Guidance for Industry

Available Therapy

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

Center for Biologics Evaluation and Research (CBER)

July 2004

Clinical Medical 
Guidance for Industry

Available Therapy

Additional copies are available from:

Office of Training and Communications

Division of Drug Information, HFD-240

Center for Drug Evaluation and Research

Food and Drug Administration

5600 Fishers Lane

Rockville, MD 20857

(Tel) 301-827-4573

http://www.fda.gov/cder/guidance/index.htm

or

 Office of Communication, Training and 

Manufacturers Assistance, HFM-40 

Center for Biologics Evaluation and Research

 Food and Drug Administration

1401 Rockville Pike, Rockville, MD 20852-1448 

http://www.fda.gov/cber/guidelines.htm

Phone: the Voice Information System at 800-835-4709 or 301-827-1800

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

Center for Biologics Evaluation and Research (CBER)

July 2004

Clinical Medical 
Table of Contents

I. INTRODUCTION................................................................................................................. 1

II. BACKGROUND ................................................................................................................... 1

III. AFFECTED REGULATIONS AND POLICY STATEMENTS ...................................... 2

A. Treatment INDs .............................................................................................................................2

B. Subpart E Regulations...................................................................................................................2

C. Accelerated Approval Regulations...............................................................................................2

D. Fast Track Drug Development Programs....................................................................................3

E. Priority Review Policies.................................................................................................................3

IV. POLICY: DEFINITION OF AVAILABLE THERAPY.................................................. 4

REFERENCES.............................................................................................................................. 6
Contains Nonbinding Recommendations

1

Guidance for Industry1

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. 

I. INTRODUCTION

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.

II. BACKGROUND

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. 

 

1 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. 
Contains Nonbinding Recommendations

2

III. AFFECTED REGULATIONS AND POLICY STATEMENTS

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.

A. Treatment INDs

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. 

B. Subpart E Regulations

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). 

C. Accelerated Approval Regulations

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). 
Contains Nonbinding Recommendations

3

D. Fast Track Drug Development Programs

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.

E. Priority Review Policies

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.
Contains Nonbinding Recommendations

4

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.2

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. 

IV. POLICY: DEFINITION OF AVAILABLE THERAPY

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.

 

2 CDER Manual of Policies and Procedures (MaPP) 6020.3 explains the priority review policy and procedures. 

CBER Manual of Standard Operating Procedures and Policies 8405 explains the process for Complete Review and

Issuance of Action Letters.

3 Approved labeling refers to claims approved conventionally or under FDA’s accelerated approval procedures.
Contains Nonbinding Recommendations

5

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.
Contains Nonbinding Recommendations

6

REFERENCES

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