Federal Register / Vol. 71, No. 240 / Thursday, December 14, 2006 / Proposed Rules 75147 

the FAA proposes to amend 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. The Federal Aviation 

Administration (FAA) amends § 39.13 

by adding the following new 

airworthiness directive (AD): 

Airbus: Docket No. FAA–2006–26120; 

Directorate Identifier 2006–NM–184–AD. 

Comments Due Date 

(a) The FAA must receive comments on 

this AD action by January 16, 2007. 

Affected ADs 

(b) None. 

Applicability 

(c) This AD applies to all Airbus Model 

A300 B4–601, B4–603, B4–620, and B4–622 

airplanes; Model A300 B4–605R and B4–

622R airplanes; Model A300 F4–605R and 

F4–622R airplanes; and Model A300 C4–

605R Variant F airplanes; certificated in any 

category. 

Note 1: This AD requires revisions to 

certain operator maintenance documents to 

include new inspections and critical design 

configuration control limitations (CDCCLs). 

Compliance with the operator maintenance 

documents is required by 14 CFR 91.403(c). 

For airplanes that have been previously 

modified, altered, or repaired in the areas 

addressed by these inspections and CDCCLs, 

the operator may not be able to accomplish 

the inspections and CDCCLs described in the 

revisions. In this situation, to comply with 14 

CFR 91.403(c), the operator must request 

approval for an alternative method of 

compliance according to paragraph (j) of this 

AD. The request should include a description 

of changes to the required inspections and 

CDCCLs that will preserve the critical 

ignition source prevention feature of the 

affected fuel system. 

Unsafe Condition 

(d) This AD results from fuel system 

reviews conducted by the manufacturer. We 

are issuing this AD to prevent the potential 

of ignition sources inside fuel tanks, which, 

in combination with flammable fuel vapors 

caused by latent failures, alterations, repairs, 

or maintenance actions, could result in fuel 

tank explosions and consequent loss of the 

airplane. 

Compliance 

(e) You are responsible for having the 

actions required by this AD performed within 

the compliance times specified, unless the 

actions have already been done. 

Revise Airworthiness Limitations Section 

(ALS) To Incorporate Fuel Maintenance and 

Inspection Tasks 

(f) Within 3 months after the effective date 

of this AD, revise the ALS of the Instructions 

for Continued Airworthiness to incorporate 

Airbus A300–600 ALS Part 5—Fuel 

Airworthiness Limitations, dated May 31, 

2006, as defined in Airbus A300–600 Fuel 

Airworthiness Limitations, Document 

95A.1929/05, Issue 1, dated December 19, 

2005 (approved by the European Aviation 

Safety Agency (EASA) on March 13, 2006), 

Section 1, ‘‘Maintenance/Inspection Tasks.’’

For all tasks identified in Section 1 of 

Document 95A.1929/05, the initial 

compliance times start from the effective date 

of this AD and must be accomplished within 

the repetitive interval specified in Section 1 

of Document 95A.1929/05, except as 

provided by paragraph (g) of this AD. 

Initial Compliance Time for Task 28–18–00–

03–1 

(g) For Task 28–18–00–03–1, ‘‘Operational 

check of lo-level/underfull/calibration 

sensors,’’ identified in Section 1, 

‘‘Maintenance/Inspection Tasks,’’ of Airbus 

A300–600 Fuel Airworthiness Limitations, 

Document 95A.1929/05, Issue 1, dated 

December 19, 2005: The initial compliance 

time is the later of the times specified in 

paragraphs (g)(1) and (g)(2) of this AD. 

Thereafter, Task 28–18–00–03–1 must be 

accomplished within the repetitive interval 

specified in Section 1 of Document 

95A.1929/05. 

(1) Prior to the accumulation of 34,000 

total flight hours. 

(2) Within 72 months or 20,000 flight hours 

after the effective date of this AD, whichever 

occurs first. 

Revise ALS To Incorporate CDCCLs 

(h) Within 12 months after the effective 

date of this AD, revise the ALS of the 

Instructions for Continued Airworthiness to 

incorporate Airbus A300–600 ALS Part 5—

Fuel Airworthiness Limitations, dated May 

31, 2006, as defined in Airbus A300–600 

Fuel Airworthiness Limitations, Document 

95A.1929/05, Issue 1, dated December 19, 

2005 (approved by the EASA on March 13, 

2006), Section 2, ‘‘Critical Design 

Configuration Control Limitations.’’

No Alternative Inspections, Inspection 

Intervals, or CDCCLs 

(i) Except as provided by paragraph (j) of 

this AD: After accomplishing the actions 

specified in paragraphs (f) and (h) of this AD, 

no alternative inspections, inspection 

intervals, or CDCCLs may be used. 

Alternative Methods of Compliance 

(AMOCs) 

(j)(1) The Manager, International Branch, 

ANM–116, Transport Airplane Directorate, 

FAA, has the authority to approve AMOCs 

for this AD, if requested in accordance with 

the procedures found in 14 CFR 39.19. 

(2) Before using any AMOC approved in 

accordance with § 39.19 on any airplane to 

which the AMOC applies, notify the 

appropriate principal inspector in the FAA 

Flight Standards Certificate Holding District 

Office. 

Related Information 

(k) EASA airworthiness directive 2006–

0201, dated July 11, 2006, also addresses the 

subject of this AD. 

Issued in Renton, Washington, on October 

17, 2006. 

Jeffrey E. Duven, 

Acting Manager, Transport Airplane 

Directorate, Aircraft Certification Service. 

[FR Doc. E6–21262 Filed 12–13–06; 8:45 am] 

BILLING CODE 4910–13–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

21 CFR Part 312 

[Docket No. 2006N–0062] 

RIN 0910–AF14 

Expanded Access to Investigational 

Drugs for Treatment Use 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Proposed rule. 

SUMMARY: The Food and Drug 

Administration (FDA) is proposing to 

amend its regulations on access to 

investigational new drugs for the 

treatment of patients. The proposed rule 

would clarify existing regulations and 

add new types of expanded access for 

treatment use. Under the proposal, 

expanded access to investigational 

drugs for treatment use would be 

available to individual patients, 

including in emergencies; intermediatesize patient populations; and larger 

populations under a treatment protocol 

or treatment investigational new drug 

application (IND). The proposed rule is 

intended to improve access to 

investigational drugs for patients with 

serious or immediately life-threatening 

diseases or conditions, who lack other 

therapeutic options and who may 

benefit from such therapies. 

DATES: Submit written or electronic 

comments by March 14, 2007. Submit 

written comments on the information 

collection requirements by January 16, 

2007. 

ADDRESSES: You may submit comments, 

identified by Docket No. 2006N–0062 

and RIN 0910–AF14, by any of the 

following methods: 

Electronic Submissions 

Submit electronic comments in the 

following ways: 

• Federal eRulemaking Portal: http:// 

www.regulations.gov. Follow the 

instructions for submitting comments. 

• Agency Web site: http:// 

www.fda.gov/dockets/ecomments. 


jlentini on PROD1PC65 with PROPOSAL
75148 Federal Register / Vol. 71, No. 240 / Thursday, December 14, 2006 / Proposed Rules 

Follow the instructions for submitting 

comments on the agency Web site. 

Written Submissions 

Submit written submissions in the 

following ways: 

• FAX: 301–827–6870. 

• Mail/Hand delivery/Courier [For 

paper, disk, or CD–ROM submissions]: 

Division of Dockets Management (HFA–

305), Food and Drug Administration, 

5630 Fishers Lane, rm. 1061, Rockville, 

MD 20852. 

To ensure more timely processing of 

comments, FDA is no longer accepting 

comments submitted to the agency by email. FDA encourages you to continue 

to submit electronic comments by using 

the Federal eRulemaking Portal or the 

agency Web site, as described in the 

Electronic Submissions portion of this 

paragraph. 

Instructions: All submissions received 

must include the agency name and 

docket number and Regulatory 

Information Number (RIN) for this 

rulemaking. All comments received may 

be posted without change to http:// 

www.fda.gov/ohrms/dockets/ 

default.htm, including any personal 

information provided. For additional 

information on submitting comments, 

see the ‘‘Comments’’ heading of the 

SUPPLEMENTARY INFORMATION section of 

this document. 

Docket: For access to the docket to 

read background documents or 

comments received, go to http:// 

www.fda.gov/ohrms/dockets/ 

default.htm and insert the docket 

number, found in brackets in the 

heading of this document, into the 

‘‘Search’’ box and follow the prompts 

and/or go to the Division of Dockets 

Management, 5630 Fishers Lane, rm. 

1061, Rockville, MD 20852. 

The Office of Management and Budget 

(OMB) is still experiencing significant 

delays in the regular mail, including 

first class and express mail, and 

messenger deliveries are not being 

accepted. To ensure that comments on 

the information collection are received, 

OMB recommends that written 

comments be faxed to the Office of 

Information and Regulatory Affairs, 

OMB, Attn: Desk Officer for FDA, FAX: 

202–395–6974. 

FOR FURTHER INFORMATION CONTACT: 

Colleen L. Locicero, Center for Drug 

Evaluation and Research, Food and 

Drug Administration, 10903 New 

Hampshire Ave., Bldg. 22, rm. 4200, 

Silver Spring, MD 20993–0002, 301–

796–2270; or Steve Ripley, Center for 

Biologics Evaluation and Research 

(HFM–17), Food and Drug 

Administration, 1401 Rockville Pike, 

Rockville, MD 20852, 301–827–6210. 

SUPPLEMENTARY INFORMATION: 

Table of Contents 

I. Background 

A. Informal Access to Drugs for Treatment 

Use 

B. Current Regulations Concerning 

Expanded Access for Treatment Use 

C. Concerns About Treatment Use 

Programs 

D. The Food and Drug Administration 

Modernization Act of 1997 

II. Why FDA Is Proposing This Rule 

III. Goals and Limitations of the Proposed 

Rule 

IV. Description of the Proposed Rule 

A. Sections Removed 

B. Clinical Holds 

C. Expanded Access Overview 

D. General Provisions 

E. Requirements for All Expanded Access 

Uses (Proposed § 312.305) 

F. Expanded Access for Individual Patients 

(Proposed § 312.310) 

G. Expanded Access for Intermediate-Size 

Patient Populations (Proposed § 312.315) 

H. Expanded Access Treatment IND or 

Treatment Protocol (Proposed § 312.320) 

I. Open-Label Safety Studies 

J. Continuation Phase of a Clinical Trial 

V. Legal Authority 

VI. Environmental Impact 

VII. Analysis of Economic Impacts 

A. Objectives of the Proposed Action 

B. Nature of the Problem Being Addressed 

C. Baseline for the Analysis 

D. Nature of the Impact 

E. Benefits of the Proposed Rule 

F. Costs of the Proposed Rule 

G. Minimizing the Impact on Small Entities 

VIII. Paperwork Reduction Act of 1995 

A. The Proposed Rule 

B. Estimates of Reporting Burden 

IX. Request for Comments 

X. Federalism 

I. Background 

A. Informal Access to Drugs for 

Treatment Use 

FDA has a long history of permitting 

access to investigational drugs to treat 

serious or immediately life-threatening 

diseases or conditions without adequate 

available therapy under INDs, generally 

for drugs being evaluated in clinical 

studies intended to support marketing. 

The distinction between these and the 

usual studies covered under an IND is 

that the treatment uses are not primarily 

to answer safety or effectiveness 

questions about the drug, but are 

intended to treat the patient. Before 

1987, there was no formal recognition of 

such treatment use in the IND 

regulations, but investigational drugs 

were made available for treatment use 

informally. ‘‘Compassionate use INDs,’’

‘‘single-patient protocol exceptions,’’

and ‘‘large open protocols’’ are some of 

the terms that have been used to refer 

to such informal access. The vast 

majority of these INDs were used to 

make an investigational drug available 

to an individual patient, but some of the 

expanded access programs made 

particularly promising investigational 

drugs available to large populations. For 

example, more than 10,000 patients 

obtained access through treatment 

access programs to the first 

cardioselective beta-blockers and the 

first calcium channel blockers for 

vasospastic angina. 

B. Current Regulations Concerning 

Expanded Access for Treatment Use 

In 1987, FDA revised the IND 

regulations in part 312 (21 CFR part 

312) to explicitly provide for one 

specific kind of treatment use of 

investigational drugs (52 FR 19466, May 

22, 1987). Section 312.34 authorizes 

broad access to investigational drugs 

under a treatment protocol or treatment 

IND when the following criteria are met: 

• The drug is intended to treat a 

serious or immediately life-threatening 

disease; 

• There is no comparable or 

satisfactory alternative drug or other 

therapy available to treat that stage of 

the disease in the intended patient 

population; 

• The drug is under investigation in 

a controlled clinical trial under an IND 

in effect for the trial, or all clinical trials 

have been completed; and 

• The sponsor of the controlled 

clinical trial is actively pursuing 

marketing approval of the 

investigational drug with due diligence. 

Section 312.34 states that for a serious 

disease, data from phase 3 trials or, in 

appropriate circumstances, data from 

phase 2 trials would ordinarily be 

needed to permit treatment use in a 

substantial population. For an 

immediately life-threatening disease, 

less evidence of safety and effectiveness 

is needed for treatment use. The 

standard for treatment use for 

immediately life-threatening conditions 

is that the available scientific evidence, 

taken as a whole, provides a reasonable 

basis to conclude that the drug may be 

effective and would not expose patients 

to an unreasonable and significant 

additional risk of illness or injury. FDA 

estimates that more than 100,000 

patients have received investigational 

drugs through treatment INDs. 

The 1987 IND regulations recognized 

only one kind of treatment use, the 

treatment protocol or treatment IND, 

generally providing availability to a 

broad population. However, it also 

implicitly acknowledged the existence 

of other kinds of treatment use, notably 

use in individual patients, by adding a 

provision describing an expedited 

procedure to obtain an investigational 

drug for treatment use in an emergency 


jlentini on PROD1PC65 with PROPOSAL
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situation (§ 312.36). However, § 312.36 

does not describe criteria or 

requirements that must be met to 

authorize individual patient treatment 

use. 

C. Concerns About Treatment Use 

Programs 

FDA has been criticized for its failure 

to explain in regulation or guidance the 

basis for agency decisionmaking on 

individual patient treatment use and 

other treatment use programs not 

currently described in FDA’s 

regulations. One concern is that the lack 

of specific criteria and submission 

requirements results in disparate access 

to treatment use for different types of 

patients and diseases. Some have 

asserted that knowledge of FDA’s 

policies on these other kinds of 

treatment use tends to be concentrated 

among physicians in academic medical 

centers who are familiar with 

investigational drugs and FDA 

procedures. Consequently, according to 

this line of criticism, patients treated 

outside of academic medical centers are 

less likely to have access to 

investigational drugs for treatment use. 

There has also been concern that access 

to investigational drugs for treatment 

use has focused primarily on cancerand human immunodeficiency virus 

(HIV)-related conditions, and that 

patients with other types of serious 

diseases or conditions have not had 

comparable access to appropriate 

treatment use of unapproved drugs. 

D. The Food and Drug Administration 

Modernization Act of 1997 

In response to these concerns about 

inconsistent policies, inequitable access, 

and preferential access for certain 

categories of disease, in the Food and 

Drug Administration Modernization Act 

of 1997 (FDAMA) (Public Law 105–

115), Congress amended the Federal 

Food, Drug, and Cosmetic Act (the act) 

to include specific provisions 

concerning expanded access to 

investigational drugs for treatment use 

(Expanded Access to Unapproved 

Therapies and Diagnostics, section 561 

(21 U.S.C. 360bbb) of the act). By 

incorporating specific expanded access 

provisions in the statute, Congress 

intended to emphasize that 

‘‘opportunities to participate in 

expanded access programs are available 

to every individual with a lifethreatening or seriously debilitating 

illness for which there is not an 

effective, approved therapy’’ (Joint 

Explanatory Statement of the Committee 

of Conference in House Report 105–399, 

November 9, 1997, p. 100). 

Section 561(a) of the act provides 

specific statutory authority to make 

investigational drugs available for the 

diagnosis, monitoring, or treatment of a 

serious disease or condition in an 

emergency situation. The Secretary of 

Health and Human Services (the 

Secretary) is to determine appropriate 

conditions under which an 

investigational drug may be made 

available in an emergency situation. 

Section 561(b) of the act permits any 

person, acting through a licensed 

physician, to request access to an 

investigational drug to diagnose, 

monitor, or treat a serious disease or 

condition provided that the following 

conditions are met: 

• The licensed physician determines 

that the person has no comparable or 

satisfactory alternative therapy to 

diagnose, monitor, or treat the disease or 

condition, and that the probable risk 

from the investigational drug is not 

greater than the probable risk from the 

disease or condition; 

• The Secretary determines that there 

is sufficient evidence of safety and 

effectiveness to support the use of the 

investigational drug; 

• The Secretary determines that 

provision of the investigational drug 

will not interfere with the initiation, 

conduct, or completion of clinical 

investigations to support marketing 

approval; and 

• The sponsor or clinical investigator 

submits a protocol consistent with the 

requirements of section 505(i) of the act 

(21 U.S.C 355(i)) and its implementing 

regulations in part 312, which describe 

use of the drug in a single patient or a 

small group of patients. 

