Testimony on Rosiglitazone (Avandia) Safety
July 14, 2010
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 what
can 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 rosiglitazone, 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 rosiglitazone is less safe than
pioglitazone, and if so, whether that additional risk might somehow be
justified by a particular therapeutic advantage. No one – not even those advocating continued
use of rosiglitazone – has suggested that it might confer a therapeutic
advantage over pioglitazone, and so the question reduces to a very simple one: Is rosiglitazone less safe than
pioglitazone? 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 ischemic
cardiovascular events (where the differences between rosiglitazone and
pioglitazone 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 rosiglitazone is less safe than pioglitazone. 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 rosiglitazone is less safe than
pioglitazone, 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
rosiglitazone, as has been the case for too long, should not be considered
innocent until proven guilty.
What should happen
in 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 rosiglitazone really is more
dangerous than pioglitazone, 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 rosiglitazone has nothing to offer over pioglitazone 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 when
so many other regulatory decisions (troglitazone is a particularly relevant
example here) are based upon case reports and case series.
If the advisory committee
meeting concludes with a recommendation that rosiglitazone 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 rosiglitazone 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 rosiglitazone, 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 calculation
no 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 those
of OSE (previously the Office of Drug
Safety) when there is a conflict between the two. The most common circumstance
is 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
rosiglitazone as shown in the following two slides:
In October 2008, Public Citizen petitioned the FDA to ban rosiglitazone 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 of
OSE 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.