[Federal Register: December 14, 2006 (Volume 71, Number 240)]
[Proposed Rules]
[Page 75147-75168]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr14de06-16]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 312
[Docket No. 2006N-0062]
RIN 0910-AF14
Expanded Access to Investigational Drugs for Treatment Use
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend
its regulations on access to investigational new drugs for the
treatment of patients. The proposed rule would clarify existing
regulations and add new types of expanded access for treatment use.
Under the proposal, expanded access to investigational drugs for
treatment use would be available to individual patients, including in
emergencies; intermediate-size patient populations; and larger
populations under a treatment protocol or treatment investigational new
drug application (IND). The proposed rule is intended to improve access
to investigational drugs for patients with serious or immediately life-
threatening diseases or conditions, who lack other therapeutic options
and who may benefit from such therapies.
DATES: Submit written or electronic comments by March 14, 2007. Submit
written comments on the information collection requirements by January
16, 2007.
ADDRESSES: You may submit comments, identified by Docket No. 2006N-
0062 and RIN 0910-AF14, by any of the following methods:
Electronic Submissions
Submit electronic comments in the following ways:
Federal eRulemaking Portal: http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.regulations.gov.
Follow the instructions for submitting comments.
Agency Web site: http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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:
FAX: 301-827-6870.
Mail/Hand delivery/Courier [For paper, disk, or CD-ROM
submissions]: Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
To ensure more timely processing of comments, FDA is no longer
accepting comments submitted to the agency by e-mail. FDA encourages
you to continue to submit electronic comments by using the Federal
eRulemaking Portal or the agency Web site, as described in the
Electronic Submissions portion of this paragraph.
Instructions: All submissions received must include the agency name
and docket number and Regulatory Information Number (RIN) for this
rulemaking. All comments received may be posted without change to
http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&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:
The drug is intended to treat a serious or immediately
life-threatening disease;
There is no comparable or satisfactory alternative drug or
other therapy available to treat that stage of the disease in the
intended patient population;
The drug is under investigation in a controlled clinical
trial under an IND in effect for the trial, or all clinical trials have
been completed; and
The sponsor of the controlled clinical trial is actively
pursuing marketing approval of the investigational drug with due
diligence.
Section 312.34 states that for a serious disease, data from phase 3
trials or, in appropriate circumstances, data from phase 2 trials would
ordinarily be needed to permit treatment use in a substantial
population. For an immediately life-threatening disease, less evidence
of safety and effectiveness is needed for treatment use. The standard
for treatment use for immediately life-threatening conditions is that
the available scientific evidence, taken as a whole, provides a
reasonable basis to conclude that the drug may be effective and would
not expose patients to an unreasonable and significant additional risk
of illness or injury. FDA estimates that more than 100,000 patients
have received investigational drugs through treatment INDs.
The 1987 IND regulations recognized only one kind of treatment use,
the treatment protocol or treatment IND, generally providing
availability to a broad population. However, it also implicitly
acknowledged the existence of other kinds of treatment use, notably use
in individual patients, by adding a provision describing an expedited
procedure to obtain an investigational drug for treatment use in an
emergency
[[Page 75149]]
situation (Sec. 312.36). However, Sec. 312.36 does not describe
criteria or requirements that must be met to authorize individual
patient treatment use.
C. Concerns About Treatment Use Programs
FDA has been criticized for its failure to explain in regulation or
guidance the basis for agency decisionmaking on individual patient
treatment use and other treatment use programs not currently described
in FDA's regulations. One concern is that the lack of specific criteria
and submission requirements results in disparate access to treatment
use for different types of patients and diseases. Some have asserted
that knowledge of FDA's policies on these other kinds of treatment use
tends to be concentrated among physicians in academic medical centers
who are familiar with investigational drugs and FDA procedures.
Consequently, according to this line of criticism, patients treated
outside of academic medical centers are less likely to have access to
investigational drugs for treatment use. There has also been concern
that access to investigational drugs for treatment use has focused
primarily on cancer- and human immunodeficiency virus (HIV)-related
conditions, and that patients with other types of serious diseases or
conditions have not had comparable access to appropriate treatment use
of unapproved drugs.
D. The Food and Drug Administration Modernization Act of 1997
In response to these concerns about inconsistent policies,
inequitable access, and preferential access for certain categories of
disease, in the Food and Drug Administration Modernization Act of 1997
(FDAMA) (Public Law 105-115), Congress amended the Federal Food, Drug,
and Cosmetic Act (the act) to include specific provisions concerning
expanded access to investigational drugs for treatment use (Expanded
Access to Unapproved Therapies and Diagnostics, section 561 (21 U.S.C.
360bbb) of the act). By incorporating specific expanded access
provisions in the statute, Congress intended to emphasize that
``opportunities to participate in expanded access programs are
available to every individual with a life-threatening or seriously
debilitating illness for which there is not an effective, approved
therapy'' (Joint Explanatory Statement of the Committee of Conference
in House Report 105-399, November 9, 1997, p. 100).
Section 561(a) of the act provides specific statutory authority to
make investigational drugs available for the diagnosis, monitoring, or
treatment of a serious disease or condition in an emergency situation.
The Secretary of Health and Human Services (the Secretary) is to
determine appropriate conditions under which an investigational drug
may be made available in an emergency situation.
Section 561(b) of the act permits any person, acting through a
licensed physician, to request access to an investigational drug to
diagnose, monitor, or treat a serious disease or condition provided
that the following conditions are met:
The licensed physician determines that the person has no
comparable or satisfactory alternative therapy to diagnose, monitor, or
treat the disease or condition, and that the probable risk from the
investigational drug is not greater than the probable risk from the
disease or condition;
The Secretary determines that there is sufficient evidence
of safety and effectiveness to support the use of the investigational
drug;
The Secretary determines that provision of the
investigational drug will not interfere with the initiation, conduct,
or completion of clinical investigations to support marketing approval;
and
The sponsor or clinical investigator submits a protocol
consistent with the requirements of section 505(i) of the act (21 U.S.C
355(i)) and its implementing regulations in part 312, which describe
use of the drug in a single patient or a small group of patients.