Section 561(c) of the act closely tracks 

existing § 312.34 of the IND regulations. 

Section 561(c) authorizes the Secretary 

to permit an investigational drug to be 

made available for widespread access if 

the following determinations have been 

made: 

1. The investigational drug is 

intended for use in the diagnosis, 

monitoring, or treatment of a serious or 

immediately life-threatening disease or 

condition; 

2. There is no comparable or 

satisfactory alternative therapy available 

to diagnose, monitor, or treat that stage 

of disease or condition in a particular 

patient population; 

3. The investigational drug is under 

investigation in a controlled clinical 

trial under an IND, or all clinical trials 

necessary for approval of the use have 

been completed; 

4. The sponsor of the controlled 

clinical trial is actively pursuing 

marketing approval with due diligence; 

5. The provision of the investigational 

drug will not interfere with the 

enrollment of patients in ongoing 

clinical investigations; 

6. In the case of serious diseases, there 

is sufficient evidence of safety and 

effectiveness to support the use; 

7. In the case of immediately lifethreatening diseases, the available 

scientific evidence, taken as a whole, 

provides a reasonable basis to conclude 

that the investigational drug may be 

effective for its intended use and would 

not expose patients to an unreasonable 

and significant risk of illness or injury. 

Section 561(c) also provides that a 

protocol for an expanded access 

treatment IND shall be subject to the 

requirements of section 505(i) of the act 

and FDA’s implementing regulations in 

part 312. 

To specifically address concerns that 

physicians and their patients are often 

unaware of the availability of 

investigational drugs under access 

programs, section 561(c) of the act also 

allows the Secretary to inform national, 

State, and local medical associations 

and societies, voluntary health 

associations, and other appropriate 

persons about the availability of 

expanded access treatment INDs or 

treatment protocols. 

II. Why FDA Is Proposing This Rule 

This proposed rule is intended to 

further address the concerns that 

motivated Congress to include in the act 

specific provisions on expanded access 

to investigational drugs for treatment 

use. As discussed in section I of this 

document, these concerns included 

inconsistent application of access 

policies and programs and inequities in 

access based on the relative 

sophistication of the setting in which a 

patient is treated or on the patient’s 

disease or condition. By describing in 

detail in the proposed rule the criteria, 

submission requirements, and 

safeguards for the different types of 

expanded access for treatment uses of 

investigational drugs, the agency seeks 

to increase awareness and knowledge of 

expanded access programs and the 

procedures for obtaining investigational 

drugs. Increased knowledge and 

awareness about expanded access 

options should make investigational 

drugs more widely available in 

appropriate situations. Clearly 

articulated procedures for obtaining 

investigational drugs for treatment use 

should ease the administrative burdens 

on individual physicians seeking 

investigational drugs for their patients, 

as well as the burdens on sponsors who 

make investigational drugs available for 

treatment use. In addition, we expect 


jlentini on PROD1PC65 with PROPOSAL
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1A submission seeking to allow an expanded 

access use of an investigational drug may come to 

FDA either in the form of a new, separate IND or 

as a new protocol submitted to an already existing 

IND. 

that clearly articulating procedures and 

standards for expanded access will 

result in more patients with serious or 

immediately life-threatening diseases or 

conditions getting the earliest possible 

access to these therapies. 

III. Goals and Limitations of the 

Proposed Rule 

Recognizing that FDA’s authority 

derives from the act, the proposed rule 

attempts to reconcile individual 

patients’ desires to make their own 

decisions about their health care with 

society’s need for drugs to be developed 

for marketing. It recognizes the need for 

the risks and benefits of drugs to be well 

characterized and the need for 

appropriate protection of human 

subjects in an investigation. These 

interests are not always easily 

reconciled. Allowing individual 

patients relatively unfettered access to 

an investigational drug at a preliminary 

stage in its development, for example, 

may expose them to significant and 

unacceptable risks. 

In addition, patients may find 

participation in a clinical trial less 

desirable than receiving the drug for 

treatment use for a variety of reasons. 

For example, clinical trial participants 

may receive a treatment other than the 

study drug, and clinical trials may have 

more onerous monitoring requirements 

(such as laboratory and other tests). 

Thus, a system of blindly permitting 

uncontrolled access to investigational 

drugs could make it difficult or 

impossible to enroll adequate numbers 

of patients in clinical trials to establish 

the safety and effectiveness of the drug 

for marketing approval. 

FDA has a statutory responsibility to 

ensure that marketed drugs are safe and 

effective, and its rules should not 

compromise the integrity of the drug 

development process. In this proposed 

rule, as envisioned by the act, the 

agency has tried to strike the 

appropriate balance between 

authorizing access to promising drugs 

for treatment use under our expanded 

access authority and ensuring the 

integrity of the drug approval process. 

While this proposed rule aims to 

clarify, and thereby expand, the 

situations in which expanded access to 

unapproved drugs could be available, 

under its existing authority, FDA cannot 

compel a drug manufacturer to provide 

access to investigational drugs for 

treatment use. 

IV. Description of the Proposed Rule 

FDA is proposing to amend its 

regulations on INDs by removing the 

current sections on treatment use, 

revising the section on clinical holds, 

and adding subpart I on expanded 

access. The term ‘‘expanded access’’ is 

used here to refer to all types of 

treatment uses. The term ‘‘treatment 

protocol or treatment IND’’ continues to 

refer to one specific kind of treatment 

use, the large access protocol. 

A. Sections Removed 

The proposed rule would remove the 

following three sections of FDA’s 

regulations: 

• Current § 312.34 concerning the 

treatment use of an investigational new 

drug; 

• Current § 312.35 concerning 

submissions for treatment use; and 

• Current § 312.36 concerning 

emergency use of an investigational new 

drug. 

B. Clinical Holds 

The proposed rule would amend 

§ 312.42 Clinical holds and requests for 

modification by providing for clinical 

holds, when necessary, of any of the 

types of expanded access uses described 

in this proposed rule. A clinical hold is 

an order issued by FDA to the sponsor 

to delay a proposed clinical 

investigation or suspend an ongoing 

investigation (§ 312.42(a)). Proposed 

§ 312.42(b)(3)(i) provides that FDA may 

place an expanded access IND or 

protocol1 on clinical hold if it is 

determined that the pertinent criteria in 

proposed subpart I for permitting the 

expanded access use to begin are not 

satisfied or the IND or protocol does not 

comply with the requirements for 

expanded access submissions in 

proposed subpart I. 

Proposed § 312.42(b)(3)(ii) provides 

that FDA may place an ongoing 

expanded access IND or protocol on 

clinical hold if it is determined that the 

pertinent criteria in proposed subpart I 

for permitting the expanded access are 

no longer satisfied (e.g., a satisfactory 

alternative therapy becomes available). 

C. Expanded Access Overview 

The agency is proposing to add new 

subpart I to part 312. Proposed subpart 

I describes the following ways that 

expanded access to treatment use of 

investigational drugs would be 

available: 

• Expanded access for individual 

patients, including emergency 

procedures; 

• Expanded access for intermediatesize patient populations (smaller than 

those typical of a treatment IND or 

treatment protocol); and 

• Expanded access treatment IND or 

treatment protocol (described in current 

§§ 312.34 and 312.35). 

The following items are set forth in 

the proposed rule: (1) Criteria that must 

be met to authorize the expanded access 

use, (2) requirements for expanded 

access submissions, and (3) safeguards 

to protect patients and preserve the 

ability to develop meaningful data about 

treatment use. 

D. General Provisions 

Proposed § 312.300(a) states that the 

aim of subpart I is to facilitate the 

availability of investigational new drugs 

to seriously ill patients when there is no 

comparable or satisfactory alternative 

therapy to diagnose, monitor, or treat 

the patient’s disease or condition. 

Proposed § 312.300(b) provides a 

definition of the term ‘‘immediately lifethreatening disease’’ as a stage of 

disease in which there is reasonable 

likelihood that death will occur within 

a matter of months or in which 

premature death is likely without early 

treatment. 

E. Requirements for All Expanded 

Access Uses (Proposed § 312.305) 

Proposed § 312.305 contains the 

general requirements for the use of 

investigational drugs when the primary 

purpose is to diagnose, monitor, or treat 

a patient’s disease or condition, rather 

than to generate safety and effectiveness 

data to support a marketing application. 

Proposed § 312.305 contains criteria, 

submission requirements, and 

safeguards that apply to all expanded 

access uses described in proposed 

subpart I. Additional criteria, 

submission requirements, and 

safeguards that apply to specific types of 

expanded access use are described in 

the sections of the proposed rule 

describing those expanded access types. 

1. Criteria for All Expanded Access Uses 

Proposed § 312.305(a) sets forth three 

criteria that apply to all types of 

expanded access use: 

a. First criterion. Under proposed 

§ 312.305(a)(1), FDA must determine 

that the patient (or patients) to be 

treated has a serious or immediately 

life-threatening disease or condition, 

and there is no comparable or 

satisfactory alternative therapy to 

diagnose, monitor, or treat the disease or 

condition. Because, by definition, the 

risks and benefits of investigational 

drugs are not as well characterized as 

those of approved drugs, the agency 

believes, and the act contemplates, that 

expanded access to investigational 


jlentini on PROD1PC65 with PROPOSAL
Federal Register / Vol. 71, No. 240 / Thursday, December 14, 2006 / Proposed Rules 75151 

2This proposed rule continues to describe the 

specific type of expanded access for treatment use 

that makes investigational drugs available to large 

populations as the ‘‘treatment IND’’ or ‘‘treatment 

protocol.’’ We recognize that it may be confusing to 

carry over this terminology from our current 

regulations (§§ 312.34 and 312.35). However, this 

terminology has been used since 1987, and we 

believe it would be more confusing to change 

terminology when the nature of this type of 

treatment use remains essentially unchanged. The 

broader term ‘‘expanded access’’ refers to all kinds 

of treatment use. We solicit comment on this 

approach. 

drugs is warranted only under these 

conditions. Section 561(c)(1) and (c)(2) 

of the act expressly requires FDA to 

make these determinations in order to 

authorize a treatment IND or treatment 

protocol, and section 561(b)(1) and 

(b)(2) of the act likewise requires FDA 

to determine that there is sufficient 

evidence of safety and effectiveness to 

support the use of the unapproved drug 

in treating an individual patient or a 

small group of patients. Determining 

that the patient has a serious or 

immediately life-threatening disease or 

condition and that there is no 

comparable or satisfactory alternative 

therapy are integral parts of determining 

whether there is sufficient evidence of 

safety and effectiveness to support the 

proposed use in the situation described 

by the physician or sponsor seeking the 

authorization. 

In various documents, the agency has 

described or illustrated what is meant 

by a serious condition (see, e.g., FDA’s 

guidance for industry entitled ‘‘Fast 

Track Drug Development Programs—

Designation, Development, and 

Application Review’’ (63 FR 64093, 

November 18, 1998), revised 2004, pp. 

3–4; preamble to the 1992 proposed rule 

on accelerated approval of new drugs 

for serious or life-threatening illnesses 

(57 FR 13234 at 13235, April 15, 1992)). 

As discussed in these documents, the 

‘‘serious disease or condition’’

requirement refers to conditions that 

have an important effect on functioning 

(e.g., stroke, schizophrenia, rheumatoid 

arthritis, osteoarthritis) or on other 

aspects of quality of life (e.g., chronic 

depression, seizures). Alzheimer’s 

dementia, Amyotrophic Lateral 

Sclerosis (ALS), and narcolepsy are 

specific examples of serious conditions 

for which FDA has granted expanded 

access to investigational drugs in the 

past. Short-lived and self-limiting 

morbidity will usually not be sufficient 

to qualify a condition as serious, but the 

morbidity need not be irreversible, 

provided it is persistent or recurrent. 

Similarly, the proposed requirement 

here that treatment be for a ‘‘serious 

disease or condition’’ is not intended to 

be unnecessarily restrictive. It is 

primarily intended to exclude expanded 

access to investigational drugs for 

conditions that are clearly not serious 

(e.g., symptomatic relief of minor pain 

or allergic symptoms and other selflimiting conditions not associated with 

major morbidity). Because of the 

difficulty of specifically describing the 

criteria that characterize a ‘‘serious 

disease or condition,’’ the proposed rule 

itself does not provide a definition of 

‘‘serious,’’ though it does provide a 

definition of ‘‘immediately lifethreatening.’’ See proposed § 312.300(b). 

We solicit comments on this approach. 

If a disease or condition were to be both 

serious and immediately lifethreatening, for the purpose of this 

proposed rule, it would be considered 

‘‘immediately life-threatening.’’

Ordinarily, a lack of comparable or 

satisfactory therapeutic alternatives 

would mean that there exists no other 

available therapy to treat the patient’s 

condition or that the patient has tried 

available therapies and failed to respond 

adequately or is intolerant to them. 

Available therapy, as defined in FDA’s 

guidance for industry entitled 

‘‘Available Therapy’’ (69 FR 44039, July 

23, 2004), generally refers to FDAapproved products that are labeled to be 

used for the relevant disease or 

condition. In some cases, however, 

available therapy might mean a 

treatment that is not regulated by FDA 

(e.g., surgery) or one that is not labeled 

for use for the relevant disease or 

condition, but is supported by 

compelling literature evidence. 

b. Second criterion. Under proposed 

§ 312.305(a)(2), FDA must determine 

that the potential patient benefit 

justifies the potential risks of the 

treatment use and that those potential 

risks are not unreasonable in the context 

of the disease or condition to be treated. 

FDA is required to make this 

determination under sections 561(b)(2), 

(c)(6), and (c)(7) of the act. 

c. Third criterion. Under proposed 

§ 312.305(a)(3), FDA must determine 

that providing the investigational drug 

for the requested use will not interfere 

with the initiation, conduct, or 

completion of clinical investigations 

that could support marketing approval 

of the expanded access use or otherwise 

compromise the potential development 

of the expanded access use. Section 

561(b)(3) and (c)(5) of the act requires 

FDA to make this determination. The 

most efficient and effective way to make 

a drug available to all those who can 

benefit from the drug, is to market it. 

Therefore, it is important to ensure that 

expanded access use does not 

compromise enrollment in the trials 

needed to demonstrate the safety and 

effectiveness of the drug. 

Proposed § 312.305(a) does not 

elaborate on the safety and/or 

effectiveness showing that must be 

made to merit authorization of the 

expanded access use. Rather, the 

showing is described in the criteria that 

pertain to each type of expanded access 

because the evidence needed to 

demonstrate the safety and potential 

benefit of a proposed use varies with the 

size of the population to be treated and 

the relative seriousness of the disease or 

condition to be treated. Treatment of a 

large patient population through a 

treatment IND or treatment protocol2

generally would require more evidence 

of safety and effectiveness than 

treatment of just a few patients. The 

evidence required to support expanded 

access for an intermediate-size patient 

population would be somewhere 

between that needed for expanded 

access for an individual patient and that 

needed for a treatment IND or treatment 

protocol. 

In addition, as the seriousness of the 

disease increases, it may be appropriate 

to authorize expanded access use based 

on less data, still taking the size of the 

population into account. For example, 

to support expanded access for an 

individual patient when the patient has 

an immediately life-threatening 

condition that is not responsive to 

available therapy, ordinarily, completed 

phase 1 safety testing in humans at 

doses similar to those to be used in the 

treatment use, together with preliminary 

evidence suggesting possible 

effectiveness, would be sufficient to 

support such a use. In some cases, 

however, there may be no relevant 

clinical experience, and the case for the 

potential benefit may be based on 

preclinical data or on the mechanism of 

action. 

In contrast, much more safety and 

effectiveness data would be needed to 

support a treatment IND or treatment 

protocol that anticipated enrollment of 

several thousand patients with a 

serious, but not imminently lifethreatening, condition. Ordinarily, 

evidence of safety and effectiveness 

from phase 3 clinical trials would be 

needed to support such an expanded 

access use in these significantly larger 

populations. If the disease being treated 

under a treatment IND or treatment 

protocol were immediately lifethreatening, however, compelling data 

from phase 2 trials might be sufficient 

to permit expanded access use. 

2. Submission Requirements for All 

Expanded Access Uses 

Proposed § 312.305(b)(1) states that an 

expanded access submission is required 


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for each type of expanded access use. 

The submission may be a new IND or 

a protocol amendment to an existing 

IND. Information required for a 

submission may be supplied by 

referring to pertinent information 

contained in an existing IND if the 

sponsor of the existing IND grants a 

right of reference to the IND. 

