Avandia Advisory Committee Re-Review Reflects Well On FDA

The FDA advisory committee re-review of cardiovascular safety risks with GlaxoSmithKline's Avandia (rosiglitazone) will not end calls from agency critics to create a separate drug safety center. However, the transparency of internal scientific disputes on display at the July 13-14 meeting and the committee's recommendations could take some ammunition away from those who assert the Center for Drug Evaluation and Research has given short shrift to safety issues.

The mixed recommendations of the Endocrinologic and Metabolic Drugs and Drug Safety and Risk Management Advisory Committees also provide ample justification for FDA in any final decision it makes on Avandia's fate.

If agency leaders decide to pull Avandia off the market, they could argue that more panel members, 12 of 33, voted for withdrawal than any of the other four regulatory options presented. On the other hand, if FDA allows Avandia to stay as is, or to impose new label warnings or use restrictions, leadership could point out that 20 members, more than half of the committee, supported keeping the drug available in some fashion.

Traction For OSE, Vindication For OND

During the first advisory committee review of Avandia's CV safety in July 2007, only one of 23 members voted that the drug's risk/benefit profile did not support continued marketing.

That meeting was marked by a very public split between the Office of Surveillance and Epidemiology and Office of New Drugs over the CV risks and regulatory future of Avandia, with OSE arguing the drug should be withdrawn and OND believing data were insufficient to warrant such an action (¹ (Also see "CDER Offices Go Public With “Fundamental Disagreement” Over Avandia" - Pink Sheet, 6 Aug, 2007.)).

This time around, OSE's arguments gained considerable traction, as revealed by the 12 votes in favor of withdrawal. After the meeting, the drug's critics were quick to point out that even those panelists who did not support withdrawal nevertheless saw a need for stronger labeling and use restrictions.

Yet, the outcome can also be seen as a vindication of OND's longstanding view that Avandia should remain available as a treatment option for type 2 diabetics.

OND's decision-making on Avandia has repeatedly been called into question, not only by OSE staff but also by Sen. Charles Grassley (R-Iowa) and Rep. Rosa DeLauro (D-Conn.).

In the days leading up to the advisory committee, DeLauro said an updated meta-analysis by the Cleveland Clinic's Steven Nissen and a Medicare cohort study by OSE Associate Director for Science and Medicine David Graham, both of which suggested increased CV risks with rosiglitazone, left no doubt in her mind that Avandia should be pulled (² (Also see "Avandia Safety Rhetoric Ramps Up Ahead Of Advisory Committee Review" - Pink Sheet, 5 Jul, 2010.)).

DeLauro, who chairs the FDA Agriculture appropriations subcommittee, issued a statement immediately after the advisory committee meeting making clear she is unwilling to drop the issue.

"Given the compelling evidence revealed in the weeks leading up to this advisory committee meeting, it is incomprehensible that 20 committee members still would vote to keep Avandia on the market," she said. "I intend to ask FDA some serious questions as to whether the advisory committee proceedings were a result of the agency's ongoing internal debate and in some way helped to ensure that Avandia would not be pulled from the market."

She added that the upcoming regulatory decision on Avandia "will be the defining moment for the agency under the Obama Administration."

Another staunch advocate for Avandia's withdrawal has been Public Citizen's Sidney Wolfe, a member of the Drug Safety and Risk Management Advisory Committee, who petitioned FDA to ban the drug. Wolfe did not participate in the Avandia re-review as a panel member but gave a presentation during the open public hearing urging market withdrawal.

Praise For Woodcock

The meeting outcome also would appear to bolster the reputation of CDER Director Janet Woodcock.

In a Jan. 2, 2008 decisional memo that formalized regulatory actions announced in November 2007, Woodcock said rosiglitazone should remain on the market with a "black box" warning about myocardial infarction risk and GSK should be required to conduct a randomized trial assessing Avandia's CV safety against that of the competing thiazolidinedione, Takeda's Actos (pioglitazone). The memo was included among the 765 pages of agency background material released in advance of the committee meeting.

