Guidance for Industry
Available Therapy
This
guidance represents the Food and Drug Administration's (FDA's)
current thinking on this topic. It does not create or
confer any rights for or on any person and does not operate to
bind FDA or the public. You can use an alternative
approach if the approach satisfies the requirements of the
applicable statutes and regulations. If you want to
discuss an alternative approach, contact the FDA staff
responsible for implementing this guidance. If you cannot
identify the appropriate FDA staff, call the appropriate number
listed on the title page of this guidance.
This document is intended to provide guidance
to industry on the meaning of the term available therapy as
currently used by the Center for Drug Evaluation and Research
(CDER) and the Center for Biologics Evaluation and Research (CBER)
in the Food and Drug Administration (FDA) in the specific
circumstances described in this guidance.
FDA's guidance documents, including this
guidance, do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency's current thinking on a
topic and should be viewed only as recommendations, unless
specific regulatory or statutory requirements are cited. The
use of the word should in Agency guidances means that
something is suggested or recommended, but not required.
Available therapy and related terms,
such as existing treatments and existing therapy,
appear in a number of regulations and policy statements issued by
CDER and CBER, but these terms have never been formally defined by
the Agency. Some confusion has arisen regarding whether
available therapy refers only to products approved by FDA for
the use in question, or whether the term could also refer to
products used off-label or to treatments not regulated by FDA,
such as surgery. This guidance is intended to inform the
public of the Agency's interpretation of available therapy
as used in the regulations and policy statements described in Part
III.
The regulations and policies described below
incorporate the concept that the Agency can regulate a particular
product in a certain manner because of a lack of available therapy
or because of the product's advantage over available therapy.
The language incorporating this concept is printed in bold
italicized print for emphasis.
FDA's regulations
allow the use of an investigational drug for treatment under a
treatment protocol or treatment investigational new drug
application (IND). According to 21 CFR 312.34(b), the
investigational drug can only be used for this purpose if 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”
(312.34(b)(ii).
·
The drug is being investigated under an IND in
effect for the trial, or all clinical trials have been completed.
·
The sponsor of the clinical trial is actively
pursuing marketing approval of the investigational drug.
The Agency's
procedures in subpart E of 21 CFR part 312, which expedite the
development, evaluation, and marketing of promising therapies to
treat individuals with life-threatening and severely debilitating
illnesses, reflect that the Agency must make a medical
risk-benefit judgment in deciding whether to approve a drug or
biological product. As part of this risk-benefit analysis,
the Agency will "tak[e] into consideration the severity of the
disease and the absence of satisfactory alternative therapy”
(21 CFR 312.84).
FDA's accelerated
approval procedures and restricted distribution provisions in 21
CFR subpart H are available for new drug and biological products
(1) that have been studied to treat serious or life-threatening
illnesses and (2) "that provide meaningful therapeutic benefit to
patients over existing treatments (e.g., ability to treat
patients unresponsive to, or intolerant of, available therapy, or
improved patient response over available therapy)"
(21 CFR 314.500 and 601.40).
FDA's fast track
drug development programs are designed to facilitate the
development and expedite the review of drug and biological
products that are intended to treat serious or life-threatening
conditions and that demonstrate the potential to address unmet
medical needs (FDA guidance for industry on Fast Track Drug
Development Programs: Designation, Development, and Application
Review). In the guidance, the Agency defined an unmet
medical need as a "medical need that is not addressed
adequately by an existing therapy."
As described in the
guidance, where there is no available therapy for a
condition (or the only available therapy is approved under the
accelerated approval regulations), a product in a drug development
plan designed to evaluate the drug's potential to address the
condition would meet the factors to address an unmet medical need.
Where there is available therapy for the condition, the drug
development program would address unmet medical needs if it
evaluated any of the following:
·
Improved effects on serious outcomes of the
condition that are affected by alternate therapies
·
Effects on serious outcomes of the condition
not known to be affected by the alternatives
·
Ability to provide benefits in patients who
are unable to tolerate or are unresponsive to alternative agents,
or ability to be used effectively in combination with other
critical agents that cannot be combined with available therapy
·
Ability to provide benefits similar to those
of alternatives, while avoiding serious toxicity that is present
in existing therapies, or avoiding less serious toxicity that is
common and causes discontinuation of treatment of a serious
disease
·
Ability to provide benefits similar to those
of alternatives but with improvement in some factor, such as
compliance or convenience, that is shown to lead to improved
effects on serious outcomes.