Proposed § 312.305(b)(2) describes the 

expanded access submission 

requirements. The following items must 

be included: 

• A cover sheet (Form FDA 1571) 

meeting the requirements of § 312.23(a); 

• The rationale for the intended use 

of the drug, including a list of available 

therapeutic options that would 

ordinarily be tried before resorting to 

the investigational drug or an 

explanation of why the use of the 

investigational drug is preferable to the 

use of available therapeutic options; 

• The criteria for patient selection or, 

for an individual patient, a description 

of the patient’s disease or condition, 

including recent medical history and 

previous treatments of the disease or 

condition; 

• The method of administration of the 

drug, dose, and duration of therapy; 

• A description of the facility where 

the drug will be manufactured; 

• Chemistry, manufacturing, and 

controls information adequate to ensure 

the proper identification, quality, 

purity, and strength of the 

investigational drug; 

• Pharmacology and toxicology 

information adequate to conclude that 

the drug is reasonably safe at the dose 

and duration proposed for treatment use 

(ordinarily, information that would be 

adequate to permit clinical testing of the 

drug in a population of the size 

expected to be treated); and 

• A description of clinical 

procedures, laboratory tests, or other 

monitoring necessary to evaluate the 

effects of the drug and minimize its 

risks. 

If this proposed rule becomes final, 

FDA will make educational programs 

and materials available to help 

physicians and sponsors understand the 

expanded access use submission 

requirements in general, as well as the 

additional information necessary to 

justify the different types of expanded 

access. 

Proposed § 312.300(b)(3) requires the 

expanded access submission and its 

mailing cover to be plainly marked 

‘‘EXPANDED ACCESS SUBMISSION.’’

If the expanded access submission is for 

a treatment IND or treatment protocol, 

the applicable box on Form FDA 1571 

must be checked. 

3. Safeguards for All Expanded Access 

Uses 

Proposed § 312.305(c) explains how 

the responsibilities of sponsors and 

investigators set forth in subpart D of 

part 312 apply to expanded access. 

Proposed § 312.305(c)(1) states that a 

licensed physician under whose 

immediate direction an investigational 

drug is administered or dispensed for 

expanded access use under subpart I is 

considered an investigator for purposes 

of part 312 and must comply with the 

responsibilities for investigators set 

forth in subpart D of part 312 to the 

extent they are applicable to the 

expanded access use. A nonexclusive 

list of duties of investigators—those 

duties that apply in all types of 

expanded access—is set forth in 

proposed § 312.305(c)(4), and is 

explained further in the following 

paragraphs. 

Proposed § 312.305(c)(2) provides that 

an individual or entity that submits an 

IND or protocol for expanded access 

under subpart I is considered a sponsor 

for purposes of part 312 and must 

comply with the responsibilities for 

sponsors set forth in subpart D of part 

312 to the extent they are applicable to 

the expanded access use. 

Proposed § 312.305(c)(3) provides that 

a licensed physician under whose 

immediate direction an investigational 

drug is administered or dispensed, and 

who submits an IND for expanded 

access under subpart I, is considered a 

sponsor-investigator for purposes of part 

312 and must comply with the 

responsibilities for sponsors and 

investigators set forth in subpart D of 

part 312 to the extent they are 

applicable to the expanded access use. 

Proposed § 312.305(c)(4) provides that, 

in all types of expanded access, 

investigators have the following 

responsibilities: 

• Reporting adverse drug experiences 

to the sponsor, 

• Ensuring that the informed consent 

requirements of 21 CFR part 50 are met, 

• Ensuring that Institutional Review 

Board (IRB) review of the expanded 

access use is obtained in a manner 

consistent with the requirements of part 

56 (21 CFR part 56), and 

• Maintaining accurate case histories 

and drug disposition records and 

retaining records in a manner consistent 

with the requirements of § 312.62. 

However, this list of duties under 

subpart D of part 312 is not exclusive, 

and other requirements may apply, 

depending on the particular type of 

expanded access. 

Proposed § 312.305(c)(5) provides 

that, in all cases, sponsors have the 

following responsibilities: 

• Submitting IND safety reports and 

annual reports (when the IND or 

protocol continues for 1 year or longer) 

to FDA as required by §§ 312.32 and 

312.33, 

• Ensuring that licensed physicians 

are qualified to administer the 

investigational drug for the expanded 

access use, 

• Providing licensed physicians with 

the information needed to minimize the 

risk and maximize the potential benefits 

of the investigational drug (e.g., 

providing the investigator’s brochure, if 

there is one), 

• Maintaining an effective IND for the 

expanded access use, and 

• Maintaining adequate drug 

disposition records and retaining 

records in a manner consistent with the 

requirements of § 312.57. 

As with the list of investigator’s duties 

under proposed § 312.305(c)(4), this list 

of sponsor’s duties under subpart D of 

part 312 is not exclusive, and other 

requirements may apply, depending on 

the particular type of expanded access. 

4. When Expanded Access Use May 

Begin 

Proposed § 312.305(d) explains when 

expanded access use may begin, 

assuming FDA has not placed a clinical 

hold on the expanded access use. Under 

IND rules, a study described in a 

protocol in a newly submitted IND can 

begin 30 days after FDA receipt of the 

IND (or on earlier notification by FDA 

that the study may proceed), unless 

FDA puts the study on hold. Once there 

is an IND in place, new protocols 

submitted to that IND may begin on the 

date of submission. 

Proposed § 312.300(d)(1) states that an 

expanded access IND goes into effect 30 

days after FDA receives the IND or on 

earlier notification by FDA that the 

expanded access use may begin, 

consistent with FDA’s normal practice. 

Proposed § 312.300(d)(2) explains 

when expanded access use may begin, 

if the expanded access submission is in 

the form of a new protocol submitted 

under an existing IND. The proposed 

rule states that expanded access use 

under a protocol submitted under an 

existing IND may begin as described in 

§ 312.30(a). Section 312.30(a) provides 

that the study under the protocol may 

begin provided two conditions are met: 

(1) The sponsor has submitted the 

protocol to FDA for its review and (2) 

the protocol has been approved by the 

IRB with responsibility for review and 

approval of the study in accordance 

with the requirements of part 56. 

Section 312.30(a) states that the sponsor 

may comply with these two conditions 

in either order. 


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The proposed rule provides two 

exceptions to the general rules 

concerning when expanded access use 

under a new protocol may begin. First, 

proposed § 312.305(d)(2)(i) provides 

that treatment under a protocol for 

individual patient expanded access in 

an emergency situation may begin when 

it is authorized by the FDA reviewing 

official. Second, proposed 

§ 312.305(d)(2)(ii) states that expanded 

access use under proposed § 312.320 

(the treatment IND or treatment protocol 

described in §§ 312.34 and 312.35 of the 

current IND regulations) may begin 30 

days after FDA receives the protocol (or 

on earlier notification by FDA that the 

treatment use may begin); that is, there 

would be a 30-day wait even for a 

protocol submitted under an existing 

IND. Expanded access use under a 

treatment IND or treatment protocol 

often involves thousands of patients. 

The agency believes it is important to 

build in time for agency review of a 

proposed expanded access use with the 

potential to affect so many people. 

Proposed § 312.300(d)(3) states that 

FDA may place any expanded access 

IND or protocol on clinical hold as 

described in § 312.42. 

F. Expanded Access for Individual 

Patients (Proposed § 312.310) 

Proposed § 312.310 would permit an 

investigational drug to be used for the 

treatment of an individual patient by a 

licensed physician. 

1. Expanded Access for Individual 

Patients—Criteria 

In addition to the proposed criteria for 

all expanded access uses, proposed 

§ 312.310(a) sets forth two criteria for 

permitting an investigational drug to be 

used for the treatment of an individual 

patient by a licensed physician. 

• First, the physician must determine 

that the probable risk to the person from 

the investigational drug is not greater 

than the probable risk from the disease 

or condition (proposed § 312.310(a)(1)). 

• Second, FDA must determine that 

the patient cannot obtain the drug under 

another type of IND (proposed 

§ 312.310(a)(2)). (Section 561(b)(3) of the 

act requires that FDA determine that 

provision of the investigational drug 

will not interfere with the initiation, 

conduct, or completion of clinical 

investigations to support marketing 

approval.) Thus, expanded access for an 

individual patient would not be 

available, for example, if the patient can 

participate in a clinical trial of the 

investigational drug. However, 

participation in a clinical trial may not 

be possible for many reasons. A patient 

may have a stage of the disease different 

from the stage being studied. The 

patient may have failed on, or be 

intolerant of, the active control in a 

randomized active-control trial. It may 

be geographically impossible for the 

patient to participate in a clinical trial. 

One of the proposed general criteria 

for any expanded access use is that FDA 

must determine that the potential 

benefit to the patient justifies the 

potential risks of the expanded access 

use and those potential risks are not 

unreasonable in the context of the 

disease or condition to be treated. The 

evidence needed to make this 

determination for expanded access for 

an individual patient will vary. For a 

patient with an immediately lifethreatening condition, the evidentiary 

burden could be very low—little if any 

clinical evidence to suggest a potential 

benefit or possibly only animal data to 

support safety of the use. For a patient 

with a serious, but not immediately lifethreatening, condition who could expect 

to enjoy a reasonable quality of life for 

an extended time without any 

treatment, the evidentiary burden would 

be higher. 

2. Expanded Access for Individual 

Patients—Submission Requirements 

In addition to the proposed 

submission requirements for all 

expanded access uses, proposed 

§ 312.310(b) provides that the expanded 

access submission must include 

information adequate to demonstrate 

that the general criteria for expanded 

access use and those specific to 

expanded access for individual patients 

have been met. 

Proposed § 312.310(b) provides that if 

the drug is the subject of an existing 

IND, the expanded access submission 

may be made by the sponsor or by a 

licensed physician. A sponsor may 

satisfy the submission requirements by 

amending its existing IND to include a 

protocol for individual patient 

expanded access. Sponsors are strongly 

encouraged to include individual 

patient expanded access protocols 

under their own INDs. 

Proposed § 312.310(b) provides that a 

licensed physician may satisfy the 

submission requirements by obtaining 

from the sponsor permission for FDA to 

refer to any information in the IND that 

would be needed to support the 

individual patient expanded access 

request (right of reference) and by 

providing any other required 

information not contained in the IND 

(usually only the information specific to 

the individual patient). Obtaining a 

right of reference is consistent with 

current practice. Sponsors who agree to 

make an investigational drug available 

to an individual patient, but prefer that 

it be provided under an IND obtained by 

the licensed physician rather than under 

the sponsor’s IND, routinely provide a 

right of reference to necessary 

information in the existing IND, and 

such a right of reference is necessary for 

FDA to be able to make the necessary 

determinations about whether the 

expanded access use may proceed. 

3. Expanded Access for Individual 

Patients—Safeguards 

Proposed § 312.310(c) sets forth 

safeguards that apply specifically to 

expanded access for individual patients. 

These proposed safeguards are listed as 

follows: 

• Treatment of an individual patient 

with an investigational drug is generally 

limited to a single course of therapy for 

a specified duration, unless FDA 

expressly authorizes multiple courses or 

chronic therapy. 

• FDA may require sponsors to 

monitor an individual patient expanded 

access use if the use is for an extended 

duration. 

• At the conclusion of treatment, the 

licensed physician or sponsor (whoever 

made the expanded access submission) 

must provide a written summary of the 

results of the treatment use, including 

unexpected adverse drug experiences. 

• When FDA receives a significant 

number of similar requests for 

individual patient expanded access, the 

agency may ask the sponsor to submit 

an IND or protocol for the use under 

§ 312.315 or § 312.320. 

What constitutes a significant number 

of similar requests will vary depending 

on the indication, the number of 

patients with no available therapeutic 

options, and the extent to which the 

drug has the potential to benefit those 

patients. In general, when the agency 

receives 10 or more requests for the 

same individual patient expanded 

access use within a relatively short time 

period (e.g., less than 6 months), FDA 

will consider whether to request that a 

potential sponsor submit an 

intermediate-size patient population 

IND or protocol for the expanded access 

use and, possibly, conduct a clinical 

trial of the expanded access use. 

4. Expanded Access for Individual 

Patients—Emergency Procedures 

Proposed § 312.310(d) sets out 

emergency procedures for expanded 

access for individual patients. If there is 

an emergency that requires a patient to 

be treated before a written submission 

can be made, FDA may authorize the 

expanded access use to begin without a 

written submission. Under the proposed 

rule, the FDA reviewing official may 


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authorize the emergency use by 

telephone. Emergency expanded access 

use may be requested by telephone, 

facsimile, or other means of electronic 

communications. The proposed rule 

also provides phone numbers for 

requests for investigational drugs and 

investigational biological drug products, 

and an after-hours contact number. 

Proposed § 312.310(d)(2) requires the 

licensed physician or sponsor to explain 

how the expanded access use will meet 

the requirements of proposed §§ 312.305 

and 312.310 and requires agreement to 

submit an expanded access submission 

that complies with proposed §§ 312.305 

and 312.310 within 5 working days of 

FDA’s authorization of the expanded 

access use. 

For individual patient expanded 

access use situations in which there is 

time to make a written submission, the 

expedited procedures would not be 

available. Lack of a prior written 

submission decreases FDA’s ability to 

review the proposed use. Furthermore, 

FDA’s experience with emergency 

treatment use is that the written 

submission and followup information 

on the outcome of the treatment use 

frequently have not been provided. By 

limiting use of the emergency 

procedures to true emergencies, the 

agency hopes to better monitor 

individual patient expanded access use. 

G. Expanded Access for IntermediateSize Patient Populations (Proposed 

§ 312.315) 

Proposed § 312.315 provides for 

expanded access use by patient 

populations smaller than those typical 

in treatment INDs or treatment 

protocols. FDA may ask a sponsor to 

consolidate expanded access use under 

this section when the agency has 

received a significant number of 

requests for individual patient 

expanded access to an investigational 

drug for the same use. 

Proposed § 312.315(a) states that 

expanded access use under the section 

may be needed in the following 

situations: 

• Drug not being developed. The drug 

is not being developed, for example, 

because the disease or condition is so 

rare that the sponsor is unable to recruit 

patients for a clinical trial. Nonetheless, 

the drug may represent the only 

promising therapy for the people with 

the disease or condition (proposed 

§ 312.315(a)(1)). 

• Drug being developed. The drug is 

being studied in a clinical trial, but 

patients requesting the drug for 

expanded access use are unable to 

participate in the trial. Patients may not 

be able to participate in the trial, for 

example, because they have a different 

disease or stage of disease from the one 

being studied or otherwise do not meet 

the enrollment criteria; because 

enrollment in the trial is closed; or 

because the trial site is not 

geographically accessible (proposed 

§ 312.315(a)(2)). 

• Approved or related drug. The drug 

is an approved drug product that is no 

longer marketed for safety reasons or is 

unavailable through marketing due to 

failure to meet the conditions of the 

approved application (proposed 

§ 312.315(a)(3)(i)), or the drug contains 

the same active moiety as an approved 

drug product that is unavailable through 

marketing due to failure to meet the 

conditions of the approved application 

or a drug shortage (proposed 

§ 312.315(a)(3)(ii)). 

When a drug is no longer marketed 

due to safety reasons, there may be a 

subset of patients for whom the benefits 

of treatment are believed to outweigh 

the risks and who lack satisfactory 

alternative therapies. Under proposed 

§ 312.315(a)(3)(i), those patients could 

continue to receive the drug under an 

intermediate-size patient population 

IND for expanded access use. 

This provision is also intended to 

allow uninterrupted therapy when an 

approved drug is not being 

manufactured in a manner consistent 

with the specifications on which the 

approval is based (good manufacturing 

practice (GMP) violations) and therefore 

cannot be marketed under the new drug 

application (NDA). Under proposed 

§ 312.315(a)(3)(i), the drug could be 

made available to patients for whom the 

drug is a medical necessity until the 

GMP violations are addressed (assuming 

that, despite those violations, the 

product does not pose a risk that is 

unreasonable in the context of the 

disease or condition to be treated, per 

proposed § 312.305(a)(2)). If the product 

does pose a risk because of GMP 

concerns, proposed § 312.315(a)(3)(ii) 

could be used to make available an 

unapproved drug product containing 

the same active moiety (e.g., a drug 

product approved in another country). 

Proposed § 312.315(a)(3)(ii) could also 

be used in a drug shortage situation to 

make available an unapproved drug 

containing the same active moiety as the 

approved drug that is in short supply 

(e.g., a drug product approved in 

another country). 

1. Expanded Access for IntermediateSize Patient Populations—Criteria 

In addition to the proposed criteria for 

all expanded access uses, proposed 

§ 312.315(b) sets forth the criteria that 

apply specifically to expanded access 

use for intermediate-size patient 

populations. 

• The first criterion requires that 

there be enough evidence that the drug 

is safe at the dose and duration 

proposed for expanded access use to 

justify a clinical trial of the drug in the 

approximate number of patients 

expected to receive the drug for 

expanded access use (proposed 

§ 312.315(b)(1)). 