The postmarketing safety trial, known as TIDE, (Thiazolidinedione Intervention with Vitamin D Evaluation), began enrolling in May 2009. The advisory committee recommended it should continue even though accrual has been slowed by the debate over rosiglitazone's safety (³ (Also see "Avandia's TIDE May Come In Smaller" - Pink Sheet, 14 Jul, 2010.)).

In a December 2009 memo, Woodcock directed OND and OSE to evaluate newly available data on rosiglitazone's CV safety with the aim of bringing the issues back to the advisory committee in Spring 2010.

Woodcock attended the entire two-day committee re-review, and she won praise from some panelists for her handling of the Avandia issues.

"I really want to congratulate Dr. Woodcock for the way she handled it and brought it to this meeting, which I think was an enormously successful and positive move by the FDA," said temporary voting member and cardiologist Marvin Konstam, Tufts-New England Medical Center.

The advisory committee proceedings also should reflect well on FDA Commissioner Margaret Hamburg, who, along with Principal Deputy Commissioner Joshua Sharfstein, has made increased transparency behind regulatory decisions a key priority since joining the agency.

The Avandia meeting served as a very public forum for Hamburg's transparency agenda, with an extraordinary airing of diverging opinions from two cardiology experts within OND on whether GSK's RECORD study absolved Avandia of CV harm (see ⁴ (Also see "FDA's Marciniak vs. Unger: Cardio Experts Divided On GSK's RECORD Study" - Pink Sheet, 19 Jul, 2010.) ).

So important is the Avandia matter to the agency, its credibility and future that Hamburg, who is expected to be the final arbiter of Avandia's fate, briefly spoke at the meeting.

"It is not typical for an FDA commissioner to address an advisory committee ... but with the amount of attention that this meeting and this issue has been receiving I thought it important to speak with you for a few minutes as this session begins," Hamburg said.

For some meetings, "all of the FDA opinions line up nicely with each other, the issues are clear and all of the agency's scientists are in agreement," she said. "As you know, that is not the case today. Rather than try to summarize or synthesize these competing perspectives into a set of bland documents or presentations, we thought it best for you to read their words for yourselves, hear from the key scientists at the agency directly and factor their perspectives into your thinking."

She urged the committee to "follow the science, wherever it leads, and the rest will fall into place."

Separating OSE

Like DeLauro, Grassley, the Senate Finance Committee ranking member, is unlikely to lessen his scrutiny of Avandia now that the advisory committee has rendered its verdict for a second time.

On the morning of July 13, Grassley and Finance Committee Chairman Max Baucus (D-Mont.) made a splash by releasing more than 150 pages of documents they alleged show that GSK failed to timely publish studies that found CV problems with Avandia, and that the drug was part of the company's "ghostwriting" program for medical journal articles (⁵ (Also see "Grassley And Baucus Turn Up Heat On GSK With Attack On Avandia Data Handling" - Pink Sheet, 13 Jul, 2010.)).

The document was a follow-up to a February report that criticized the handling of Avandia's CV safety by FDA and GSK (⁶ (Also see "Avandia Advisory Cmte. Is FDA's Primary Response To Congressional Pressure" - Pink Sheet, 1 Mar, 2010.)).

During the run-up to passage of the FDA Amendments Act in 2007, Grassley failed to win support for a provision to create a separate drug safety center within FDA. Nevertheless, he has continued to push the idea, with support from such voices as Wolfe and Nissen. The idea is expected to get renewed attention in negotiations over the next reauthorization of the Prescription Drug User Fee Act.

The political pressure on FDA did not go unnoticed by the Avandia advisory committee members.

"There's been a lot written in the last few days and weeks about the FDA being broken," said Konstam, who voted for marketing withdrawal. "As someone who has worked with the FDA for over 20 years, I don't believe it's at all broken, and I think this meeting has been an enormous testimony of that."

"I don't think it needs any reorganization from the outside. I think that perhaps some of the people inside the FDA might work on getting along better together, but maybe they can figure that out inside their walls."

- Sue Sutter ( ⁷ [email protected] )