Section 561(c) of the act closely tracks existing Sec. 312.34 of
the IND regulations. Section 561(c) authorizes the Secretary to permit
an investigational drug to be made available for widespread access if
the following determinations have been made:
1. The investigational drug is intended for use in the diagnosis,
monitoring, or treatment of a serious or immediately life-threatening
disease or condition;
2. There is no comparable or satisfactory alternative therapy
available to diagnose, monitor, or treat that stage of disease or
condition in a particular patient population;
3. The investigational drug is under investigation in a controlled
clinical trial under an IND, or all clinical trials necessary for
approval of the use have been completed;
4. The sponsor of the controlled clinical trial is actively
pursuing marketing approval with due diligence;
5. The provision of the investigational drug will not interfere
with the enrollment of patients in ongoing clinical investigations;
6. In the case of serious diseases, there is sufficient evidence of
safety and effectiveness to support the use;
7. In the case of immediately life-threatening diseases, the
available scientific evidence, taken as a whole, provides a reasonable
basis to conclude that the investigational drug may be effective for
its intended use and would not expose patients to an unreasonable and
significant risk of illness or injury.
Section 561(c) also provides that a protocol for an expanded access
treatment IND shall be subject to the requirements of section 505(i) of
the act and FDA's implementing regulations in part 312.
To specifically address concerns that physicians and their patients
are often unaware of the availability of investigational drugs under
access programs, section 561(c) of the act also allows the Secretary to
inform national, State, and local medical associations and societies,
voluntary health associations, and other appropriate persons about the
availability of expanded access treatment INDs or treatment protocols.
II. Why FDA Is Proposing This Rule
This proposed rule is intended to further address the concerns that
motivated Congress to include in the act specific provisions on
expanded access to investigational drugs for treatment use. As
discussed in section I of this document, these concerns included
inconsistent application of access policies and programs and inequities
in access based on the relative sophistication of the setting in which
a patient is treated or on the patient's disease or condition. By
describing in detail in the proposed rule the criteria, submission
requirements, and safeguards for the different types of expanded access
for treatment uses of investigational drugs, the agency seeks to
increase awareness and knowledge of expanded access programs and the
procedures for obtaining investigational drugs. Increased knowledge and
awareness about expanded access options should make investigational
drugs more widely available in appropriate situations. Clearly
articulated procedures for obtaining investigational drugs for
treatment use should ease the administrative burdens on individual
physicians seeking investigational drugs for their patients, as well as
the burdens on sponsors who make investigational drugs available for
treatment use. In addition, we expect
[[Page 75150]]
that clearly articulating procedures and standards for expanded access
will result in more patients with serious or immediately life-
threatening diseases or conditions getting the earliest possible access
to these therapies.
III. Goals and Limitations of the Proposed Rule
Recognizing that FDA's authority derives from the act, the proposed
rule attempts to reconcile individual patients' desires to make their
own decisions about their health care with society's need for drugs to
be developed for marketing. It recognizes the need for the risks and
benefits of drugs to be well characterized and the need for appropriate
protection of human subjects in an investigation. These interests are
not always easily reconciled. Allowing individual patients relatively
unfettered access to an investigational drug at a preliminary stage in
its development, for example, may expose them to significant and
unacceptable risks.
In addition, patients may find participation in a clinical trial
less desirable than receiving the drug for treatment use for a variety
of reasons. For example, clinical trial participants may receive a
treatment other than the study drug, and clinical trials may have more
onerous monitoring requirements (such as laboratory and other tests).
Thus, a system of blindly permitting uncontrolled access to
investigational drugs could make it difficult or impossible to enroll
adequate numbers of patients in clinical trials to establish the safety
and effectiveness of the drug for marketing approval.
FDA has a statutory responsibility to ensure that marketed drugs
are safe and effective, and its rules should not compromise the
integrity of the drug development process. In this proposed rule, as
envisioned by the act, the agency has tried to strike the appropriate
balance between authorizing access to promising drugs for treatment use
under our expanded access authority and ensuring the integrity of the
drug approval process.
While this proposed rule aims to clarify, and thereby expand, the
situations in which expanded access to unapproved drugs could be
available, under its existing authority, FDA cannot compel a drug
manufacturer to provide access to investigational drugs for treatment
use.
IV. Description of the Proposed Rule
FDA is proposing to amend its regulations on INDs by removing the
current sections on treatment use, revising the section on clinical
holds, and adding subpart I on expanded access. The term ``expanded
access'' is used here to refer to all types of treatment uses. The term
``treatment protocol or treatment IND'' continues to refer to one
specific kind of treatment use, the large access protocol.
A. Sections Removed
The proposed rule would remove the following three sections of
FDA's regulations:
Current Sec. 312.34 concerning the treatment use of an
investigational new drug;
Current Sec. 312.35 concerning submissions for treatment
use; and
Current Sec. 312.36 concerning emergency use of an
investigational new drug.
B. Clinical Holds
The proposed rule would amend Sec. 312.42 Clinical holds and
requests for modification by providing for clinical holds, when
necessary, of any of the types of expanded access uses described in
this proposed rule. A clinical hold is an order issued by FDA to the
sponsor to delay a proposed clinical investigation or suspend an
ongoing investigation (Sec. 312.42(a)). Proposed Sec. 312.42(b)(3)(i)
provides that FDA may place an expanded access IND or protocol\1\ on
clinical hold if it is determined that the pertinent criteria in
proposed subpart I for permitting the expanded access use to begin are
not satisfied or the IND or protocol does not comply with the
requirements for expanded access submissions in proposed subpart I.
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\1\A submission seeking to allow an expanded access use of an
investigational drug may come to FDA either in the form of a new,
separate IND or as a new protocol submitted to an already existing
IND.
