Special Protocol Assessments: The Database
A great deal of interest surrounds companies that have an active Phase 3 clinical program underway and the assessment of their future potential regulatory risk when subsequent New Drug Applications (NDA) are reviewed. One measure which has been designed to mitigate some of this regulatory risk is the Special Protocol Assessment (SPA) agreement between a sponsor (often drug companies) and the Food & Drug Administration (FDA), which first issued guidance on the process in 2002.
What does a SPA mean for regulatory risk?
A SPA is a written agreement between the FDA and the trial sponsor that a Phase 3 study conducted according to the agreed-upon protocol design, size, study end points, and outcomes will be sufficient, from a regulatory stand point, to file for an efficacy claim in a subsequent marketing application. A SPA does not guarantee that a trial will be successful, nor does it guarantee regulatory success. However, if a trial is successfully conducted according to a SPA agreement, meeting all pre-specified efficacy end points, it is highly unlikely that the FDA will reject a marketing application on the basis of requiring more clinical information. In essence, a SPA is a measure to mitigate clinical efficacy risk. It does not, however, mitigate issues pertaining to preclinical toxicology, manufacturing, and other clinical safety issues that can result in a marketing application receiving a Complete Response Letter (CRL).
Protocols that can be submitted for Special Protocol Assessment include animal carcinogenicity studies, final product stability studies, and clinical protocols for Phase 3 trials whose data will form the primary basis for an efficacy claim, if the trials had been the subject of discussion at an end-of-Phase 2/pre-Phase 3 meeting with the FDA’s review division. In some cases, the division agrees to such a review because the division is aware of the developmental context in which the protocol is being reviewed, and questions are being answered. The clinical protocols for Phase 3 trials can relate to efficacy claims that will be part of an original New Drug Application or biologics license applications (BLA), or that will be part of an efficacy supplement to an approved NDA or BLA clinical protocol for Phase 3 registration studies.
How does a sponsor obtain a SPA?
Typically, a sponsor must submit a written request to either the Center for Drug Evaluation and Research (CDER) or the Center for Biologics Evaluation and Research (CBER) detailing the goals of the protocol and overall development context at least 90 days prior to the projected start of the study, following an end of Phase 2 meeting. The Agency will then review the protocol and provide comments related to protocol design, study conduct and execution, data analysis, and implications for labeling within 45 calendar days of the receipt of the initial request. The Agency’s assessment will be based primarily on the questions posed by the sponsor, the underlying data, assumptions, information described by the sponsor, and relevant Agency policies and guidance documents. It is quite common for the Agency and sponsor to discuss revisions and changes to the protocol prior to the issuance of a formal response via a Type A meeting.
Type A meetings can be requested via a formal process after an applicant has submitted the initial request for a SPA and should be scheduled to occur within 30 days of receipt of request for such a meeting. Typically, the CBER or CDER division director who receives a meeting request will determine whether to hold the meeting and will respond to the sponsor or applicant by granting or denying the meeting within 14 days of receipt of the request for Type A meeting. Sponsors will provide the Agency with specific objectives, goals and review materials prior to the meeting. During the live discussion, and prior to the conclusion, both sides will summarize the important discussion points, agreements, clarifications, and action items. The FDA is the official record keeper of the meeting and will issue finalized minutes to all attendees within 30 days of the meeting. If new issues require clarifications that were not discussed at the initial meeting, this necessitates a new Type A request.
Following the receipt of the minutes, a sponsor can submit a revised protocol, at which point the agency will consider this as a new SPA request and will act on the revised version within the prescribed 45 day timeline. Any subsequent amendments to the agreed upon protocol will render the SPA invalid, unless the agency has a chance to review and approve any such changes.
Hence, in a best case scenario, the process to obtain a SPA could take as little as 45 days, but when Type A meetings and revisions are required, it can take upwards of 120 days to reach mutual agreement.
What has been the regulatory success rate for SPA applicants that submitted an NDA or BLA in 2012?
In my estimation, there have been approximately 114 PDUFA decisions relating to NDA/BLA and sNDA/sBLA’s in 2012. Of these, 97 applicants received drug approvals and 17 received complete response letters (CRL). We’ve put together a case study of these five applicants, which offers thorough analysis of the process and outcomes. For this cohort of approvals, n=5 applicants submitted clinical data for studies that were completed pursuant to a SPA agreement. For a full analysis, see the link below to see a detailed case study of some SPA trials and their regulatory outcomes.