In ordinary drug development, it is 

usual practice to gradually increase the 

number of subjects exposed to a drug 

(from first human exposure in a very 

small number of subjects through large 

phase 3 trials). This practice limits the 

risk from drugs that turn out to have 

significant adverse effects, as more and 

better information (e.g., about dosing) is 

obtained about the drug before larger 

numbers of subjects are treated. The 

same rationale would apply in the 

expanded access use setting. There 

should be more clinical experience for 

an intermediate-size patient population 

than for an individual patient, and the 

amount of clinical experience to justify 

expanded access use in a certain 

population should be roughly the same 

as would justify a clinical trial in that 

size population. FDA anticipates that 

the typical intermediate-size patient 

population treatment use IND or 

protocol will provide access to between 

10 and 100 patients. 

• The second criterion requires that 

there be at least preliminary clinical 

evidence of effectiveness of the drug or 

of a plausible pharmacologic effect of 

the drug to make expanded access use 

a reasonable therapeutic option in the 

anticipated patient population 

(proposed § 312.315(b)(2)). 

2. Expanded Access for IntermediateSize Patient Populations—Submission 

Requirements 

In addition to the proposed 

submission requirements for all 

expanded access uses, proposed 

§ 312.315(c) sets forth the submission 

requirements that apply specifically to 

expanded access use by intermediatesize patient populations. The expanded 

access use submission must do the 

following: 

• State whether the drug is being 

developed or is not being developed and 

describe the patient population to be 

treated (proposed § 312.315(c)(1)); 

• Include an explanation by the 

sponsor, if the drug is not being actively 

developed, of why the drug cannot 

currently be developed for the expanded 

access use and under what 

circumstances the drug could be 

developed (proposed § 312.315(c)(2)); 

and 


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• Include an explanation by the 

sponsor, if the drug is being studied in 

a clinical trial, of why the patients to be 

treated cannot be enrolled in the clinical 

trial and under what circumstances the 

sponsor would conduct a clinical trial 

in these patients (proposed 

§ 312.315(c)(3)). 

3. Expanded Access for IntermediateSize Patient Populations—Safeguards 

Proposed § 312.315(d) sets forth the 

safeguards that apply specifically to 

expanded access use by intermediatesize populations. Upon review of the 

IND annual report, FDA will determine 

whether it is appropriate for the use to 

continue under this section. If the drug 

is not being actively developed or if the 

expanded access use is not being 

developed (but another use is being 

developed), FDA will consider whether 

it is possible to conduct a clinical study 

to develop the expanded access use for 

marketing (proposed § 312.315(d)(1)(i)). 

If the drug is being actively developed, 

FDA will consider whether providing 

the investigational drug for expanded 

access use is interfering with the 

clinical development of the drug 

(proposed § 312.315(d)(1)(ii)). As the 

number of patients enrolled increases, 

FDA will also consider whether to 

request that a sponsor submit a 

treatment IND or treatment protocol as 

described in § 312.320 for the expanded 

access use (proposed 

§ 312.315(d)(1)(iii)). The sponsor is 

responsible for monitoring the 

expanded access protocol to ensure that 

licensed physicians comply with the 

protocol and the regulations applicable 

to investigators (proposed 

§ 312.315(d)(2)). 

H. Expanded Access Treatment IND or 

Treatment Protocol (Proposed 

§ 312.320) 

Proposed § 312.320 describes the 

treatment IND or treatment protocol 

mechanism that is currently provided in 

§§ 312.34 and 312.35. Proposed 

§ 312.320 retains the basic terminology 

‘‘treatment IND’’ and ‘‘treatment 

protocol’’ from current §§ 312.34 and 

312.35. 

1. Expanded Access Treatment IND or 

Treatment Protocol—Criteria 

In addition to the proposed criteria for 

all expanded access uses, proposed 

§ 312.320(a) provides the criteria that 

apply specifically to a treatment IND or 

treatment protocol. 

Proposed § 312.320(a)(1) requires that 

either the drug is being investigated in 

a controlled clinical trial under an IND 

designed to support a marketing 

application for the expanded access use 

(proposed § 312.320(a)(1)(i)), or all 

clinical trials of the drug have been 

completed (proposed § 312.320(a)(1)(ii)). 

In addition, the sponsor must be 

actively pursuing marketing approval of 

the drug for the expanded access use 

with due diligence (proposed 

§ 312.320(a)(2)). 

Proposed § 312.320(a)(3)(i) provides 

that, when the expanded access use is 

for a serious disease or condition, there 

must be sufficient clinical evidence of 

safety and effectiveness to support the 

expanded access use. Such evidence 

would ordinarily consist of data from 

phase 3 trials, but could consist of 

compelling data from completed phase 

2 trials. 

Proposed § 312.320(a)(2)(ii) provides 

that, when the expanded access use is 

for an immediately life-threatening 

disease or condition, the available 

scientific evidence, taken as a whole, 

provides a reasonable basis to conclude 

that the investigational drug may be 

effective for the expanded access use 

and would not expose patients to an 

unreasonable and significant risk of 

illness or injury. This evidence would 

ordinarily consist of clinical data from 

phase 3 or phase 2 trials, but could be 

based on more preliminary clinical 

evidence. 

2. Expanded Access Treatment IND or 

Treatment Protocol—Submission 

Requirements 

In addition to the proposed 

submission requirements for all 

expanded access uses, proposed 

§ 312.320(b) states that the expanded 

access submission must include 

information adequate to satisfy FDA that 

the general criteria for expanded access 

use and those specific to the treatment 

IND or treatment protocol have been 

met. 

3. Expanded Access Treatment IND or 

Treatment Protocol—Safeguards 

Proposed § 312.320(c) provides a 

safeguard that applies specifically to 

treatment protocols. The sponsor is 

responsible for monitoring the treatment 

protocol to ensure that licensed 

physicians comply with the protocol 

and the regulations applicable to 

investigators. 

I. Open-Label Safety Studies 

The primary purpose of the treatment 

IND or treatment protocol is to make 

investigational drugs available to 

patients with serious or immediately 

life-threatening diseases or conditions 

when there is a reasonable evidentiary 

basis to support the use in a substantial 

population, but the evidence needed for 

marketing approval either has not been 

entirely collected or has been collected 

but not yet analyzed and reviewed by 

the agency. 

FDA is concerned that sponsors have 

used programs other than treatment 

INDs or treatment protocols to make 

investigational drugs available to large 

populations for treatment use, 

particularly by identifying such 

programs as ‘‘open-label safety studies.’’

The goal of an open-label safety study 

is to better characterize the safety of a 

drug late in its development. However, 

in practice, many studies that are 

described as open-label safety studies 

have characteristics that appear to be 

more consistent with treatment INDs or 

treatment protocols. For example: 

• The investigators are not selected 

by the sponsor but can be any physician 

(sometimes with specified 

qualifications), 

• The population receiving the drug 

is quite large, 

• Collection of data is minimal, and 

• The studies may not generate the 

kind of reliable information that would 

be developed in a study designed to 

meaningfully assess safety endpoints. 

Consequently, in the future, the 

agency intends to evaluate whether 

proposals for open-label safety studies 

should be treatment INDs or treatment 

protocols that would have to meet the 

criteria in proposed § 312.320. A study 

described as an open-label safety study 

that provides broad access to an 

investigational drug in the later stages of 

development, but lacks planned, 

systematic data collection and a design 

appropriate to evaluation of a safety 

issue is likely to be considered a 

treatment IND or treatment protocol. 

The agency believes treatment INDs or 

treatment protocols are more 

appropriate programs to provide 

treatment because the authorization for 

such expanded access uses will require 

a more formal review process that 

would explicitly consider the impact of 

expanded access on enrollment in 

clinical trials and the progress of drug 

development generally. 

J. Continuation Phase of a Clinical Trial 

The continuation phase of a clinical 

trial may have characteristics in 

common with open-label safety studies 

or expanded access, or both. In the 

continuation phase of a clinical trial, 

patients have the option of receiving the 

study drug after completing the 

controlled portion of the trial (continue 

on the study drug or cross over from a 

control treatment to the study drug), 

often as an inducement to enroll in the 

clinical study. All patients receive the 

study drug. The primary intent may be 

to develop additional safety data or to 


jlentini on PROD1PC65 with PROPOSAL
75156 Federal Register / Vol. 71, No. 240 / Thursday, December 14, 2006 / Proposed Rules 

3In light of section 903(d) of the act (21 U.S.C. 

393(d)) and the Secretary’s delegations to the 

Commissioner of Food and Drugs, statutory 

references to ‘‘the Secretary’’ in the discussion of 

legal authority have been changed to ‘‘FDA’’ or ‘‘the 

agency.’’

treat the patient’s condition. 

Notwithstanding the intent, however, 

because enrollment is limited to only 

clinical study participants, the use is 

considered a part of the clinical study 

rather than an expanded access use for 

purposes of proposed subpart I. 

V. Legal Authority 

The agency believes it has the 

authority to impose requirements 

regarding expanded access to 

investigational drugs under various 

sections of the act, including sections 

505(i); 561; and 701(a) (21 U.S.C. 

371(a)). 

Section 505(i) of the act directs the 

agency3 to issue regulations exempting 

from the operation of the new drug 

approval requirements drugs intended 

solely for investigational use by experts 

qualified by scientific training and 

expertise to investigate the safety and 

effectiveness of drugs. The proposed 

rule explains procedures for obtaining 

FDA authorization for expanded access 

uses of investigational drugs and factors 

relevant to making necessary 

determinations. 

Section 561 of the act, added by 

FDAMA, provides significant additional 

authority for this proposed rule. Section 

561(a) of the act states that FDA may, 

under appropriate conditions 

determined by the agency, authorize the 

shipment of investigational drugs for the 

diagnosis, monitoring, or treatment of a 

serious disease or condition in 

emergency situations. This proposed 

rule sets forth factors that the agency 

will consider in determining whether to 

authorize shipment of investigational 

drugs in emergency situations. 

Section 561(b) of the act allows any 

person, acting through a physician 

licensed in accordance with State law, 

to request from a manufacturer or 

distributor an investigational drug for 

the diagnosis, monitoring, or treatment 

of a serious disease or condition if four 

conditions are met: (1) The physician 

must determine that the person has no 

comparable or satisfactory alternative 

therapy available and the probable risk 

to the person from the investigational 

drug is not greater than the probable risk 

from the disease or condition; (2) FDA 

must determine that there is sufficient 

evidence of safety and effectiveness to 

support the use of the investigational 

drug in the particular case; (3) FDA 

must determine that provision of the 

investigational drug will not interfere 

with the initiation, conduct, or 

completion of clinical investigations to 

support marketing approval; and (4) the 

sponsor or clinical investigator of the 

investigational drug submits a clinical 

protocol consistent with the provisions 

of section 505 of the act describing the 

use of the investigational drug in a 

single patient or a small group of 

patients. The proposed rule sets forth 

factors that FDA will consider in 

making the necessary determinations 

and explains the procedures and criteria 

for physicians, sponsors, and/or 

investigators to make the necessary 

representations and submissions to 

FDA. 

Section 561(c) of the act specifically 

authorizes expanded access under a 

treatment IND if FDA makes the 

following determinations: (1) Under the 

treatment IND, the investigational drug 

is intended for use in diagnosing, 

monitoring, or treating a serious or 

immediately life-threatening disease or 

condition; (2) there is no comparable or 

satisfactory alternative therapy available 

to diagnose, monitor, or treat that stage 

of disease or condition in the 

population of patients to which the 

investigational drug is intended to be 

administered; (3) the investigational 

drug is already under investigation in a 

controlled clinical trial for the same use 

under an IND under section 505(i) of the 

act, or all clinical trials necessary for 

approval of that use of the 

investigational drug have been 

completed; (4) the sponsor of the 

controlled clinical trials is actively 

pursuing marketing approval of the 

investigational drug, with due diligence, 

for the same intended use; (5) provision 

of the investigational drug will not 

interfere with the enrollment of patients 

in ongoing clinical investigations under 

section 505(i) of the act; (6) in the case 

of serious diseases, there is sufficient 

evidence of safety and effectiveness to 

support the intended use; and (7) in the 

case of immediately life-threatening 

diseases, the available scientific 

evidence, taken as a whole, provides a 

reasonable basis to conclude that the 

investigational drug may be effective for 

its intended use and would not expose 

patients to an unreasonable and 

significant risk of illness and injury. The 

proposed rule sets forth factors that FDA 

will consider in making the necessary 

determinations. 

Section 561 of the act further requires 

that protocols submitted under section 

561 be subject to section 505(i) of the act 

including regulations issued under 

section 505(i). Section 561(d) of the act 

permits the agency to terminate 

expanded access for failure to comply 

with the requirements of section 561 of 

the act. The proposed rule sets forth the 

conditions under which FDA will place 

an expanded access use on clinical 

hold. 

In this proposed rule, the agency 

proposes three categories of expanded 

access. While authority for individual 

patient access is based on section 561(b) 

of the act, and authority for treatment 

INDs and treatment protocols is based 

on section 561(c) of the act, there is also 

authority in the statute for FDA to issue 

regulations for intermediate-size patient 

populations. Section 561(b)(4) of the act 

requires submission of a protocol for the 

expanded access use that is consistent 

with the requirements of the IND 

regulations describing the use of the 

investigational drug in a single patient 

or a small group of patients. The 

provisions of the proposed rule 

concerning expanded access for 

intermediate-size patient populations 

address the use of the investigational 

drug in the small groups of patients 

mentioned in the statute. 

Section 701(a) of the act provides 

general authority to issue regulations for 

the efficient enforcement of the act. By 

clarifying the criteria and procedures 

relating to expanded access to 

investigational products, this proposed 

rule is expected to aid in the efficient 

enforcement of the act. 

VI. Environmental Impact 

The agency has determined under 21 

CFR 25.30(h) 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. 

VII. Analysis of Economic Impacts 

FDA has examined the impacts of the 

proposed rule under Executive Order 

12866 and the Regulatory Flexibility Act 

(5 U.S.C. 601–612), and under 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). The agency 

believes that this proposed rule is not an 

economically significant regulatory 

action as defined by the Executive 

Order. 

The Regulatory Flexibility Act 

requires agencies to analyze regulatory 

options that would minimize any 

significant impact of a rule on small 


jlentini on PROD1PC65 with PROPOSAL
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entities. Currently, the agency does not 

believe that the proposed rule will have 

a significant economic impact on a 

substantial number of small entities. 

Nevertheless, we recognize our 

uncertainty regarding the number and 

size distribution of affected entities, as 

well as the economic impact of the 

proposed rule on those entities. 

Therefore, this economic analysis, 

together with other relevant sections of 

this document, constitutes the agency’s 

initial regulatory flexibility analysis. 

The agency specifically requests 

detailed public comment regarding the 

number of affected small entities as well 

as the potential economic impact of the 

proposed rule on those 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 an 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 

approximately $122 million, using the 

most current (2005) Implicit Price 

Deflator for the Gross Domestic Product. 

FDA does not expect this proposed rule 

to result in any 1-year expenditure that 

would meet or exceed this amount. 

A. Objectives of the Proposed Action 

FDA is proposing this action to 

describe in greater detail all of the ways 

patients may obtain expanded access to 

investigational drugs for treatment use. 

Specifically, the proposed rule 

establishes eligibility criteria, 

submission requirements, and 

safeguards for the expanded access use 

of investigational drugs by individual 

patients, including in emergencies; 

intermediate size patient populations; 

and larger populations under a 

treatment protocol or treatment IND. 

The proposal is also intended to 

increase public knowledge and 

awareness of expanded access and, thus, 

to make investigational drugs more 

widely available. In addition, by 

establishing clear eligibility criteria and 

submission requirements, the proposed 

rule would ease administrative burdens 

on physicians seeking investigational 

drugs for their patients and on sponsors 

who are willing to make promising 

unapproved therapies available for 

treatment use. The agency believes that 

the proposed rule would achieve these 

objectives in a way that fairly addresses 

the interests of patients, drug sponsors, 

and society as a whole. 

B. Nature of the Problem Being 

Addressed 

The fundamental problem addressed 

by the proposed rule is one of 

incomplete information. In some 

circumstances, a lack of clearly defined 

eligibility criteria and submission 

requirements has created inefficiencies 

that limit patient access to potentially 

beneficial investigational drugs. The 

proposed rule is also intended to 

address concerns that, historically, 

cancer and AIDS patients have had 

better access to investigational drugs 

than patients with other serious diseases 

or conditions, and that patients under 

the care of physicians based in 

academic medical centers are more 

likely to obtain such access than 

patients whose physicians practice 

outside such centers. In addition, the 

lack of clearly defined eligibility criteria 

and submission requirements has led 

some physicians and drug sponsors to 

devote more resources than necessary to 

the preparation of expanded access 

submissions. Through this proposed 

rule, the agency seeks to correct these 

shortcomings. 

The proposed rule establishes general 

eligibility criteria, submission 

requirements, and safeguards for the 

expanded access use of investigational 

drugs. The requirements that apply to 

all types of expanded access use are 

described in detail in section IV.E of 

this document. The proposed rule also 

describes more specific eligibility 

criteria, submission requirements, and 

safeguards for three specific categories 

of expanded access: (1) Expanded access 

for individual patients, (2) expanded 

access for intermediate-size patient 

populations, and (3) expanded access 

under a treatment protocol or treatment 

IND. These types of expanded access 

uses are described in detail in sections 

IV.F, IV.G, and IV.H of this document, 

respectively. 

