May 11, 2010 (Washington DC) — Both the diabetes drug rosiglitazone (Avandia, GlaxoSmithKline) and the way the FDA has handled concerns about it took another severe battering at a recent US Congressional hearing of the committee that has jurisdiction over the FDA.
The House Appropriations Subcommittee on Agriculture, Rural Development, Food and Drug Administration, and Related Agencies met on April 28 to discuss the report on rosiglitazone released in February by the Committee on Finance of the US Senate.
The report , by Sens Max Baucus (D-MT) Charles Grassley (R-IA), concluded that there are "serious health risks associated with Avandia." It also criticized the structure of the FDA, particularly the fact that those who make decisions about drug approvals are the same experts who must later oversee drug safety.
Introducing the Congressional hearing, subcommittee chair Rep Rosa DeLauro (D-CT) said: "This report poses several troubling questions for this subcommittee. Most obviously, if Avandia is unsafe, how did it ever get on the market in the first place? For that matter, why is it still on the market, right now? And what does the case of Avandia tell us about the FDA's current ability to conduct its drug safety responsibilities?" .
Several commentators explained to heartwire that this subcommittee, while providing the FDA with its funding, will probably not overrule any decisions made by the agency on individual drugs. It is more concerned with ensuring that drug-safety reviews are being conducted properly. The FDA is due to review the safety of rosiglitazone again at an advisory committee meeting in July. This Congressional hearing, along with the recent Senate report, is seen as a building up of pressure on the FDA to take some action at that advisory committee meeting.
Painting a Sorry Story
The subcommittee heard testimony from three experts: Grassley, Dr Harlan Krumholz (Yale University School of Medicine), and Dr Sidney Wolfe (Public Citizen). All painted a very sorry picture of rosiglitazone, the FDA, and the system that allows companies to suppress negative clinical data on their drugs.
Grassley summarized the main findings of his report--that GlaxoSmithKline knew years before Nissen's meta-analysis was published that rosiglitazone may increase the risk of MI but suppressed that information and that safety experts at the FDA had also expressed concerns about the drug, but these were ignored by the leaders at the agency .
Wolfe, who has petitioned for rosiglitazone to be banned, reviewed all the data that suggest the drug to be harmful and called again for the Thiazolidinedione Intervention with Vitamin D Evaluation (TIDE) trial to be halted . "The TIDE trial continues to recruit patients despite a lack of clinical equipoise, exposing thousands of high-risk patients with diabetes to a drug with an unfavorable safety profile and no clinical advantage over its comparator. It is almost certain that prospective study subjects are deprived of the opportunity to make a fully informed decision, because the consent form does not present an accurate portrayal of existing safety concerns," he said. He added that the trial could continue only with the misplaced objective of proving that rosiglitazone is indeed more dangerous than pioglitazone (Actos, Takeda) and that "the price of such definitive proof will almost certainly be measured in the lives of study subjects who have been incompletely informed about the available evidence regarding the risks and benefits of participation."
Similarities to Vioxx
In his testimony , Krumholz drew parallels between the cases of rosiglitazone and rofecoxib (Vioxx, Merck), saying that for both drugs safety concerns would have been discovered earlier had all the raw data from clinical trials, which was held by the companies, been made available. He called for increased transparency in the clinical-trial research process, with raw data files being made available, and if concerns are raised then, an independent evaluation of the data should be conducted by at least two groups of experts and the results made available to the public.
Krumholz added that better communication of drug data to patients was also needed. "Many patients assume that treating their diabetes will improve their outcomes by reducing their risk of many health problems, including heart attacks and heart failure. They would be surprised to learn that the opposite seems true," he said. Referring to rosiglitazone, he added: "I do not know why any clinician would prescribe a medication that is associated with such risk when so many alternative drugs are available on the market. So why does the drug remain among the most popular for diabetes?"
So What Happens Next?
Communications director of the agriculture subcommittee, Ellis Brachman, explained to heartwire that the purpose of the hearing was to look at the specific and general issues that have been raised by the Avandia saga, with focus on the way that the drug was evaluated, the questions that have been raised, and the second review of the drug by the FDA.
"Sen Grassley's committee had issued a report on it, and as the agriculture committee has jurisdiction over the FDA, it also needed to investigate the issues raised. This hearing is part of that process--to see what the problems are at the FDA," Brachman commented.
He added: "This committee decides on funding and oversight issues concerning the FDA. We don't tell the FDA what to do when it comes to decisions on specific drugs, but we want to know if the processes used by the FDA to make such decisions are working or not. If there are problems with the process, we can recommend that it is changed," he elaborated.
