By Harsh Sancheti, MSPS, MSRS, Ph.D., Medical Writer at Cato Research and
Joanne McNelis, Ph.D., Scientist at Cato Research
FDA Revises Guidance on Special Protocol Assessments
What is a Special Protocol Assessment (SPA)?
SPA is a process where a study sponsor and the FDA reach agreement on the critical components of a stability protocol, a pivotal clinical trial, or animal carcinogenicity study to determine if their design and size adequately addresses the specific scientific and regulatory requirements. An FDA agreement on the SPA indicates that the agency agrees 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 ensure that the trial conducted under this protocol has the potential to support the regulatory requirements for a future marketing application.
Importantly, the SPA process is beneficial for the sponsor to gain insight into FDA’s thinking and get agreement with the FDA on critical aspects of the protocol; CDER has issued more than 1000 SPA agreements since the program was established in 1997.
What is Included in the May 2016 SPA Draft Guidance?
With the aim of improving the quality and appropriateness of SPA requests, and the resulting interaction with sponsors, FDA addressed several key areas of concern in the new draft guidance to reflect alterations in the regulatory landscape and policy since its 2002 predecessor. The new guidance expanded the protocol eligibility for SPA and provided clarification on the overall submission process. Specifically, the topics addressed include:
- Clarifying which protocols are eligible for SPA
- Adding animal rule efficacy protocols intended to support approval of drugs and biological products
- Adding protocols intended to support approval of biosimilar biological products
- Providing greater detail about the content of an SPA submission
- Clarifying the process for rescinding an SPA agreement.
What Protocols are Eligible for SPA?
The types of protocols that can be reviewed under an SPA are limited, and according to the 2002 guidance include: (1) Carcinogenicity protocols, (2) Final product stability protocols, or (3) Clinical protocols for Phase 3 trials whose data will form the primary basis for an efficacy claim. Perhaps the most significant revision to the May 2016 draft guidance was the expansion of eligibility for SPA. Consistent with new performance goals for SPA, mandated in the Prescription Drug User Fee Amendments of 2012 (PDUFA V) and with the Biosimilar User Fee Act of 2012 (BsUFA), efficacy protocols that meet the animal rule and protocols intended to support approval of biosimilar biological products will also be eligible, in addition to the previously accepted protocols.
Increased Details of the SPA Content and Process
The new draft guidance also describes in greater detail the procedures for submitting a request, the content of the request submission, the FDA assessment process, and the obligations the FDA has in responding to sponsors.
Before submitting an SPA Request, the FDA strongly suggests that the sponsor meets with the FDA to discuss the trial for its regulatory context. Under PDUFA V and BsUFA goals, a protocol will qualify for SPA only if the sponsor has had an end-of-phase 2/pre-phase 3 meeting or end-of-phase 1 meeting, as appropriate, or Biosimilar Biological Product Development (BPD) Type 2 or Type 3 meeting, respectively. The guidance states that the complete protocol and statistical analysis plan should be submitted along with “a limited number of specific questions about protocol design and scientific and regulatory requirements.” In particular, the FDA calls on sponsors to “identify unusual or potentially problematic aspects of the protocol” in the SPA request.
Typically, the agency reviews an SPA relatively quickly and is within 45 days. There are established procedures and timing for requesting an SPA. Both, CDER and CBER recommends submitting the SPA protocol to the Agency at least 90 days prior to the anticipated study starting date. The protocol should be complete, and enough time should be allowed to discuss and resolve any issues before the study begins. It must be noted that SPA will not be provided by the FDA after a study has begun and if they are evaluated by the FDA, it will not qualify for the 45-day time frame FDA review. The SPA protocol should be submitted as a separate amendment to the sponsor’s IND (with additional filing details listed in the 2002 guidance).
After completing the SPA review, FDA issues a letter including an assessment of the protocol, agreement or non-agreement with the proposed protocol and answers to the sponsors initiated questions. The FDA will address the critical elements to the protocol design. For example, the FDA may convey their agreement “with the proposed primary endpoint or sample size estimate, but might not include a detailed review of the case report form”. If a no‑agreement letter is issued, FDA will discuss the specific design parameters with which the FDA does not agree. In addition, the May 2016 draft guidance recommends that a Type A or Type 1 meeting be held to discuss outstanding issues.
The Benefits and Risks of an SPA
The SPA can be a very valuable process for a sponsor. It can provide additional assurance, above other regulatory guidance, that innovative clinical trial designs and study endpoints are adequate for marketing approval. When used appropriately, it can promote the use of novel approaches to drug development, potentially reducing the associated time and monetary costs. However, it should be noted that an SPA agreement is not binding in all circumstances. FDA’s guidance states, “an agreement may not be changed by the manufacturer or the agency unless through a written agreement of the two entities, or if FDA determines a substantial scientific issue essential to determining the safety or effectiveness of the drug”. The clause of substantial scientific issue is necessary to prevent the approval of drugs that are realized to have safety and efficacy concerns after new scientific information has come to light. In the past, the FDA has come under fire for changing SPA agreements late in clinical development, and for a lack of transparency of this process. Since the impact of rescinding an SPA agreement is so large — potentially setting a sponsor back years in clinical development and costing millions of dollars — the increased level of detail in the new guidance will be welcomed by drug developers. It is hoped by all stakeholders that the increased clarity of the SPA process provided in this draft guidance will foster a more useful interaction between sponsors and the FDA, and reduce the uncertainty and risk of the drug development process.
Comments on the May 2016 Draft Guidance are due by July 5, 2016 here.