C. Baseline for the Analysis 

During the period 1997 through 2005, 

FDA received an average of 2,046.6 

INDs per year. Of this number, on 

average, approximately 659, or 32.2 

percent (0.322 = 659 / 2,046.6) were 

individual patient or emergency INDs. 

In addition, FDA received 

approximately 4.6 treatment IND or 

treatment protocol submissions per year 

during this time period. Thus, treatment 

IND or treatment protocol submissions 

represent about 0.2 percent (0.022 = 4.6 

/ 2,046.6) of all INDs received by the 

agency each year. Because expanded 

access for intermediate size patient 

populations is not currently established 

in regulation, FDA does not have a 

record of the number of submissions in 

this category. However, based on an 

internal survey of drug review divisions, 

FDA estimates that approximately 55 

other expanded access submissions 

were received each year between 2000 

and 2002. While it is not possible to 

determine the precise number that 

would be considered intermediate size 

patient population expanded access 

submissions, FDA experts believe that 

most of the 55 other submissions each 

year would fall under this category. 

Thus, approximately 2.7 percent (0.0268 

= 55 / 2,046.6) of all INDs received by 

FDA each year may be associated with 

intermediate size patient population 

expanded access requests. The 

information presented above is 

summarized in table 1 of this document. 

TABLE 1.—BASELINE DATA FOR THE NUMBER OF INDS AND EXPANDED ACCESS REQUESTS BY 

CATEGORY 

Category Total INDs Individual Patient or 

Emergency IND 

Treatment IND 

or Protocol Other 

Number 2,046 .6 659 .0 4 .6 55 .0 

Percent of all INDs 100% 32 .2% 0 .2% 2 .7% 

D. Nature of the Impact 

The proposed rule would affect 

patients who lack effective therapeutic 

alternatives and may benefit from access 

to investigational drugs, physicians 

attempting to obtain investigational 

drugs for their patients, drug sponsors 

who make investigational drugs 

available to patients, and FDA in its 

oversight role in the process for making 

investigational drugs available for 

expanded access use. As discussed 


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further in section I.D of this document, 

a major purpose of this proposed rule is 

to expand access to investigational 

drugs for patients with serious and 

immediately life-threatening conditions 

who lack satisfactory therapeutic 

alternatives. Therefore, FDA anticipates 

that the proposed rule would increase 

the number of patients who obtain 

access to investigational drugs for 

treatment use. This increase in volume 

would lead to more expanded access 

submissions from sponsors and 

physicians seeking investigational drugs 

for their patients and, as a consequence, 

would require FDA to review more 

submissions. Given the relatively small 

percentage of all INDs received by the 

agency that are associated with 

expanded access use submissions, FDA 

expects that the overall impact of the 

proposed rule will not be significant. 

The proposed rule also attempts to 

minimize the potential administrative 

burdens for physicians, sponsors, and 

FDA that would result from an 

increased volume of patients obtaining 

investigational drugs for expanded 

access use. The proposed rule 

encourages the consolidation of 

multiple individual patient INDs or 

protocols for a given use under an 

intermediate-size patient population 

IND or protocol (see sections VII.D.2 

and VII.F of this document for 

additional discussion). By reducing the 

total volume of submissions that would 

have been prepared if all patients were 

to obtain a drug under individual 

patient INDs or protocols, consolidation 

will limit the additional administrative 

burdens from increased patient access. 

In addition, by explicitly clarifying the 

eligibility criteria and submission 

requirements for expanded access, the 

proposed rule should make the process 

of obtaining access to investigational 

drugs more efficient for all affected 

parties. 

It is expected that any increase in the 

volume of submissions would result 

primarily from greater numbers of 

patients obtaining investigational drugs 

under expanded access INDs or 

protocols for individual patients and 

intermediate-size patient populations. 

Because this proposed rule does not 

significantly change the existing 

regulation concerning treatment INDs or 

treatment protocols, the number of 

patients receiving investigational drugs 

under these mechanisms should be 

largely unaffected. 

1. Individual Patient Expanded Access 

Submissions 

By increasing awareness of the ways 

individual patients can obtain expanded 

access to investigational drugs for 

treatment use, and decreasing the 

perceived difficulty of obtaining such 

access, the proposed rule should 

increase the number of individual 

patients seeking access to 

investigational drugs. FDA anticipates 

that this increase in individual patient 

expanded access submissions would be 

greatest in the years immediately 

following implementation of a final rule 

and would at some point level off, or 

possibly even decline. This leveling off 

or decline would occur when a 

significant volume of individual patient 

expanded access has accumulated for a 

variety of drugs, and the individual 

patient expanded access INDs or 

protocols for those drugs are then 

replaced with intermediate-size patient 

population INDs or protocols that enroll 

multiple subjects. Making the transition 

from multiple individual patient INDs 

or protocols to a single intermediate-size 

patient population IND or protocol 

should reduce the overall administrative 

burden associated with making a 

particular investigational drug available 

for treatment use. 

From 1997 to 2005, FDA received, on 

average, approximately 659 individual 

patient and emergency IND submissions 

per year. Although FDA is confident 

this proposed rule would increase this 

volume, it is difficult to predict with 

precision the extent of the increase. 

There is uncertainty concerning the 

extent to which patients who desire 

expanded access to investigational 

drugs are unable to obtain them; the 

extent to which better information about 

the mechanisms and processes for 

obtaining access to investigational drugs 

will stimulate more patients, or their 

physicians, to seek investigational drugs 

for expanded access use; and the extent 

to which drug manufacturers will be 

willing to make investigational drugs 

more broadly available for expanded 

access use. Although FDA is confident 

there will be an increase in the volume 

of individual patient expanded access 

use if this rulemaking is finalized, 

because of these uncertainties the 

agency can provide only an estimate of 

the range of potential increase. FDA 

believes, after publication of a final rule, 

that it is reasonable to anticipate a 40 to 

60 percent increase in the volume of 

individual patient expanded access 

submissions by year 3. As discussed 

previously in this document, we 

anticipate that growth would be most 

rapid in the years immediately 

following publication of a final rule and 

would eventually plateau, or possibly 

even decline. The implications of these 

assumptions for the total number of 

individual patient expanded access 

submissions are summarized in table 2 

of this document. 

TABLE 2.—EXPECTED PERCENT 

INCREASE AND ESTIMATED 

NUMBER OF INDIVIDUAL PATIENT EXPANDED ACCESS 

SUBMISSIONS 

Year After 

Implementation of 

Final Rule 

Expected Percent Increase in 

Individual Patient Submissions 

Expected 

Number of 

Individual 

Patient Submissions1

1 20% to 40% 791 to 923 

2 30% to 50% 857 to 988 

3 40% to 60% 923 to 1,054 

4 0% 923 to 1,054 

5 0% 923 to 1,054 

1Based on the current average of 659 individual patient treatment use submissions per 

year and the estimated percent increases in 

column 2. 

2. Intermediate Size Patient Population 

Expanded Access Submissions 

Although intermediate-size patient 

population expanded access has not 

previously been described in regulation, 

this general type of mechanism has been 

used informally to make investigational 

drugs available for treatment use. Based 

on an internal survey of review 

divisions, FDA estimates that for the 

period 2000 through 2002 it received 

approximately 55 submissions per year 

that would be considered intermediate 

size patient population expanded access 

submissions under the proposed 

criteria. The agency anticipates that this 

proposed rule would increase the 

number of such submissions. Because 

this previously informal mechanism 

will be described in regulation for the 

first time, there will be greater 

awareness, which is likely to stimulate 

submissions. In addition, the 

anticipated increase in volume of 

individual patient expanded access 

submissions discussed previously in 

this document is expected to increase 

the number of intermediate size patient 

population expanded access 

submissions because the proposed rule 

encourages the consolidation of 

multiple individual patient INDs or 

protocols for a given expanded access 

use. 

The extent to which submissions for 

expanded access for intermediate-size 

patient populations will increase is 

uncertain. Section 312.315 of the 

proposed rule concerns expanded 

access for intermediate-size patient 

populations. This section provides that 


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Federal Register / Vol. 71, No. 240 / Thursday, December 14, 2006 / Proposed Rules 75159 

FDA may ask a sponsor to consolidate 

expanded access under this section 

when the agency has received a 

significant number of requests for 

individual patient expanded access to 

an investigational drug for the same use. 

FDA does not have historical 

information that would permit us to 

accurately predict what portion of 

individual patient expanded access 

submissions are likely to be appropriate 

for consolidation. Based on our 

experience, we believe that many of the 

individual patient expanded access 

submissions we receive will be 

appropriate for consolidation. However, 

some individual patient expanded 

access submissions will be for expanded 

access uses that are sufficiently rare that 

it is unlikely that there will be enough 

similar uses to consolidate them under 

an intermediate-size patient population 

IND or protocol. There is also 

uncertainty about the extent to which 

sponsors will be willing to make 

investigational drugs available for 

expanded access use under 

intermediate-size patient population 

INDs or protocols. Although FDA is 

confident that there will be growth in 

the volume of intermediate-size patient 

population expanded access INDs or 

protocols, because of the uncertainties 

identified, we can provide only an 

estimate of the range of potential 

increase. FDA believes it is reasonable 

to anticipate a 25 to 50 percent growth 

in the volume of submissions for 

intermediate-size population expanded 

access INDs or protocols over a 5-year 

period. 

Compared to the growth in individual 

patient expanded access submissions, 

this increase is likely to be more gradual 

in the years immediately following 

implementation of a final rule, and will 

increase more sharply after 2 to 3 years 

as some of the increase in volume of 

individual patient expanded access 

submissions is shifted to intermediate 

size population INDs or protocols. As in 

the case of expanded access for 

individual patients, growth in the 

number of submissions is expected to 

plateau or even decline after a few 

years. The implications of these 

assumptions for the number of 

individual patient expanded access 

submissions are summarized in table 3 

of this document. 

TABLE 3.—EXPECTED PERCENT 

INCREASE AND ESTIMATED 

NUMBER OF INTERMEDIATE 

SIZE PATIENT POPULATION EXPANDED ACCESS SUBMISSIONS 

Year After 

Implementation of 

Final Rule 

Expected Percent Increase in 

Intermediate 

Size Patient 

Population Submissions 

Expected 

Number of 

Intermediate 

Size Patient 

Population 

Submissions1

1 5% to 10% 58 to 61 

2 10% to 20% 61 to 66 

3 20% to 40% 66 to 77 

4 25% to 50% 69 to 82 

5 0% 69 to 82 

1Based on the current average of 55 intermediate size patient population submissions 

per year and the estimated percent increases 

in column 2. 

3. Expanded Access Under Treatment 

INDs and Treatment Protocols 

The number of treatment INDs and 

treatment protocols should be largely 

unaffected by the proposed rule. The 

concept of large access programs is well 

established and most drugs that meet an 

unmet medical need for a serious or 

immediately life-threatening condition 

have had some kind of large access 

program late in their development. 

Therefore, the number of large access 

programs is primarily a function of the 

number of new drugs to treat serious 

and immediately life-threatening 

conditions that reach the latter stages of 

drug development (e.g., become NDA 

submissions). This rule is unlikely to 

influence that number. 

As discussed previously in this 

document, sponsors have instituted 

large expanded access programs under 

treatment INDs or treatment protocols or 

under less formal open-label or openaccess protocols (see section IV.I of this 

document). The agency intends to be 

more vigilant in ensuring that a use of 

an investigational drug that has the 

characteristics of a treatment IND or 

treatment protocol is submitted and 

authorized as such, rather than as an 

open-label protocol. While this 

increased vigilance may increase the 

number of treatment INDs or treatment 

protocols, any increase will be primarily 

attributable to reclassifying open-label 

safety studies as treatment INDs or 

treatment protocols rather than a net 

increase in the overall number of large 

access programs. This reclassification 

should also improve safety monitoring 

of large access programs without 

significantly increasing administrative 

costs, because the costs for a treatment 

IND or treatment protocol and an openlabel protocol are similar. 

Reclassification of an open-label 

protocol as a treatment IND or treatment 

protocol may also increase publicity for, 

and awareness of, the access program. 

Sponsors of treatment INDs or treatment 

protocols are required to list those 

programs at http:// 

www.clinicaltrials.gov, a Web site 

maintained by the National Institutes of 

Health as a resource for patients seeking 

to enroll in clinical trials or obtain 

access to investigational drugs for 

treatment use. The additional exposure 

generated by this site may attract more 

patients than would have had access 

under an open-label protocol. As a 

result, any given treatment IND or 

treatment protocol may be somewhat 

more costly than a less publicized openlabel protocol due to the volume of 

patients enrolled. FDA is not able to 

predict the impact on patient volume as 

a result of reclassifying open-label or 

open-access protocols as treatment INDs 

or treatment protocols. However, FDA 

anticipates that there would be some 

economies of scale, so that the 

incremental costs would be relatively 

small on a per-patient basis. FDA 

believes any added costs would be 

justified by the potentially greater 

number of patients who would benefit 

from access to investigational drugs. 

E. Benefits of the Proposed Rule 

Because FDA currently has no data 

that would allow us to predict the 

extent to which the proposed 

amendments to existing IND regulations 

would generate direct benefits for 

consumers, it is not possible to 

accurately quantify the magnitude of 

any expected incremental benefits at 

this time. The number of patients 

obtaining expanded access to 

investigational drugs is expected to 

increase. However, because eligible 

patients will have serious or 

immediately life-threatening conditions 

that have failed to respond to available 

therapies, and because the 

investigational drugs are unproven, FDA 

cannot predict the extent to which 

individual patients would benefit from 

access to these drugs. Thus, the 

following discussion describes, in 

general terms, the nature of the potential 

benefits associated with the proposed 

rule. 

The benefits of the proposed rule are 

expected to result from improved 

patient access to investigational drugs 

generally and from expanded access 

being made available for a broader 

variety of disease conditions and 


jlentini on PROD1PC65 with PROPOSAL
75160 Federal Register / Vol. 71, No. 240 / Thursday, December 14, 2006 / Proposed Rules 

4See http://www.bls.gov/news.release/ 

ecec.toc.htm. (FDA has verified the Web site 

address, but FDA is not responsible for any 

subsequent changes to the Web site after this 

document publishes in the Federal Register.) 

5See http://swz.salary.com/salarywizard/ 

layouthtmls/ 

swzl_compresult_national_HC07000054.html. (FDA 

has verified the Web site address, but FDA is not 

responsible for any subsequent changes to the Web 

site after this document publishes in the Federal 

Register.) 

treatment settings. In particular, the 

clarification of eligibility criteria and 

submission requirements would 

enhance patient access by easing the 

administrative burdens on individual 

physicians seeking investigational drugs 

for their patients and on sponsors who 

make investigational drugs available for 

expanded access use. Expanded access 

to investigational drugs may generate 

both private and social benefits. Private 

benefits would accrue to individual 

patients receiving drugs for expanded 

access use, whereas social benefits 

would accrue if these private benefits 

are also valued by society at large, or if 

any information obtained contributes to 

the development of new therapies 

generally. 

The proposed rule is also designed to 

address concerns that many physicians 

and their patients, particularly those 

outside of academic medical centers, are 

unaware of the availability of 

investigational drugs for expanded 

access use. In FDAMA, Congress 

included language in section 561(c) of 

the act to authorize the Secretary to 

inform medical associations, medical 

societies, and other appropriate persons 

of the availability of investigational 

drugs under treatment INDs or treatment 

protocols. FDA believes that this action, 

along with detailed eligibility criteria 

and submission requirements 

established in the proposed rule, would 

improve access to investigational drugs 

and result in making expanded access 

use more widely available to patients 

regardless of treatment setting. 

In formulating the proposed rule, FDA 

considered its statutory mandate, the 

interests of individuals and special 

patient populations, drug sponsors, and 

the general public. The agency found 

that in many situations, individuals or 

special patient populations have 

benefited from increased access to a 

drug that has not yet been approved for 

marketing (e.g., in the case of cancer or 

HIV therapies, etc.). These individuals 

or patient groups generally have serious 

or immediately life-threatening 

conditions and have not responded to 

available therapies or cannot participate 

in ongoing clinical trials for some 

reason. 

On the other hand unrestricted access 

to investigational drugs for treatment 

use could negatively affect enrollment 

in the clinical trials required to 

demonstrate safety and efficacy in 

support of new drug marketing 

applications. If expanded access to 

investigational drugs were to adversely 

affect the marketing approval process, 

the general population would 

experience diminished social benefits 

due to the reduced or delayed 

availability of new therapies approved 

for marketing by FDA. 

