The overarching goal of the Special Protocol Assessment Draft Guidance for Industry May 2016 (HHS, FDA, CDER, & CBER) is to improve the quality of new drug applications (NDAs) and biologic license applications (BLAs) by providing more certainty in the clinical protocol design process. Among its several purposes, the Special Protocol Assessment (SPA) affords an opportunity for the FDA and product sponsors to reach agreement, prior to study initiation, on the design of clinical trials intended to form the primary basis for an efficacy claim in a product marketing application. For sponsors, the overall value of an SPA is tied to the benefits gained by receiving preliminary input and agreement from the FDA on protocol design. By reducing uncertainty and thereby mitigating risk for the sponsor, an SPA can serve as a beneficial and valuable tool to accelerate late-stage drug development programs.

SPA Submission and Review Process

Protocols eligible for SPA agreement include:

• protocols for trials intended to form the primary basis of an efficacy claim
• animal carcinogenicity protocols
• drug substance and drug product stability protocols
• animal efficacy protocols for studies intended to provide primary evidence of effectiveness required for approval or licensure for products developed under the animal rule
• any necessary trials to prove biosimilarity and/or interchangeability)

The SPA guidance recommends submission of an SPA request at least 90 days prior to study initiation.  During the PDUFA-mandated 45-day SPA review period, the FDA evaluates protocols for “adequacy and acceptability of critical elements of overall protocol design and analysis” and the sponsor and the FDA attempt to negotiate a mutual agreement on a finalized study plan. It is not uncommon for SPA reviews to extend beyond 45 days and to comprise multiple review cycles, so sponsors should plan accordingly.

At the end of the review period, the FDA provides a response to the sponsor, including an assessment of the protocol, agreement or nonagreement with the proposed protocol, and answers to the sponsor’s relevant questions.

Further Considerations with SPAs

An SPA agreement may not be reached with the FDA. However, if an SPA agreement is reached, it will become an official part of the sponsor’s development plan record.

• What is the likelihood of reaching an SPA agreement and eventually submitting it as part of an NDA/BLA?
• For an estimation of the answer to this question, agreement was reached on 132 of the 532 SPAs submitted to the FDA’s Office of Hematology and Oncology Products (OHOP) between January 2003 and January 2013, with just 23% of agreed upon SPAs reaching NDA/BLA submission as of the date of publication. Of the remaining not-submitted SPA agreements, 33% of trials did not demonstrate a benefit for the study drug, 20% are still recruiting patients, 12% were not conducted, 8% have completed accrual and are awaiting results, and the status of 4% is unknown (Maher et al. 2014).

SPA Rescission and Controversy

While an SPA agreement indicates the FDA has established that a sponsor’s proposed study is adequately designed to support the FDA acceptance criteria for their NDA or BLA, an SPA does not guarantee a successful outcome for the product application. SPA agreement recission may occur if the sponsor does not fully adhere to the agreed-upon protocol or if final trial results are not supportive.  Even if the trial is carried out as planned and the agreed-upon endpoints are successfully met, the FDA may still refuse to file or approve the application.

Conditions for SPA Agreement Changes

Once the FDA and a sponsor enter into an SPA agreement, there are two conditions for changes to the SPA:

1. Written agreement between FDA and the sponsor, or
2. The FDA’s division director determination that “a substantial scientific issue essential to determining the safety or effectiveness of the drug has been identified after the testing has begun.”

The FDA’s interpretation and enforcement of the latter of these two conditions has been the source of some highly publicized controversies.

SPA Case Study

In 2013, the FDA rescinded an SPA agreement with Amarin Corporation to expand the existing indication of their severe hypertriglyceridemia drug, Vascepa®, to include patients with elevated triglyceride levels.  The FDA and Amarin entered into an SPA agreement for Vascepa in 2009.  Amarin successfully executed the clinical trial and met the endpoints which were agreed upon in the SPA. Based on the positive outcome of their trial, Amarin submitted an NDA and the FDA accepted the application for standard review. The company subsequently announced that the FDA had approved Vascepa for the treatment of elevated triglycerides in adult patients. However, during the review of Amarin’s NDA submission, the FDA determined that in the time since the protocol for the expanded indication SPA was agreed, new scientific evidence had come to light which cast significant doubt on the meaningfulness of the study’s clinical endpoints. As a result, FDA rescinded the SPA agreement with Amarin and issued a Complete Response Letter informing Amarin that they would need to provide direct evidence of reduction in cardiovascular events in order to make such a claim. After exhaustive and repetitive legal bids for repeal of the rescission, Amarin and the FDA eventually reached a settlement agreement allowing for “truthful and non-misleading” promotion of off-label use for Vascepa.

The Amarin Vascepa SPA rescission controversy along with the reported low likelihood of reaching a consensus with the FDA could threaten to diminish the perceived value of such agreements. The FDA updated the original SPA Guidance in May 2016 and addressed SPA rescission concerns by highlighting that less than 1% of the 1,000+ SPA agreements which have been issued since the Food and Drug Modernization Act of 1997 (FDAMA) was enacted have been rescinded. The updated guidance also clarifies the FDA’s definition of a “substantial scientific issue essential to determining the safety or effectiveness” for which the FDA has the ability to rescind an SPA agreement. Specific examples of substantial scientific issues include, but are not limited to:

• 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 the FDA

While helpful in outlining the types of new information the FDA may consider significant enough to merit rescission of an SPA, the guidance examples provided are worded such that their usefulness as clear and predictive guidelines is limited. Moreover, the guidance also identifies “an evolving understanding of protocol design; knowledge obtained from ongoing clinical trials; and accrual of data regarding similar product development programs” as additional scientific and medical innovations which could potentially merit SPA rescission. Without a more detailed and specific description of what qualifies as a substantial scientific issue, uncertainty surrounding the SPA program will persist.

Is an SPA Right for You?

SPA agreements provide distinct advantages but may not always be the most appropriate option. An SPA significantly mitigates risks in the clinical trial design process by enhancing the overall predictability and certainty of the drug development program. However, the SPA process can often take several rounds of FDA review before agreement is reached and the FDA may require a more robust trial design than what would have otherwise been considered adequate, which could result in unnecessary delays and increased costs. As with all aspects of drug development, a sponsor should carefully weigh their priorities before entering into an SPA agreement with the FDA.

The path to a successful SPA involves thorough preparation and seamless execution. Premier Consulting has extensive experience developing successful SPA agreements with the FDA and can help navigate the uncertainty surrounding SPAs. Contact us for well-informed strategic recommendations for the effective use of an SPA in a drug product development program.