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Proposed Sec. 312.42(b)(3)(ii) provides that FDA may place an
ongoing expanded access IND or protocol on clinical hold if it is
determined that the pertinent criteria in proposed subpart I for
permitting the expanded access are no longer satisfied (e.g., a
satisfactory alternative therapy becomes available).
C. Expanded Access Overview
The agency is proposing to add new subpart I to part 312. Proposed
subpart I describes the following ways that expanded access to
treatment use of investigational drugs would be available:
Expanded access for individual patients, including
emergency procedures;
Expanded access for intermediate-size patient populations
(smaller than those typical of a treatment IND or treatment protocol);
and
Expanded access treatment IND or treatment protocol
(described in current Sec. Sec. 312.34 and 312.35).
The following items are set forth in the proposed rule: (1)
Criteria that must be met to authorize the expanded access use, (2)
requirements for expanded access submissions, and (3) safeguards to
protect patients and preserve the ability to develop meaningful data
about treatment use.
D. General Provisions
Proposed Sec. 312.300(a) states that the aim of subpart I is to
facilitate the availability of investigational new drugs to seriously
ill patients when there is no comparable or satisfactory alternative
therapy to diagnose, monitor, or treat the patient's disease or
condition. Proposed Sec. 312.300(b) provides a definition of the term
``immediately life-threatening disease'' as a stage of disease in which
there is reasonable likelihood that death will occur within a matter of
months or in which premature death is likely without early treatment.
E. Requirements for All Expanded Access Uses (Proposed Sec. 312.305)
Proposed Sec. 312.305 contains the general requirements for the
use of investigational drugs when the primary purpose is to diagnose,
monitor, or treat a patient's disease or condition, rather than to
generate safety and effectiveness data to support a marketing
application. Proposed Sec. 312.305 contains criteria, submission
requirements, and safeguards that apply to all expanded access uses
described in proposed subpart I. Additional criteria, submission
requirements, and safeguards that apply to specific types of expanded
access use are described in the sections of the proposed rule
describing those expanded access types.
1. Criteria for All Expanded Access Uses
Proposed Sec. 312.305(a) sets forth three criteria that apply to
all types of expanded access use:
a. First criterion. Under proposed Sec. 312.305(a)(1), FDA must
determine that the patient (or patients) to be treated has a serious or
immediately life-threatening disease or condition, and there is no
comparable or satisfactory alternative therapy to diagnose, monitor, or
treat the disease or condition. Because, by definition, the risks and
benefits of investigational drugs are not as well characterized as
those of approved drugs, the agency believes, and the act contemplates,
that expanded access to investigational
[[Page 75151]]
drugs is warranted only under these conditions. Section 561(c)(1) and
(c)(2) of the act expressly requires FDA to make these determinations
in order to authorize a treatment IND or treatment protocol, and
section 561(b)(1) and (b)(2) of the act likewise requires FDA to
determine that there is sufficient evidence of safety and effectiveness
to support the use of the unapproved drug in treating an individual
patient or a small group of patients. Determining that the patient has
a serious or immediately life-threatening disease or condition and that
there is no comparable or satisfactory alternative therapy are integral
parts of determining whether there is sufficient evidence of safety and
effectiveness to support the proposed use in the situation described by
the physician or sponsor seeking the authorization.
In various documents, the agency has described or illustrated what
is meant by a serious condition (see, e.g., FDA's guidance for industry
entitled ``Fast Track Drug Development Programs--Designation,
Development, and Application Review'' (63 FR 64093, November 18, 1998),
revised 2004, pp. 3-4; preamble to the 1992 proposed rule on
accelerated approval of new drugs for serious or life-threatening
illnesses (57 FR 13234 at 13235, April 15, 1992)). As discussed in
these documents, the ``serious disease or condition'' requirement
refers to conditions that have an important effect on functioning
(e.g., stroke, schizophrenia, rheumatoid arthritis, osteoarthritis) or
on other aspects of quality of life (e.g., chronic depression,
seizures). Alzheimer's dementia, Amyotrophic Lateral Sclerosis (ALS),
and narcolepsy are specific examples of serious conditions for which
FDA has granted expanded access to investigational drugs in the past.
Short-lived and self-limiting morbidity will usually not be sufficient
to qualify a condition as serious, but the morbidity need not be
irreversible, provided it is persistent or recurrent. Similarly, the
proposed requirement here that treatment be for a ``serious disease or
condition'' is not intended to be unnecessarily restrictive. It is
primarily intended to exclude expanded access to investigational drugs
for conditions that are clearly not serious (e.g., symptomatic relief
of minor pain or allergic symptoms and other self-limiting conditions
not associated with major morbidity). Because of the difficulty of
specifically describing the criteria that characterize a ``serious
disease or condition,'' the proposed rule itself does not provide a
definition of ``serious,'' though it does provide a definition of
``immediately life-threatening.'' See proposed Sec. 312.300(b). We
solicit comments on this approach. If a disease or condition were to be
both serious and immediately life-threatening, for the purpose of this
proposed rule, it would be considered ``immediately life-threatening.''
Ordinarily, a lack of comparable or satisfactory therapeutic
alternatives would mean that there exists no other available therapy to
treat the patient's condition or that the patient has tried available
therapies and failed to respond adequately or is intolerant to them.
Available therapy, as defined in FDA's guidance for industry entitled
``Available Therapy'' (69 FR 44039, July 23, 2004), generally refers to
FDA-approved products that are labeled to be used for the relevant
disease or condition. In some cases, however, available therapy might
mean a treatment that is not regulated by FDA (e.g., surgery) or one
that is not labeled for use for the relevant disease or condition, but
is supported by compelling literature evidence.
b. Second criterion. Under proposed Sec. 312.305(a)(2), FDA must
determine that the potential patient benefit justifies the potential
risks of the treatment use and that those potential risks are not
unreasonable in the context of the disease or condition to be treated.
