR 41642 at 41643).
    Nevertheless, because we knew that some firms insisted that section 
802(c) of the act allows transshipment, the preamble to the proposed 
rule stated that we would interpret section 802(c) of the act as 
permitting investigational new drugs to be sent to principal 
investigators in a listed country who then use the investigational new 
drug in an unlisted country, provided that 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), we stated that we would interpret section 802(c) of 
the act as permitting exportation of the investigational new drug, 
without prior FDA authorization, as 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 
conducted the clinical investigation in accordance with Norwegian 
requirements and any requirements in the unlisted country where the 
investigational new drug is administered.
    (Comment 1) Three comments disagreed with this limited 
transshipment position. The comments acknowledged that the law is 
subject to

[[Page 70723]]

various interpretations, but argued against allowing transshipment from 
listed countries to unlisted countries. The comments explained that a 
clinical investigator may have little ability to control how a drug is 
moved, stored, or used ``if he or she is not supported by the laws of 
the land'' and so expecting the clinical investigator ``to enforce the 
laws, regulations and practices of the listed country in the unlisted 
country (even assuming there are no contradictions between them) is, we 
believe, quite unrealistic and exposes the investigator, the sponsor 
and, not least, the patients to significant risks.'' Consequently, two 
comments recommended that we not allow transshipment from listed 
countries to unlisted countries. Another comment stated that we should 
not allow transshipment from listed countries to unlisted countries, 
but then stated that transshipment of investigational new drugs should 
be ``the responsibility of the sponsor alone.''
    (Response) We have reconsidered our interpretation of section 
802(c) of the act and agree that transshipment should not be permitted 
under section 802(c) of the act. Although our limited transshipment 
policy was intended to accommodate the industry, we agree with the 
pharmaceutical industry comments that a clinical investigator's ability 
to apply a listed country's laws and regulations in an unlisted country 
may be difficult at best. Therefore, we do not interpret section 802(c) 
of the act or Sec.  312.110(b)(3) as allowing transshipment from listed 
countries to unlisted countries.
    Furthermore, we do not agree that transshipment should be the 
sponsor's responsibility alone because that would mean that a sponsor 
could consider itself free to transship an investigational new drug 
regardless of our interpretation of section 802(c) of the act.
    As for proposed Sec.  312.110(b)(3) itself, we received no comments 
on the provision and have finalized it without change.

E. What Changes Are Being Made to the ``312 Program?''

    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, and we expected that the provision would be used by 
persons who intend to export a drug that does not have valid marketing 
authorization from a listed country for investigational use to an 
unlisted country. Proposed Sec.  312.110(b)(4) would modify the 312 
program by eliminating the requirement of prior FDA authorization. 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 us. 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 
various conditions or criteria had been met, such as:
     The drug is intended for export;
     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 CGMPs;
     The drug is not adulterated within the meaning of section 
501(a)(1), (a)(2)(A), (a)(3), (c), or (d) of the act;
     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.
    The preamble to the proposed rule explained that we were proposing 
to accept certifications because our experience with the 312 program 
indicated that very few investigational new drug exports under the 
existing program raise any public health concerns. The certification 
would eliminate the requirement of prior FDA authorization of a request 
to export a drug for investigational use (67 FR 41642 at 41644). 
Additionally, 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 subject to internationally recognized requirements for 
clinical investigations (id. at 41645). The proposal would also require 
the exporter of the investigational new drug to retain records showing 
its compliance with the provision's requirements.
    (Comment 2) Several comments expressed strong support for 
streamlining the 312 program. For example, one comment called the 
proposal a ``bold but considered move'' that would reduce 
administrative burdens on FDA and sponsors without waiving any 
significant obligations.
    Three comments questioned why proposed Sec.  312.110(b)(4)(xii) 
would require the exporter to certify that the investigational new drug 
``is promoted in accordance with its labeling.'' The comments said that 
the requirement is unnecessary because investigational new drugs are 
not the subject of promotion and requested that we clarify or delete 
the requirement.
    (Response) We agree with the comments that investigational new 
drugs are not to be promoted, and we have deleted the language 
regarding promotion from Sec.  312.110(b)(4).
    However, one comment's claim that proposed Sec.  312.110(b)(4) 
would reduce administrative burdens without waiving any significant 
obligations prompted us to consider whether a person exporting a drug 
under Sec.  312.110(b)(4) should be able to export an investigational 
new drug in an emergency without satisfying certain criteria. For 
example, in recent years, we have seen growing concern over the 
possible use of biological, chemical, or other weapons in a terrorist 
attack. These concerns have prompted interest by some foreign countries 
in stockpiling drugs and biological products for possible use if such 
an attack occurs. We have also seen the sudden emergence of new 
diseases, such as Severe Acute Respiratory Syndrome (SARS), and can 
foresee situations where a foreign country might seek importation of an 
investigational new drug to respond to a sudden and immediate disease 
outbreak. In such situations, the need to stockpile drugs or to provide 
potentially helpful treatment quickly to a large number of patients may 
be incompatible with certain criteria in Sec.  312.110(b)(4).
    Therefore, the final rule includes a new Sec.  312.110(b)(5) to 
address the exportation of investigational new drugs due to a national 
emergency in a foreign country. New Sec.  312.110(b)(5) contemplates 
two different national emergency scenarios. The first scenario, at 
Sec.  312.110(b)(5)(i), provides for exportation of an investigational 
new drug in a foreign country to be stored for possible use if and when 
a national emergency in that foreign country arises. Under Sec.  
312.110(b)(5)(i), a person may export the investigational new drug 
under Sec.  312.110(b)(4) and may exclude