The proposed rule addresses these 

competing interests by allowing 

investigational drugs to be made 

available for expanded access use only 

if providing the drug for the requested 

use will not interfere with the initiation, 

conduct, or completion of clinical 

investigations that could support 

marketing approval, or otherwise 

compromise the potential development 

of the expanded access use. In this way, 

the proposed rule effectively balances 

the interests of those patient 

populations who would benefit from 

having greater access to investigational 

drugs, with the broader interests of 

society in having safe and effective new 

therapies approved for marketing and 

widely available. 

The agency is also aware that 

allowing expanded access to 

investigational drugs before they are 

fully evaluated for safety may have 

adverse consequences for the seriously 

ill patients who receive them. The 

safeguards in the proposed rule are also 

designed with this concern in mind. 

Authorization of a particular expanded 

access use is generally contingent upon 

a number of factors, including some 

evidence of the drug’s safety and 

effectiveness, obtaining the informed 

consent of the patient, approval of an 

IRB, and a careful assessment of the 

potential risks and benefits to the 

patient. In addition, the proposed rule 

would place limits on the scope and 

duration of certain types of expanded 

access use, require that sponsors of such 

INDs or protocols monitor the expanded 

access use and comply with safety and 

annual reporting requirements for INDs, 

and subject ongoing INDs or protocols to 

periodic reassessment. The agency 

believes these safeguards would 

adequately protect the safety and 

welfare of patients who would seek, and 

may benefit from, expanded access to 

investigational drugs. 

F. Costs of the Proposed Rule 

To the extent that the proposed rule 

results in an increase in the number of 

expanded access submissions, drug 

sponsors and physicians requesting 

investigational drugs on behalf of their 

patients will incur some additional 

costs. Because the proposed rule does 

not include any mandatory reporting 

requirements, the agency believes that 

the one-time costs associated with this 

rule will be negligible. Thus, the 

incremental burden imposed by this 

proposed rule will be in the form of 

additional annual or recurring costs 

associated with the increased number of 

expanded access submissions estimated 

previously in this document. 

The agency estimates that preparation 

and submission of an individual patient 

expanded access submission would 

require a total of approximately 8 hours. 

This time burden would be divided 

among physicians (approximately 15 

percent or 1.2 hours) and nurses, nurse 

practitioners, or medical administrators 

(approximately 85 percent or 6.8 hours). 

According to the U.S. Department of 

Labor, Bureau of Labor Statistics,4 total 

employer costs per hour worked for 

employee compensation for registered 

nurses in the health care and social 

assistance sector was $36.21 as of June 

24, 2004. Thus, the cost of the estimated 

6.8 hours of nurse time required to 

prepare and submit an individual 

patient expanded access submission 

would be approximately $245 ($36.21 

per hour x 6.8 hours). 

Historically, most of the treatment use 

requests submitted to the agency have 

been prepared by physicians in the 

hematology/oncology specialty category. 

Data available on the Internet indicate 

that the median expected total 

compensation for a hematologist/ 

oncologist in the United States was 

$287,016 as of October 2004.5 This 

median total compensation figure 

corresponds to approximately $138 per 

hour ($137.99 = $287,016 / 2,080 hours). 

Thus the cost for the 1.2 hours of 

physician time required to prepare and 

submit an individual patient expanded 

access submission is about $165 ($138 

per hour x 1.2 hours). Therefore, the 

agency estimates that the total cost to 

prepare and submit an individual 

patient expanded access submission 

would be about $410 ($410 = $245 + 

$165). Applying this cost figure to the 

number of additional individual patient 

expanded access submissions estimated 

previously in this document suggests 

the pattern of incremental annual costs 

summarized in table 4 of this document. 


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6See http://www.executivesonly.com/preview/ 

exresults.cfm under the Pharmaceutical specialty 

category. Viewed January 3, 2005. (FDA has verified 

the Web site address, but FDA is not responsible for 

any subsequent changes to the Web site after this 

document publishes in the Federal Register.) 

TABLE 4.—NUMBER OF ADDITIONAL INDIVIDUAL PATIENT 

EXPANDED ACCESS SUBMISSIONS AND ESTIMATED ANNUAL COSTS 

Year After 

Implementation of 

Final Rule 

Expected Increase in the 

Number of Individual Patient 

Submissions1

Expected 

Cost of Additional Individual Patient Submissions2

1 132 to 264 $54,120 to 

$108,240 

2 198 to 329 $81,180 to 

$134,890 

3 264 to 395 $108,240 to 

$161,950 

4 264 to 395 $108,240 to 

$161,950 

5 264 to 395 $108,240 to 

$161,950 

1Based on increases in the number of individual patient expanded access submissions 

implied by the estimates presented in table 2 

of this document. 2Based on an estimated cost of $410 per individual patient expanded access submission. 

Preparation and submission of an 

intermediate size patient population 

expanded access IND or protocol is 

expected to require a total of about 120 

hours of staff time. This time burden 

would be divided between a Director of 

Clinical Research, typically a medical 

doctor (approximately 50 percent or 60 

hours), a Director of Regulatory Affairs 

(approximately 20 percent or 24 hours), 

and a Clinical Research Associate 

(approximately 30 percent or 36 hours). 

Information available on the Internet 

and from industry sources suggests that 

the average salary for a Director of 

Clinical Research is about $200,000 per 

year.6 Assuming that benefits represent 

approximately 30 percent of salary 

implies a total annual compensation 

estimate of $260,000. This translates 

into an estimated hourly total 

compensation figure of about $125 

($260,000 / 2,080 hours). Thus, the cost 

associated with the 60 hours of Clinical 

Research Director time required to 

prepare and submit an intermediate size 

patient population expanded access 

submission is approximately $7,500 (60 

hours x $125). 

Information available on the Internet 

and from industry sources also indicates 

that the average salary for a Director of 

Regulatory Affairs is approximately 

$160,000 per year.6 Assuming that 

benefits represent about 30 percent of 

this salary implies a total annual 

compensation estimate of $208,000. 

This translates into an estimated hourly 

total compensation figure of about $100 

($209,000 / 2,080 hours). Thus, the cost 

associated with the 24 hours of Director 

of Regulatory Affairs time required to 

prepare and submit an intermediate size 

patient population expanded access 

submission is approximately $2,400 (24 

hours x $100). 

Finally, information available on the 

Internet indicates that the median total 

compensation for a Clinical Research 

Associate is approximately $70,000 per 

year.6 This translates into an estimated 

hourly total compensation figure of 

about $33.65 ($70,000 / 2,080 hours). 

Thus, the cost associated with the 36 

hours of Clinical Research Associate 

time required to prepare and submit an 

intermediate size patient population 

expanded access submission is 

approximately $1,200 (36 hours x 

$33.65). 

Based on the information presented, 

the agency estimates that the total cost 

to prepare and submit an intermediate 

size patient population expanded access 

submission would be approximately 

$11,100 ($11,100 = $7,500 + $2,400 + 

$1,200). Applying this figure to the 

increases in the number of intermediate 

size patient population expanded access 

submissions estimated previously in 

this document suggests the pattern of 

annual cost increases summarized in 

table 5 of this document. 

TABLE 5.—NUMBER OF ADDITIONAL INTERMEDIATE SIZE 

PATIENT POPULATION EXPANDED ACCESS SUBMISSIONS AND ESTIMATED ANNUAL COSTS 

Year After 

Implementation of 

Final Rule 

Expected Increase in the 

Number of Intermediate Size 

Patient Population Submissions1

Expected 

Cost of Additional Intermediate 

Size Patient 

Population 

Submissions2

1 3 to 6 $33,300 to 

$66,600 

2 5 to 11 $55,500 to 

$122,100 

3 11 to 22 $122,100 to 

$244,200 

4 14 to 27 $155,400 to 

$299,700 

TABLE 5.—NUMBER OF ADDITIONAL INTERMEDIATE SIZE 

PATIENT POPULATION EXPANDED ACCESS SUBMISSIONS AND ESTIMATED ANNUAL COSTS—Continued 

Year After 

Implementation of 

Final Rule 

Expected Increase in the 

Number of Intermediate Size 

Patient Population Submissions1

Expected 

Cost of Additional Intermediate 

Size Patient 

Population 

Submissions2

5 14 to 27 $155,400 to 

$299,700 

1Based on increases in the number of intermediate size patient population expanded access submissions implied by the estimates 

presented in table 3 of this document. 2Based on an estimated cost of $11,000 per 

intermediate size patient population expanded 

access submission. 

For reasons discussed previously in 

this document, the agency does not 

expect that the proposed rule will have 

an impact on the overall number of 

treatment INDs or treatment protocols. 

Therefore, FDA does not expect the 

provisions of this proposed rule 

regarding treatment INDs or treatment 

protocols to impose any incremental 

cost burden. 

The total estimated annual and 

annualized cost burdens associated with 

this proposed rule are summarized in 

table 6 of this document. 

TABLE 6.—COST SUMMARY 

Year After 

Implementation 

of Final 

Rule 

OneTime 

Cost 

Annual 

Cost 

Annualized 

Cost1

1 $0 $87,240 

to 

$174,840 

$87,240 to 

$174,840 

2 $0 $136,680 

to 

$256,990 

$136,680 to 

$256,990 

3 $0 $230,340 

to 

$406,150 

$230,340 to 

$406,150 

4 $0 $263,340 

to 

$461,650 

$263,340 to 

$461,650 

5 $0 $263,340 

to 

$461,650 

$263,340 to 

$461,650 

1Since estimated one-time costs are negligible, annual costs and annualized costs will 

be the same regardless of the interest rate. 

For reasons discussed previously in 

this document, the agency expects that 

the total one-time costs of the proposed 


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rule will be negligible. FDA expects that 

the annual and annualized costs of this 

proposed rule will range from a low of 

about $87,000 to $175,000 in the first 

year following publication of any final 

rule based on this proposal, to a high of 

about $263,000 to $406,000 in the fourth 

and fifth years. These estimates suggest 

total annual and annualized costs for 

the proposed rule of between $1.0 and 

$1.8 million for the 5-year period 

following implementation of any final 

rule based on this proposal. 

The agency expects that the estimated 

incremental cost burdens associated 

with this proposed rule are likely to be 

widely dispersed among affected 

entities for several reasons. First, given 

the historical volume of various types of 

treatment use submissions, the agency 

believes that a particular drug sponsor—

or a physician acting on behalf of a 

patient—would submit a request for 

expanded access to investigational 

drugs fairly infrequently. Second, as 

noted previously, the proposed rule 

encourages the consolidation of 

multiple expanded access INDs or 

protocols for individual patients for a 

particular expanded access use under an 

intermediate size patient population 

expanded access IND or protocol. Such 

consolidation should, to some extent, 

offset incremental administrative 

burdens caused by increased patient 

access. Making the transition from 

multiple individual patient expanded 

access INDs or protocols to a single IND 

or protocol for an intermediate size 

patient population should reduce for 

sponsors the administrative burdens 

associated with making a drug available 

for expanded access use. In addition, 

provisions of the proposed rule are 

designed to minimize the amount of 

information and paperwork required to 

support a particular expanded access 

request. Physicians and drug sponsors 

would need to review the rule to 

become familiar with its provisions and 

to gather the evidence and information 

necessary to support an expanded 

access submission. However, in 

instances where a current IND already 

exists, a sponsor need only submit an 

amendment describing the information 

relevant to the expanded access 

protocol. Also, another sponsor or 

individual physician acting on behalf of 

a patient may, with the written 

permission of the original sponsor, 

reference information in the current IND 

already on file. The agency believes that 

a majority of expanded access 

submissions would have such a right of 

reference, either because the sponsor is 

also the drug developer or the developer 

would generally be willing to grant the 

request. To the extent that these 

provisions minimize the informational 

burden on potential sponsors or 

physicians, the proposed rule would 

enhance both efficiency and cost 

effectiveness. 

G. Minimizing the Impact on Small 

Entities 

The agency does not believe the 

proposed rule will have a significant 

economic impact on a substantial 

number of small entities. Nevertheless, 

we recognize our uncertainty regarding 

the number and size distribution of 

affected entities, as well as the 

economic impact of the proposed rule 

on those entities. Therefore, the agency 

specifically requests detailed public 

comment on these issues. 

Agency records indicate that the 

majority of submissions for treatment 

use of investigational drugs (about 78 

percent) are submitted by commercial 

drug sponsors. Other entities making 

treatment use submissions include 

government agencies (approximately 14 

percent), individual physicians (7 

percent), and academic institutions (1 

percent). Thus, the agency believes that 

the vast majority (92 percent) of 

sponsors of expanded access INDs or 

protocols (consisting of commercial 

drug sponsors or government agencies) 

would not be considered small entities. 

The remaining 8 percent of treatment 

use submissions are made by individual 

physicians and academic institutions 

that the agency believes would meet 

Small Business Administration small 

business criteria. 

Of the average of 659 individual 

patient treatment use submissions 

submitted annually, very few are 

associated with commercial sponsors. 

The vast majority are submitted by 

individual physicians and various other 

unidentified sponsors for research 

purposes. Because nearly all individual 

patient treatment use submissions are 

made by various types of entities for 

research purposes, the agency believes 

that most of these entities would be 

classified as small entities. 

Because there is currently no formal 

mechanism in place for tracking the 

other types of expanded access (e.g., 

intermediate size patient population 

submissions), no data exist that would 

allow the agency to identify the number 

of sponsors in this category that would 

qualify as small entities. 

Thus, while highly uncertain, the 

agency believes that at least some of the 

entities submitting expanded access 

requests would qualify as small entities. 

Because of this uncertainty, the agency 

specifically requests detailed public 

comment regarding the number and size 

distribution of entities affected by the 

proposed rule. As discussed in section 

VII.E of this document, the agency 

expects that any incremental burden 

associated with the proposed rule will 

be small and widely dispersed among 

affected entities. 

FDA considered several alternatives 

to the proposed rule. They are discussed 

in the following paragraphs. 

1. Do Not Propose Implementing 

Regulations for the Expanded Access 

Provisions of FDAMA 

FDAMA revised the act to specifically 

authorize the use of investigational new 

drugs by licensed physicians to 

diagnose, monitor, or treat individual 

patients who have a serious disease or 

condition if, among other things, the 

physician determines that the person 

has no comparable or satisfactory 

alternative therapy to diagnose, monitor, 

or treat the disease or condition, and 

that the probable risk from the 

investigational drug is not greater than 

the probable risk from the disease or 

condition; and FDA determines that 

there is sufficient evidence of safety and 

effectiveness to support the use of the 

investigational drug. FDAMA also 

largely incorporated into the act FDA’s 

current regulation concerning treatment 

INDs or treatment protocols under 

which large populations currently 

receive investigational drugs for 

treatment use. Because FDAMA did not 

require that FDA adopt implementing 

regulations, the agency could have 

chosen not to do so. 

However, the agency believes that 

implementing regulations would further 

improve expanded access to 

investigational drugs for treatment use. 

One of the major criticisms about access 

to investigational drugs is that the 

criteria for authorizing access are 

unclear and that there is not broad 

knowledge among affected, or 

potentially affected, parties about the 

mechanisms or procedures to obtain 

access. FDA believes the proposed 

regulations are needed to address these 

concerns. The regulations provide to 

sponsors, patients, and licensed 

physicians who will be seeking 

investigational drugs for their patients 

clear direction about the criteria for 

authorizing expanded access and what 

information must be submitted to the 

agency to enable it to evaluate a 

proposed expanded access submission. 

Clearer direction and greater knowledge 

of the mechanisms and procedures for 

obtaining investigational drugs for 

expanded access use should reduce 

barriers to access. 


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2. Propose a Regulation Describing Only 

Individual Patient Expanded Access and 

the Treatment IND or Treatment 

Protocol 

As discussed in the previous 

paragraphs, FDAMA specifically 

authorized the use of investigational 

new drugs by licensed physicians to 

diagnose, monitor, or treat individual 

patients in certain circumstances. 

FDAMA also essentially repeated FDA’s 

current regulation concerning treatment 

INDs or treatment protocols under 

which large populations currently 

receive investigational drugs for 

treatment use. 

FDA could have chosen to adopt 

regulations that described only these 

two categories of expanded access. 

However, FDA has had a long history of 

using an informal mechanism to make 

investigational drugs available to 

intermediate size patient populations. 

This mechanism would not be 

appropriate for either expanded access 

for individual patients or for treatment 

INDs or treatment protocols. The agency 

concluded that, consistent with the 

terminology of section 561(b)(4) of the 

act, it would be preferable to establish 

an intermediate category for expanded 

access, with additional criteria and 

monitoring requirements, that would be 

used for more than an individual 

patient, but fewer than the large 

numbers of patients in treatment INDs 

or treatment protocols. 

In FDA’s experience, there is often a 

need for a middle ground between an 

individual patient IND or protocol and 

a treatment IND or treatment protocol. 

For some drugs in development, there is 

considerable demand for expanded 

access before the use meets the criteria 

for a treatment IND or treatment 

protocol. There are also situations in 

which investigational drugs that are not 

being actively developed are the best 

available therapy for a significant 

number of patients and should be made 

available to patients under an expanded 

access process. In these situations, 

making the drug available under a series 

of individual patient expanded access 

INDs or protocols is burdensome on 

physicians, sponsors, and FDA, and 

makes it difficult to monitor the 

expanded access use to identify 

significant safety concerns such as 

serious adverse events. 