FDA is required to make this determination under sections 561(b)(2),
(c)(6), and (c)(7) of the act.
c. Third criterion. Under proposed Sec. 312.305(a)(3), FDA must
determine that providing the investigational drug for the requested use
will not interfere with the initiation, conduct, or completion of
clinical investigations that could support marketing approval of the
expanded access use or otherwise compromise the potential development
of the expanded access use. Section 561(b)(3) and (c)(5) of the act
requires FDA to make this determination. The most efficient and
effective way to make a drug available to all those who can benefit
from the drug, is to market it. Therefore, it is important to ensure
that expanded access use does not compromise enrollment in the trials
needed to demonstrate the safety and effectiveness of the drug.
Proposed Sec. 312.305(a) does not elaborate on the safety and/or
effectiveness showing that must be made to merit authorization of the
expanded access use. Rather, the showing is described in the criteria
that pertain to each type of expanded access because the evidence
needed to demonstrate the safety and potential benefit of a proposed
use varies with the size of the population to be treated and the
relative seriousness of the disease or condition to be treated.
Treatment of a large patient population through a treatment IND or
treatment protocol\2\ generally would require more evidence of safety
and effectiveness than treatment of just a few patients. The evidence
required to support expanded access for an intermediate-size patient
population would be somewhere between that needed for expanded access
for an individual patient and that needed for a treatment IND or
treatment protocol.
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\2\This proposed rule continues to describe the specific type of
expanded access for treatment use that makes investigational drugs
available to large populations as the ``treatment IND'' or
``treatment protocol.'' We recognize that it may be confusing to
carry over this terminology from our current regulations (Sec. Sec.
312.34 and 312.35). However, this terminology has been used since
1987, and we believe it would be more confusing to change
terminology when the nature of this type of treatment use remains
essentially unchanged. The broader term ``expanded access'' refers
to all kinds of treatment use. We solicit comment on this approach.
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In addition, as the seriousness of the disease increases, it may be
appropriate to authorize expanded access use based on less data, still
taking the size of the population into account. For example, to support
expanded access for an individual patient when the patient has an
immediately life-threatening condition that is not responsive to
available therapy, ordinarily, completed phase 1 safety testing in
humans at doses similar to those to be used in the treatment use,
together with preliminary evidence suggesting possible effectiveness,
would be sufficient to support such a use. In some cases, however,
there may be no relevant clinical experience, and the case for the
potential benefit may be based on preclinical data or on the mechanism
of action.
In contrast, much more safety and effectiveness data would be
needed to support a treatment IND or treatment protocol that
anticipated enrollment of several thousand patients with a serious, but
not imminently life-threatening, condition. Ordinarily, evidence of
safety and effectiveness from phase 3 clinical trials would be needed
to support such an expanded access use in these significantly larger
populations. If the disease being treated under a treatment IND or
treatment protocol were immediately life-threatening, however,
compelling data from phase 2 trials might be sufficient to permit
expanded access use.
2. Submission Requirements for All Expanded Access Uses
Proposed Sec. 312.305(b)(1) states that an expanded access
submission is required
[[Page 75152]]
for each type of expanded access use. The submission may be a new IND
or a protocol amendment to an existing IND. Information required for a
submission may be supplied by referring to pertinent information
contained in an existing IND if the sponsor of the existing IND grants
a right of reference to the IND.
Proposed Sec. 312.305(b)(2) describes the expanded access
submission requirements. The following items must be included:
A cover sheet (Form FDA 1571) meeting the requirements of
Sec. 312.23(a);
The rationale for the intended use of the drug, including
a list of available therapeutic options that would ordinarily be tried
before resorting to the investigational drug or an explanation of why
the use of the investigational drug is preferable to the use of
available therapeutic options;
The criteria for patient selection or, for an individual
patient, a description of the patient's disease or condition, including
recent medical history and previous treatments of the disease or
condition;
The method of administration of the drug, dose, and
duration of therapy;
A description of the facility where the drug will be
manufactured;
Chemistry, manufacturing, and controls information
adequate to ensure the proper identification, quality, purity, and
strength of the investigational drug;
Pharmacology and toxicology information adequate to
conclude that the drug is reasonably safe at the dose and duration
proposed for treatment use (ordinarily, information that would be
adequate to permit clinical testing of the drug in a population of the
size expected to be treated); and
A description of clinical procedures, laboratory tests, or
other monitoring necessary to evaluate the effects of the drug and
minimize its risks.
If this proposed rule becomes final, FDA will make educational
programs and materials available to help physicians and sponsors
understand the expanded access use submission requirements in general,
as well as the additional information necessary to justify the
different types of expanded access.
Proposed Sec. 312.300(b)(3) requires the expanded access
submission and its mailing cover to be plainly marked ``EXPANDED ACCESS
SUBMISSION.'' If the expanded access submission is for a treatment IND
or treatment protocol, the applicable box on Form FDA 1571 must be
checked.
3. Safeguards for All Expanded Access Uses
Proposed Sec. 312.305(c) explains how the responsibilities of
sponsors and investigators set forth in subpart D of part 312 apply to
expanded access.
Proposed Sec. 312.305(c)(1) states that a licensed physician under
whose immediate direction an investigational drug is administered or
dispensed for expanded access use under subpart I is considered an
investigator for purposes of part 312 and must comply with the
responsibilities for investigators set forth in subpart D of part 312
to the extent they are applicable to the expanded access use. A
nonexclusive list of duties of investigators--those duties that apply
in all types of expanded access--is set forth in proposed Sec.
312.305(c)(4), and is explained further in the following paragraphs.
Proposed Sec. 312.305(c)(2) provides that an individual or entity
that submits an IND or protocol for expanded access under subpart I is
considered a sponsor for purposes of part 312 and must comply with the
responsibilities for sponsors set forth in subpart D of part 312 to the
extent they are applicable to the expanded access use.