[[Page 70724]]

from its certification an affirmation with respect to any one or more 
of paragraphs (b)(4)(i), (b)(4)(iv), (b)(4)(vi), (b)(4)(vii), 
(b)(4)(viii), and/or (b)(4)(ix), provided that he or she:
     Provides a written statement, under Sec.  
312.110(b)(5)(i)(A)(1), explaining why compliance with each such 
paragraph is not feasible or is contrary to the best interests of the 
individuals who may receive the investigational new drug;
     Provides a written statement from an authorized official 
of the importing country's government. The statement must attest that 
the official agrees with the exporter's statement made under Sec.  
312.110(b)(5)(i)(A)(1); explain that the drug is to be stockpiled 
solely for use of the importing country in a national emergency; and 
describe the potential national emergency that warrants exportation of 
the investigational new drug under this provision; and
     Provides a written statement showing that the Secretary of 
Health and Human Services (the Secretary), or his or her designee, 
agrees with the findings of the authorized official of the importing 
country's government.
    We decided that in a national emergency, ``stockpiling'' scenario, 
exporters should be able to drop the affirmations in paragraphs 
(b)(4)(i), (b)(4)(iv), (b)(4)(vi), (b)(4)(vii), (b)(4)(viii), and/or 
(b)(4)(ix) from their certifications if, due to the potential national 
emergency for which the drug is being stockpiled, compliance with that 
paragraph is infeasible or contrary to the best interests of the 
individuals who may receive the investigational new drug. For example, 
several foreign governments have asked for our help in exporting 
investigational vaccines to their countries to reduce their citizens' 
vulnerability to a certain pathogen. Vaccine production is very 
complex, so it is unlikely that a manufacturer could respond quickly to 
a large-scale national emergency in a foreign country. Thus, if we were 
to insist that all investigational vaccines exported in a national 
emergency scenario be ``intended for export'' (as otherwise required by 
Sec.  312.110(b)(4)(i)), vaccines that had been intended for domestic 
use could not be exported to address a national emergency in a foreign 
country because those vaccines would not have been ``intended for 
export'' when they were first made. Providing for the deletion of the 
``intended for export'' requirement in a national emergency, 
stockpiling scenario makes it possible to export products originally 
intended for domestic use to meet a more important foreign need.
    In the national emergency, ``stockpiling'' scenario, exportation 
may not proceed without prior FDA authorization. We decided to require 
FDA authorization to ensure that exportation of a drug based on this 
scenario is limited to the requirements set out in Sec.  
312.110(b)(5)(i) and not used for other situations for which other 
regulatory requirements apply.
    The second national emergency scenario is at Sec.  
312.110(b)(5)(ii). This provision would apply where the national 
emergency is both sudden and immediate. For example, Sec.  
312.110(b)(5)(ii) could be used when a bioterrorist attack has occurred 
in a foreign country and has created an immediate need to export an 
investigational new drug for use in the foreign country. It could also 
apply where the national emergency is imminent, but has not yet 
occurred. For example, Sec.  312.110(b)(5)(ii) might be applicable 
where a foreign government has evidence showing that a particular novel 
disease outbreak is about to occur and that prompt administration of an 
investigational new drug is needed to treat or immunize its citizens 
before the disease assumes epidemic proportions. Thus, in these 
examples, the words ``sudden'' and ``immediate'' are meant to convey a 
sense that the national emergency resulted from unforeseen 
