The Guidance for Industry: Special Protocol Assessment (SPA) was issued in May of 2002, with the express purpose of enabling the Food and Drug Administration (FDA) to provide input into the design of certain studies critical to marketing approval prior to initiation. By meeting prior to the start of a study, FDA and sponsors can streamline the approvals process because the scientific and regulatory requirements have already been agreed upon. In 2009, FDA released Guidance for Industry: Formal Meetings Between the FDA and Sponsors or Applicants, also developed to encourage sponsor-FDA interaction prior to initiating Phase 3 programs. The timing and strategy may differ from sponsor to sponsor, depending on the details of each program. This article will provide strategic recommendations for the effective use of SPAs in product development, and whether or not a sponsor would need to participate in both guidance processes or only one.
The Successes and Failures of the SPA Experience
Since the implementation of the 2002 SPA Guidance, examples of accelerated development have been heralded as evidence of the success of the process. However, there have been at least as many stories painting the SPA process as difficult and time-consuming. Lack of success may be multifactorial, but typically result from one or more of the following problems.
First, Phase 3 protocol design is among the most difficult steps in any product development program, and needs time and resources to be completed thoroughly. Answers to investigational product development questions, such as minimum effective dosage, appropriate subject population and a clear and quantifiable definition of success, in a Phase 2 program are extremely important in ensuring the primary clinical endpoint of your Phase 3 protocol design is properly identified and vetted – clinically, scientifically, statistically and regulatorily. Failure to provide FDA with these details in the initial SPA request can lead to a failure of the SPA process.
By viewing FDA as a confirmatory body, and not a product development consultant, sponsors can begin to see the level of due diligence required to make an SPA successful. If clinical endpoints are not rock solid, alternate approaches such as an end of Phase 2 (EOP2) meeting or a Type C meeting would allow sponsors to resolve uncertainties before embarking on an SPA.
Next, refining the questions in the SPA request so they provide clarity and concision is important. With few opportunities to interact with FDA, it is important to craft high-level questions very thoughtfully. Ideally, protocols will be fully vetted with solid statistical analysis plans that can be presented to the FDA with just one question, “Does the agency agree that the protocol design will potentially result in data required for FDA review for approval of the proposed indication.” If FDA does not agree, they will provide input needed to address existing issues.
The third scenario occurs more than you might think, and can be solved by open-minded listening to suggestions. Some sponsors, consciously or not, submit SPAs with no intention to negotiate with FDA on sound scientific grounds. Monetary constraints can certainly be at the root of this, but failure to hear advice with an open scientific mind can lead to protracted discussions of limited value.
How to Get the Most Out of an SPA
FDA must have some knowledge of the development program prior to the submission of an SPA. Products from outside the United States or from companies with creative new formulations sometimes conduct Phase 3 early in US development, meaning that FDA must provide feedback on Phase 3 protocols while other approval rate limiting activities, such as Chemistry, Manufacturing and Controls (CMC), take place.
Sponsors should be aware that the FDA must have some knowledge of the development program before an SPA can be submitted. This can typically be accommodated by requesting a Type B (Pre-IND or EOP2) meeting to discuss questions regarding other disciplinary elements of your development program, prior to its implementation in the US. If the Type B meeting helps finalize the design of the Phase 3 study, the design can then be submitted in the IND application itself. If a safety or clinical pharmacology study must be conducted prior to opening the IND, the SPA can help finalize the design and analysis plan of the Phase 3 study in parallel with the conduct of the Phase 1 study.
Considering Alternatives to SPA
There is one alternative to SPA meetings which can help streamline the overall development process. When sponsors are seeking input on a Phase 3 protocol design and proposed analysis, the full protocol can be submitted as an appendix to your EOP2 meeting package thereby eliminating the need for an SPA. The question relating to the protocol contained in the EOP2 meeting package would be exactly the same as that proposed above for the SPA communication. The final EOP2 meeting minutes obtained from FDA will document their agreement on the Phase 3 study design in the same way as an SPA.
When multi-disciplinary questions exist, dividing EOP2 interactions into two separate meetings to focus on specific questions might be the best approach. For example, one meeting might focus on the marketing application requirements for the preclinical and CMC activities, while another would discuss only the protocol design and analysis suggestions offered by FDA. By splitting up the meetings, sponsors can ensure that enough time is available to sufficiently answer questions in each discipline.
To SPA or Not To SPA?
By providing FDA with a clear picture of how the results from a successful study will support the label claim for the intended indication, the SPA process can certainly be a valuable way to speed product development. Without this clear picture, though, SPA is not recommended for all development programs.
If it is not yet possible to submit thoroughly vetted clinical protocols and statistical analysis plans, it would be a better use of sponsor resources to gather this information prior to submitting the request – even if that means using alternative FDA meeting options first. Without these clear details, meetings will be unproductive, draining sponsor and FDA time.
David Shoemaker, Ph.D., is the senior vice president of Research and Development at Rho, where he ensures efficient compliance with applicable regulations and guidance documents. Shoemaker holds a Bachelor of Science degree in Chemistry from Trinity College in Connecticut and a Ph.D. in Physiology and Pharmacology from Duke University.