Proposed Sec. 312.305(c)(3) provides that a licensed physician
under whose immediate direction an investigational drug is administered
or dispensed, and who submits an IND for expanded access under subpart
I, is considered a sponsor-investigator for purposes of part 312 and
must comply with the responsibilities for sponsors and investigators
set forth in subpart D of part 312 to the extent they are applicable to
the expanded access use. Proposed Sec. 312.305(c)(4) provides that, in
all types of expanded access, investigators have the following
responsibilities:
Reporting adverse drug experiences to the sponsor,
Ensuring that the informed consent requirements of 21 CFR
part 50 are met,
Ensuring that Institutional Review Board (IRB) review of
the expanded access use is obtained in a manner consistent with the
requirements of part 56 (21 CFR part 56), and
Maintaining accurate case histories and drug disposition
records and retaining records in a manner consistent with the
requirements of Sec. 312.62.
However, this list of duties under subpart D of part 312 is not
exclusive, and other requirements may apply, depending on the
particular type of expanded access.
Proposed Sec. 312.305(c)(5) provides that, in all cases, sponsors
have the following responsibilities:
Submitting IND safety reports and annual reports (when the
IND or protocol continues for 1 year or longer) to FDA as required by
Sec. Sec. 312.32 and 312.33,
Ensuring that licensed physicians are qualified to
administer the investigational drug for the expanded access use,
Providing licensed physicians with the information needed
to minimize the risk and maximize the potential benefits of the
investigational drug (e.g., providing the investigator's brochure, if
there is one),
Maintaining an effective IND for the expanded access use,
and
Maintaining adequate drug disposition records and
retaining records in a manner consistent with the requirements of Sec.
312.57.
As with the list of investigator's duties under proposed Sec.
312.305(c)(4), this list of sponsor's duties under subpart D of part
312 is not exclusive, and other requirements may apply, depending on
the particular type of expanded access.
4. When Expanded Access Use May Begin
Proposed Sec. 312.305(d) explains when expanded access use may
begin, assuming FDA has not placed a clinical hold on the expanded
access use. Under IND rules, a study described in a protocol in a newly
submitted IND can begin 30 days after FDA receipt of the IND (or on
earlier notification by FDA that the study may proceed), unless FDA
puts the study on hold. Once there is an IND in place, new protocols
submitted to that IND may begin on the date of submission.
Proposed Sec. 312.300(d)(1) states that an expanded access IND
goes into effect 30 days after FDA receives the IND or on earlier
notification by FDA that the expanded access use may begin, consistent
with FDA's normal practice.
Proposed Sec. 312.300(d)(2) explains when expanded access use may
begin, if the expanded access submission is in the form of a new
protocol submitted under an existing IND. The proposed rule states that
expanded access use under a protocol submitted under an existing IND
may begin as described in Sec. 312.30(a). Section 312.30(a) provides
that the study under the protocol may begin provided two conditions are
met: (1) The sponsor has submitted the protocol to FDA for its review
and (2) the protocol has been approved by the IRB with responsibility
for review and approval of the study in accordance with the
requirements of part 56. Section 312.30(a) states that the sponsor may
comply with these two conditions in either order.
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The proposed rule provides two exceptions to the general rules
concerning when expanded access use under a new protocol may begin.
First, proposed Sec. 312.305(d)(2)(i) provides that treatment under a
protocol for individual patient expanded access in an emergency
situation may begin when it is authorized by the FDA reviewing
official. Second, proposed Sec. 312.305(d)(2)(ii) states that expanded
access use under proposed Sec. 312.320 (the treatment IND or treatment
protocol described in Sec. Sec. 312.34 and 312.35 of the current IND
regulations) may begin 30 days after FDA receives the protocol (or on
earlier notification by FDA that the treatment use may begin); that is,
there would be a 30-day wait even for a protocol submitted under an
existing IND. Expanded access use under a treatment IND or treatment
protocol often involves thousands of patients. The agency believes it
is important to build in time for agency review of a proposed expanded
access use with the potential to affect so many people.
Proposed Sec. 312.300(d)(3) states that FDA may place any expanded
access IND or protocol on clinical hold as described in Sec. 312.42.
F. Expanded Access for Individual Patients (Proposed Sec. 312.310)
Proposed Sec. 312.310 would permit an investigational drug to be
used for the treatment of an individual patient by a licensed
physician.
1. Expanded Access for Individual Patients--Criteria
In addition to the proposed criteria for all expanded access uses,
proposed Sec. 312.310(a) sets forth two criteria for permitting an
investigational drug to be used for the treatment of an individual
patient by a licensed physician.
First, the physician must determine that the probable risk
to the person from the investigational drug is not greater than the
probable risk from the disease or condition (proposed Sec.
312.310(a)(1)).
Second, FDA must determine that the patient cannot obtain
the drug under another type of IND (proposed Sec. 312.310(a)(2)).
(Section 561(b)(3) of the act requires that FDA determine that
provision of the investigational drug will not interfere with the
initiation, conduct, or completion of clinical investigations to
support marketing approval.) Thus, expanded access for an individual
patient would not be available, for example, if the patient can
participate in a clinical trial of the investigational drug. However,
participation in a clinical trial may not be possible for many reasons.
A patient may have a stage of the disease different from the stage
being studied. The patient may have failed on, or be intolerant of, the
active control in a randomized active-control trial. It may be
geographically impossible for the patient to participate in a clinical
trial.
One of the proposed general criteria for any expanded access use is
that FDA must determine that the potential benefit to the patient
justifies the potential risks of the expanded access use and those
potential risks are not unreasonable in the context of the disease or
condition to be treated. The evidence needed to make this determination
for expanded access for an individual patient will vary. For a patient
with an immediately life-threatening condition, the evidentiary burden
could be very low--little if any clinical evidence to suggest a
potential benefit or possibly only animal data to support safety of the
use. For a patient with a serious, but not immediately life-
threatening, condition who could expect to enjoy a reasonable quality
of life for an extended time without any treatment, the evidentiary
burden would be higher.
2. Expanded Access for Individual Patients--Submission Requirements
In addition to the proposed submission requirements for all
expanded access uses, proposed Sec. 312.310(b) provides that the
expanded access submission must include information adequate to
demonstrate that the general criteria for expanded access use and those
specific to expanded access for individual patients have been met.