circumstances and that the exported drug is needed quickly in order to 
address the national emergency, and we expect Sec.  312.110(b)(5)(ii) 
to be used in very rare circumstances. In other words, Sec.  
312.110(b)(5)(ii) should not be used in situations where a person 
simply wants to export a drug to address longstanding public health 
concerns (such as a disease which is and has been prevalent in the 
foreign country for years).
    Under Sec.  312.110(b)(5)(ii), a person may export an 
investigational new drug under Sec.  312.110(b)(4) and exclude from its 
certification an affirmation with respect to any one or more of 
paragraphs (b)(4)(i), (b)(4)(iv), (b)(4)(v), (b)(4)(vi), (b)(4)(vii), 
(b)(4)(viii), (b)(4)(ix), and/or (b)(4)(xi), provided that he or she:
     Provides a written statement, under Sec.  
312.110(b)(5)(ii)(A)(1), explaining why compliance with each such 
paragraph is not feasible or is contrary to the best interests of the 
individuals who are expected to receive the investigational new drug; 
and
     Provides sufficient information from an authorized 
official of the importing country's government to enable the Secretary, 
or his or her designee, to decide whether a national emergency has 
developed or is developing in the importing country, whether the 
investigational new drug will be used solely for that national 
emergency, and whether prompt exportation of the investigational new 
drug is necessary.
    We decided that, in the case of a sudden and immediate national 
emergency in a foreign country, the exporter's certification may omit 
an affirmation addressing paragraphs (b)(4)(i), (b)(4)(iv), (b)(4)(v), 
(b)(4)(vi), (b)(4)(vii), (b)(4)(viii), (b)(4)(ix) and/or (b)(4)(xi) if, 
due to the sudden and immediate national emergency, compliance with 
that paragraph or paragraphs are infeasible or contrary to the best 
interests of the individuals who may receive the investigational new 
drug. For example, it would not be necessary to insist that the 
exported drug be labeled in accordance with the foreign country's laws 
where the foreign country itself had agreed that compliance with its 
labeling requirements was unnecessary during the national emergency.
    Additionally, in contrast to the ``stockpiling'' scenario in Sec.  
312.110(b)(5)(i), exportation to meet a sudden and immediate national 
emergency may not proceed until the Secretary has decided whether a 
national emergency has developed or is developing in the importing 
country, whether the investigational new drug will be used solely for 
that national emergency, and whether prompt exportation of the 
investigational new drug is necessary. We reiterate that, given its 
reference to a ``sudden and immediate'' national emergency, Sec.  
312.110(b)(5)(ii) should be very rarely used.
    Persons who wish to obtain a written statement from the Secretary 
under Sec.  312.110(b)(5)(i) or to request that the Secretary make the 
determinations under Sec.  312.110(b)(5)(ii) should direct their 
requests to: Secretary's Operations Center, Office of Emergency 
Operations and Security Programs, Office of Public Health Emergency 
Preparedness, Office of the Secretary, Department of Health and Human 
Services, 200 Independence Ave. SW., Washington, DC 20201.
    Requests may be also be sent by FAX: 202-619-7870 or by e-mail: 
HHS.SOC@hhs.gov.
    To complement these changes, we have revised Sec.  312.110(c)(4) to 
state that exportation is not allowed under Sec.  312.110(b)(4) if the 
conditions underlying the certification or the statements submitted 
under Sec.  312.110(b)(5) are no longer met.
    (Comment 3) One comment appeared to inquire whether transshipment 
could occur under the 312 program. The comment suggested that 
transshipment should be allowed if the sponsor amended its 
``certification'' requesting shipment of an investigational new drug