Describing this intermediate category 

in regulation is also consistent with 

FDA’s goal of maximizing awareness of 

expanded access programs by being 

more transparent about the processes for 

making drugs available for expanded 

access. As stated previously, FDA has 

used this intermediate category 

informally in the past and believes it 

will have reason to use this category in 

the future. Therefore, FDA believes it is 

appropriate to formalize and fully 

describe in regulation the intermediate 

expanded access category, as well as the 

two other categories of expanded access. 

3. Propose a Regulation Describing More 

Than Three Expanded Access Categories 

FDA also considered proposing a rule 

that would include more than three 

expanded access categories, but rejected 

this alternative. In internal discussions, 

FDA found that the distinctions 

between the proposed categories and the 

additional categories it considered were 

unclear. FDA was concerned that the 

additional categories would create 

confusion, rather than provide the 

clarity that is the goal of the proposed 

regulations. FDA concluded that the 

additional categories could be merged 

into the three proposed categories and 

that these categories will be able to 

provide access to investigational drugs 

in all situations FDA is likely to 

encounter. 

VIII. Paperwork Reduction Act of 1995 

This proposed rule contains 

collections of information 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). ‘‘Collection of 

information’’ includes any request or 

requirement that persons obtain, 

maintain, retain, or report information 

to the agency, or disclose information to 

a third party or to the public (44 U.S.C. 

3502(3) and 5 CFR 1320.3(c)). The title, 

description, and respondent description 

of the information collection are shown 

in the following paragraphs with an 

estimate of the annual reporting burden. 

Included in the estimate is the time for 

reviewing instructions, gathering and 

maintaining the data needed, and 

completing and reviewing the collection 

of information. 

FDA invites comments on these 

topics: (1) Whether the proposed 

collection of information is necessary 

for proper performance of FDA’s 

functions, including whether the 

information will have practical utility; 

(2) the accuracy of FDA’s estimate of the 

burden of the proposed collection of 

information, including the validity of 

the methodology and assumptions used; 

(3) ways to enhance the quality, utility, 

and clarity of the information to be 

collected; and (4) ways to minimize the 

burden of the collection of information 

on respondents, including through the 

use of automated collection techniques 

and other forms of information 

technology, when appropriate. 

Title: Expanded Access to 

Investigational Drugs for Treatment Use 

Description: The proposed rule would 

clarify existing regulations and expand 

on them by adding new types of 

expanded access for treatment use. 

Under the proposal, expanded access to 

investigational drugs would be available 

to individual patients, including in 

emergencies; to intermediate size 

patient populations; and to larger 

populations under a treatment protocol 

or IND. The proposed rule is intended 

to improve access to investigational 

drugs for patients with serious or 

immediately life-threatening diseases or 

conditions who lack other therapeutic 

options and may benefit from such 

therapies. 

A. The Proposed Rule 

1. Submission Requirements for All 

Expanded Access Uses 

Proposed § 312.305(b) describes the 

submission requirements applicable to 

all types of expanded access. Proposed 

§ 312.305(b)(1) states that an expanded 

access submission is required for each 

type of expanded access. The 

submission may be a new IND or a 

protocol amendment to an existing IND. 

Information required for a submission 

may be supplied by referring to 

pertinent information contained in an 

existing IND if the sponsor of the 

existing IND grants a right of reference 

to the IND. 

Proposed § 312.305(b)(2) describes the 

expanded access submission 

requirements. The following items must 

be included: 

• A cover sheet (Form FDA 1571) 

meeting the requirements of § 312.23(a); 

• The rationale for the intended use 

of the drug, including a list of available 

therapeutic options that would 

ordinarily be tried before resorting to 

the investigational drug or an 

explanation of why the use of the 

investigational drug is preferable to the 

use of available therapeutic options; 

• The criteria for patient selection; or, 

for an individual patient, a description 

of the patient’s disease or condition, 

including recent medical history and 

previous treatments used for the disease 

or condition; 

• The method of administration of the 

drug, dose, and duration of therapy; 

• A description of the facility where 

the drug will be manufactured; 

• Chemistry, manufacturing, and 

controls information adequate to ensure 

the proper identification, quality, 

purity, and strength of the 

investigational drug; 

• Pharmacology and toxicology 

information adequate to conclude that 


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the drug is reasonably safe at the dose 

and duration proposed for expanded 

access use (ordinarily, information that 

would be adequate to permit clinical 

testing of the drug in a population of the 

size expected to be treated); and 

• A description of clinical 

procedures, laboratory tests, or other 

monitoring necessary to evaluate the 

effects of the drug and minimize its 

risks. 

2. Individual Patient Expanded Access 

Proposed § 312.310(b) contains 

additional submission requirements that 

apply to use of an investigational drug 

for the treatment of an individual 

patient by a licensed physician. The 

expanded access submission must 

include information adequate to satisfy 

FDA that the criteria for all expanded 

access uses and those specific to 

individual patient expanded access 

have been met. The individual patient 

expanded access criteria are: (1) The 

physician must determine that the 

probable risk to the person from the 

investigational drug is not greater than 

the probable risk from the disease or 

condition and (2) FDA must determine 

that the patient cannot obtain the drug 

under another type of IND. 

Proposed § 312.310(b)(1) states that if 

the drug is the subject of an existing 

IND, the expanded access submission 

may be made by a commercial sponsor 

or by a licensed physician. Proposed 

§ 312.310(b)(2) states that a sponsor may 

satisfy the submission requirements by 

amending its existing IND to include an 

individual patient expanded access 

protocol. Proposed § 312.310(b)(3) states 

that a licensed physician may satisfy the 

submission requirements by obtaining a 

right of reference to pertinent 

information in the IND and providing 

any other required information not 

contained in the IND (usually only the 

information specific to the individual 

patient). 

3. Intermediate Size Patient Populations 

Proposed § 312.315(c) states that an 

expanded access submission for an 

intermediate size patient population 

must include information adequate to 

satisfy FDA that the criteria for all 

expanded access uses and those specific 

to intermediate size patient populations 

have been met. The intermediate size 

patient population criteria are: (1) There 

is enough evidence that the drug is safe 

at the dose and duration proposed for 

treatment use to justify a clinical trial of 

the drug in the approximate number of 

patients expected to receive the drug for 

treatment use and (2) there is at least 

preliminary clinical evidence of 

effectiveness of the drug or of a 

plausible pharmacologic effect of the 

drug to make expanded access use a 

reasonable therapeutic option in the 

anticipated patient population. 

Proposed § 312.315(c) contains 

additional submission requirements that 

apply to use of an investigational drug 

for intermediate size patient 

populations. The expanded access 

submission must state whether the drug 

is being developed or is not being 

developed and describe the patient 

population to be treated. If the drug is 

not being actively developed, the 

sponsor must explain why the drug 

cannot currently be developed for the 

expanded access use and under what 

circumstances the drug could be 

developed. If the drug is being studied 

in a clinical trial, the sponsor must 

explain why the patients to be treated 

cannot be enrolled in the clinical trial 

and under what circumstances the 

sponsor would conduct a clinical trial 

in these patients. 

4. Treatment IND or Protocol 

Proposed § 312.320 describes the 

treatment IND or treatment protocol 

currently codified in §§ 312.34 and 

312.35. Proposed § 312.320(b) states that 

the expanded access submission must 

include information adequate to satisfy 

FDA that the criteria for all expanded 

access uses and those specific to the 

treatment IND or protocol have been 

met. The criteria specific to a treatment 

IND or treatment protocol are: (1) The 

drug is being investigated in a 

controlled clinical trial designed to 

support a marketing application for the 

expanded access use or all clinical trials 

of the drug have been completed, (2) the 

sponsor is pursuing marketing approval 

of the drug for the expanded access use 

with due diligence, and (3) there is 

sufficient clinical evidence of safety and 

effectiveness to support the treatment 

use. Such evidence would ordinarily 

consist of data from phase 3 trials, but 

could consist of compelling data from 

completed phase 2 trials. When the 

expanded access use is for an 

immediately life-threatening disease or 

condition, the available scientific 

evidence, taken as a whole, could 

provide a reasonable basis to conclude 

that the investigational drug may be 

effective for the expanded access use 

and would not expose patients to an 

unreasonable and significant risk of 

illness or injury. This evidence would 

ordinarily consist of clinical data from 

phase 3 or phase 2 trials, but could be 

based on more preliminary clinical 

evidence. 

B. Estimates of Reporting Burden 

FDA’s estimate of the amount of time 

required to complete an expanded 

access submission is based on the 

assumption that either the submission 

will be made by the drug developer or 

the submitter will have obtained a right 

of reference from the drug developer. 

FDA expects that, if finalized, the 

proposed rule would result in an 

increase in the number of submissions 

for expanded access for individual 

patients and for intermediate size 

patient populations. 

1. Individual Patient Expanded Access 

From 1997 to 2005, FDA received on 

average approximately 659 submissions 

for the treatment use of investigational 

drugs by individual patients per year. 

This estimate is based on FDA records 

on the number of individual patient IND 

submissions (primarily from physicians) 

and a survey of review divisions on the 

prevalence of individual patient 

protocol exception submissions 

received from commercial drug 

sponsors. The agency expects an 

increase in the number of individual 

patient expanded access submissions as 

a result of the proposed rule because the 

proposed rule would increase awareness 

of the option for individual patients to 

gain access to investigational drugs and 

decrease the perceived difficulty of 

obtaining such access. FDA anticipates 

that the increase in individual patient 

expanded access INDs or protocols 

would be greatest in the years 

immediately following implementation 

of a final rule and would at some point 

level off, or possibly even decline. This 

leveling off or decline would occur 

when a significant volume of individual 

patient expanded access INDs or 

protocols have accumulated for a variety 

of drugs, and the individual patient 

expanded access INDs or protocols for 

those drugs are then replaced with 

intermediate size patient population 

expanded access INDs or protocols that 

enroll multiple subjects. 

The agency estimates that preparation 

and submission of an individual patient 

expanded access IND or protocol 

submission would require a total of 

approximately 8 hours. 

2. Intermediate Size Patient Population 

Expanded Access 

Although intermediate size patient 

population expanded access INDs or 

protocols have not previously been 

described in regulation, investigational 

drugs have been made available 

informally for treatment use to such 

populations. Based on an internal 

survey of review divisions, FDA 


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estimates that, for the period 2000 

through 2002, it received approximately 

55 submissions per year that would be 

considered expanded access for an 

intermediate size patient population 

under the proposed criteria. The agency 

anticipates that this proposed rule 

would increase the number of such 

submissions because there will be 

greater awareness of this option. In 

addition, the anticipated increase in 

volume of submissions for expanded 

access for individual patients discussed 

previously is expected to increase the 

number of submissions for expanded 

access for intermediate size patient 

populations because the proposed rule 

encourages the consolidation of 

multiple individual patient INDs or 

protocols for a given expanded access 

use. 

Information provided by FDA review 

division staff indicates that preparation 

and submission of an intermediate size 

patient population IND would require a 

total of about 120 hours of staff time. 

3. Treatment IND or Treatment Protocol 

The agency does not expect that the 

proposed rule will have an impact on 

the overall number of treatment INDs or 

treatment protocols because this type of 

expanded access is already established 

in FDA’s regulations. Therefore, FDA 

does not expect the provisions of this 

proposed rule regarding treatment INDs 

or treatment protocols to impose any 

increased paperwork burden. 

4. Capital Costs 

There are capital costs associated with 

this proposed rulemaking. These costs 

are discussed in section VII of this 

document, ‘‘Analysis of Economic 

Impacts.’’

Description of Respondents: Licensed 

physicians and manufacturers, 

including small business manufacturers. 

Table 7 of this document presents the 

annualized reporting burden for the 

total number of expanded access 

submissions, broken down by type of 

expanded access use. The figures in the 

table are based on the analysis of 

economic impacts (section VII of this 

document) and are derived by averaging 

the projected number of submissions for 

the first 3 years after implementation of 

a final rule based on this proposed rule. 

TABLE 7.—ESTIMATED REPORTING BURDEN 

21 CFR section No. of 

Respondents 

No. of Responses 

per Respondent Total Responses Hours per Response Total Hours 

312.310(b) Individual patient expanded access and 

310.305(b) submission requirements generally 1,054 1 1,054 8 8,432 

312.315(c) Intermediate size patient population expanded access and 310.305(b) submission requirements generally 77 1 77 120 9,240 

312.320 Treatment IND or protocol and 310.305(b) 

submission requirements generally 5 1 5 300 1,500 

Total 19,172 

In compliance with section 3507(d) of 

the Paperwork Reduction Act of 1995 

(44 U.S.C. 3507(d)), the agency has 

submitted the information collection 

provisions of this proposed rule to OMB 

for review. Interested persons are 

requested to send comments regarding 

information collection (see ADDRESSES). 

IX. Request for Comments 

Interested persons may submit to the 

Division of Dockets Management (see 

ADDRESSES) written or electronic 

comments regarding this document. 

Submit a single copy of electronic 

comments or two paper copies of any 

mailed comments, except that 

individuals may submit one paper copy. 

Comments are to be identified with the 

docket number found in brackets in the 

heading of this document. Received 

comments may be seen in the Division 

of Dockets Management between 9 a.m. 

and 4 p.m., Monday through Friday. 

X. Federalism 

FDA has analyzed this proposed rule 

in accordance with the principles set 

forth in Executive Order 13132. FDA 

has tentatively 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 tentatively concluded that 

the rule does not contain policies that 

have federalism implications as defined 

in the order and, consequently, a 

federalism summary impact statement is 

not required. 

List of Subjects in 21 CFR Part 312 

Drugs, Exports, Imports, 

Investigations, Labeling, Medical 

research, Reporting and recordkeeping 

requirements, and Safety. 

Therefore, under the Federal Food, 

Drug, and Cosmetic Act and under 

authority delegated to the Commissioner 

of Food and Drugs, it is proposed that 

21 CFR part 312 be amended as follows: 

PART 312—INVESTIGATIONAL NEW 

DRUG APPLICATION 

1. The authority citation for 21 CFR 

part 312 is revised to read as follows: 

Authority: 21 U.S.C. 321, 331, 351, 352, 

353, 355, 360bbb, 371; 42 U.S.C. 262. 

§ 312.34 [Removed] 

2. Section 312.34 Treatment use of an 

investigational new drug is removed. 

§ 312.35 [Removed] 

3. Section 312.35 Submissions for 

treatment use is removed. 

§ 312.36 [Removed] 

4. Section 312.36 Emergency use of an 

investigational new drug (IND) is 

removed. 

5. Section 312.42 is amended by 

revising paragraph (b)(3) to read as 

follows: 

§ 312.42 Clinical holds and requests for 

modification. 

* * * * * 

(b) * * * 

(3) Clinical hold of an expanded 

access IND or expanded access 

protocol. FDA may place an expanded 

access IND or expanded access protocol 

on clinical hold under the following 

conditions: 

(i) Proposed use. FDA may place a 

proposed expanded access IND or 

treatment use protocol on clinical hold 

if it is determined that: 


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(A) The pertinent criteria in subpart I 

of this part for permitting the expanded 

access use to begin are not satisfied; or 

(B) The expanded access IND or 

expanded access protocol does not 

comply with the requirements for 

expanded access submissions in subpart 

I of this part. 

(ii) Ongoing use. FDA may place an 

ongoing expanded access IND or 

expanded access protocol on clinical 

hold if it is determined that the 

pertinent criteria in subpart I of this part 

for permitting the expanded access are 

no longer satisfied. 

* * * * * 

6. Part 312 is amended by adding and 

reserving subpart H, and by adding 

subpart I, consisting of §§ 312.300 

through 312.320, to read as follows: 

Subpart H—[Reserved] 

Subpart I—Expanded Access to 

Investigational Drugs for Treatment Use 

Sec. 

312.300 General. 

312.305 Requirements for all expanded 

access uses. 

312.310 Individual patients, including for 

emergency use. 

312.315 Intermediate size patient 

populations. 

312.320 Treatment IND or treatment 

protocol. 

§ 312.300 General. 

(a) Scope. This subpart contains the 

requirements for the use of 

investigational new drugs when the 

primary purpose is to diagnose, 

monitor, or treat a patient’s disease or 

condition. The aim of this subpart is to 

facilitate the availability of 

investigational new drugs to seriously 

ill patients when there is no comparable 

or satisfactory alternative therapy to 

diagnose, monitor, or treat the patient’s 

disease or condition. 

(b) Definition. In this subpart, the 

term immediately life-threatening 

disease means a stage of disease in 

which there is reasonable likelihood 

that death will occur within a matter of 

months or in which premature death is 

likely without early treatment. 

§ 312.305 Requirements for all expanded 

access uses. 

The criteria, submission 

requirements, safeguards, and beginning 

treatment information set out in this 

section apply to all expanded access 

uses described in this subpart. 

