A number of scientists with greatly different backgrounds can come up with completely different assessments.
– Richard Leakey
One question that we hear frequently is: Can we apply for a Special Protocol Assessment (SPA) for our Phase 3 trial? The answer is always “Yes, you can apply.”…but should you? That is an entirely different question.
So, what is an SPA and why are so many people interested in them? As I’ve mentioned before, SPAs are an important option to consider during drug development. An SPA is a way to come to an agreement with the FDA on the design of the following types of protocols:
- Animal carcinogenicity
- Final product stability
- Pivotal Phase 3 trials
The most interesting SPAs, at least the most talked-about, are the ones for Phase 3 trials. Google will gladly tell you that no one issues press releases for the first two. The reason is that Phase 3 trials are the make-or-break for marketing applications. Having an SPA can give you, and let’s not forget about investors, confidence in your program.
Getting FDA agreement (read: buy-in) on your Phase 3 protocol can be critical to your development plan. It means the FDA is familiar with your program and feels that the protocol is adequately designed to address the endpoints proposed. However, don’t fall into the trap of thinking that SPAs are all flowers and rainbows. Agreement does not mean guaranteed; agreement does not equal eventual approval of the drug/biologic; and agreement does not mean fool-proof. The term used when talking about SPA agreements is “binding”…which really means “binding unless something changes”.
Ok, I must confess that I actually sat down to write about the pros and cons of SPAs, but (after staring at a screen full of my disconnected SPA-related anecdotes) it occurred to me that each program is so specialized, so contextualized, that coming up with ‘general’ pros and cons is nigh-impossible. So instead, let me impart a few tips on requesting SPAs and reaching agreement with the FDA:
- Ask yourself if you should apply for an SPA. There are obvious benefits to having an SPA, but there are also risks. Think “binding” and then think “be careful what you wish for.”
- Talk to the FDA early and often. This is always good advice, of course. (If you don’t believe me, ask the FDA.) However, the SPA guidance specifically mentions the importance of the FDA understanding the developmental context of the protocol (e.g., Section A.3 on page 5). Besides, you really wouldn’t want the FDA to analyze your protocol from a cold reading.
- Respect the FDA’s time. By requesting an SPA, you are asking the review teams to put themselves on a tight timeline. Discuss the possibility of an SPA with the FDA well before you plan to request one.
- Ensure that your protocol has been carefully reviewed before presenting it to the FDA. Once you have an SPA, you will want to strictly limit potential protocol revisions. As I’m sure you know, there are a million and one reasons to amend a protocol. Any amendment must be submitted to the FDA, as usual, but be aware that amendments can affect status of your SPA.
- Related to the above point, identify which aspects of your protocol design are critical (i.e., you feel should be unchanged) and which points are more flexible. And then be ready to think creatively about the less-flexible parts.
- Be prepared that the FDA may ask for an advisory committee review of your protocol. This isn’t terribly common at the moment, but the mood in the air is that we will all be seeing more advisory committee meetings in the future.
Don’t re-invent the wheel. Talk to people who have successfully navigated the SPA process (ahem).