Proposed Sec. 312.310(b) provides that if the drug is the subject
of an existing IND, the expanded access submission may be made by the
sponsor or by a licensed physician. A sponsor may satisfy the
submission requirements by amending its existing IND to include a
protocol for individual patient expanded access. Sponsors are strongly
encouraged to include individual patient expanded access protocols
under their own INDs.
Proposed Sec. 312.310(b) provides that a licensed physician may
satisfy the submission requirements by obtaining from the sponsor
permission for FDA to refer to any information in the IND that would be
needed to support the individual patient expanded access request (right
of reference) and by providing any other required information not
contained in the IND (usually only the information specific to the
individual patient). Obtaining a right of reference is consistent with
current practice. Sponsors who agree to make an investigational drug
available to an individual patient, but prefer that it be provided
under an IND obtained by the licensed physician rather than under the
sponsor's IND, routinely provide a right of reference to necessary
information in the existing IND, and such a right of reference is
necessary for FDA to be able to make the necessary determinations about
whether the expanded access use may proceed.
3. Expanded Access for Individual Patients--Safeguards
Proposed Sec. 312.310(c) sets forth safeguards that apply
specifically to expanded access for individual patients. These proposed
safeguards are listed as follows:
Treatment of an individual patient with an investigational
drug is generally limited to a single course of therapy for a specified
duration, unless FDA expressly authorizes multiple courses or chronic
therapy.
FDA may require sponsors to monitor an individual patient
expanded access use if the use is for an extended duration.
At the conclusion of treatment, the licensed physician or
sponsor (whoever made the expanded access submission) must provide a
written summary of the results of the treatment use, including
unexpected adverse drug experiences.
When FDA receives a significant number of similar requests
for individual patient expanded access, the agency may ask the sponsor
to submit an IND or protocol for the use under Sec. 312.315 or Sec.
312.320.
What constitutes a significant number of similar requests will vary
depending on the indication, the number of patients with no available
therapeutic options, and the extent to which the drug has the potential
to benefit those patients. In general, when the agency receives 10 or
more requests for the same individual patient expanded access use
within a relatively short time period (e.g., less than 6 months), FDA
will consider whether to request that a potential sponsor submit an
intermediate-size patient population IND or protocol for the expanded
access use and, possibly, conduct a clinical trial of the expanded
access use.
4. Expanded Access for Individual Patients--Emergency Procedures
Proposed Sec. 312.310(d) sets out emergency procedures for
expanded access for individual patients. If there is an emergency that
requires a patient to be treated before a written submission can be
made, FDA may authorize the expanded access use to begin without a
written submission. Under the proposed rule, the FDA reviewing official
may
[[Page 75154]]
authorize the emergency use by telephone. Emergency expanded access use
may be requested by telephone, facsimile, or other means of electronic
communications. The proposed rule also provides phone numbers for
requests for investigational drugs and investigational biological drug
products, and an after-hours contact number.
Proposed Sec. 312.310(d)(2) requires the licensed physician or
sponsor to explain how the expanded access use will meet the
requirements of proposed Sec. Sec. 312.305 and 312.310 and requires
agreement to submit an expanded access submission that complies with
proposed Sec. Sec. 312.305 and 312.310 within 5 working days of FDA's
authorization of the expanded access use.
For individual patient expanded access use situations in which
there is time to make a written submission, the expedited procedures
would not be available. Lack of a prior written submission decreases
FDA's ability to review the proposed use. Furthermore, FDA's experience
with emergency treatment use is that the written submission and
followup information on the outcome of the treatment use frequently
have not been provided. By limiting use of the emergency procedures to
true emergencies, the agency hopes to better monitor individual patient
expanded access use.
G. Expanded Access for Intermediate-Size Patient Populations (Proposed
Sec. 312.315)
Proposed Sec. 312.315 provides for expanded access use by patient
populations smaller than those typical in treatment INDs or treatment
protocols. FDA may ask a sponsor to consolidate expanded access use
under this section when the agency has received a significant number of
requests for individual patient expanded access to an investigational
drug for the same use.
Proposed Sec. 312.315(a) states that expanded access use under the
section may be needed in the following situations:
Drug not being developed. The drug is not being developed,
for example, because the disease or condition is so rare that the
sponsor is unable to recruit patients for a clinical trial.
Nonetheless, the drug may represent the only promising therapy for the
people with the disease or condition (proposed Sec. 312.315(a)(1)).
Drug being developed. The drug is being studied in a
clinical trial, but patients requesting the drug for expanded access
use are unable to participate in the trial. Patients may not be able to
participate in the trial, for example, because they have a different
disease or stage of disease from the one being studied or otherwise do
not meet the enrollment criteria; because enrollment in the trial is
closed; or because the trial site is not geographically accessible
(proposed Sec. 312.315(a)(2)).
Approved or related drug. The drug is an approved drug
product that is no longer marketed for safety reasons or is unavailable
through marketing due to failure to meet the conditions of the approved
application (proposed Sec. 312.315(a)(3)(i)), or the drug contains the
same active moiety as an approved drug product that is unavailable
through marketing due to failure to meet the conditions of the approved
application or a drug shortage (proposed Sec. 312.315(a)(3)(ii)).
When a drug is no longer marketed due to safety reasons, there may
be a subset of patients for whom the benefits of treatment are believed
to outweigh the risks and who lack satisfactory alternative therapies.
Under proposed Sec. 312.315(a)(3)(i), those patients could continue to
receive the drug under an intermediate-size patient population IND for
expanded access use.
This provision is also intended to allow uninterrupted therapy when
an approved drug is not being manufactured in a manner consistent with
the specifications on which the approval is based (good manufacturing
practice (GMP) violations) and therefore cannot be marketed under the
new drug application (NDA). Under proposed Sec. 312.315(a)(3)(i), the
drug could be made available to patients for whom the drug is a medical
necessity until the GMP violations are addressed (assuming that,
despite those violations, the product does not pose a risk that is
unreasonable in the context of the disease or condition to be treated,
per proposed Sec. 312.305(a)(2)). If the product does pose a risk
because of GMP concerns, proposed Sec. 312.315(a)(3)(ii) could be used
to make available an unapproved drug product containing the same active
moiety (e.g., a drug product approved in another country).
