Avandia’s TIDE Is Stopped

Remember TIDE (Thiazolidinedione Intervention with Vitamin D Evaluation), the study that was designed to provide definitive results about the risk–or lack thereof–for myocardial infarctions and cardiovascular death from rosiglitazone (Avandia, Avandamet, Avandaryl; GlaxoSmithKline)?  It got underway in 2009.1

Enrollment of patients was sluggish, possibly because of the adverse publicity about rosiglitazone’s safety.2  Food and Drug Administration (FDA) epidemiologists David Graham and Kate Gelperin, arguing that GlaxoSmithKline had never proved that rosiglitazone was equivalent to pioglitazone (ACTOS, Takeda), called TIDE “unethical and exploitative.”2  Of course, this was disingenuous, since Drs. Graham and Gelperin knew full well both that TIDE was designed to prove that rosiglitazone was equivalent to pioglitazone and that they had newly minted the “standard” on which they were basing their arguments.  But even equivalence would not have been enough for Drs. Graham and Gelperin:  “That is, there must be equal evidence favoring both therapies.  But that is not the case here because no one has argued that rosiglitazone is safer than or preferable to pioglitazone.”2  So, Drs. Graham and Gelperin, is the standard equivalence, is it superiority, or is it flexible (whatever it takes for you to eliminate rosiglitazone)?

“Given the weight of evidence regarding cardiovascular risks with rosiglitazone, we believe that TIDE is an unethical study and that it was unethical before it was started,” opined Drs. Graham and Gelperin.  On the contrary, even then, the “weight” of the evidence against rosiglitazone was highly controversial,  I would argue that, ethically, head-to-head comparisons ought to be the norm.  Without them, drug choices, whether at the regulatory or the clinical level, are arbitrary opinions, rather than evidence-based decisions.  I would particularly argue that ethics required a study comparing rosiglitazone and pioglitazone, such as TIDE.

“In our view,” Drs. Graham and Gelperin continued, “the TIDE trial is unethical because it subjects human beings to unnecessary risks without any possibility of a meaningful, unique health benefit from rosiglitazone.”2  In the first place, such a question can only be answered by a direct comparison, such as TIDE, and in the second place, the standard for drugs is “safe and effective” for the intended use, not “meaningful, unique health benefits.”

“Patients bear the full burden of risk of AMI [acute myocardial infarction, “heart attack”], heart failure, and death, for the purpose of establishing with definitive certainty that rosiglitazone increases cardiovascular risk (the null hypothesis for the non-inferiority components of this trial), with no likely expectation of unique benefit.”  Really?  By definition, a “null hypothesis” is a hypothesis that the effect or difference is null–nothing.  To establish “that rosiglitazone increases cardiovascular risk” would require rejecting the null hypothesis of equivalency.  Obviously, these two either do not know what a “null hypothesis” is, or they are being dishonest.  Either way, they are discredited.

“Is it ethical to enroll patients in a clinical trial where the goal is to prove harm?” Dr. Graham asked during last week’s joint meeting of the Endocrinology and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee.3  Of course, this begs the question (a logical fallacy) that the goal was to prove harm.  It was not.  On the contrary, the main goal of the study was to prove that rosiglitazone was no worse than placebo, and then that it was superior to placebo for myocardial infarctions and cardiovascular deaths; the secondary goal was to prove that rosiglitazone was no more than 20% worse than pioglitazone (which was considered to have neutral effects).1  Drs. Graham and Gelperin should have known better; were they making things up to fit their agenda?

According to Dr. Graham, “The best” that participants could “hope for is to not get a drug that causes a problem.”3  Again, whether or not rosiglitazone causes problems, other than congestive heart failure–as pioglitazone does and as troglitazone (Rezulin, Warner-Lambert) did–can only be established by in a properly designed study, such as TIDE.

Drs. Graham and Gelperin’s criticism of the vitamin D component of the study was a red-herring–the same kind of distraction that they accused GlaxoSmithKline of using by including that part of the study.  While I believe that studies of vitamin D (actually, “hormone D”) need to be done, I agree that it was not relevant to a study of a drug that was under fire.  Instead of distracting from negative publicity about the risks of rosiglitazone, however, I believe that the vitamin D component was a distraction from conducting the essential rosiglitazone arm of the study.

In my opinion, it was the conduct of the likes of Drs. Graham and Gelperin that was unethical, not TIDE.  The only ethically acceptable justification for scuttling TIDE was the fact that improper criticisms had probably made continuation of the TIDE unfeasible.  Participants would have had to be informed that rosiglitazone might cause more cardiovascular events than pioglitazone, told about the Risk Evaluation and Mitigation Strategy use restrictions, and advised that they were unlikely to receive rosiglitazone outside of the study.3

The Food and Drug Administration had required GlaxoSmithKline to perform TIDE.  A majority of the members of the Advisory Committee and of the Office of New Drugs recommended continuing TIDE.   Janet Woodcock, M.D., Director of Center for Drug Evaluation and Research (CDER) over-ruled them, because of the restrictions that she had decided were necessary and of “the level of concern about its cardiovascular safety.”1

TIDE was stopped in 2010.1  What legend holds that King Canute had failed to do was now a fait accompli.  While Dr. Woodcock said that the Food and Drug Administration still required GlaxoSmithKline to conduct a study comparing rosiglitazone with pioglitazone “if feasible and appropriate,”1 it is highly unlikely that this could be done, now.  Stopping TIDE virtually guaranteed that an answer about rosiglitazone will never be obtained and that opponents of rosiglitazone, such as Drs. Nissen, Graham, and Gelperin, will always be able to promote themselves by calling attention to uncertainties about the drug.

Maybe that was their goal.

© 2013 Myron Shank, M.D., Ph.D.

1 Parks Mary H.  Introduction memorandum.  Readjudication of the Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes Trial (RECORD):  Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee June 5—6, 2013. http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm354859.pdf

2 Graham David J., Gelperin Kate.  Comments on RECORD, TIDE, and the benefit-risk assessment of rosiglitazone vs. pioglitazone. In: FDA Briefing Document Advisory Committee Meeting for NDA 21071 Avandia (rosiglitazone maleate) tablet July 13 and 14, 2010.  http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM218493.pdf

3 Woodcock Janet, Sharfstein Joshua M., Hamburg Margaret.  Regulatory action on rosiglitazone by the U.S. Food and Drug Administration. New England Journal of Medicine 2010; 363:1489-1491.


3 thoughts on “Avandia’s TIDE Is Stopped

  1. Pingback: ADOPT the DREAM of a RECORD for Avandia | Dr. Shank

  2. Pingback: “Where’s the Beef?” for Avandia’s Risk? | Dr. Shank

  3. Pingback: Dr. Nissen: “Just Say No” to Learning About Avandia | Dr. Shank

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