A Special Protocol Assessment is no guarantee of FDA approval, or even a smooth development path.

That's the lesson Debiovision is learning regarding the study it designed with the agency under an SPA in response to a 2004 "approvable letter" for Sanvar . Vapreotide is proposed for use as adjunctive therapy to endoscopic intervention for control of acute esophageal bleeding as a result of portal hypertension (¹ Also see "H3 Pharma Plans First Quarter Response To Sanvar IR "Approvable" Letter" - Pink Sheet, 4 January, 2005.).

Though the results of SPA-designed trials are still subject to FDA review, sponsors can typically be assured that the trial design agreed upon with the agency through the SPA process is at very least a viable path to proving the drug's efficacy. Debiovision, however, was left May 19 defending the trial before an FDA advisory committee that ultimately voted that what little efficacy signal could be detected for the drug was inconclusive and unsupported due to a flawed trial protocol (² Also see "Did A Special Protocol Assessment Actually Hurt Debiovision’s Sanvar?" - Pink Sheet, 19 May, 2009.).

The agency and its Gastrointestinal Drug Advisory Committee cited a laundry list of problems in the study. They said the open-label, single-arm design introduced bias, the study was not powered for statistical significance, there was no appropriate historical control against which to compare the new results, and because the endoscopic standard of care had changed (from sclerotherapy to band ligation), the trial populations were not comparable and any efficacy seen with Sanvar could have been attributed to the treatment advances rather than to the drug.

The committee questioned why FDA signed off on the trial, noting that the agency did agree to the open-label, single-arm design of the study, and that at the time the protocol was being discussed, the standard endoscopic treatment was already moving from sclerotherapy to band ligation, meaning the trial procedures would differ.

"I think what we're hearing are things we should have looked for and didn't," said FDA Office of Drug Evaluation III Director Julie Beitz, adding that if they did it again, "we would be a lot smarter about how we do it."

Hindsight Is 20/20, But Heed Prospective Warnings

For the firm's part, one clear warning sign should have been more strongly heeded: disagreement between FDA statistical and medical reviewers on the study's ability to address the statistical deficiencies specified in the approvable letter.

In SPA correspondence with the firm, medical reviewers agreed that "there is no need to demonstrate statistically robust results," stating that "We will judge the results of your proposed single arm clinical trial based upon clinical significance" and that "We agree with the proposed study design based upon clinical consideration, and we appreciate that the study design lacks statistical rigor."

However, agency statisticians involved in the SPA process disagreed at the time, concluding that the study design was not acceptable to prove Sanvar's efficacy.

During the advisory committee review, panel member James Neaton, University of Minnesota, noted the distinction between "clinical" and "statistical" significance as suspect: "I don't understand the difference between statistical and clinical guidance ... that this study was going to be looked at qualitatively for clinical significance as opposed to statistical significance - that's just out in left field as far as I'm concerned."

The panel's industry representative Debra Silberg, from AstraZeneca, understood Debiovision's decision to proceed with the trial despite different agency opinions. "When industry comes to FDA, we take your word for what your suggestions are. It appears in this case that there may have been a disagreement, but overall, the study design was agreed on with FDA and the sponsor," she said. "So how is the sponsor supposed to respond now to this criticism when they are taking the advice of FDA as a whole, not just one aspect? It's fine to have 20/20 hindsight, but we have to do studies prospectively."

At the end of the day, the trial just couldn't produce the efficacy needed for the committee to recommend approval, and they had little to offer as to suggestions of how future studies could resolve the issue (see ³ Also see "Sanvar Salvation May Lie In Reanalyzing Data From Flawed Trial, Panel Says" - Pink Sheet, 25 May, 2009.).

- Jamie Hammon (j.hammon@elsevier.com)

Good Trials Built On Sturdy Protocols, Not Just SPA Agreements With FDA

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