FDA has neither the information, the process nor the resources to re-adjudicate clinical trial data, agency officials told the Endocrinologic and Metabolic Drugs and Drug Safety and Risk Management Advisory Committees June 5 during day one of a two-day session to reconsider the cardiovascular risk of GlaxoSmithKline PLC’s Avandia (rosiglitazone maleate).

That reconsideration is based on re-adjudication of the cardiovascular events in the RECORD cardiovascular outcomes trial by Duke Clinical Research Institute Also see "Avandia Advisory Committee: Can Poking Old Wounds Be Good For FDA?" - Pink Sheet, 4 June, 2013.. The fact that the re-adjudication was funded by GSK has been among the central critiques of its value.

In response to questions from patient representative Rebecca Killion about whether FDA could have conducted the re-adjudication and the reliability of data used for the DCRI evaluation, Center for Drug Evaluation and Research Deputy Director for Clinical Science Bob Temple noted that FDA lacked a considerable amount of data made available to DCRI.

“We only get certain case report forms. We don’t get them all,” Temple pointed out. Under FDA regulations, sponsors must include with their drug applications case report forms (CRFs) for patients who died during a clinical trial or who discontinued the study because of an adverse event. FDA can request additional CFRs, or waive the requirement for their submission.

That information was only a portion of the data DCRI had to work with. GSK sent the researchers case report forms for all 4,447 patients in the study. “These were paper case report forms, as well as all the electronic data sets that we derived from the case report forms,” Alex Cobitz, executive director of clinical development at GSK for the metabolic pathways and cardiovascular therapy area, said.

The company also provided 1,643 endpoint packages from the original adjudication of CV events, documents that originally were part of the CRFs and endpoint packages, some e-mail correspondence and all serious adverse event case files and related materials prepared by GSK pharmacovigilence staff, he said.

Even if FDA had all the information, it would have to determine how to use it. Within the Division of Metabolism and Endocrinology Products, which reviewed rosiglitazone, there is “no standard process” for conducting such a re-adjudication, outgoing Director Mary Parks noted.

Parks is moving up to become the deputy director of the Office of Drug Evaluation II, and remains active in the metabolism division as part of a transition period while the agency seeks a replacement Also see "FDA’s Parks Expands REMS Portfolio With Move To ODE II Deputy Slot" - Pink Sheet, 31 May, 2013.

“For the most part, when we review data, we don’t review it in a blinded fashion,” Parks explained. “Information comes in to us. We have the datasets. We have the patient ID numbers. So it’s very hard for us to say we could sit here and do that. … We’d have to set up a process very similar to what DCRI and what other AROs [academic research organizations] have done.”

Nor does the Division of Cardiovascular and Renal Products routinely take on such an assignment, noted Ellis Unger, director of the Office of Drug Evaluation I, which includes DCRP. It would be a “tall order” to get the resources to adjudicate every outcomes trial, he said.

GSK reports that it paid DCRI almost $4 million for the re-adjudication project. Those funds included $2.99 million in 2012 and $791,097 in 2011.

Sometimes FDA staff digs into trials, Unger noted, but there has to be a “map,” a protocol approved at very high levels of management. And when that happens, it generally is for a few sites and not for an entire trial, he said.

Trial Data Belongs To Sponsors

In the case of ensuring data integrity, there is also no getting around the fact that the data comes from the drug companies that own it, the agency officials told the committee.

FDA, rather than GSK, should have provided clinical trial data to DCRI to ensure its integrity, Thomas Marciniak, a medical team leader in the Division of Cardiovascular and Renal Products, had suggested in his critique of the re-adjudication. David Cooke, Johns Hopkins University, asked for a comment on that approach.

Temple pointed out that ultimately, the data FDA has comes from the sponsor. If the agency had supplied DCRI with the data for the re-adjudication, it would have had to ask GSK for the missing pieces, he noted. “We didn’t have it so [GSK was] going to be the source of it.”

“I think there’s an underlying thought that maybe the data [GSK] sent to us was perfect and then it was modified for later” when it was sent to DCRI, he said. “But our data came from GSK as well.”

The re-adjudication was a post-marketing requirement imposed by CDER Director Janet Woodcock when she decided to allow rosiglitizone to remain on the market with a Risk Evaluation and Mitigation Strategy Also see "Anatomy Of The Avandia Decision: FDA’s Woodcock Splits The Difference Between OND, OSE Views" - Pink Sheet, 4 October, 2010..

Parks noted that the requirement gives the sponsor a legal impetus to stay honest. “In some ways, the post-marking itself is telling GSK that they must provide that information to DCRI. So it should be the expectation that [with] this requirement under FDAAA [FDA Amendments Act of 2007], GSK is bound to give full information to DCRI.”

Avandia Trial Re-Adjudication Beyond FDA’s Abilities, Agency Officials Say

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