Tag Archives: Food and Drug Administration rosiglitazone

More Concerns With Nissen’s Avandia Analysis

The patron saint of meta-analysis, Richard Peto, who helped bring the approach back from what we used to dismiss as ‘unplanned pooling,’ stressed approaches that would avoid bias and error, including selection of endpoints before the trials are analyzed and a reasonably high level of statistical significance.1

Nissen and Wolski said they used the Peto method, for their original meta-analysis of rosiglitazone (Avandia; GlaxoSmithKline).2  So, how did they measure up?

As noted in my January 27, 2014 post, Concerns at FDA:  Nissen’s Avandia Analysis, Deputy Director Robert Temple, in a  memo to Janet Woodcock, Director of the Food and Drug Administration’s Center for Drug Evaluation and Research, was critical of Nissen and Wolski’s2 peculiar and unblinded1 selective choices of studies (from among those that met their inclusion criteria).3  Dr. Temple also raised questions about the (improper) inclusion in their meta-analysis of the DREAM study, on which their hypothesis had been based.4  About the Nissen and Wolski meta-analysis, Dr. Temple concluded that “there was potential bias in its development (or at least the analysis was done with knowledge of what would emerge).”1

Nissen and Wolski reported doing eight different comparisons in their original meta-analysis.2  If these eight comparisons had been independent of (unrelated to) each other, the probability that they would have found a difference by chance, where none existed, would really have been 0.34,5 instead of the 0.05 that they claimed.2   In other words, instead of the probability of erroneously concluding, by chance, that there were differences between treatment with and without rosiglitazone being one-in-twenty, as they implied, the probability  would be more than one-in-three.

Unfortunately, acute myocardial infarctions and cardiovascular deaths are linked; whatever factors affect one, affect the other. “If the comparisons are not independent, it really is impossible to compute the probability . . . .”6  The truth lies somewhere between “p”=0.05 and “p”=0.34–a useless result.

One common technique is to make the threshold for statistical significance much stricter, adjusting  by dividing the required “p” value for significance by the number of comparisons made–in this case, 0.05/8=0.00625.7  This is the Bonferroni adjustment8  The Bonferroni adjustment is approximate and only appropriate if the comparisons are independent of each other.9

Some other techniques only test the individual components if the over-all comparison is significant–in other words, if (and only if) we know that there is a difference, we are entitled to find out where it is.  This is known as a multiple-stage test.10

There are other techniques, each of which has its own uses and limitations.10

Nissen and Wolski used none of these.

Return for concerns about what the Nissen and Wolski meta-analysis2 left out.

© 2014 Myron Shank, M.D., Ph.D.11

1 Temple Robert.  Memorandum to Janet Woodcock:  Data on Rosiglitazone, August 8, 2010.  http://www.fda.gov/downloads/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm226066.pdf

2 Nissen Steven E., Wolski Kathy.  Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes.  The New England Journal of Medicine 2007; 356:2457-2471.

3 Schachtman Nathan A.  Learning to embrace flawed evidence–the Avandia MDL’s Daubert opinion.  Schachtman Law January 10th, 2011. http://schachtmanlaw.com/learning-to-embrace-flawed-evidence-the-avandia-mdls-daubert-opinion/.

4 As I pointed out, “It is never appropriate to test a hypothesis with the same data that was used to generate it.”  I also noted that this was inexcusable behavior from a statistician, such as Dr. Nissen’s co-author, Kathy Wolski.  For the statistically literate, I pointed out that excluding DREAM’s statistical “degrees of freedom,” which were improperly included, would have been sufficient, by itself, to have eliminated any pretense of statistical significance for Nissen and Wolski’s meta-analysis.

5 1.00-0.958=0.34.

6 Anonymous. The multiple comparisons problem. GraphPad Statistics Guide http://www.graphpad.com/guides/prism/6/statistics/index.htm?stat_the_problem_of_multiple_compar.htm. Accessed January 26, 2014.

7 The exact calculation is 1.00-0.95-8=0.0064 (Notice the negative sign on the exponent; this is the 8th-root of 0.95.).

8 Anonymous.  Glossary of statistical terms:  “Bonferroni adjustment,” The Institute for Statistics Education.   http://www.statistics.com/index.php?page=glossary&term_id=611. Accessed January 26, 2014.11 Again, this is inexcusable for a statistician, such as Kathy Wolski.

9 Anonymous.  Bonferroni.  Simple Interactive Statistical Analysis  http://www.quantitativeskills.com/sisa/calculations/bonhlp.htm>. Accessed January 26, 2014.

