70720 Federal Register / Vol. 70, No. 225 / Wednesday, November 23, 2005 / Rules and Regulations 

promoting safe flight of civil aircraft in 

air commerce by prescribing regulations 

for practices, methods, and procedures 

the Administrator finds necessary for 

safety in air commerce. This regulation 

is within the scope of that authority 

because it addresses an unsafe condition 

that is likely to exist or develop on 

products identified in this rulemaking 

action. 

List of Subjects in 14 CFR Part 39 

Air transportation, Aircraft, Aviation 

safety, Safety. 

Adoption of the Amendment 

■ Accordingly, pursuant to the authority 

delegated to me by the Administrator, 

the Federal Aviation Administration 

amends part 39 of the Federal Aviation 

Regulations (14 CFR part 39) as follows: 

PART 39—AIRWORTHINESS 

DIRECTIVES 

■ 1. The authority citation for part 39 

continues to read as follows: 

Authority: 49 U.S.C. 106(g), 40113, 44701. 

§ 39.13 [Amended] 

■ 2. Section 39.13 is amended by adding 

a new airworthiness directive to read as 

follows: 

2005–24–05 Boeing Vertol (Boeing): 

Amendment 39–14385. Docket No. 

FAA–2005–23085; Directorate Identifier 

2005–SW–25–AD. 

Applicability: Model 107–II helicopters, all 

serial numbers, with a quill shaft, part 

number (P/N) 107D2067, all dash numbers, 

and a spiral bevel pinion gear (pinion gear), 

P/N 107D2215, installed, certificated in any 

category. 

Compliance: Required as indicated. 

To detect a fatigue crack in a quill shaft to 

prevent separation of the quill shaft between 

the aft transmission and the mix box 

assembly, loss of rotor synchronization, and 

subsequent loss of control of the helicopter, 

accomplish the following: 

(a) For a helicopter with a pinion gear 

installed with the following hours time-inservice (TIS): 

Pinion gear hours TIS Compliance time 

700 or more hours TIS ............................................................................. Within 50 hours TIS, unless accomplished within the previous 350 

hours TIS. 

Less than 700 hours TIS .......................................................................... On or before reaching 750 hours TIS. 

(1) Remove the aft transmission assembly, 

separate the mix box assembly from the aft 

transmission, and remove the quill shaft from 

the pinion gear assembly; 

(2) Visually inspect the external spline of 

the quill shaft for a chipped or cracked tooth 

around the pinhole; and 

(3) Magnetic particle inspect the quill shaft 

for a crack. 

(b) Before further flight, replace any quill 

shaft that has a crack or a chipped or cracked 

tooth with an airworthy quill shaft. 

Note 1: Boeing Service Bulletin No. 107–

63–1005, Revision 1, dated April 27, 2005, 

pertains to the subject of this AD. 

Note 2: Replacement quill shafts 

manufactured by Kawasaki Heavy Industries 

(KHI) for use on their Model KV107–II 

helicopters must be approved by the 

geographic Aircraft Certification Office 

(ACO) on a case-by-case basis for installation 

on a Boeing Model 107–II helicopter. 

(c) To request a different method of 

compliance or a different compliance time 

for this AD, follow the procedures in 14 CFR 

39.19. Contact the Manager, New York ACO, 

Engine and Propeller Directorate, FAA, for 

information about previously approved 

alternative methods of compliance. 

(d) Special flight permits will not be 

issued. 

(e) This amendment becomes effective on 

December 8, 2005. 

Issued in Fort Worth, Texas, on November 

16, 2005. 

Scott A. Horn, 

Acting Manager, Rotorcraft Directorate, 

Aircraft Certification Service. 

[FR Doc. 05–23156 Filed 11–22–05; 8:45 am] 

BILLING CODE 4910–13–P 

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. 

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 § 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 

§ 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 § 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 

Federal Register / Vol. 70, No. 225 / Wednesday, November 23, 2005 / Rules and Regulations 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 

§ 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 § 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 

§ 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 § 312.57 (if the 

foreign clinical trial is under an IND) or 

§ 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 § 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 § 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 

§ 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 § 312.110, pertain only to the 

requirements of the act. Other Federal 

laws, such as those relating to customs 

or controlled substances or barring 

70722 Federal Register / Vol. 70, No. 225 / Wednesday, November 23, 2005 / Rules and Regulations 

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 § 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 § 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 § 1.101. 

We received no comments on this 

provision and have finalized it without 

change. 

However, regarding the export 

notification and recordkeeping 

requirements at § 1.101, we note that we 

received a petition for reconsideration 

that challenges, among other things, the 

recordkeeping requirement at 

§ 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 

§ 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 § 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 

§ 1.101. 

D. Can Investigational New Drugs Be 

Exported Directly to Certain Countries 

Without FDA Approval? 

Proposed § 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 

§ 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 § 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 

§ 312.110(b)(3) would also require 

compliance with the relevant 

recordkeeping requirements at § 1.101. 