Proposed Sec. 312.315(a)(3)(ii) could also be used in a drug
shortage situation to make available an unapproved drug containing the
same active moiety as the approved drug that is in short supply (e.g.,
a drug product approved in another country).
1. Expanded Access for Intermediate-Size Patient Populations--Criteria
In addition to the proposed criteria for all expanded access uses,
proposed Sec. 312.315(b) sets forth the criteria that apply
specifically to expanded access use for intermediate-size patient
populations.
The first criterion requires that there be enough evidence
that the drug is safe at the dose and duration proposed for expanded
access use to justify a clinical trial of the drug in the approximate
number of patients expected to receive the drug for expanded access use
(proposed Sec. 312.315(b)(1)).
In ordinary drug development, it is usual practice to gradually
increase the number of subjects exposed to a drug (from first human
exposure in a very small number of subjects through large phase 3
trials). This practice limits the risk from drugs that turn out to have
significant adverse effects, as more and better information (e.g.,
about dosing) is obtained about the drug before larger numbers of
subjects are treated. The same rationale would apply in the expanded
access use setting. There should be more clinical experience for an
intermediate-size patient population than for an individual patient,
and the amount of clinical experience to justify expanded access use in
a certain population should be roughly the same as would justify a
clinical trial in that size population. FDA anticipates that the
typical intermediate-size patient population treatment use IND or
protocol will provide access to between 10 and 100 patients.
The second criterion requires that there be at least
preliminary clinical evidence of effectiveness of the drug or of a
plausible pharmacologic effect of the drug to make expanded access use
a reasonable therapeutic option in the anticipated patient population
(proposed Sec. 312.315(b)(2)).
2. Expanded Access for Intermediate-Size Patient Populations--
Submission Requirements
In addition to the proposed submission requirements for all
expanded access uses, proposed Sec. 312.315(c) sets forth the
submission requirements that apply specifically to expanded access use
by intermediate-size patient populations. The expanded access use
submission must do the following:
State whether the drug is being developed or is not being
developed and describe the patient population to be treated (proposed
Sec. 312.315(c)(1));
Include an explanation by the sponsor, if the drug is not
being actively developed, of why the drug cannot currently be developed
for the expanded access use and under what circumstances the drug could
be developed (proposed Sec. 312.315(c)(2)); and
[[Page 75155]]
Include an explanation by the sponsor, if the drug is
being studied in a clinical trial, of why the patients to be treated
cannot be enrolled in the clinical trial and under what circumstances
the sponsor would conduct a clinical trial in these patients (proposed
Sec. 312.315(c)(3)).
3. Expanded Access for Intermediate-Size Patient Populations--
Safeguards
Proposed Sec. 312.315(d) sets forth the safeguards that apply
specifically to expanded access use by intermediate-size populations.
Upon review of the IND annual report, FDA will determine whether it is
appropriate for the use to continue under this section. If the drug is
not being actively developed or if the expanded access use is not being
developed (but another use is being developed), FDA will consider
whether it is possible to conduct a clinical study to develop the
expanded access use for marketing (proposed Sec. 312.315(d)(1)(i)). If
the drug is being actively developed, FDA will consider whether
providing the investigational drug for expanded access use is
interfering with the clinical development of the drug (proposed Sec.
312.315(d)(1)(ii)). As the number of patients enrolled increases, FDA
will also consider whether to request that a sponsor submit a treatment
IND or treatment protocol as described in Sec. 312.320 for the
expanded access use (proposed Sec. 312.315(d)(1)(iii)). The sponsor is
responsible for monitoring the expanded access protocol to ensure that
licensed physicians comply with the protocol and the regulations
applicable to investigators (proposed Sec. 312.315(d)(2)).
H. Expanded Access Treatment IND or Treatment Protocol (Proposed Sec.
312.320)
Proposed Sec. 312.320 describes the treatment IND or treatment
protocol mechanism that is currently provided in Sec. Sec. 312.34 and
312.35. Proposed Sec. 312.320 retains the basic terminology
``treatment IND'' and ``treatment protocol'' from current Sec. Sec.
312.34 and 312.35.
1. Expanded Access Treatment IND or Treatment Protocol--Criteria
In addition to the proposed criteria for all expanded access uses,
proposed Sec. 312.320(a) provides the criteria that apply specifically
to a treatment IND or treatment protocol.
Proposed Sec. 312.320(a)(1) requires that either the drug is being
investigated in a controlled clinical trial under an IND designed to
support a marketing application for the expanded access use (proposed
Sec. 312.320(a)(1)(i)), or all clinical trials of the drug have been
completed (proposed Sec. 312.320(a)(1)(ii)).
In addition, the sponsor must be actively pursuing marketing
approval of the drug for the expanded access use with due diligence
(proposed Sec. 312.320(a)(2)).
Proposed Sec. 312.320(a)(3)(i) provides that, when the expanded
access use is for a serious disease or condition, there must be
sufficient clinical evidence of safety and effectiveness to support the
expanded access use. Such evidence would ordinarily consist of data
from phase 3 trials, but could consist of compelling data from
completed phase 2 trials.
Proposed Sec. 312.320(a)(2)(ii) provides that, when the expanded
access use is for an immediately life-threatening disease or condition,
the available scientific evidence, taken as a whole, provides a
reasonable basis to conclude that the investigational drug may be
effective for the expanded access use and would not expose patients to
an unreasonable and significant risk of illness or injury. This
evidence would ordinarily consist of clinical data from phase 3 or
phase 2 trials, but could be based on more preliminary clinical
evidence.
2. Expanded Access Treatment IND or Treatment Protocol--Submission
Requirements
In addition to the proposed submission requirements for all
expanded access uses, proposed Sec. 312.320(b) states that the
expanded access submission must include information adequate to satisfy
FDA that the general criteria for expanded access use and those
specific to the treatment IND or treatment protocol have been met.