Brachman said it is unlikely that the committee will make any immediate changes or recommendations based on just this one hearing and that it was more part of an ongoing process. Any changes recommended will more likely be incorporated into the next Agricultural Appropriation bill.
Nissen: Congress Is Watching FDA Closely
Dr Steve Nissen (Cleveland Clinic, OH), author of the meta-analysis that started the whole rosiglitazone controversy, commented to heartwire : "This committee is responsible for FDA appropriations. They don't run the FDA, but they do control the purse strings. They are looking into how well the FDA is doing its job, and the issue of Avandia is one of the issues they are investigating."
Nissen added: "With the change of government, there have been big changes in management at the FDA recently. Clearly, the old management made extremely poor leaders and they made some catastrophic errors. But now there is a new era, and everyone wants to know whether the new leadership can turn the giant battleship around to promote and protect public health."
He said the current Avandia hearing of the agricultural subcommittee could be construed as a message to the FDA that "Congress is watching you closely. . . . They are telling the FDA that they will take very seriously the outcome of the forthcoming FDA Avandia advisory committee meeting and they hope that the FDA makes the right decision for public health and safety."
"Time to Learn About the Problem Before Acting"
Krumholz commented to heartwire : "I was really impressed by the House members--they were eager to learn about how this process could be improved. The hearing was bipartisan and bicameral--everyone was aligned--something rare in DC these days. I did not detect an effort to find blame for past problems, but more of an interest in finding better approaches going forward. This is how it should be--time to learn about the problem before acting."
Krumholz added: "I believe the subcommittee and those who testified respect the FDA and the challenges they face. The comments were made in the spirit of improving drug safety--separating the divisions that approve drugs from those who subsequently evaluate them, strengthening the postmarketing surveillance, freeing the companies from having to pay for FDA services, and so on. When the commissioner next testifies in front of the committee I would anticipate that she will be asked about these issues. The comments by the representatives are a message to the FDA that there are issues that concern them."
Is There Enough Evidence for Withdrawal?
Asked to comment on the hearing for heartwire , Dr Sanjay Kaul (Cedars Sinai Medical Center, Los Angeles, CA) said he didn't think there was anything new or revelatory in the testimonies. "The fundamental problem here is that there is a genuine debate among the parties regarding the safety signal with Avandia. One party, including some members of the Office of Drug Safety at the FDA, is convinced that the information is actionable, whereas others in the FDA and in academia can see shades of gray in the evidence. How can one be sure which one is right?" Kaul asked.
He added: "My position is that there is not enough evidence to make a decision. We need a definitive trial, and that trial--TIDE--is ongoing. If TIDE is stopped because it is unethical to continue, then the drug will have to be withdrawn, but if TIDE is allowed to continue, the consent form needs to point out that that there has been a suggestion of increased risk of MI and cardiac death with this drug. There is no easy solution for Avandia. But to avoid this happening in the future, we need to bring in life-cycle evaluation. If a drug is approved on surrogate end points, the company must be forced to conduct a clinical-outcomes trial or approval will be withdrawn."
Kaul also noted that the FDA has asked the Institute of Medicine to weigh in on the quality and quantity of evidence needed for withdrawing rosiglitazone from the market, and that report is expected to be delivered before the advisory committee meeting in July.
GlaxoSmithKline issued a statement reiterating points the company has made repeatedly in the past, emphasizing that the best evidence to date comes from RECORD, which showed no safety issues with Avandia, and that judgment should be reserved until the FDA-directed TIDE trial has been completed and analyzed. "In the years since the FDA convened the joint advisory committee meeting to address questions about the cardiovascular safety of Avandia, six large, prospective, randomized, clinical trials have reported results. None of these randomized clinical trials . . . shows a statistically significant association between Avandia and myocardial infarction or other ischemic cardiovascular events," the statement reads. GlaxoSmithKline also rejects suggestions made in the February Senate report that the company failed to present an accurate, balanced, or complete view of the currently available information on Avandia. "A fair examination of the company's record will show that GlaxoSmithKline has been diligent in its efforts to thoroughly study the safety and effectiveness of rosiglitazone and to widely communicate that information to governments, regulatory authorities, scientific peers, physicians, and others in a variety of ways," it says.
Nissen has previously disclosed receiving research support through his institution from Pfizer, AstraZeneca, Novartis, Roche, Daiichi-Sankyo, Takeda, Sanofi-Aventis, Resverlogix, and Eli Lilly and reports that he consults for many pharmaceutical companies and requires them to donate all compensation directly to charity. Kaul has previously disclosed having served as an advisor or consultant for Novo Nordisk and Hoffmann-La Roche. Krumholz reports being on a scientific advisory committee for United Health Care.