Proposed § 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 § 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 

Federal Register / Vol. 70, No. 225 / Wednesday, November 23, 2005 / Rules and Regulations 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 

§ 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 § 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 § 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 

§ 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 

§ 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 § 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 § 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 § 312.110(b)(4). 

However, one comment’s claim that 

proposed § 312.110(b)(4) would reduce 

administrative burdens without waiving 

any significant obligations prompted us 

to consider whether a person exporting 

a drug under § 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 § 312.110(b)(4). 

Therefore, the final rule includes a 

new § 312.110(b)(5) to address the 

exportation of investigational new drugs 

due to a national emergency in a foreign 

country. New § 312.110(b)(5) 

contemplates two different national 

emergency scenarios. The first scenario, 

at § 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 § 312.110(b)(5)(i), a person 

may export the investigational new drug 

under § 312.110(b)(4) and may exclude 

70724 Federal Register / Vol. 70, No. 225 / Wednesday, November 23, 2005 / Rules and Regulations 

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 

§ 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 

§ 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 

§ 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 § 312.110(b)(5)(i) and not used 

for other situations for which other 

regulatory requirements apply. 

The second national emergency 

scenario is at § 312.110(b)(5)(ii). This 

provision would apply where the 

national emergency is both sudden and 

immediate. For example, 

§ 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, § 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 § 312.110(b)(5)(ii) to be used in 

very rare circumstances. In other words, 

§ 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 § 312.110(b)(5)(ii), a person 

may export an investigational new drug 

under § 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 

§ 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 

§ 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, 

§ 312.110(b)(5)(ii) should be very rarely 

used. 

Persons who wish to obtain a written 

statement from the Secretary under 

§ 312.110(b)(5)(i) or to request that the 

Secretary make the determinations 

under § 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 § 312.110(c)(4) to state that 

exportation is not allowed under 

§ 312.110(b)(4) if the conditions 

underlying the certification or the 

statements submitted under 

§ 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 

Federal Register / Vol. 70, No. 225 / Wednesday, November 23, 2005 / Rules and Regulations 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 § 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 § 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 § 312.110(b)(4) to export 

an investigational new drug to a listed 

country, it would create unnecessary 

work for itself because, under 

§ 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 

§ 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 § 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 

§ 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 

§ 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 § 312.110(b)(4) that 

would enable sponsors to transship 

investigational new drugs without 

observing several important obligations 

in § 312.110(b)(4) itself. 

F. Are There Any Restrictions on 

Investigational New Drug Exports? 

Proposed § 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 

§ 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 

§ 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 § 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 

§ 312.110(b)(4) in such national 

emergencies. Consequently, we have 

revised § 312.110(c)(4) to state that 

exportation is not allowed under 

§ 312.110(b)(4) if the conditions 

underlying the certification or the 

statements submitted under 

§ 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 § 312.110(b)(4) as new 

§ 312.110(d) to state that the export 

requirements in § 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 § 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 § 312.110(b)(3) 

stating that the export requirements in 

§ 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 

§ 312.110(b)(4). 

70726 Federal Register / Vol. 70, No. 225 / Wednesday, November 23, 2005 / Rules and Regulations 

(Comment 4) Some comments 

opposed making information on drugs 

exported under proposed § 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 § 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 

§ 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 crossreferences 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 § 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 selfexecuting 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 

§ 312.110(b)(1), (b)(2), or (b)(3), and the 

requirements in § 312.110(b)(4) may be 

streamlined or modified in the event of 

Federal Register / Vol. 70, No. 225 / Wednesday, November 23, 2005 / Rules and Regulations 70727 

a national emergency in a foreign 

country (see § 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 § 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 

§ 312.110(b)(1) pertains to drugs that are 

the subject of an IND and § 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 § 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, § 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. 

70728 Federal Register / Vol. 70, No. 225 / Wednesday, November 23, 2005 / Rules and Regulations 

TABLE 1.—ESTIMATED ANNUAL RECORDKEEPING BURDEN1

21 CFR Section No. of 

Recordkeepers 

Annual Frequency 

per Recordkeeping 

Total Annual 

Records 

Hours per 

Recordkeeper Total Hours 

312.110(b)(2) and (b)(3) 370 1 370 3 1,110 

312.110(b)(4) 200 1 200 1 200 

Total 1,310 

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

TABLE 2.—ESTIMATED ANNUAL REPORTING BURDEN1

21 CFR Section No. of 

Respondents 

Annual Frequency 

per Response 

Total Annual 

Responses 

Hours per 

Response Total Hours 

312.110(b)(4) 200 1 200 12 2,400 

Total 2,400 

1There 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 § 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 § 1.101 (66 

FR 65429), and the estimated burden 

hours for the relevant parts of § 1.101 

total 3 hours. Thus, the total record 

burden hours for § 312.110(b)(2) and 

(b)(3) would be 1,110 hours (370 records 

multiplied by 3 hours per record). 

