Wondering what the FDA's special protocol assessments (SPAs) are all about, but too afraid to ask? Last year's Drug Information Association's (DIA) 45th annual meeting was especially helpful, as representatives of Bristol-Myers Squibb, GlaxoSmithKline (GSK) and the FDA's Office of New Drugs within the Center for Drug Evaluation and Research (CDER) presented on the topic.

An SPA, they explained, is a declaration from the FDA that an uncompleted Phase III trial's design, clinical endpoints, and statistical analyses are acceptable for support of regulatory approval later, after the trial has concluded. It's the FDA's way of saying: If you execute this trial exactly as you promise you will, and the data are there, this drug will get approved.

And that's bind. Unless the science around the research changes or a new public health concern emerges that impacts the agreement, the FDA has to honor it once the Phase III trial is done. That is, as long as the sponsor has followed the agreed-upon protocol to the letter, and the data support the efficacy and safety of the product.

“It's an opportunity to take some specific steps under SPA to cement some agreements as best as can be done during the dynamic development process,” said David Cocchetto, V.P. of U.S. regulatory affairs for GSK. During the session, he quoted a blogger as saying, “An SPA is about as binding a deal as you can get with a government agency.” Cocchetto laughed, and agreed.

45-Day Turnaround

Not only that, but SPAs happen fast, he explained. The FDA asserts that, if the sponsor duly completes the request package, the agency will turn around a SPA in 45 days. That includes answers to the sponsor's questions about the protocol and detailed comments on it.

SPAs have been around since the 1997 reauthorization of the Prescription Drug User Fee Act (PDUFA). What brought them into being? Said Cocchetto, “Interest among industry and FDA in adding more certainty around review time lines on a very specific and limited list of drug development documents.” Here's the SPA guidance document.

The areas of research in which SPAs are available are: carcinogenicity; final protocol stability; and primary efficacy studies. “All three of these require a considerable amount of time, quite large investments—both on the industry side and the FDA side—and it's important to get these right to set the stage for new drug applications that can be accepted,” said Cocchetto, who has helped GSK put together many such requests.

Three Categories

An SPA is not affected by any personnel changes at FDA, unlike other reviews. “This type of scientific feedback should not ebb and flow as personnel change over time,” said Cocchetto. “That's an important feature of the agreement.” Kim Quaintance, associate director for regulatory affairs with the FDA's Office of New Drugs, explained that about half of all SPAs are for clinical/primary efficacy studies, about a third relate to carcinogenicity studies, and a small percentage apply to final protocol stability.

There are 15 different divisions within FDA that review SPA requests. Each has a different approach since, as Quaintance notes, “one size doesn't fit all.” Some divisions can be very interactive. Others, not so much. Some give sponsors a second chance after their first try for a SPA doesn't work out. Others don't. Quaintance's advice to sponsors during the DIA session, though, applies to most divisions working on SPAs, she said.

Advance Notice

When should a sponsor let the FDA know that it plans to send a SPA request? The ideal time is at the end-of-Phase-II (EOP2) meeting, said Quaintance. For carcinogenicity studies, the FDA asks that sponsors notify the appropriate office 30 days before sending a SPA request. “These are special cases, and they need that extra time to gear up for the process,” said Quaintance.

If the protocol is especially complex, like for adaptive design? The same advice applies: it's best to let the appropriate division know 30 days in advance of sending your package, said Quaintance.

The SPA request package should include the protocol, background information and supporting studies. Don't leave anything out, Quaintance advises. “If there's data missing, we're going to have delays,” she said.

No Drafts

And sponsors, whatever you do, don't submit a draft protocol. “Our staff don't like to see the word 'draft' stamped on a protocol that's submitted,” said Quaintance. “That tells us you haven't decided what you're going to do, and the review staff has a major concern about starting down a very intensive 45-day review on something that they think might change because you haven't really considered where you are with it.” If a sponsor makes changes to the protocol along the way, the clock resets, and another 45 day interval begins.

Quaintance also suggested to sponsors that they carefully plan the questions they want to ask the FDA. Make them specific, she said, and about the protocol only. There's no set number specified in the guidance. Both Quaintance and Cocchetto said, “Two dozen is too many.”

And submitting all the background information is better than holding some of it back. “For all of this to work, it requires an incredible amount of cooperation and transparency by both us and you,” said Quaintance.

Mission Accomplished

Suppose 45 days pass and you receive an approved SPA. Now what? Quaintance said sponsors can probably look forward to a smooth road to final approval. But not necessarily.

“Approval is going to be based on the data and our assessment of risk versus benefit,” she explained. “And while SPAs generally focus on the efficacy side of things, safety data matters. Yeah, the trial may have been designed and may have played out like we agreed to, but the data aren't working. It always comes down, at the end of the day, to the data.”

What if the paperwork comes back saying “No Agreement” at the top? Quaintance suggests reading and carefully considering the review team's comments. Then sponsors can request a “Type A meeting,” which is limited to a discussion of the protocol and what it still lacks. Sponsors hoping for Type A meetings must also submit a revised protocol in response to the team's comments on the first protocol. It must be noted, though, that some divisions within FDA allow Type A meetings; others don't. Sometimes when you get your “No Agreement” notice, that's the end of the road, SPA-wise.

Another common scenario, said Quaintance, is that a sponsor gets the SPA but decides it doesn't want to conduct the trial exactly as stated. “That's okay,” says Quaintance. “There's this feeling of we made FDA go through a 45-day review and now we're changing our minds and boy are they going to be mad. But that's not the case.”

She advised sponsors in that situation to simply send in their revised protocol when starting their study, “But be sure and let us know: Hey, this isn't exactly what we agreed to,” said Quaintance, adding, “You're not sunk; if your alternative pathway is scientifically sound and of course if your data are supportive, your not following the agreement is not going to be a barrier to approval.”

by Suz Redfearn

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