Testimony of Sidney Wolfe, M.D.
Health Research Group of Public Citizen
and David Juurlink, M.D. Ph.D., FRCPC, Toronto
FDA Drug Safety and Risk Management and Endocrine and Metabolic Drugs Advisory Committee
Dose-response cure for PPAR gamma activation for rosi and pio
As can be seen in this slide, cardiac damage in dogs was found at exposure rations of only 1.2-times the human dose.
Focusing on whatcan and cannot be inferred from individual studies is a favorite pastime of academics, and it is an important exercise generally. But in the context of rosiglita zone, a detailed study-by-study critique (and in particular, dwelling on the largely uninterpretable RECORD study) runs the risk of distracting the committee from the far more important issue at hand. The fundamental question is whether rosiglita zone is less safe than pioglita zone, and if so, whether that additional risk might somehow be justified by a particular therapeutic advantage. No one – not even those advocating continueduse of rosiglita zone – has suggested that it might confer a therapeutic advantage over pioglita zone, and so the question reduces to a very simple one: Is rosiglita zone less safe than pioglita zone? Importantly, “safety”encompasses not just myocardial ischemic events, but also heart failure, stroke and death.
The committee has been tasked with answering nine questions. These questions are poorly constructed for two reasons. First, many of them focus specifically on is chemiccardiovascular events (where the differences between rosiglita zone and pioglita zone are least dramatic) rather than a more comprehensive definition of harm (where the differences are large.) Second,they are constructed in a way that forces committee members to provide a binary response in the face of continuous and imperfect data; alternately, you can admit uncertainty. The restrictive nature of these questions should not prevent the panel from addressing the key question of whether rosiglita zone is less safe than pioglita zone. For patients and doctors, this question is the important one, even though it is regrettably not among the nine posed of you.
Based upon the available data, the only honest answer to this question is “Probably, yes.” This answer is not dichotomous because it respects the uncertainty in the data. However, it accurately characterizes the fact that converging lines of evidence from RCTs, meta-analyses and observational studies provide an overwhelming message that rosiglita zone is less safe than pioglita zone, an assessment supported by strong biological plausibility. To be fair, however, the data do not permit certainty. If this were a criminal trial, the corresponding verdict would be “probably guilty.” Fortunately, since this is a scientific debate rather than a legal one, “probably guilty” is allowable, and rosiglita zone, as has been the case for too long, should not be considered innocent until proven guilty.
What should happenin the face of uncertainty? Some authorities have advocated establishing certainty for certainty’s sake –specifically, completion of the TIDE trial.This is a seriously misguided position that effectively puts study subjects at risk in an effort to prove that rosiglita zone really is more dangerous than pioglita zone, as the existing data suggests. Committee members may wish to consider whether they or a member of their family would volunteer for this trial, with the knowledge that rosiglita zone has nothing to offer over pioglita zone other than the distinct potential for additional harm. From a regulatory perspective, it is inconceivable that a randomized controlled trial should be necessary to inform decision making in light of such a large body of available evidence, particularly whenso many other regulatory decisions (troglita zone is a particularly relevant example here) are based upon case reports and case series.
If the advisory committeemeeting concludes with a recommendation that rosiglita zone be removed from the market and the TIDE trial terminated, no one suffers as a result, with the possible exception of those whose finances or reputations are linked to the drug’s fate. On the other hand, if the committee recommends that rosiglita zone remain available and the TIDE trial continue simply because the existing data are not truly definitive, a great many patients in the United States and around the world will continue to receive rosiglita zone, regardless of any additional warnings or restrictions on the drug’s use that might be imposed. Exactly how many patients will be harmed or die as a result of such a decision is unknown. Hopefully this is a calculationno one will ever have to make.
The decision-making process has, for too long, favored the conclusions of the Office of New Drugs (OND) over thoseof OSE (previously the Office of Drug Safety) when there is a conflict between the two. The most common circumstanceis one in which OSE decides a drug has risks outweighing its benefits and should be removed from the market. This is clearly illustrated in the case of rosiglita zone as shown in the following two slides:
In October 2008, Public Citizen petitioned the FDA to ban rosiglita zone and an expert committee of the American and European Diabetes associates stated that:
The future of the FDA’s effort to restore its damaged reputation concerning drug safety rests on the authority ofOSE to over-rule OND, and have it confirmed by the Commissioner, if OND resists taking a drug off the market when there is evidence as clear as in the present case. Given that the CDER Director, as exemplified by Dr. Woodcock, invariably sides with OND, not with OSE, there is an extremely strong case for moving OSE out of CDER into an independent and more empowered position within FDA, as urged by Senator Grassley, Congresswoman DeLauro and others. If not, we will continue to have more cases like Avandia, Darvon and Meridia that tarnish FDA, cause thousands of preventable deaths and injuries, and challenge the FDA’s place in the Public Health Service.