[[Page 70725]]

from either a listed or unlisted country to another unlisted country 
``where the protocol is unchanged and all applicable laws are met.'' 
The comment added that only products under the sponsor's direct control 
would be permitted for transshipment.
    (Response) The comment may have misinterpreted the rule. Exports of 
an investigational new drug to a listed country fall within section 
802(c) of the act and Sec.  312.110(b)(3), and no certification is 
required. Consequently, if an investigational new drug is exported to a 
listed country under section 802(c) of the act, there is no 
``certification'' to amend, and, as our response to comment 1 of this 
document stated, we will not interpret section 802(c) of the act as 
allowing transshipment from a listed country to an unlisted country.
    As for exports under the 312 program and Sec.  312.110(b)(4), we 
concede that our proposed revision of the 312 program did not prohibit 
its use for exports to listed countries. However, if a sponsor decided 
to use Sec.  312.110(b)(4) to export an investigational new drug to a 
listed country, it would create unnecessary work for itself because, 
under Sec.  312.110(b)(3), it could export the investigational new drug 
to the listed country without providing any documentation to us.
    If the comment sought to use Sec.  312.110(b)(4) to export an 
investigational new drug to an unlisted country and then transship that 
drug to another unlisted country, we would agree that Sec.  
312.110(b)(4) could be used, but only if both unlisted countries are 
identified in the original certification to us. In other words, the 
original certification would have to state that the investigational new 
drug is being sent to one unlisted country and then shipped to another 
unlisted country. We do not intend to permit sponsors to use Sec.  
312.110(b)(4) to ship investigational new drugs to an unlisted country 
and, at some later, unspecified date, amend the certification in the 
manner described by the comment. We are concerned that allowing 
amendments to certifications that would change the country receiving 
the exported drug would enable an unscrupulous person to avoid several 
critical obligations, particularly those that are specific to the 
receiving country, such as ensuring that:
     The clinical investigation will be conducted in accordance 
with Sec.  312.120;
     The drug meets the foreign purchaser's or consignee's 
specifications; and
     The drug does not present an imminent hazard to the public 
health in the foreign country.
    Given these concerns, we decline to revise the rule to allow 
amended certifications under Sec.  312.110(b)(4) that would enable 
sponsors to transship investigational new drugs without observing 
several important obligations in Sec.  312.110(b)(4) itself.

F. Are There Any Restrictions on Investigational New Drug Exports?

    Proposed Sec.  312.110(c) would prohibit exports under certain 
conditions. For example, for drugs under an IND that are exported under 
proposed 312.110(b)(1), exportation would not be allowed if the IND is 
no longer in effect. 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 
proposed Sec.  312.110, exportation would not be allowed if the drug no 
longer complied with the laws of the importing country.
    We received no comments on this provision. However, as explained in 
section II.E of this document, we have created a Sec.  312.110(b)(5) to 
address exportation of investigational new drugs to meet national 
emergencies in a foreign country. This new provision establishes new 
conditions on the export requirements under Sec.  312.110(b)(4) in such 
national emergencies. Consequently, we have revised Sec.  312.110(c)(4) 
to state that exportation is not allowed under Sec.  312.110(b)(4) if 
the conditions underlying the certification or the statements submitted 
under Sec.  312.110(b)(5) are no longer met.

G. What Other Changes Did FDA Propose?

    The proposed rule would also make several minor amendments to 
reflect or update statutory requirements and to redesignate paragraphs 
(to accommodate other proposed changes). In brief, the proposal would:
     Redesignate Sec.  312.110(b)(4) as new Sec.  312.110(d) 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.
     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 FDA Export Reform and Enhancement Act eliminated most 
FDA approval requirements for exported drugs. 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. We also noted 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) (see 67 FR 41642 at 41645).
     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.
     Remove the text at Sec.  312.110(b)(3) stating 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. We proposed to 
delete this language because the proposed rule expressly refers to 
exports of investigational new drugs for use in clinical 
investigations.
    We received no comments on these provisions or changes and have 
finalized them without change.

H. What Other Comments Did FDA Receive?

    Several comments responded to specific questions we had presented 
in the preamble to the proposed rule or discussed other issues related 
to the export of investigational new drugs or the conduct of foreign 
clinical trials.
    The preamble to the proposed rule noted that section 402(j) of the 
Public Health Service Act (42 U.S.C. 282(j)) directs the Secretary to 
establish, maintain, and operate a data bank of information on clinical 
trials for drugs for serious or life-threatening diseases and 
conditions (67 FR 41642 at 41645). We invited comment on whether we 
should make available information on clinical trials involving 
investigational new drugs exported under proposed Sec.  312.110(b)(4).