10 Anonymous. The GLM procedure:  multiple comparisons.  SAS/STAT User’s Guide. http://v8doc.sas.com/sashtml/stat/chap30/sect35.htm.  Accessed January 26, 2014.

11  I served:  in the speaker program for Takeda Pharmaceuticals America, Inc. and Eli Lilly and Company, Chicago, Illinois, August 7, 1999; as a consultant for Takeda Pharmaceuticals America, Inc. and Eli Lilly and Company, “Current Update and Discussion of the Glitazone Class of Oral Antidiabetics,” January 3, 2001; on Avandia Regional Advisory Panels in Cleveland, Ohio (February 4, 1999), Toledo, Ohio (September 15, 1999), San Juan, Puerto Rico (February 2000), and Beverly Hills, California (April 2000); as a preceptor for SmithKline Beechum, Lima, Ohio (June 23-25, 1999); and in a “Meet-the-Specialist,” SmithKline Beecham, Lima, Ohio, (2000).  In 2000, SmithKline Beechum merged with GlaxoWellcome, to form GlaxoSmithKline.  Before it became impractical to continue prescribing rosiglitazone (Avandia, Avandamet, Avandaryl; GlaxoSmithKline), I prescribed both it and pioglitazone (ACTOS, ACTOSPlusMet, DuetAct; Takeda).

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“But wait! There’s more!” The RECORD on Avandia

A Recap

In my post, “Where’s the Beef?” for Avandia’s Risk?, I had several occasions to point out the weaknesses of both of Nissen and Wolski’s meta-analyses,1,2 the fact that the review accompanying their first meta-analysis1 had to admit “the fragility of their findings,”3 the fact that their own “updated meta-analysis”2 could not confirm their original meta-analysis,1 and the fact that the Food and Drug Administration’s review,4 after not only raising questions about both the quality of their first meta-analysis1 and its integrity, concluded, “When considering all data available at this time [2010], however, the overall evidence of increased myocardial ischemic event risk with rosiglitazone is weak.”   In Nissen and Wolski’s Avandia “Significance”, January 15, 2014, I pointed out that Hiatt, Kaul, and Smith obtained very different results, in their meta-analysis5 of exactly the same set of data as Nissen and Wolski’s original1 meta-analysis.

As the saying goes, “But wait!  There’s more!”

The Interim Analysis of RECORD

Unlike the meta-analyses that preceded it, RECORD was  a randomized study of rosiglitazone for type 2 (non insulin-dependent) diabetes mellitus (specifically Avandia; GlaxoSmithKline), as compared to metformin (Glucophage; Bristol Myers Squibb) and the various sulfonylureas (members of a group of drugs that increase insulin secretion).

According to the Food and Drug Administration’s own criteria, the interim analysis of RECORD’s results showed that rosiglitazone was not associated with an unacceptable increase in the risk of major adverse cardiovascular events.6  Not only was the prespecified hypothesis (that the relative risk of of cardiovascular hospitalization or death for rosiglitazone was greater than or equal to 1.2, as compared to metformin, sulfonylureas, or their combination) not confirmed, but it actually appeared that rosiglitazone might have less risk than the other drugs.  In other words, while not statistically significant, most of the trends favored rosiglitazone, not Nissen and Wolski.

There were challenges to the original evaluation of RECORD.  Although they were often overstated, some of the challenges had merit.   On the other hand, there were also strengths in the study.  I have listed a few of them, below:

  • Randomization was preserved in RECORD.
  • Unlike Nissen and Wolski’s meta-analyses,1,2 statistical heterogeneity (attempting to draw conclusions by combining studies that are extremely unlike each other) was not a problem in RECORD.
  • Unlike the observational studies included in Nissen and Wolski’s meta-analyses,1,2 unmeasured confounders (factors) were not a problem in RECORD.
  • There were more major adverse cardiovascular events (myocardial infarctions or “heart attacks,” anginal chest pain, strokes, and cardiovascular deaths) available for evaluation in RECORD than in all of the studies in the Food and Drug Administration’s 2007 meta-analysis, combined, but there was no evidence of an increased risk from rosiglitazone for any of them, except for congestive heart failure (which is also increased with pioglitazone, just as with troglitazone, before it was taken off of the market).
  • Analyses by subgroups generally gave results similar to those obtained with the main analyses and for analyses for myocardial infarctions (“heart attacks”).
  • Analysis based upon the time period during which patients were actually on the specified treatments were generally consistent with those based upon the treatments that were originally planned for them, showing that there was no difference between the effects of actual treatments and those to which patients had been randomly (by chance) assigned.
  • Even the upper limits (highest value) of the estimates for major adverse cardiovascular events met the Food and Drug Administration’s own standards for showing that rosiglitazone was not associated with an unacceptable increased in the risk.
  • The overall death rates favored treatment with rosiglitazone over treatment without rosiglitazone, the opposite direction of what Nissen and Wolski1,2 claim.