For § 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 

§ 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 

§ 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 § 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 

Federal Register / Vol. 70, No. 225 / Wednesday, November 23, 2005 / Rules and Regulations 70729 

that will result in an expenditure of 

$100 million or more in any one year, 

FDA is not required to perform a costbenefit 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. 

■ 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 

■ 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. 

■ 2. Section 312.110 is amended by 

revising paragraph (b) and by adding 

paragraphs (c) and (d) to read as follows: 

§ 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 § 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 § 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 § 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 § 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 

§ 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 

70730 Federal Register / Vol. 70, No. 225 / Wednesday, November 23, 2005 / Rules and Regulations 

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 

DEPARTMENT OF HOMELAND 

SECURITY 

Coast Guard 

33 CFR Part 165 

[COTP Jacksonville 05–154] 

RIN 1625–AA87 

Security Zone; St. John’s River, 

Jacksonville, FL to Ribault Bay 

AGENCY: Coast Guard, DHS. 

ACTION: Temporary final rule. 

SUMMARY: The Coast Guard is 

establishing a temporary moving 

security zone around foreign naval 

submarines in transit within the area 

between 12 nautical miles seaward from 

the baseline at the mouth of the St. 

John’s River to Ribault Bay. The security 

zone includes all waters within 500 

yards in any direction of the submarine. 

This rule prohibits entry into the 

security zone without the permission of 

the Captain of the Port (COTP) 

Jacksonville or his designated 

representative. Persons or vessels that 

receive permission to enter the security 

zone must proceed at a minimum safe 

speed, must comply with all orders 

issued by the COTP or his designated 

representative, and must not proceed 

any closer than 100 yards, in any 

direction, to the submarine. This 

security zone is needed to ensure public 

safety and to prevent sabotage or 

terrorist acts against the submarine. 

DATES: This rule is effective from 8 a.m. 

on November 9, 2005, until 11:59 p.m. 

on December 1, 2005. 

ADDRESSES: Documents mentioned in 

this preamble as being available in the 

docket are part of docket [COTP 

Jacksonville 05–154] and are available 

for inspection and copying at Coast 

Guard Sector Jacksonville Prevention 

Department, 7820 Arlington 

Expressway, Suite 400, Jacksonville, 

Florida 32211, between 8 a.m. and 4 

p.m., Monday through Friday, except 

Federal holidays. 

FOR FURTHER INFORMATION CONTACT: 

Ensign Kira Peterson at Coast Guard 

Sector Jacksonville Prevention 

Department, Florida telephone: (904) 

232–2640, ext. 108. 

SUPPLEMENTARY INFORMATION: 

Regulatory Information 

We did not publish a notice of 

proposed rulemaking (NPRM) for this 

regulation. Under 5 U.S.C. 553(b)(B), the 

Coast Guard finds that good cause exists 

for not publishing a NRPM. Publishing 

a NPRM, which would incorporate a 

comment period before a final rule 

could be issued, and delay the rule’s 

effective date, is contrary to the public 

interest because immediate action is 

necessary to protect the public and 

waters of the United States. 

For the same reasons, under 5 U.S.C. 

553(d)(3), the Coast Guard finds that 

good cause exists for making this rule 

effective less than 30 days after 

publication in the Federal Register. The 

Coast Guard will issue a broadcast 

notice to mariners and will place Coast 

Guard vessels in the vicinity of this 

zone to advise mariners of the 

restrictions. 

Background and Purpose 

This rule is needed to protect foreign 

navy submarines from damage or injury 

from sabotage or other subversive acts, 

accidents or other causes of a similar 

nature, or to secure the observance of 

rights and obligations of the United 

States. Although this rule is effective 

from 8 a.m. on November 9, 2005, until 

11:59 p.m. on December 1, 2005, the 

Coast Guard will only enforce this rule 

when a foreign navy submarine is 

transiting within the area between 12 

nautical miles seaward from the 

baseline at the mouth of the St. John’s 

River to Ribault Bay. Anchoring, 

mooring, or transiting within this zone 

is prohibited, unless authorized by the 

Captain of the Port, Jacksonville, 

Florida, or his designated 

representative. The temporary security 

zone encompasses all waters within 500 

yards around the foreign naval 

submarine. Vessels or persons 

authorized to enter the zone must 

proceed at a minimum safe speed, must 

comply with all orders issued by the 

COTP or his designated representative, 

and must not proceed any closer than 

100 yards, in any direction, to the 

submarine. 

Regulatory Evaluation 

This regulation is not a significant 

regulatory action under section 3(f) of 

Executive Order 12866, Regulatory 

Planning and Review, and does not 

require an assessment of potential cost 

and benefits under section 6(a)(3) of that 

Order. The Office of Management and 

Budget has not reviewed it under the 

order. It is not ‘‘significant’’ under the 

regulatory policies and procedures of 

the Department of Homeland Security 

(DHS) because these regulations will 

only be in effect for a short period of 

time and the impact on routine 

navigation is expected to be minimal. 

Small Entities 

Under the Regulatory Flexibility Act 

(5 U.S.C. 601–612), we considered 

whether this rule would have a