[[Page 70726]]

    (Comment 4) Some comments opposed making information on drugs 
exported under proposed Sec.  312.110(b)(4) publicly available. The 
comments argued that section 402(j) of the Public Health Service Act 
was intended to provide clinical trial information to American patients 
and that we had no legal authority to collect or disclose information 
on foreign clinical trials.
    (Response) We agree with the comments that section 402(j) of the 
Public Health Service Act does not apply to exports under Sec.  
312.110(b)(4), but disagree as to the rationale. Section 402(j) of the 
Public Health Service Act refers to ``clinical trials'' without any 
express requirement that the clinical trials be conducted in the United 
States. However, we believe that this provision only applies to 
clinical trials conducted under an IND.
    The Senate Committee on Labor and Human Resources' report on the 
``Food and Drug Administration Modernization and Accountability Act of 
1997'' describes the data bank as requiring sponsors of clinical trials 
to provide certain clinical trial information to the National 
Institutes of Health ``not later than 21 days after the approval by the 
FDA'' (see S. Rept. 105-43, ``Food and Drug Administration 
Modernization and Accountability Act of 1997,'' 105th Cong., 1st sess. 
at p. 99 (July 1, 1997)). The report apparently meant not later than 21 
days after the IND goes into effect since, strictly speaking, FDA does 
not ``approve'' clinical trials or INDs. Rather, an IND goes into 
effect after 30 days if FDA does not notify the sponsor that the trials 
are subject to a clinical hold before then, or earlier than 30 days if 
FDA so notifies the sponsor that the trials may begin. Nonetheless, 
this statement strongly suggests that only trials that are conducted 
under an IND are to be included in the data bank. Therefore, based on 
this legislative history, we do not interpret section 402(j) of the 
Public Health Service Act as applying to exports under Sec.  
312.110(b)(4).
    (Comment 5) One comment focused on the proposed rule's cross-
references to statutory provisions. The comment said that the cross-
references ``greatly complicate the reading and practical understanding 
of the regulation'' and suggested that we incorporate the statutory 
language directly into the rule.
    (Response) We decline to amend the rule as suggested by the 
comment. While we understand that cross-references in a regulation can 
make it more difficult to read and to understand a particular 
requirement, there are several practical reasons for not inserting 
statutory language into a rule. First, several of the cited statutory 
provisions contain cross-references themselves. Section 802(f) of the 
act, which is mentioned in Sec.  312.110(b)(2), (b)(3), (c)(2), and 
(c)(3), refers to certain adulteration provisions in section 501 of the 
act and to export requirements at section 801(e)(1) of the act. Thus, 
inserting statutory language into the rule would still result in cross-
references to other statutory provisions. Second, if we were to use 
statutory language in the rule and if Congress amended that particular 
statute later, we would be obliged to begin new rulemaking to reflect 
the new statutory language, even if the revised statutory language had 
no significant impact on the rule itself. Otherwise, the regulation 
would be inconsistent with the act, and differences between the act and 
the regulatory language could result in needless disagreements or 
disputes. Third, inserting statutory language into a rule would make 
the rule much longer and have limited value because a firm should be 
conscious of both statutory and regulatory requirements. In general, we 
may issue a regulation to describe our interpretation of a particular 
statutory requirement and to create a consistent, enforceable 
obligation on affected parties and on the agency itself. If a 
particular statutory provision is self-executing or self-explanatory, 
we may feel that no regulation is necessary. Given these 
considerations, we decline to insert the statutory language into the 
rule.
    (Comment 6) One comment opposed the rule entirely. The comment 
questioned why a foreign country would accept a drug that could not be 
used in the United States and alleged that companies exported 
investigational new drugs to avoid breaking U.S. law and to ``exploit 
people in other countries.'' The comment suggested that companies 
supporting the proposed rule ``should be investigated for unethical 
conduct.''
    (Response) We disagree with the comment. The mechanisms for 
exporting an investigational new drug reflect statutory provisions in 
sections 505(i), 802(b)(1), and 802(c) of the act. As a result, 
contrary to the comment's assertion, firms exporting a drug for 
investigational use in a foreign country in accordance with this rule 
would be acting in compliance with the act. Given that fact, we have no 
basis for attributing an improper or unethical motive to those who 
would export such products or those who support this rulemaking.
    (Comment 7) Several comments, in discussing their position against 
transshipment, recommended that we ``work diligently to approve 
unlisted countries and add them to the listed countries.''
    (Response) We interpret the comments' suggestion of ``adding'' 
countries as referring to section 802(b)(1)(B) of the act, which states 
that the Secretary ``may designate an additional country to be included 
in the list of countries described in [section 802(b)(1)(A) of the 
act]'' if certain requirements are met. However, section 802(b)(1)(B) 
of the act also states that the authority to add countries to the list 
cannot be delegated. As a result, FDA has no authority or ability to 
add countries to the list.
    We note that, since the FDA Export Reform and Enhancement Act 
became law in 1996, we have not received any substantive inquiries 
about adding a particular country to the group of listed countries. We 
are not aware of any similar inquiries to the Department of Health and 
Human Services.