The Re-Analysis of RECORD

The Food and Drug Administration commissioned the Duke University’s Clinical Research Institute to independently re-adjudicate (re-judge) the data from RECORD.  From everything that I can tell, they did a masterful job of it.  “This well-conceived and comprehensive re-adjudication of the RECORD trial mortality experience demonstrated no evidence of a difference in all-cause mortality, cardiovascular plus unknown-cause mortality or non-cardiovascular mortality between the RSG [rosiglitazone] and MET/SU [metformin/sulfonylurea] treatment arms of RECORD.”7  In fact, for every one of the numerous sensitivity analyses’ multiple comparisons (each of which increased the likelihood of a false finding against rosiglitazone;8 see “Nissen, Wolski, and How Not to Do Meta-Analyses“), a lower death rate was found with rosiglitazone than for metformin/sulfonylurea.9  For fatal and non-fatal myocardial infarctions (“heart attacks”) and strokes, alone or in combinations, there was no evidence for any difference between rosiglitazone and metformin/sulfonylureas.9  In the end, there was no evidence of an increased risk from rosiglitazone for all-cause mortality, major adverse cardiovascular events, strokes, or myocardial infarctions.10

Commentary

At best, the evidence against rosiglitazone was always doubtful, no matter how much the Nissen-Wolski duet acted otherwise.  As will become increasingly evident, at worst, Steven Nissen, himself, was doubtful.

© 2014 Myron Shank, M.D., Ph.D.

1 Nissen Steven E., Wolski Kathy.   Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes.  The New England Journal of Medicine 2007; 356:2457-2471.

2 Nissen Steven E., Wolski Kathy.  Rosiglitazone revisited:  an updated meta-analysis of risk for myocardial infarction and cardiovascular mortality.  Archives of Internal Medicine 2010; 170:1191-1201.

3 Psaty Bruce M., Furberg Curt D.  Rosiglitazone and cardiovascular risk.  New England Journal of Medicine 2007; 356:2522-2524.

4 Parks Mary H.  (Untitled).  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

5 Hiatt William R., Kaul Sanjay, Smith Robert J. The cardiovascular safety of diabetes drugs—insights from the rosiglitazone experience. New England Journal of Medicine 2013; 369:1285-1287.

6 Mahoney Karen Murry.  Advisory committee clinical briefing document: preliminary Endocrine Medical Officer review of the RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes) trial, and update on cardiovascular safety information from large clinical trials of rosiglitazone New Drug Application 21071 Avandia® (rosiglitazone maleate).  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

7 Dunnmon Preston M.  DCRP consult to review and to comment on both all-cause and CV deaths from the Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of glycaemia and Diabetes trial (RECORD, BRL-049653/231), according to the Phase-I re-adjudication of the trial’s mortality outcomes by the Duke Clinical Research Institute (DCRI). http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm354859.pdf

8 Remember that performing these “subgroup analyses” within a category that has already been found not to show a statistically significant difference risks making it appear that there are differences when there are none. See “Nissen, Wolski, and How Not to Do Meta-Analyses. The fact that this did not happen, despite so many comparisons, is testimony that the overall results were not even close.  Although I do not have access to their raw statistical analysis, the Clinical Research Institute described this as a “sensitivity analysis,” strongly suggesting not only that they recognized the problem, but that they also interpreted negative results despite multiple comparisons as demonstrating the robustness of their overall negative conclusions.

9 Dunnmon Preston M.  Center for Drug Evaluation and Research Division of Cardiovascular and Renal Products consultation for NDA 021071 SDN 1652.  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

10 Andraca-Carrera Eugenio, Soukup Mat, Chakravarty Aloka.  Background information for advisory committee on rosiglitazone: statistical briefing material for the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee Meeting, June 5-6, 2013.  http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm354859.pdf

“Where’s the Beef?” for Avandia’s Risk?

Readers may remember the 1984 through 1985 Wendy’s hamburger television commercials with the famous line, “Where’s the beef?”   The idea was that some other hamburgers were all bun and no meat–all show and no substance.  The same could be said for the controversies surrounding rosiglitazone (Avandia, Avandamet, Avandaryl; GlaxoSmithKline).

