Special Protocol Assessment, a Blessing or a Bane?

At last December’s ASH conference, Calistoga Pharmaceuticals presented encouraging data on CAL-101. The company announced that is was developing a protocol for a pivotal study in chronic lymphocytic leukemia patients. In an interview with Xconomy’s Luke Timmerman, Calistoga’s CEO, Carol Gallagher, noted that the company hadn’t sought a written agreement from the FDA on the study design—what’s known as a Special Protocol Assessment—because that could take six months or more, and the company is racing to stay ahead of competitors.

Why do some companies choose to proceed directly to Phase III while others choose the SPA process?

As an extension to the PDUFA Act of 1992, the FDA in 1997 agreed to review three distinct classes of time-line critical protocols within 45 days of submission. Of these, product stability and animal carcinogenicity do not get nearly as much attention as the third class; phase III clinical trial protocols. This is logical, since Phase III data will form the primary basis for a future efficacy claim.

Since its introduction, the Special Protocol Assessment or SPA has quickly become a buzzword in pharma-land and a standard feature in press releases. A frequent question in the board room and from investors and analysts when discussing a planned Phase III program is “do you have an SPA for that study”?

It is not difficult to see why an agreed upon SPA would be desirable to have. The qualifier “agreed upon” is crucial, however, as an SPA is, in itself, nothing more than the FDA’s comments on a proposal, delivered within a 45 day time limit. An SPA can be appealing to the industry since it is sometimes difficult to get timely feedback from the agency, Once FDA has indicated it accepts the protocol, a company will assume it has a written contract with the reviewing division assuring acceptance of the proposed efficacy claim if the data fit the prospectively defined success criteria. This is perceived to reduce risk by eliminating the fear that a positive outcome in Phase III might not result in approval if the trial design is not acceptable to FDA. Obviously that kind of risk minimization is alluring to analysts and board members. But, as always in life, things are not as straightforward as they may seem on first glance.

First of all, it must be clear that, even if FDA will never admit to it, the agency does not like the SPA process for two reasons:

1. The process is a drain on scarce reviewing resources
2. FDA has an aversion to written agreements that may need to be revisited in the future if circumstances or medical knowledge change

Therefore, if a sponsor chooses to pursue an SPA, it is essential that the filing be prepared carefully with unambiguous questions so that FDA does not reject it on the basis of a formality. A flawed filing can make you lose time or, worse, get a wrong answer.

It is also important to be realistic about the SPA time frame. While, FDA has to respond to an SPA in 45 days, they certainly do not have to come to an agreement in that time frame. FDA can reply by simply stating that they do not agree and provide their reasons. They do not have to provide an acceptable alternative and can put the onus straight back on the company.

In this way the SPA process has, at times, become a protracted early battleground for future efficacy claims. Very often the disagreements are centered on the primary outcome variable and intended statistical analysis. Of course those are intimately related to future label claims and size of the study, possibly the most vital elements in a development program.

It is important to remember, that there is no obligation for a company to use the SPA process for a phase III pivotal study. A sponsor can certainly save time by moving directly into pivotal trials if one is willing to rely on the feedback from the end-of-Phase II meeting. Unfortunately, a decision to forgo the SPA may be difficult to explain convincingly to investors and directors.

What are the take home messages?

• Make sure you really need an SPA. It may take longer to obtain one than you think.
• If you choose to pursue an SPA, be unambiguous in the questions you ask and meticulous in your filing. Be realistic about the timing.
• Be prepared to explain your reasoning to investors and board members.

What do you think? Under what circumstances does it make sense to pursue an SPA?

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