The third advisory committee to assess the cardiovascular safety of GlaxoSmithKline PLC’s Avandia (rosiglitazone) indicated that a randomized clinical trial demonstrating CV risk is needed to remove a diabetes drug from the market.

That conclusion is a relief for both sponsor and regulator to affirm their approach since questions about the product’s safety surfaced six years ago. And while the outcome is a function of the additional data that has come to light since then, it is also a result of the changing culture surrounding drug safety.

When an advisory committee last convened to consider Avandia safety in 2010, it reviewed the RECORD trial, which employed metformin/sulfonylureas as the comparator. Panelists questioned that study’s findings because of its open-label design and possible biases in how the cardiovascular events were submitted for adjudication, and FDA ultimately kept the product on the market with significant restrictions.

The 2010 meeting fell during what appears to have been the high watermark for use of Risk Mitigation and Evaluation Strategies at the agency. The following year FDA would begin to eliminate “MedGuide-only” REMS and would issue new REMS at a much lower pace Also see "FDAAA Impact Analysis (Year 5): The REMS Paradox" - Pink Sheet, 8 May, 2013..

The 2010 advisory committee also represented the peak for the number of votes to withdraw the product – and the highest number of panelists serving on an Avandia advisory committee (see chart).

The Ebb And Flow Of Withdrawal Votes On Avandia Advisory Committees

The 2013 go-round on Avandia centered on the re-adjudication of cardiovascular events in RECORD. The re-adjudication by Duke Clinical Research Institute reassured members of the Endocrinologic and Metabolic Drugs and Drug Safety and Risk Management Advisory Committees during the June 5-6 meeting that as many events as possible were factored into the study analysis and the findings are reliable Also see "Avandia Committee Gives Split Vote To Drug, But FDA Clear Winner" - Pink Sheet, 10 June, 2013..

Residual concerns remained, however, as the re-adjudication could not eliminate flaws in the study itself. Panel members called for a randomized, placebo-controlled clinical trial to answer the safety question definitively, but acknowledged that such a trial is unlikely to be feasible (see related story, Also see "Avandia Panel Wants Another Trial: Pipe Dream Or Post-market Benchmark?" - Pink Sheet, 17 June, 2013.).

Sanjay Kaul, UCLA, noted that the RECORD trial design only allowed a comparison of cardiovascular safety to metformin/sulfonylureas and the signal for cardiovascular risk has been found only in placebo-controlled trials. “The issue still remains whether this drug is definitively proven to be safe from the cardiovascular point of view.”

If RECORD had been a randomized, controlled, blinded trial conducted earlier in use of the drug it could have been relied upon for a definitive answer, according to Susan Heckbert, University of Washington in Seattle. But since it did not, she noted, the cardiovascular signals found by meta-analyses and observational studies must be considered.

“I feel that we are still dealing with the cardiovascular safety signal regarding rosiglitazone and I am not convinced, even by what I think was a very nice re-adjudication. Those do not allay all my concerns about that trial,” she said.

The re-adjudication provided a better understanding of the RECORD data and confidence in its reliability, but the design remains flawed, Robert Smith, Brown University, noted, and “I am unwilling to write off the meta-analysis data.”

The re-adjudication found hazard ratios of 0.86 (068, 1.08 for mortality; 1.15 (0.82, 1.62) for myocardial infarction; 0.82 (0.57, 1.18) for stroke; and 0.97 (0.79, 1.18) for Major Adverse Cardiac Events, a combination of the three events, according to FDA’s statistical analysis of the re-adjudication outcomes.

An FDA analysis of 16 epidemiologic studies comparing cardiovascular risk of rosiglitazone versus Takeda Pharmaceutical Co. Ltd.’s Actos (pioglitazone) found that rosiglitazone was associated with a statistically significant increased risk of myocardial infarction (an odds ratio of 1.16, 95% CI: 1.07-1.24); heart failure (OR of 1.22, 95 CI of 1.14-1.31) and all-cause mortality (OR of 1.14, 95% CI: 1.09-1.20).

Despite the remaining concerns, the panel voted 24-1 against withdrawing rosiglitazone from the market, a drop from the 13 of 33 members who sought that move in 2010 Also see "Avandia Can Be Saved With New Warnings and REMS, Advisory Cmte. Says" - Pink Sheet, 14 July, 2010.. Of the eight panelists who participated in all three meetings over the years, most consistently favored the least restrictive option (see related story,[A#00130617007]).

