[Federal Register Volume 71, Number 240 (Thursday, December 14, 2006)]
[Proposed Rules]
[Pages 75147-75168]
From the Federal Register Online via the Government Publishing 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:
    <bullet> Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments.
    <bullet> Agency Web site: http://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:
    <bullet> FAX: 301-827-6870.
    <bullet> 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 
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 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:
    <bullet> The drug is intended to treat a serious or immediately 
life-threatening disease;
    <bullet> There is no comparable or satisfactory alternative drug or 
other therapy available to treat that stage of the disease in the 
intended patient population;
    <bullet> 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
    <bullet> 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:
    <bullet> 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;
    <bullet> The Secretary determines that there is sufficient evidence 
of safety and effectiveness to support the use of the investigational 
drug;
    <bullet> 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
    <bullet> 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:
    <bullet> Current Sec.  312.34 concerning the treatment use of an 
investigational new drug;
    <bullet> Current Sec.  312.35 concerning submissions for treatment 
use; and
    <bullet> 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:
    <bullet> Expanded access for individual patients, including 
emergency procedures;
    <bullet> Expanded access for intermediate-size patient populations 
(smaller than those typical of a treatment IND or treatment protocol); 
and
    <bullet> 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.
---------------------------------------------------------------------------

    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:
    <bullet> A cover sheet (Form FDA 1571) meeting the requirements of 
Sec.  312.23(a);
    <bullet> 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;
    <bullet> 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;
    <bullet> The method of administration of the drug, dose, and 
duration of therapy;
    <bullet> A description of the facility where the drug will be 
manufactured;
    <bullet> Chemistry, manufacturing, and controls information 
adequate to ensure the proper identification, quality, purity, and 
strength of the investigational drug;
    <bullet> 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
    <bullet> 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:
    <bullet> Reporting adverse drug experiences to the sponsor,
    <bullet> Ensuring that the informed consent requirements of 21 CFR 
part 50 are met,
    <bullet> 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
    <bullet> 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:
    <bullet> 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,
    <bullet> Ensuring that licensed physicians are qualified to 
administer the investigational drug for the expanded access use,
    <bullet> 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),
    <bullet> Maintaining an effective IND for the expanded access use, 
and
    <bullet> 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.

[[Page 75153]]

    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.
    <bullet> 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)).
    <bullet> 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:
    <bullet> 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.
    <bullet> FDA may require sponsors to monitor an individual patient 
expanded access use if the use is for an extended duration.
    <bullet> 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.
    <bullet> 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:
    <bullet> 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)).
    <bullet> 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)).
    <bullet> 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.
    <bullet> 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.
    <bullet> 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:
    <bullet> 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));
    <bullet> 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]]

    <bullet> 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:
    <bullet> The investigators are not selected by the sponsor but can 
be any physician (sometimes with specified qualifications),
    <bullet> The population receiving the drug is quite large,
    <bullet> Collection of data is minimal, and
    <bullet> 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 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

[[Page 75157]]

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
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                               Individual Patient or         Treatment IND  or
                       Category                             Total INDs             Emergency IND                 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

[[Page 75158]]

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
------------------------------------------------------------------------
                             Expected Percent
       Year After              Increase in          Expected Number of
 Implementation of Final    Individual Patient      Individual Patient
          Rule                 Submissions            Submissions\1\
------------------------------------------------------------------------
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
------------------------------------------------------------------------
\1\Based 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

[[Page 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
------------------------------------------------------------------------
                             Expected Percent
       Year After              Increase in          Expected Number of
 Implementation of Final    Intermediate Size       Intermediate Size
          Rule              Patient Population      Patient Population
                               Submissions            Submissions\1\
------------------------------------------------------------------------
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
------------------------------------------------------------------------
\1\Based 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 open-access 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 open-label 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 open-label 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

[[Page 75160]]

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).
---------------------------------------------------------------------------

    \4\See 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.)
---------------------------------------------------------------------------

    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.
---------------------------------------------------------------------------

    \5\See 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.)

[[Page 75161]]



    TABLE 4.--NUMBER OF ADDITIONAL INDIVIDUAL PATIENT EXPANDED ACCESS
                 SUBMISSIONS AND ESTIMATED ANNUAL COSTS
------------------------------------------------------------------------
                           Expected Increase in
       Year After             the Number of          Expected Cost of
Implementation of Final     Individual Patient     Additional Individual
          Rule                Submissions\1\      Patient Submissions\2\
------------------------------------------------------------------------
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
------------------------------------------------------------------------
\1\Based on increases in the number of individual patient expanded
  access submissions implied by the estimates presented in table 2 of
  this document.
\2\Based 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).
---------------------------------------------------------------------------

    \6\See 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.)
---------------------------------------------------------------------------

