FDA Revises Guidance on Special Protocol Assessments, Attempts to Reduce Uncertainty

By James E. Valentine & Alexander J. Varond –

FDA recently issued draft guidance, entitled “Special Protocol Assessment,” which, when finalized, will replace FDA’s 2002 final guidance by the same title. At 23-pages long, the draft guidance is much more thorough than its predecessor (only 11 pages) and warrants attention. The draft guidance provides a detailed overview of the policies and procedures adopted by CDER and CBER for special protocol assessment (SPA). SPA is a mechanism through which sponsors seek to reach an agreement with FDA on the size and design of certain types of studies to assess whether the studies have the ability to adequately address scientific and regulatory requirements. According to the draft guidance, CDER has issued more than 1,000 SPA agreements since the program was established in 1997.

Before initiating certain studies, including pivotal Phase 3 studies, a sponsor may submit a study protocol to FDA under the SPA program to obtain feedback about the sufficiency of the study’s design to support the development program and ultimately the product’s marketing application. Federal Food, Drug, and Cosmetic Act (FDC Act) § 505(b)(4)(B)&(C). FDA recommends that an SPA request, including specific questions about the proposed protocol, be submitted at least 90 days prior to the anticipated start of the study. In reality, a sponsor should submit its protocol much earlier than this, as the process is often subject to delays and potentially lengthy negotiation.

The Agency generally responds to SPA requests within 45 days. If agreement is reached on the design of the study, FDA will put the agreement in writing as part of the development plan’s administrative record which indicates that the study is appropriately designed to produce the type of data that could support the sponsor’s application. Otherwise, FDA will issue a “No Agreement Letter” discussing specific design parameters with which FDA does not agree. As we discuss below, even if an agreement is reached and the study is carried out as planned and meets its predefined objectives, FDA has the ability to rescind an SPA agreement for a number of reasons, including on the basis of a “substantial scientific issue” such as a “paradigm shift in disease diagnosis or management.”

The following protocol types are eligible for an SPA:

• 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 for licensure for products developed under the animal rule;
• Protocols for clinical trials or studies intended to form the primary basis of an efficacy claim, regardless of the product development phase (g., Phase 2 or Phase 3); and
• Protocols for clinical studies necessary to prove biosimilarity and/or interchangeability.

FDA’s draft guidance includes the following significant changes:

• Clarifies the types of protocols eligible for SPA, adding:
  • Animal rule efficacy protocols intended to support approval under part 314 subpart I, and part 601 subpart H, for drugs and biological products, respectively; and
  • Protocols intended to support approval of a biosimilar biological product;
• Provides greater detail about the content of an SPA submission; and
• Clarifies FDA’s process for rescinding an SPA agreement.

We discuss this last change in greater detail below.

Rescinding an SPA Agreement

In drug development, a predictable regulatory framework is key to facilitating investment in new, innovative therapies by industry and investors. The SPA program was introduced by Congress in response to industry concerns that late changes in personnel or thinking within a review division could serve to impose new requirements on study design despite general agreement at an EOP2 meeting and long after a study had been initiated. The SPA program was designed to provide an additional level of certainty about the adequacy and acceptability of specific critical elements of overall protocol design to ensure that the trial conducted under the protocol will support regulatory requirements for approval. However, for some time stakeholders have raised concerns about FDA’s procedures for adhering to its commitments under an SPA agreement, especially in instances where there may be inconsistent interpretations of the underlying science supporting an SPA (see BIO statement here). Each time a commitment is rescinded by FDA – particularly for studies that are near completion or complete – the value of the SPA process is eroded.

FDA’s authority to rescind an SPA agreement is set out in FDC Act § 505(b)(5)(C), which prescribes that, once an SPA agreement has been agreed to, the division director may only change or rescind the SPA if “a substantial scientific issue essential to determining the safety or effectiveness of the drug has been identified after the testing has begun.” Despite this broad statutory standard, FDA’s May 2002 SPA guidance document did not provide any insight into what the Agency would consider as a suitable basis for rescinding an SPA.

The recent example of FDA rescinding an SPA agreement late in the conduct of the trial for Amarin’s drug, Vascepa, demonstrates the type of scenario that has lead to diminished confidence in the SPA program (see our previous post for additional background on Amarin). Vascepa is approved to treat patients with severe hypertriglyceridemia (>500 mg/dL), and Amarin sought to expand its indication to include patients with “persistently high” triglycerides (>200 and ≤ 500 mg/dL). Amarin and FDA negotiated an SPA agreement in 2009 for a single Phase 3 clinical trial to support this new indication. The Amarin study met its primary endpoint, demonstrating statistically significant reductions in triglyceride levels in subjects on Vascepa when compared with the subjects on placebo. The study also met its secondary endpoints. Amarin subsequently submitted a supplemental application for the expanded indication, believing it had satisfied all of FDA’s requirements per the SPA agreement.

In 2013, after Amarin submitted its supplemental NDA, FDA convened an Advisory Committee during which the Agency called into question the clinical validity of the Phase 3 study endpoint of triglyceride lowering, despite having agreed to that endpoint in the SPA. According to FDA, data from several cardiovascular outcomes trials, some of which were reported out after the SPA was entered into by FDA and Amarin, had cast doubt on the clinical benefit of triglyceride lowering while also fostering uncertainty as to whether a reduction in triglyceride levels would translate into a reduction in cardiovascular events, in general. FDA asked the Advisory Committee to weigh in on whether Vascepa’s triglyceride lowering effect was sufficient to approve the drug for use in patients with persistently high triglycerides. The Advisory Committee voted against approval of Vascepa for that indication. Subsequently, FDA rescinded the SPA agreement and issued a complete response letter to Amarin indicating the need for data showing a reduction in cardiovascular events.

The rescission of the Amarin SPA agreement, largely because it was a fully competed and positive trial, led to heightened public scrutiny of the scope of FDA’s basis for rescinding an SPA. It appears FDA, in its new May 2016 draft guidance document, is attempting to assuage some of this concern by providing its view of what can constitute a “substantial scientific issue essential to determining the safety or effectiveness of the [product].” The draft guidance document provides three examples of such scientific issues:

• Identification of data that would call into question the clinical relevance of previously agreed-upon efficacy endpoint (this is what happened with the Amarin SPA agreement);
• Identification of safety concerns related to the product or its pharmacological class; and
• Paradigm shifts in disease diagnosis or management recognized by the scientific community and FDA.

FDA, Draft Guidance, SPA Guidance for Industry, 20 (May 2016).

FDA also identifies areas of scientific and medical innovation that could affect regulatory aspects of drug development (and presumably could be the basis for rescinding an SPA agreement):

• An evolving understanding of protocol design;
• Knowledge of ongoing clinical trials; and
• The accrual of data regarding other product development programs in the same, or similar, pharmacological class.

Id. at 22.

While these examples are descriptive, they neither clearly establish predictable guidelines for what qualifies as a substantial scientific issue nor clarify when such an issue is essential to determining the safety and effectiveness of the drug. If anything they appear to claim nearly unlimited discretion on the part of FDA to rescind SPA agreements. Without plainly delineating the boundaries for the SPA program, and in turn providing a more predictable framework, it is unlikely sponsors will have greater confidence in their reliance on an SPA agreement.

Comments on the Draft Guidance are due by July 5, 2016 here.