Status of Guidance
Final Guidance
Date of Guidance
July 2004
Released by
Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER)
Target audience
Developers of drugs/biologics
Laws and Regulations
This guidance refers to various sections of the 21 Code of Federal Regulations (CFR). These sections deal with investigational new drug applications, accelerated approval of new drugs and biologics for serious or life-threatening illnesses, and humanitarian use devices.
The specific sections mentioned are:
Definitions
- Accelerated approval regulations: procedures that permit quicker approval of investigational new drugs to treat serious or life-threatening diseases and provide “meaningful therapeutic benefit to patients” in a more effective manner than that already provided by existing therapies. These trials typically use surrogate endpoints.
- Fast-track drug development programs: Federal Drug Administration (FDA) programs that purposely work to speed up the review process of investigational new drugs and biologics that are not yet approved to treat life-threatening or serious conditions in a more effective manner than that already provided by existing therapies.
- IND: investigational new drug application; application for a waiver from the FDA to allow the movement of an investigational drug (not yet approved for marketing by the FDA) across state lines.
- Restricted distribution: controlled availability of a drug/biologic/medical device, with the authority to prescribe and dispense limited to preordained prescribers and pharmacists registered with the FDA’s special restricted distribution program. Patients agree to abide by special rules for use of the restricted entity.
- Subpart E regulations: regulations contained in 21 CFR part 312 that call for the quick development, review, and marketing of therapies that show ability to address life-threatening or serious medical conditions currently without appropriate treatment.
- Surrogate End Point: an endpoint used as a substitute for a primary endpoint in a clinical study because designing a study with the actual primary endpoint is not practical or safe. Surrogate endpoints are measurable and quantifiable, and represent a clinically meaningful outcome, eg, survival or improvement of symptoms
Background
No official definition has been provided previously for “available therapy” when used in documents issued by agencies of the FDA such as the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation (CBER). “Available therapy” is often used interchangeably with “existing therapy” or “existing treatments” in documents issued by these agencies.
“Available therapy” and related terms are used in many FDA programs created to speed up the review process of promising new drugs. This term can be found in the following FDA documents but without any clarification as to its specific meaning:
- Treatment investigational new drug applications (INDs) (including treatment protocols)
- Subpart E Regulations
- Accelerated approval regulations
- Fast track drug development programs
- Priority review policies
Without an official definition for “available therapy,” uncertainty has resulted over whether “available therapy” includes FDA-approved products and/or off-label use of FDA-approved products, or non–FDA regulated therapies.
Summary
This guidance clarifies what “available therapy” (and the related words “existing therapy” and “existing treatment”) refers to when included in documents created by agencies of the FDA such as the CDER and CBER. Specifically, this guidance defines available therapy/existing treatments/existing therapy as “therapy that is specified in the approved labeling of regulated products, with only rare exceptions.” “Approved labeling” in this definition refers to therapies approved under normal or accelerated approval schedules. Additionally, in certain and rare situations, “available therapy” may refer to a therapy not yet approved by the FDA but for which ample evidence exists in the published literature. This definition will be used for regulations and policy statements that do not include a specific definition for available therapy.
Rationale
Many documents issued by agencies of the FDA use the terms “available therapy,” “existing therapy,” and “existing treatment” without clarifying what these terms specifically mean. Without clarification, these terms could be interpreted to mean FDA-approved products only, FDA-approved products as well as products not approved by the FDA, and/or off-label use of FDA-approved products. Off-label use of an FDA-approved product refers to using a product for a use other than it has been approved for by the FDA.
Resulting Recommendations
· “Available therapy” (and related words existing treatment and existing therapy) should be interpreted to mean “therapy that is specified in the approved labeling of regulated products, with only rare exceptions.”
· In certain and rare situations, “available therapy” may refer to a therapy not yet approved by the FDA but for which ample evidence exists in the published literature.
· More than one therapy seeking approval for the same indication can apply for accelerated approval.
· When in reference to a therapy involved in accelerated approval regulations, the term “existing treatment” can have different meanings depending on the context of the approval. If the term is used in the context of an approval based on results from a clinical trial using a surrogate, or substitute, endpoint, then “existing treatment” will mean a treatment that has been proven efficacious “under conventional approval standards.” In contrast, if the term is used in the context of a previous approval based on “restricted distribution,” then “existing treatment” will mean a therapy already approved for the same indication without restricted distribution.
Impact
By clarifying what “available therapy” and related terms mean, the FDA will avoid potential confusion that may arise over possibly different and/or conflicting interpretations of the terms “available therapy,” “existing therapy,” and “existing treatment.” In this way, the FDA will ensure that the readers of FDA guidances will understand that in most cases the terms refer to FDA-approved products and to their use as defined by approved labeling.
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