Draft Guidance on Special Protocol Assessments

FDA has released a draft guidance on “Special Protocol Assessment (SPA)” that provides procedures and general policies adopted by CDER/CBER for such an assessment. The process allows a sponsor to request a meeting with the agency to reach agreement on the design and size of certain clinical trials, clinical studies, or animal trials to determine if they adequately address scientific and regulatory requirements.

 

“As part of this process, sponsors should submit specific questions about protocol design and scientific and regulatory requirements,” the guidance says. “After FDA completes the SPA review, FDA issues an SPA Letter including an assessment of the protocol, agreement or non-agreement with the proposed protocol, and answers to the sponsor’s relevant questions. An SPA agreement indicates concurrence by FDA with the adequacy and acceptability of specific critical elements of overall protocol design (e.g., entry criteria, dose selection, endpoints, and planned analyses). These elements are critical to ensuring that the trial conducted under the protocol has the potential to support a future submitted application’s ability to meet regulatory requirements for approval. Feedback on these issues provides the greatest benefit to sponsors in planning a late-phase development strategy. However, an SPA agreement does not indicate FDA concurrence on every protocol detail.”

 

Because an SPA evaluates protocols for trials that have not been initiated, the conduct and results of a subsequent trial are not part of the evaluation, FDA says. “Therefore, the existence of an SPA agreement does not guarantee that FDA will file (accept) a new drug application (NDA) or biologics license application (BLA), or that the trial results will be adequate to support approval,” it adds. “Those issues are addressed during the review of a submitted application; however, it is hoped that trial quality will be improved by the SPA process.”

 

In rare cases, FDA may rescind an SPA agreement. However, it says that since 1997, there have been more than 1,000 SPA agreements and less than 1% have been rescinded. “However, newly available scientific knowledge in the form of data or other information, or a reevaluation or improved understanding of relevant scientific knowledge, may challenge or cause the scientific community and FDA to question or reject previously held assumptions or beliefs supporting an earlier decision and agreement on an SPA,” the guidance says. “FDA may rescind an SPA agreement when the division director determines that a substantial scientific issue essential to determining the safety or efficacy of the product has been identified after the trial has begun.” A substantial scientific issue may include:

 

·         Identification of data that would call into question the clinical relevance of previously agreed-upon efficacy endpoints.

·         Identification of safety concerns related to the product or its pharmacological class.

·         Paradigm shifts in disease diagnosis or management recognized by the scientific community and FDA.

·         The relevant data, assumptions, or information provided by the sponsor in the SPA submission are found to be false statements or misstatements, or are found to omit relevant facts, such that the clinical relevance of critical components of trial design is called into question, or appropriate safety monitoring and human subject protection is affected.

·         Failure of a sponsor to follow the protocol that was agreed upon with FDA (e.g., change in endpoint or population). The primary endpoint is chosen to ensure that efficacy is appropriately measured, and that the results of the trial will be clinically meaningful and interpretable. Identification of the patient population reflects consideration of who may potentially benefit from the product in the context of the proposed drug dose and schedule. Changes in these or other critical design parameters may adversely affect the ability to interpret the results of the trial and affect appropriate safety monitoring and human subject protection. While failure of the sponsor to follow the protocol may not preclude approval of the product based on review of the submitted data, it can form the basis for rescission of the SPA agreement.