The US Food and Drug Administration (FDA) has published new draft guidance for its Accelerated Approval Program, which provides a process for expediting new drugs that serve unmet medical needs for serious conditions.

The guidance outlines the requirements for the two types of endpoints considered as a basis for accelerated approval. These are either surrogate or clinical endpoints.

An acceptable surrogate endpoint is one “that is considered reasonably likely to predict clinical benefit”, according to the guidance, while the clinical endpoint must be one “that can be measured earlier than irreversible morbidity or mortality (IMM) that is reasonably likely to predict an effect on IMM or other clinical benefit”.

Surrogate endpoints are defined in the guidance as “generally a biomarker, such as a laboratory measurement, radiographic image, physical sign or other measure that is thought to predict clinical benefit but is not itself a measure of clinical benefit”.

The FDA offers examples of “reasonably likely” surrogate endpoints used to support accelerated approval. These include the conversion of sputum culture from positive to negative during treatment of pulmonary tuberculosis, which has been considered “reasonably likely” to predict the clinical benefit of resolution of infection.

The FDA also defines acceptable intermediate clinical endpoints that are considered in accelerated approval applications. It requires “a measurement of a therapeutic effect that can be measured earlier than an effect on IMM and may support accelerated approval when it is considered reasonably likely to predict the drug’s effect on IMM or other clinical benefit”.

It offers the example of a study that demonstrates a short-term benefit in the treatment of chronic disease but that requires a longer duration of effect to be clinically meaningful. The FDA would consider whether it is “reasonably likely” that the short-term benefit is indicative of this.

Drugs approved via the Accelerated Approval Program must be further tested through a postapproval confirmatory trial to be granted full approval. The trial must verify and describe the clinical benefit of the drug.

The new guidelines advise that “sponsors must commit sufficient resources to conduct the trial(s) intended to verify the clinical benefit expeditiously so that a determination of whether the drug provides the expected clinical benefit can be made as soon as possible”.

They also state the need for early consultation between reviewers and sponsors, explaining that additional preclinical or clinical data may be required by review teams. It is suggested that “sponsors should seek early interactions with the FDA” to avoid delays.