    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
------------------------------------------------------------------------
                           Expected Increase in      Expected Cost of
       Year After             the Number of             Additional
Implementation of Final     Intermediate Size        Intermediate Size
          Rule              Patient Population      Patient Population
                              Submissions\1\          Submissions\2\
------------------------------------------------------------------------
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
------------------------------------------------------------------------
5                        14 to 27                 $155,400 to $299,700
------------------------------------------------------------------------
\1\Based on increases in the number of intermediate size patient
  population expanded access submissions implied by the estimates
  presented in table 3 of this document.
\2\Based 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      One-Time       Annual Cost        Annualized
      Final Rule           Cost                              Cost\1\
------------------------------------------------------------------------
1                      $0            $87,240 to         $87,240 to
                                      $174,840           $174,840
------------------------------------------------------------------------
2                      $0            $136,680 to        $136,680 to
                                      $256,990           $256,990
------------------------------------------------------------------------
3                      $0            $230,340 to        $230,340 to
                                      $406,150           $406,150
------------------------------------------------------------------------
4                      $0            $263,340 to        $263,340 to
                                      $461,650           $461,650
------------------------------------------------------------------------
5                      $0            $263,340 to        $263,340 to
                                      $461,650           $461,650
------------------------------------------------------------------------
\1\Since 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

[[Page 75162]]

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.

[[Page 75163]]

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 Sec.  312.305(b) describes the submission requirements 
applicable to all types of expanded access. Proposed Sec.  
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 Sec.  312.305(b)(2) describes the expanded access 
submission requirements. The following items must be included:
    <bullet> A cover sheet (Form FDA 1571) meeting the requirements of 
Sec.  312.23(a);
    <bullet> 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;
    <bullet> 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;
    <bullet> The method of administration of the drug, dose, and 
duration of therapy;
    <bullet> A description of the facility where the drug will be 
manufactured;
    <bullet> Chemistry, manufacturing, and controls information 
adequate to ensure the proper identification, quality, purity, and 
strength of the investigational drug;
    <bullet> Pharmacology and toxicology information adequate to 
conclude that

[[Page 75164]]

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
    <bullet> 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 Sec.  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 Sec.  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 Sec.  
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 Sec.  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 Sec.  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 Sec.  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 Sec.  312.320 describes the treatment IND or treatment 
protocol currently codified in Sec. Sec.  312.34 and 312.35. Proposed 
Sec.  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

[[Page 75165]]

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
----------------------------------------------------------------------------------------------------------------
                                      No. of       No. of Responses                      Hours per
         21 CFR section             Respondents     per Respondent     Total Responses    Response   Total Hours
----------------------------------------------------------------------------------------------------------------
312.310(b) Individual patient              1,054                   1             1,054            8        8,432
 expanded access and 310.305(b)
 submission requirements
 generally
----------------------------------------------------------------------------------------------------------------
312.315(c) Intermediate size                  77                   1                77          120        9,240
 patient population expanded
 access and 310.305(b)
 submission requirements
 generally
----------------------------------------------------------------------------------------------------------------
312.320 Treatment IND or                       5                   1                 5          300        1,500
 protocol and 310.305(b)
 submission requirements
 generally
----------------------------------------------------------------------------------------------------------------
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.


Sec.  312.34  [Removed]

    2. Section 312.34 Treatment use of an investigational new drug is 
removed.


Sec.  312.35  [Removed]

    3. Section 312.35 Submissions for treatment use is removed.


Sec.  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:


Sec.  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:

[[Page 75166]]

    (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 Sec. Sec.  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.


Sec.  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.


Sec.  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 Sec. Sec.  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 Sec.  
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 Sec.  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 Sec. Sec.  312.32 and

[[Page 75167]]

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. 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 Sec.  312.30(a).
    (i) Expanded access use under the emergency procedures described in 
Sec.  312.310(d) may begin when the use is authorized by the FDA 
reviewing official.
    (ii) Expanded access use under Sec.  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 Sec.  312.42.


Sec.  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 Sec.  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 Sec.  
312.305(a) and paragraph (a) of this section have been met. The 
expanded access submission must meet the requirements of Sec.  
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 Sec.  312.315 or Sec.  
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: 
<a href="/cdn-cgi/l/email-protection#5f303c2b323e1f3c3d3a2d71393b3e71383029"><span class="__cf_email__" data-cfemail="9cf3ffe8f1fddcfffef9eeb2faf8fdb2fbf3ea">[email protected]</span></a>. 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: <a href="/cdn-cgi/l/email-protection#4b2f393e2c22252d240b282f2e39652d2f2a652c243d"><span class="__cf_email__" data-cfemail="63071116040a0d050c23000706114d0507024d040c15">[email protected]</span></a>. After normal working hours, the request 
should be directed to the FDA Office of Emergency Operations, 301-443-
1240, e-mail: <a href="/cdn-cgi/l/email-protection#b4d1d9d1c6d3d1dad7cd9adbc4d1c6d5c0dddbdac7f4d2d0d59adcdcc79ad3dbc2"><span class="__cf_email__" data-cfemail="53363e362134363d302a7d3c23362132273a3c3d20133537327d3b3b207d343c25">[email protected]</span></a>.
    (2) The licensed physician or sponsor must explain how the expanded 
access use will meet the requirements of Sec. Sec.  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.


Sec.  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 Sec.  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

[[Page 75168]]

adequate to satisfy FDA that the criteria in Sec.  312.305(a) and 
paragraph (b) of this section have been met. The expanded access 
submission must meet the requirements of Sec.  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 Sec.  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.


Sec.  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 Sec.  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 Sec.  
312.305(a) and paragraph (a) of this section have been met. The 
expanded access submission must meet the requirements of Sec.  
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


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