Expanded Access to Investigational Drugs for Treatment Use, 75147-75168 [06-9684]

Agencies

• Food and Drug Administration
• DEPARTMENT OF HEALTH AND HUMAN SERVICES

[Federal Register Volume 71, Number 240 (Thursday, December 14, 2006)]
[Proposed Rules]
[Pages 75147-75168]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 06-9684]


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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.

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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; intermediate-size 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: https://www.regulations.gov. 
Follow the instructions for submitting comments.
     Agency Web site: https://www.fda.gov/dockets/ecomments.

[[Page 75148]]

 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 e-mail. 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 
https://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 https://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 Sec.  
312.305)
    F. Expanded Access for Individual Patients (Proposed Sec.  
312.310)
    G. Expanded Access for Intermediate-Size Patient Populations 
(Proposed Sec.  312.315)
    H. Expanded Access Treatment IND or Treatment Protocol (Proposed 
Sec.  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

[[Page 75149]]

situation (Sec.  312.36). However, Sec.  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 cancer- and 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 life-threatening 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 Sec.  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 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 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

[[Page 75150]]

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 Sec.  312.34 concerning the treatment use of an 
investigational new drug;
     Current Sec.  312.35 concerning submissions for treatment 
use; and
     Current Sec.  312.36 concerning emergency use of an 
investigational new drug.

B. Clinical Holds

    The proposed rule would amend Sec.  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 (Sec.  312.42(a)). Proposed Sec.  312.42(b)(3)(i) 
provides that FDA may place an expanded access IND or protocol\1\ 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.
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    \1\A 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.
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    Proposed Sec.  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 intermediate-size patient populations 
(smaller than those typical of a treatment IND or treatment protocol); 
and
     Expanded access treatment IND or treatment protocol 
(described in current Sec. Sec.  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 Sec.  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 Sec.  312.300(b) provides a definition of the term 
``immediately life-threatening 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 Sec.  312.305)

    Proposed Sec.  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 Sec.  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 Sec.  312.305(a) sets forth three criteria that apply to 
all types of expanded access use:
    a. First criterion. Under proposed Sec.  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

[[Page 75151]]

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 self-limiting 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 life-threatening.'' See proposed Sec.  312.300(b). We 
solicit comments on this approach. If a disease or condition were to be 
both serious and immediately life-threatening, 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 
FDA-approved 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 Sec.  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 Sec.  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 Sec.  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 protocol\2\ 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.
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    \2\This 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 (Sec. Sec.  
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.
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    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 life-threatening, 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 life-threatening, however, 
compelling data from phase 2 trials might be sufficient to permit 
expanded access use.
2. Submission Requirements for All Expanded Access Uses
    Proposed Sec.  312.305(b)(1) states that an expanded access 
submission is required

[[Page 75152]]

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 Sec.  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 
Sec.  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 Sec.  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 Sec.  312.305(c) explains how the responsibilities of 
sponsors and investigators set forth in subpart D of part 312 apply to 
expanded access.
    Proposed Sec.  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 Sec.  
312.305(c)(4), and is explained further in the following paragraphs.
    Proposed Sec.  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 Sec.  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 Sec.  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 Sec.  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 Sec.  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 
Sec. Sec.  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 Sec.  
312.57.
As with the list of investigator's duties under proposed Sec.  
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 Sec.  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 Sec.  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 Sec.  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 Sec.  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 Sec.  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 Sec.  312.305(d)(2)(ii) states that expanded 
access use under proposed Sec.  312.320 (the treatment IND or treatment 
protocol described in Sec. Sec.  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 Sec.  312.300(d)(3) states that FDA may place any expanded 
access IND or protocol on clinical hold as described in Sec.  312.42.

F. Expanded Access for Individual Patients (Proposed Sec.  312.310)

    Proposed Sec.  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 Sec.  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 Sec.  
312.310(a)(1)).
     Second, FDA must determine that the patient cannot obtain 
the drug under another type of IND (proposed Sec.  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 life-threatening 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 life-
threatening, 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 Sec.  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 Sec.  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 Sec.  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 Sec.  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 Sec.  312.315 or Sec.  
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 Sec.  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

[[Page 75154]]

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 Sec.  312.310(d)(2) requires the licensed physician or 
sponsor to explain how the expanded access use will meet the 
requirements of proposed Sec. Sec.  312.305 and 312.310 and requires 
agreement to submit an expanded access submission that complies with 
proposed Sec. Sec.  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 Intermediate-Size Patient Populations (Proposed 
Sec.  312.315)

    Proposed Sec.  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 Sec.  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 Sec.  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 Sec.  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 Sec.  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 Sec.  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 Sec.  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 Sec.  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 Sec.  312.305(a)(2)). If the product does pose a risk 
because of GMP concerns, proposed Sec.  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 Sec.  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 Intermediate-Size Patient Populations--Criteria
    In addition to the proposed criteria for all expanded access uses, 
proposed Sec.  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 Sec.  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 Sec.  312.315(b)(2)).
2. Expanded Access for Intermediate-Size Patient Populations--
Submission Requirements
    In addition to the proposed submission requirements for all 
expanded access uses, proposed Sec.  312.315(c) sets forth the 
submission requirements that apply specifically to expanded access use 
by intermediate-size 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 
Sec.  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 Sec.  312.315(c)(2)); and

[[Page 75155]]

     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 
Sec.  312.315(c)(3)).
3. Expanded Access for Intermediate-Size Patient Populations--
Safeguards
    Proposed Sec.  312.315(d) sets forth the safeguards that apply 
specifically to expanded access use by intermediate-size 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 Sec.  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 Sec.  
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 Sec.  312.320 for the 
expanded access use (proposed Sec.  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 Sec.  312.315(d)(2)).

H. Expanded Access Treatment IND or Treatment Protocol (Proposed Sec.  
312.320)

    Proposed Sec.  312.320 describes the treatment IND or treatment 
protocol mechanism that is currently provided in Sec. Sec.  312.34 and 
312.35. Proposed Sec.  312.320 retains the basic terminology 
``treatment IND'' and ``treatment protocol'' from current Sec. Sec.  
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 Sec.  312.320(a) provides the criteria that apply specifically 
to a treatment IND or treatment protocol.
    Proposed Sec.  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 
Sec.  312.320(a)(1)(i)), or all clinical trials of the drug have been 
completed (proposed Sec.  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 Sec.  312.320(a)(2)).
    Proposed Sec.  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 Sec.  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 Sec.  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 Sec.  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 
Sec.  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

[[Page 75156]]

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 agency\3\ 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.
---------------------------------------------------------------------------

    \3\In 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.''
---------------------------------------------------------------------------

    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 descr