OND, OSE Cool Their Debate

The latest rosiglitzone advisory committee was unlike the two previous sessions when disagreement between the Office of New Drugs and the Office of Surveillance and Epidemiology showed their preference for and against the drug’s withdrawal Also see "Anatomy Of The Avandia Decision: FDA’s Woodcock Splits The Difference Between OND, OSE Views" - Pink Sheet, 4 October, 2010..

This could be due to the results from GSK’s assessment of the rosiglitazone Risk Evaluation and Mitigation Strategy that shows the REMS is meeting its goal. Both patients and prescribers demonstrated good knowledge about the potential risk for myocardial infarction and patients indicated understanding of MI symptoms and the need to seek medical help, Joyce Weaver, a senior drug risk management analyst in OSE, told the committee. Fewer than 3,000 patients are enrolled in the restricted distribution REMS.

Dissention came from within OND as Thomas Marciniak, a medical team leader in the Division of Cardiovascular and Renal Products, objected that the re-adjudication was not independent because the data and the funding came from GSK and FDA should have supplied DCRI with the data.

Center for Drug Evaluation and Research Deputy Director for Clinical Science Bob Temple explained that the agency did not have all the data submitted to DCRI, and in any event, all trial data comes from the sponsor, which owns it Also see "Avandia Trial Re-Adjudication Beyond FDA’s Abilities, Agency Officials Say" - Pink Sheet, 6 June, 2013.. The committee did not raise the issue again.

During the 2010 advisory committee, Marciniak presented his own adjudication of the RECORD study using different endpoints and populations than those pre-specified by GSK to show the trial provided no reassurance of rosiglitazone’s safety, an argument accepted by panel members Also see "FDA's Marciniak vs. Unger: Cardio Experts Divided On GSK's RECORD Study" - Pink Sheet, 19 July, 2010..

Marciniak appears to be headed toward a position as an outspoken internal critic of FDA’s safety efforts. He recently went to the Wall Street Journal with complaints that the agency is not taking a tough enough stance with regard to possible lung cancers associated with angiotensin receptor blockers.

FDA quickly responded on its website that there is no evidence the blood pressure medications increase patients’ cancer risk. The advisory committee’s lukewarm response to Marciniak’s critique of Avandia suggests that his concerns about ARBs are unlikely to gain broad traction.

FDA “Not Going To Go Down That Alley Right Now”

One of the outcomes of the lengthy and public debate over rosiglitazone safety is FDA’s 2008 guidance on evaluating the cardiovascular risk of diabetes drugs. In light of the advisory committee deliberations, Kaul asked “if FDA deems that the cardiovascular risk is no longer a concern, is it going to go back and revisit the diabetes guidance because the cardiovascular risk [of rosiglitazone] was the motivation behind the guidance?

Office of Drug Evaluation II Director Cuirtis Rosebraugh characterized the question as “really an interesting question, but … we’re not going to go down that alley right now.”

The panel discussion suggested that a single component of MACE is not as important as the whole, unless it is mortality.

Kaul noted that the re-adjudication excludes a hazard ratio of 1.3 for all outcomes except myocardial infarction, but mortality is in the right direction and that outcome is insensitive to bias.

“In particular, the mortality data are very credible and, I think, very reassuring,” Marvin Konstam, Tufts University, said. “They are on the correct side of unity and I believe that should significantly influence our overall thinking.”

All-cause mortality, “which I think in this situation serves as an estimate of net clinical benefit,” and MACE, the primary endpoint in the guidance for assessing cardiovascular risk in diabetes drugs, had upper bounds that “were well below thresholds of concern,” noted William Hiatt, University of Colorado.

Addressing the higher hazard ratio for myocardial infarction, Arthur Moss, University Rochester, said “I find it difficult to take MI out of context and not do an analysis where it’s MI or death, whichever comes first. In the analysis these are co-variants and concomitant conditions and so if do you look at death as a single endpoint that’s the important thing. If you look at MI as the single endpoint but death is not increased I find that difficult” to put credence on.

Without clear guidance from FDA, sponsors of products with potential CV issues should still prepare for the possibility of lengthy studies, but should take some assurance from the latest advisory committee review of Avandia that those studies likely will serve to anchor the product, not become an albatross.

Avandia Review Endorsement Aided By Good Data, Cultural Shift On Safety

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