3. Expanded Access Treatment IND or Treatment Protocol--Safeguards
Proposed Sec. 312.320(c) provides a safeguard that applies
specifically to treatment protocols. The sponsor is responsible for
monitoring the treatment protocol to ensure that licensed physicians
comply with the protocol and the regulations applicable to
investigators.
I. Open-Label Safety Studies
The primary purpose of the treatment IND or treatment protocol is
to make investigational drugs available to patients with serious or
immediately life-threatening diseases or conditions when there is a
reasonable evidentiary basis to support the use in a substantial
population, but the evidence needed for marketing approval either has
not been entirely collected or has been collected but not yet analyzed
and reviewed by the agency.
FDA is concerned that sponsors have used programs other than
treatment INDs or treatment protocols to make investigational drugs
available to large populations for treatment use, particularly by
identifying such programs as ``open-label safety studies.'' The goal of
an open-label safety study is to better characterize the safety of a
drug late in its development. However, in practice, many studies that
are described as open-label safety studies have characteristics that
appear to be more consistent with treatment INDs or treatment
protocols. For example:
The investigators are not selected by the sponsor but can
be any physician (sometimes with specified qualifications),
The population receiving the drug is quite large,
Collection of data is minimal, and
The studies may not generate the kind of reliable
information that would be developed in a study designed to meaningfully
assess safety endpoints.
Consequently, in the future, the agency intends to evaluate whether
proposals for open-label safety studies should be treatment INDs or
treatment protocols that would have to meet the criteria in proposed
Sec. 312.320. A study described as an open-label safety study that
provides broad access to an investigational drug in the later stages of
development, but lacks planned, systematic data collection and a design
appropriate to evaluation of a safety issue is likely to be considered
a treatment IND or treatment protocol. The agency believes treatment
INDs or treatment protocols are more appropriate programs to provide
treatment because the authorization for such expanded access uses will
require a more formal review process that would explicitly consider the
impact of expanded access on enrollment in clinical trials and the
progress of drug development generally.
J. Continuation Phase of a Clinical Trial
The continuation phase of a clinical trial may have characteristics
in common with open-label safety studies or expanded access, or both.
In the continuation phase of a clinical trial, patients have the option
of receiving the study drug after completing the controlled portion of
the trial (continue on the study drug or cross over from a control
treatment to the study drug), often as an inducement to enroll in the
clinical study. All patients receive the study drug. The primary intent
may be to develop additional safety data or to
[[Page 75156]]
treat the patient's condition. Notwithstanding the intent, however,
because enrollment is limited to only clinical study participants, the
use is considered a part of the clinical study rather than an expanded
access use for purposes of proposed subpart I.
V. Legal Authority
The agency believes it has the authority to impose requirements
regarding expanded access to investigational drugs under various
sections of the act, including sections 505(i); 561; and 701(a) (21
U.S.C. 371(a)).
Section 505(i) of the act directs the agency\3\ to issue
regulations exempting from the operation of the new drug approval
requirements drugs intended solely for investigational use by experts
qualified by scientific training and expertise to investigate the
safety and effectiveness of drugs. The proposed rule explains
procedures for obtaining FDA authorization for expanded access uses of
investigational drugs and factors relevant to making necessary
determinations.
---------------------------------------------------------------------------
\3\In light of section 903(d) of the act (21 U.S.C. 393(d)) and
the Secretary's delegations to the Commissioner of Food and Drugs,
statutory references to ``the Secretary'' in the discussion of legal
authority have been changed to ``FDA'' or ``the agency.''
---------------------------------------------------------------------------
Section 561 of the act, added by FDAMA, provides significant
additional authority for this proposed rule. Section 561(a) of the act
states that FDA may, under appropriate conditions determined by the
agency, authorize the shipment of investigational drugs for the
diagnosis, monitoring, or treatment of a serious disease or condition
in emergency situations. This proposed rule sets forth factors that the
agency will consider in determining whether to authorize shipment of
investigational drugs in emergency situations.
Section 561(b) of the act allows any person, acting through a
physician licensed in accordance with State law, to request from a
manufacturer or distributor an investigational drug for the diagnosis,
monitoring, or treatment of a serious disease or condition if four
conditions are met: (1) The physician must determine that the person
has no comparable or satisfactory alternative therapy available and the
probable risk to the person from the investigational drug is not
greater than the probable risk from the disease or condition; (2) FDA
must determine that there is sufficient evidence of safety and
effectiveness to support the use of the investigational drug in the
particular case; (3) FDA must determine that provision of the
investigational drug will not interfere with the initiation, conduct,
or completion of clinical investigations to support marketing approval;
and (4) the sponsor or clinical investigator of the investigational
drug submits a clinical protocol consistent with the provisions of
section 505 of the act 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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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:
A cover sheet (Form FDA 1571) meeting the requirements of
Sec. 312.23(a);
The rationale for the intended use of the drug, including
a list of available therapeutic options that would ordinarily be tried
before resorting to the investigational drug or an explanation of why
the use of the investigational drug is preferable to the use of
available therapeutic options;
The criteria for patient selection; or, for an individual
patient, a description of the patient's disease or condition, including
recent medical history and previous treatments used for the disease or
condition;
The method of administration of the drug, dose, and
duration of therapy;
A description of the facility where the drug will be
manufactured;
Chemistry, manufacturing, and controls information
adequate to ensure the proper identification, quality, purity, and
strength of the investigational drug;
Pharmacology and toxicology information adequate to
conclude that
[[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
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:
octma@cber.fda.gov. For all other investigational drugs, the request
for authorization should be directed to the Division of Drug
Information, Center for Drug Evaluation and Research, 301-827-4570, e-
mail: druginfo@cder.fda.gov. After normal working hours, the request
should be directed to the FDA Office of Emergency Operations, 301-443-
1240, e-mail: emergency.operations@fda.hhs.gov.
(2) The licensed physician or sponsor must explain how the expanded
access use will meet the requirements of 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