CDER and CBER have established review
classifications and review policies and procedures for new drug
applications (NDAs), biologics license applications (BLAs), and
efficacy supplements to prioritize and speed their review.
Most of these Agency policies and procedures are intended to
encourage the development and expedite the review of innovative
drug products (i.e., subpart E regulations, accelerated approval
regulations, fast track drug development programs, priority review
policies), while one (treatment INDs) provides early access to
investigational therapies.
A priority designation is intended to direct
overall attention and resources to the evaluation of applications
for products that have the potential for providing a significant
treatment, preventive or diagnostic therapeutic advance, as
compared to standard applications.
Products regulated by CDER are eligible for
priority review if they provide a significant improvement
compared to marketed products in the treatment, diagnosis, or
prevention of a disease. Products regulated by CBER
are eligible for priority review if they provide a
significant improvement in the safety or effectiveness of the
treatment, diagnosis, or prevention of a serious or
life‑threatening disease.
The regulations and policies described above
do not explicitly define available therapy. CDER and
CBER have determined that in regulations and policy statements
where the terms are not otherwise defined,
available therapy
(and the terms existing treatments and existing therapy) should be
interpreted as therapy that is specified in the approved labeling of regulated products, with only rare exceptions.[3]
FDA
recognizes that there are cases where a safe and effective therapy
for a disease or condition exists but it is not approved for that
particular use by FDA. However, for purposes of the
regulations and policy statements described in Section III, which
are intended to permit prompt FDA approval of medically important
therapies, only in exceptional cases will a treatment that is not
FDA-regulated (e.g., surgery) or that is not labeled for use but
is supported by compelling literature evidence
(e.g.,
certain established oncologic treatments) be considered
available therapy.
Most
of the Agency programs that use the term available therapy
are intended to encourage the development and expedite the review
of innovative drug products. By defining available therapy
to focus on approved products with labeling for use in the disease
or condition at issue, FDA (1) emphasizes the importance of the
approval process for establishing that a drug is safe and
effective for a particular use and (2) provides the greatest
opportunity for development and approval of appropriately labeled
drugs. For these programs, products that are used off-label
for the indication at issue and products that have not had formal
FDA review are rarely considered available therapy; the
definition of available therapy in this guidance provides
only a limited exception for particularly well-documented
therapies.
Questions also have arisen concerning how the
term "meaningful therapeutic benefit to patients over existing
treatments" in the accelerated approval regulations (21 CFR
314.500 and 601.40) should be interpreted when the only available
therapy is another treatment approved under the accelerated
approval regulations. This question arises when several drugs are
under investigation or application review for a specific
indication based on a surrogate endpoint, or when the only product
on the market has restrictions on distribution.
Specifically, when one drug is approved under the accelerated
approval regulations, can additional therapies be approved under
the accelerated approval regulations?
We have determined that the approval of one
therapy under the accelerated approval regulations (either on the
basis of a surrogate endpoint or with restricted distribution)
should not preclude the approval under the accelerated approval
regulations of additional therapies. As a general matter, it
is preferable to have more than one treatment approved under the
accelerated approval provisions, because there are more bases on
which an approval under these provisions may be withdrawn, and
thus the availability of the therapy is less certain than it is
with a conventional approval. Approval under the accelerated
approval provisions may be withdrawn if, for example,
post-approval studies fail to verify clinical benefit or the
postmarketing restrictions are inadequate to assure safe use of
the drug product (21 CFR 314.530). Such a withdrawal of
approval would leave no treatment available.
Accordingly, we intend to interpret
existing treatment under the accelerated approval regulations
to mean, in the context of approval based on a surrogate, a
treatment that has demonstrated a clinical benefit under
conventional approval standards (21 CFR 314.105, 314.125, 601.2).
In the context of a prior approval based on restricted
distribution, existing treatment means a treatment approved
for the same indication without restricted distribution.
FDA, CDER Manual of Policies and Procedures (MAPP)
6020.3, Priority Review
FDA, CBER Manual of Standard Operating Procedures
and Policies 8405, Complete Review and Issuance of Action Letters
FDA guidance for industry on Providing Clinical
Evidence of Effectiveness for Human Drug and Biological Products
FDA guidance for industry on Fast Track Drug
Development Programs: Designation, Development, and Application
Review
This guidance has been prepared by the Center for Drug
Evaluation and Research (CDER) and the Center for Biologics
Evaluation and Research (CBER) at the Food and Drug
Administration.