III. Description of the Final Rule

    The final rule is substantially similar to the proposed rule as it 
describes four mechanisms for exporting a drug, including a biological 
product, for investigational use. The four mechanisms are: (1) 
Exporting an investigational new drug under an IND, where the foreign 
clinical trial is covered in the IND; (2) exporting an investigational 
new drug that has valid marketing authorization from a ``listed 
country'' identified in section 802(b)(1)(A) of the act; (3) exporting 
an investigational new drug to a listed country; or (4) providing a 
certification to FDA and exporting the investigational new drug under a 
modified ``312 program.'' In the latter case, the final rule also 
identifies the certification criteria that must be followed if the 
export is to occur under the 312 program.
    To recap the principal features of each export mechanism,
    1. Section 312.110(b)(1) could be used where the foreign clinical 
trial is the subject of an IND.
    2. Section 312.110(b)(2) could be used where the investigational 
new drug has received market authorization in any ``listed country'' 
and complies with the laws of the country to which it is being 
exported.
    3. Section 312.110(b)(3) could be used when the investigational new 
drug is to be used in a clinical investigation in a ``listed country.''
    4. Section 312.110(b)(4) could be used in situations not covered by 
Sec.  312.110(b)(1), (b)(2), or (b)(3), and the requirements in Sec.  
312.110(b)(4) may be streamlined or modified in the event of

[[Page 70727]]

a national emergency in a foreign country (see Sec.  312.110(b)(5)).
    Please note that the export mechanisms are not mutually exclusive. 
For example, if a sponsor obtains an IND for a clinical investigation 
in a listed country, the sponsor is not obliged to export the 
investigational new drug under Sec.  312.110(b)(2) or (b)(3).
    The final rule also describes the conditions under which 
exportation may not occur. In general, these conditions are: (1) When 
the export no longer complies with the statutory requirements that 
would allow the drug to be exported; (2) when the conditions underlying 
the certification in the 312 program are no longer met; or (3) when the 
exported investigational new drug no longer complies with the foreign 
country's laws.
    The final rule also states that insulin and antibiotics may be 
exported for investigational use in accordance with section 801(e)(1) 
of the act. The act specifically states that exports of insulin and 
antibiotics that are not approved for use by FDA are subject only to 
section 801(e)(1) of the act.

IV. 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 
investigational new drugs, terminate an IND under certain conditions.
    The final rule is consistent with section 505(i) of the act insofar 
as Sec.  312.110(b)(1) pertains to drugs that are the subject of an IND 
and Sec.  312.110(b)(4) requires 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 final rule also implements section 802 of the act, which 
applies to unapproved drug products intended for export. Section 802(c) 
of the act applies to exports of unapproved drug products intended for 
investigational use. As stated earlier, section 802(c) 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(c) 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 CGMPs, compliance with requirements contained in 
section 801(e)(1) of the act, and not being adulterated under certain 
provisions of section 501 of the act). Section 312.110(b)(3) pertains 
to exports of investigational new drugs to listed countries, under 
section 802(c) of the act. Additionally, Sec.  312.110(b)(2) pertains 
to drugs exported under section 802(b) of the act and requires that 
such exports comply with section 802(f) of the act.
    Authority to issue regulations to implement section 802 of the act, 
and for the efficient enforcement of the act generally, is contained in 
section 701(a) of the act (21 U.S.C. 371(a)). Section 903 of the act 
also provides general powers for implementing policies respecting FDA 
programs and activities. Thus, the final rule implements sections 
505(i) and 802 of the act. Furthermore, it is also authorized under our 
rulemaking authorities at sections 505(i) and 701(a) of the act, and 
FDA's general authority at section 903 of the act.

V. 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.

VI. Federalism

    FDA has analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. FDA has determined that the rule 
does not contain policies that have substantial direct effects on the 
States, on the relationship between the National Government and the 
States, or on the distribution of power and responsibilities among the 
various levels of government. Accordingly, the agency has concluded 
that the rule does not contain policies that have federalism 
implications as defined in the Executive order and, consequently, a 
federalism summary impact statement is not required.