Additional criteria, submission 

requirements, and safeguards that apply 

to specific types of expanded access are 

described in §§ 312.310 through 

312.320. 

(a) Criteria. FDA must determine that: 

(1) The patient or patients to be 

treated have a serious or immediately 

life-threatening disease or condition, 

and there is no comparable or 

satisfactory alternative therapy to 

diagnose, monitor, or treat the disease or 

condition; 

(2) The potential patient benefit 

justifies the potential risks of the 

treatment use and those potential risks 

are not unreasonable in the context of 

the disease or condition to be treated; 

and 

(3) Providing the investigational drug 

for the requested use will not interfere 

with the initiation, conduct, or 

completion of clinical investigations 

that could support marketing approval 

of the expanded access use or otherwise 

compromise the potential development 

of the expanded access use. 

(b) Submission. (1) An expanded 

access submission is required for each 

type of expanded access described in 

this subpart. The submission may be a 

new IND or a protocol amendment to an 

existing IND. Information required for a 

submission may be supplied by 

referring to pertinent information 

contained in an existing IND if the 

sponsor of the existing IND grants a 

right of reference to the IND. 

(2) The expanded access submission 

must include: 

(i) A cover sheet (Form FDA 1571) 

meeting the requirements of § 312.23(a); 

(ii) The rationale for the intended use 

of the drug, including a list of available 

therapeutic options that would 

ordinarily be tried before resorting to 

the investigational drug or an 

explanation of why the use of the 

investigational drug is preferable to the 

use of available therapeutic options; 

(iii) The criteria for patient selection; 

or, for an individual patient, a 

description of the patient’s disease or 

condition, including recent medical 

history and previous treatments of the 

disease or condition; 

(iv) The method of administration of 

the drug, dose, and duration of therapy; 

(v) A description of the facility where 

the drug will be manufactured; 

(vi) Chemistry, manufacturing, and 

controls information adequate to ensure 

the proper identification, quality, 

purity, and strength of the 

investigational drug; 

(vii) Pharmacology and toxicology 

information adequate to conclude that 

the drug is reasonably safe at the dose 

and duration proposed for expanded 

access use (ordinarily, information that 

would be adequate to permit clinical 

testing of the drug in a population of the 

size expected to be treated); and 

(viii) A description of clinical 

procedures, laboratory tests, or other 

monitoring necessary to evaluate the 

effects of the drug and minimize its 

risks. 

(3) The expanded access submission 

and its mailing cover must be plainly 

marked ‘‘EXPANDED ACCESS 

SUBMISSION.’’ If the expanded access 

submission is for a treatment IND or 

treatment protocol, the applicable box 

on Form FDA 1571 must be checked. 

(c) Safeguards. The responsibilities of 

sponsors and investigators set forth in 

subpart D of this part are applicable to 

expanded access use under this subpart 

as described in this paragraph. 

(1) A licensed physician under whose 

immediate direction an investigational 

drug is administered or dispensed for an 

expanded access use under this subpart 

is considered an investigator, for 

purposes of this part, and must comply 

with the responsibilities for 

investigators set forth in subpart D of 

this part to the extent they are 

applicable to the expanded access use. 

(2) An individual or entity that 

submits an expanded access IND or 

protocol under this subpart is 

considered a sponsor, for purposes of 

this part, and must comply with the 

responsibilities for sponsors set forth in 

subpart D of this part to the extent they 

are applicable to the expanded access 

use. 

(3) A licensed physician under whose 

immediate direction an investigational 

drug is administered or dispensed, and 

who submits an IND for expanded 

access use under this subpart is 

considered a sponsor-investigator, for 

purposes of this part, and must comply 

with the responsibilities for sponsors 

and investigators set forth in subpart D 

of this part to the extent they are 

applicable to the expanded access use. 

(4) Investigators. In all cases of 

expanded access, investigators are 

responsible for reporting adverse drug 

experiences to the sponsor, ensuring 

that the informed consent requirements 

of part 50 of this chapter are met, 

ensuring that IRB review of the 

expanded access use is obtained in a 

manner consistent with the 

requirements of part 56 of this chapter, 

and maintaining accurate case histories 

and drug disposition records and 

retaining records in a manner consistent 

with the requirements of § 312.62. 

Depending on the type of expanded 

access, other investigator’s 

responsibilities under subpart D may 

also apply. 

(5) Sponsors. In all cases of expanded 

access, sponsors are responsible for 

submitting IND safety reports and 

annual reports (when the IND or 

protocol continues for 1 year or longer) 

to FDA as required by §§ 312.32 and 


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312.33, ensuring that licensed 

physicians are qualified to administer 

the investigational drug for the 

expanded access use, providing licensed 

physicians with the information needed 

to minimize the risk and maximize the 

potential benefits of the investigational 

drug (e.g., providing the investigator’s 

brochure, if there is one), maintaining 

an effective IND for the expanded access 

use, and maintaining adequate drug 

disposition records and retaining 

records in a manner consistent with the 

requirements of § 312.57. Depending on 

the type of expanded access, other 

sponsor’s responsibilities under subpart 

D may also apply. 

(d) Beginning treatment. (1) INDs. An 

expanded access IND goes into effect 30 

days after FDA receives the IND or on 

earlier notification by FDA that the 

expanded access use may begin. 

(2) Protocols. With the following 

exceptions, expanded access use under 

a protocol submitted under an existing 

IND may begin as described in 

§ 312.30(a). 

(i) Expanded access use under the 

emergency procedures described in 

§ 312.310(d) may begin when the use is 

authorized by the FDA reviewing 

official. 

(ii) Expanded access use under 

§ 312.320 may begin 30 days after FDA 

receives the protocol or upon earlier 

notification by FDA that use may begin. 

(3) Clinical holds. FDA may place any 

expanded access IND or protocol on 

clinical hold as described in § 312.42. 

§ 312.310 Individual patients, including for 

emergency use. 

Under this section, FDA may permit 

an investigational drug to be used for 

the treatment of an individual patient by 

a licensed physician. 

(a) Criteria. The criteria in 

§ 312.305(a) must be met; and the 

following determinations must be made: 

(1) The physician must determine that 

the probable risk to the person from the 

investigational drug is not greater than 

the probable risk from the disease or 

condition; and 

(2) FDA must determine that the 

patient cannot obtain the drug under 

another type of IND or protocol. 

(b) Submission. The expanded access 

submission must include information 

adequate to demonstrate that the criteria 

in § 312.305(a) and paragraph (a) of this 

section have been met. The expanded 

access submission must meet the 

requirements of § 312.305(b). 

(1) If the drug is the subject of an 

existing IND, the expanded access 

submission may be made by the sponsor 

or by a licensed physician. 

(2) A sponsor may satisfy the 

submission requirements by amending 

its existing IND to include a protocol for 

individual patient expanded access. 

(3) A licensed physician may satisfy 

the submission requirements by 

obtaining from the sponsor permission 

for FDA to refer to any information in 

the IND that would be needed to 

support the expanded access request 

(right of reference) and by providing any 

other required information not 

contained in the IND (usually only the 

information specific to the individual 

patient). 

(c) Safeguards. (1) Treatment is 

generally limited to a single course of 

therapy for a specified duration unless 

FDA expressly authorizes multiple 

courses or chronic therapy. 

(2) At the conclusion of treatment, the 

licensed physician or sponsor must 

provide a written summary of the 

results of the expanded access use, 

including unexpected adverse effects. 

(3) FDA may require sponsors to 

monitor an individual patient expanded 

access use if the use is for an extended 

duration. 

(4) When a significant number of 

similar individual patient expanded 

access requests have been submitted, 

FDA may ask the sponsor to submit an 

IND or protocol for the use under 

§ 312.315 or § 312.320. 

(d) Emergency procedures. If there is 

an emergency that requires the patient 

to be treated before a written submission 

can be made, FDA may authorize the 

expanded access use to begin without a 

written submission. The FDA reviewing 

official may authorize the emergency 

use by telephone. 

(1) Emergency expanded access use 

may be requested by telephone, 

facsimile, or other means of electronic 

communications. For investigational 

biological drug products regulated by 

the Center for Biologics Evaluation and 

Research, the request should be directed 

to the Office of Communication, 

Training, and Manufacturers Assistance, 

Center for Biologics Evaluation and 

Research, 301–827–2000, e-mail: 

octma@cber.fda.gov. For all other 

investigational drugs, the request for 

authorization should be directed to the 

Division of Drug Information, Center for 

Drug Evaluation and Research, 301–

827–4570, e-mail: 

druginfo@cder.fda.gov. After normal 

working hours, the request should be 

directed to the FDA Office of Emergency 

Operations, 301–443–1240, e-mail: 

emergency.operations@fda.hhs.gov. 

(2) The licensed physician or sponsor 

must explain how the expanded access 

use will meet the requirements of 

§§ 312.305 and 312.310 and must agree 

to submit an expanded access 

submission within 5 working days of 

FDA’s authorization of the use. 

§ 312.315 Intermediate-size patient 

populations. 

Under this section, FDA may permit 

an investigational drug to be used for 

the treatment of a patient population 

smaller than that typical of a treatment 

IND or treatment protocol. FDA may ask 

a sponsor to consolidate expanded 

access under this section when the 

agency has received a significant 

number of requests for individual 

patient expanded access to an 

investigational drug for the same use. 

(a) Need for expanded access. 

Expanded access under this section may 

be needed in the following situations: 

(1) Drug not being developed. The 

drug is not being developed, for 

example, because the disease or 

condition is so rare that the sponsor is 

unable to recruit patients for a clinical 

trial. 

(2) Drug being developed. The drug is 

being studied in a clinical trial, but 

patients requesting the drug for 

expanded access use are unable to 

participate in the trial. For example, 

patients may not be able to participate 

in the trial because they have a different 

disease or stage of disease than the one 

being studied or otherwise do not meet 

the enrollment criteria, because 

enrollment in the trial is closed, or 

because the trial site is not 

geographically accessible. 

(3) Approved or related drug. (i) The 

drug is an approved drug product that 

is no longer marketed for safety reasons 

or is unavailable through marketing due 

to failure to meet the conditions of the 

approved application, or 

(ii) The drug contains the same active 

moiety as an approved drug product 

that is unavailable through marketing 

due to failure to meet the conditions of 

the approved application or a drug 

shortage. 

(b) Criteria. The criteria in 

§ 312.305(a) must be met; and FDA must 

determine that: 

(1) There is enough evidence that the 

drug is safe at the dose and duration 

proposed for expanded access use to 

justify a clinical trial of the drug in the 

approximate number of patients 

expected to receive the drug under 

expanded access; and 

(2) There is at least preliminary 

clinical evidence of effectiveness of the 

drug, or of a plausible pharmacologic 

effect of the drug to make expanded 

access use a reasonable therapeutic 

option in the anticipated patient 

population. 

(c) Submission. The expanded access 

submission must include information 


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75168 Federal Register / Vol. 71, No. 240 / Thursday, December 14, 2006 / Proposed Rules 

adequate to satisfy FDA that the criteria 

in § 312.305(a) and paragraph (b) of this 

section have been met. The expanded 

access submission must meet the 

requirements of § 312.305(b). In 

addition: 

(1) The expanded access submission 

must state whether the drug is being 

developed or is not being developed and 

describe the patient population to be 

treated. 

(2) If the drug is not being actively 

developed, the sponsor must explain 

why the drug cannot currently be 

developed for the expanded access use 

and under what circumstances the drug 

could be developed. 

(3) If the drug is being studied in a 

clinical trial, the sponsor must explain 

why the patients to be treated cannot be 

enrolled in the clinical trial and under 

what circumstances the sponsor would 

conduct a clinical trial in these patients. 

(d) Safeguards. (1) Upon review of the 

IND annual report, FDA will determine 

whether it is appropriate for the 

expanded access to continue under this 

section. 

(i) If the drug is not being actively 

developed or if the expanded access use 

is not being developed (but another use 

is being developed), FDA will consider 

whether it is possible to conduct a 

clinical study of the expanded access 

use. 

(ii) If the drug is being actively 

developed, FDA will consider whether 

providing the investigational drug for 

expanded access use is interfering with 

the clinical development of the drug. 

(iii) As the number of patients 

enrolled increases, FDA may ask the 

sponsor to submit an IND or protocol for 

the use under § 312.320. 

(2) The sponsor is responsible for 

monitoring the expanded access 

protocol to ensure that licensed 

physicians comply with the protocol 

and the regulations applicable to 

investigators. 

§ 312.320 Treatment IND or treatment 

protocol. 

Under this section, FDA may permit 

an investigational drug to be used for 

widespread treatment use. 

(a) Criteria. The criteria in 

§ 312.305(a) must be met, and FDA must 

determine that: 

(1) Trial status. (i) The drug is being 

investigated in a controlled clinical trial 

under an IND designed to support a 

marketing application for the expanded 

access use, or 

(ii) All clinical trials of the drug have 

been completed; and 

(2) Marketing status. The sponsor is 

actively pursuing marketing approval of 

the drug for the expanded access use 

with due diligence; and 

(3) Evidence. (i) When the expanded 

access use is for a serious disease or 

condition, there is sufficient clinical 

evidence of safety and effectiveness to 

support the expanded access use. Such 

evidence would ordinarily consist of 

data from phase 3 trials, but could 

consist of compelling data from 

completed phase 2 trials; or 

(ii) When the expanded access use is 

for an immediately life-threatening 

disease or condition, the available 

scientific evidence, taken as a whole, 

provides a reasonable basis to conclude 

that the investigational drug may be 

effective for the expanded access use 

and would not expose patients to an 

unreasonable and significant risk of 

illness or injury. This evidence would 

ordinarily consist of clinical data from 

phase 3 or phase 2 trials, but could be 

based on more preliminary clinical 

evidence. 

(b) Submission. The expanded access 

submission must include information 

adequate to satisfy FDA that the criteria 

in § 312.305(a) and paragraph (a) of this 

section have been met. The expanded 

access submission must meet the 

requirements of § 312.305(b). 

(c) Safeguard. The sponsor is 

responsible for monitoring the treatment 

protocol to ensure that licensed 

physicians comply with the protocol 

and the regulations applicable to 

investigators. 

Dated: December 6, 2006. 

Jeffrey Shuren, 

Assistant Commissioner for Policy. 

[FR Doc. 06–9684 Filed 12–11–06; 10:01 am] 

BILLING CODE 4160–01–S 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

21 CFR Part 312 

[Docket No. 2006N–0061] 

RIN 0910–AF13 

Charging for Investigational Drugs 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Proposed rule. 

SUMMARY: The Food and Drug 

Administration (FDA) is proposing to 

amend its investigational new drug 

application (IND) regulation concerning 

charging patients for investigational 

new drugs. FDA is proposing to revise 

the current charging regulation to clarify 

the circumstances in which charging for 

an investigational drug in a clinical trial 

is appropriate, to set forth criteria for 

charging for an investigational drug for 

the different types of expanded access 

for treatment use described in the 

agency’s proposed rule on expanded 

access for treatment use of 

investigational drugs published 

elsewhere in this issue of the Federal 

Register, and to clarify what costs can 

be recovered for an investigational drug. 

The proposed rule is intended to permit 

charging for a broader range of 

investigational and expanded access 

uses than is explicitly permitted in 

current regulations. 

DATES: Submit written or electronic 

comments by March 14, 2007. Submit 

written comments on the information 

collection requirements by January 16, 

2007. 

ADDRESSES: You may submit comments, 

identified by Docket No. 2006N–0061 

and/or RIN number 0910–AF13, by any 

of the following methods: 

Electronic Submissions 

Submit electronic comments in the 

following ways: 

• Federal eRulemaking Portal: http:// 

www.regulations.gov. Follow the 

instructions for submitting comments. 

• Agency Web site: http:// 

www.fda.gov/dockets/ecomments. 

Follow the instructions for submitting 

comments on the agency Web site. 

Written Submissions 

Submit written submissions in the 

following ways: 

• FAX: 301–827–6870. 

• Mail/Hand delivery/Courier [For 

paper, disk, or CD–ROM submissions]: 

Division of Dockets Management (HFA–

305), Food and Drug Administration, 

5630 Fishers Lane, rm. 1061, Rockville, 

MD 20852. 

To ensure more timely processing of 

comments, FDA is no longer accepting 

comments submitted to the agency by email. FDA encourages you to continue 

to submit electronic comments by using 

the Federal eRulemaking Portal or the 

agency Web site, as described in the 

Electronic Submissions portion of this 

paragraph. 

Instructions: All submissions received 

must include the agency name and 

Docket No(s). and Regulatory 

Information Number (RIN) (if a RIN 

number has been assigned) for this 

rulemaking. All comments received may 

be posted without change to http:// 

www.fda.gov/ohrms/dockets/ 

default.htm, including any personal 

information provided. For additional 

information on submitting comments, 

see the ‘‘Comments’’ heading of the 

SUPPLEMENTARY INFORMATION section of 

this document. 

Docket: For access to the docket to 

read background documents or 


jlentini on PROD1PC65 with PROPOSAL