VII. Paperwork Reduction Act of 1995

    This final 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.
    Title: Investigational New Drug Applications: Export Requirements 
for Unapproved New Drug Products.
    Description: The final rule provides four different mechanisms for 
exporting an investigational new drug. First, an investigational new 
drug may be exported under an IND to any country if the IND covers the 
foreign clinical trial. 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 CGMPs). Third, 
an investigational new drug may 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 CGMPs). Fourth, an investigational new drug 
may be exported provided that the sponsor submits a certification that 
the drug meets certain export criteria at the time the drug is 
exported. The final rule also requires 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.

[[Page 70728]]



                               Table 1.--Estimated Annual Recordkeeping Burden\1\
----------------------------------------------------------------------------------------------------------------
                      No. of         Annual Frequency       Total Annual        Hours per
21 CFR Section    Recordkeepers      per Recordkeeping        Records          Recordkeeper       Total Hours
----------------------------------------------------------------------------------------------------------------
312.110(b)(2)                 370                     1                370                  3              1,110
 and (b)(3)
----------------------------------------------------------------------------------------------------------------
312.110(b)(4)                 200                     1                200                  1                200
----------------------------------------------------------------------------------------------------------------
Total           .................  ....................  .................  .................              1,310
----------------------------------------------------------------------------------------------------------------
\1\There are no capital costs or operating and maintenance costs associated with this collection of information.


                                 Table 2.--Estimated Annual Reporting Burden\1\
----------------------------------------------------------------------------------------------------------------
                         No. of        Annual Frequency     Total Annual        Hours per
  21 CFR Section      Respondents        per Response        Responses           Response         Total Hours
----------------------------------------------------------------------------------------------------------------
312.110(b)(4)                    200                  1                200                 12              2,400
----------------------------------------------------------------------------------------------------------------
Total              .................  .................  .................  .................              2,400
----------------------------------------------------------------------------------------------------------------
\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 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 (200) to obtain an estimated 370 
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 1,110 hours (370 records 
multiplied by 3 hours per record).
    For 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 Sec.  312.110(b)(4), 
therefore, is 200 hours (200 records multiplied by 1 hour per record).
    Thus, the total recordkeeping burden would be 1,310 hours (1,110 + 
200 = 1,310). Of this recordkeeping burden, 1,110 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 
alldrugs exported and the countries to which they were exported).
    For the reporting requirement in Sec.  312.110(b)(4), FDA's 
experience under the 312 program suggests that extremely few reports 
would be submitted. Assuming that 200 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 Sec.  312.110(b)(4) would be 2,400 
hours. The reporting burden would be a regulatory (rather than 
statutory) burden.
    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 final rule to OMB for review. Prior to the effective 
date of this final rule, FDA will publish a notice in the Federal 
Register announcing OMB's decision to approve, modify, or disapprove 
the information collection provisions in this final rule. An agency may 
not conduct or sponsor, and a person is not required to respond to, a 
collection of information unless it displays a currently valid OMB 
control number.

VIII. Analysis of Impacts

    FDA has examined the impacts of the final rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), 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.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires 
that agencies prepare a written statement, which includes an assessment 
of anticipated costs and benefits, before proposing ``any rule that 
includes any Federal mandate that may result in the expenditure by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100,000,000 or more (adjusted annually for 
inflation) in any one year.'' The current threshold after adjustment 
for inflation is $115 million, using the most current (2003) Implicit 
Price Deflator for the Gross Domestic Product. FDA does not expect this 
final rule to result in any 1-year expenditure that would meet or 
exceed this amount.
    The agency has reviewed this final 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 final rule is a significant regulatory action as defined under 
paragraph 4 of section 3(f) of Executive Order 12866.
    The final rule facilitates 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 reduces the cost to the affected 
small firms. Thus, the agency certifies that this final rule does not 
have a significant economic impact on a substantial number of small 
entities. Therefore, under the Regulatory Flexibility Act, no further 
analysis is required.
    Because the final rule does not impose any mandates on State, 
local, or tribal governments, or the private sector

[[Page 70729]]

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.

List of Subjects in 21 CFR Part 312

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

0
Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR part 
312 is amended as follows:

PART 312--INVESTIGATIONAL NEW DRUG APPLICATION

0
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, 371, 
381, 382, 383, 393; 42 U.S.C. 262.

0
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) Except as provided in paragraph (b)(5) of this section, the 
person exporting the drug sends a written certification to the Office 
of International Programs (HFG-1), 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; and
    (xi) The drug is labeled in accordance with the foreign country's 
laws.
    (5) In the event of a national emergency in a foreign country, 
where the national emergency necessitates exportation of an 
investigational new drug, the requirements in paragraph (b)(4) of this 
section apply as follows:
    (i) Situations where the investigational new drug is to be 
stockpiled in anticipation of a national emergency. There may be 
instances where exportation of an investigational new drug is needed so 
that the drug may be stockpiled and made available for use by the 
importing country if and when a national emergency arises. In such 
cases:
    (A) A person may export an investigational new drug under paragraph 
(b)(4) of this section without making an affirmation with respect to 
any one or more of paragraphs (b)(4)(i), (b)(4)(iv), (b)(4)(vi), 
(b)(4)(vii), (b)(4)(viii), and/or (b)(4)(ix) of this section, provided 
that he or she:
    (1) Provides a written statement explaining why compliance with 
each such paragraph is not feasible or is contrary to the best 
interests of the individuals who may receive the investigational new 
drug;
    (2) Provides a written statement from an authorized official of the 
importing country's government. The statement must attest that the 
official agrees with the exporter's statement made under paragraph 
(b)(5)(i)(A)(1) of this section; explain that the drug is to be 
stockpiled solely for use of the importing country in a national 
emergency; and describe the potential national emergency that warrants 
exportation of the investigational new drug under this provision; and
    (3) Provides a written statement showing that the Secretary of 
Health and Human Services (the Secretary), or his or her designee, 
agrees with the findings of the authorized official of the importing 
country's government. Persons who wish to obtain a written statement 
from the Secretary should direct their requests to Secretary's 
Operations Center, Office of Emergency Operations and Security 
Programs, Office of Public Health Emergency Preparedness, Office of the 
Secretary, Department of Health and Human Services, 200 Independence 
Ave. SW., Washington, DC 20201. Requests may be also be sent by FAX: 
202-619-7870 or by e-mail: HHS.SOC@hhs.gov.
    (B) Exportation may not proceed until FDA has authorized 
exportation of the investigational new drug. FDA may deny authorization 
if the statements provided under paragraphs (b)(5)(i)(A)(1) or 
(b)(5)(i)(A)(2) of this section are inadequate or if exportation is 
contrary to public health.
    (ii) Situations where the investigational new drug is to be used 
for a sudden and immediate national emergency. There may be instances 
where exportation of an investigational new drug is needed so that the 
drug may be used in a sudden and immediate national emergency that has 
developed or is developing. In such cases:
    (A) A person may export an investigational new drug under paragraph 
(b)(4) of this section without making an affirmation with respect to 
any one or more of paragraphs (b)(4)(i), (b)(4)(iv), (b)(4)(v), 
(b)(4)(vi), (b)(4)(vii), (b)(4)(viii), (b)(4)(ix), and/or (b)(4)(xi), 
provided that he or she:
    (1) Provides a written statement explaining why compliance with 
each such paragraph is not feasible or is contrary to the best 
interests of the individuals who are expected to receive the 
investigational new drug and
    (2) Provides sufficient information from an authorized official of 
the importing country's government to enable the Secretary, or his or 
her

[[Page 70730]]

designee, to decide whether a national emergency has developed or is 
developing in the importing country, whether the investigational new 
drug will be used solely for that national emergency, and whether 
prompt exportation of the investigational new drug is necessary. 
Persons who wish to obtain a determination from the Secretary should 
direct their requests to Secretary's Operations Center, Office of 
Emergency Operations and Security Programs, Office of Public Health 
Emergency Preparedness, Office of the Secretary, Department of Health 
and Human Services, 200 Independence Ave. SW., Washington, DC 20201. 
Requests may be also be sent by FAX: 202-619-7870 or by e-mail: 
HHS.SOC@hhs.gov.
    (B) Exportation may proceed without prior FDA authorization.
    (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;
    (4) For drugs exported under paragraph (b)(4) of this section, the 
conditions underlying the certification or the statements submitted 
under paragraph (b)(5) of this section are no longer met; or
    (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: November 16, 2005.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 05-23120 Filed 11-22-05; 8:45 am]
BILLING CODE 4160-01-S