The evidence suggesting that rosiglitazone increases the risks of myocardial infarctions (“heart attacks”) and cardiovascular events (“heart attacks,” anginal chest pain, strokes, and sudden death) was always extremely weak1 (See also my previous posts, “Steven Nissen and The Not-So-Great Avandia Controversy,” December 18, 2013; “Nissen, Wolski, and How Not to Do Meta-Analyses,” December 19, 2013; “What is the Risk of Avandia?” December 23, 2013; and “Avandia’s TIDE Is Stopped,” December 24, 2013.).

A reviewer for the Food and Drug Administration was critical of Nissen and Wolski’s original meta-analysis2

  • for including highly heterogeneous studies  (They mixed studies that were extremely different from each other.)
  • for combining head-to-head trials of drugs with trials in which the drugs were merely added on when others failed (They mixed studies that had a strong design with those that had a weak design, and then treated them as the same.)
  • for arbitrarily excluding the half of the trials that lacked cardiovascular deaths (primarily “heart attacks”) (They biased their results against rosiglitazone.)
  • for falsely implying a comparison between rosiglitazone and insulin that did not exist
  • for otherwise misrepresenting the designs of the studies, and
  • for only using a single statistical technique to analyze the results (In other words, even with all of their errors, they may not have obtained the results that they did, if they had used different–and arguably more appropriate–statistical techniques.).3

Basing their analysis primarily on short-term (six-month) studies was of questionable validity, in the first place.  To illustrate:  if Nissen and Wolski had been honest enough to look at the six-month time point of PROactive, a study of the rival drug, pioglitazone (Actos, Actosplus Met, Actosplus Met XR, Duetact, Osini; Takeda), their results would have suggested an increased cardiovascular risk  that was not apparent at the end of the study.3  As we will see, the same pattern applies to rosiglitazone (Avandia, Avandamet, Avandaryl, GlaxoSmithKline).  Short-term results, such as these, are largely due to chance fluctuations in the occurrence of rare evens; with the passage of time averages them out.  Besides, which matters for drugs that are intended to be used for many years–the results at the end of a few months, or those after a few years?

Even an editorial that accompanied Nissen and Wolski’s highly controversial original meta-analysis had to admit “the fragility of their findings.”4

Their results were fragile, indeed.  Even Nissen and Wolski were unable to get the same results in their own later meta-analysis.5  In response to Nissen and Wolski’s claims,2,5 the Food and Drug Administration (FDA) did its own meta-analysis.6  It suggested that rosiglitazone might increase myocardial ischemia (mostly anginal chest pain from the heart), but not myocardial infarctions (“heart attacks”), all-cause deaths, or the combination of myocardial infarctions, strokes, and cardiovascular deaths.6  In fact, the Food and Drug Administration observed that, “When the meta-analysis was performed by placebo- vs active-controlled trials, the increase in ischemic risk was observed in only the placebo-controlled trials.  This finding suggests that the risk of myocardial ischemia is similar between rosiglitazone and other oral anti-diabetic agents to which it was compared (metformin and sulfonylureas).”7  Once again, Nissen and Wolski’s conclusions depended upon weak evidence.

“When considering all data available at this time [2010], however, the overall evidence of increased myocardial ischemic event risk with rosiglitazone is weak.”1

What was true then, as we will see, is even more true, now.  No matter how much Steven Nissen, M.D., wants us to focus on outside appearances, a closer look shows that the evidence for increased myocardial infarctions (“heart attacks”) and myocardial ischemia (anginal chest pain from the heart) with rosiglitazone (Avandia, Avandamet, Avandaryl, GlaxoSmithKline) is all bun and no beef.

Even worse, as we will also see, Dr. Nissen’s less than honorable behaviors may stem from less than honorable motives to viciously attack rosiglitazone (Avandia, Avandamet, Avandaryl, GlaxoSmithKline) and spare pioglitazone (Actos, Actosplus Met, Actosplus Met XR, Duetact, Osini; Takeda).

© 2014 Myron Shank, M.D., Ph.D.

1 Parks Mary H. (Untitled).  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

2 Nissen Steven E., Wolski Kathy.  Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes.  The New England Journal of Medicine 2007; 356:2457-2471.

3 Mele Joy, Sahlroot Todd.  Statistical review and evaluation:  addendum to review completed 6/4/07.  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

4 Psaty Bruce M., Furberg Curt D.  Rosiglitazone and cardiovascular risk.  New England Journal of Medicine 2007; 356:2522-2524.

5 Nissen Steven E., Wolski Kathy.  Rosiglitazone revisited: an updated meta-analysis of risk for myocardial infarction and cardiovascular mortality.  Archives of Internal Medicine 2010; 170:1191-1201.

6 Mahoney Karen Murry.  Preliminary Endocrine Medical Officer review of the RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes) trial, and update on cardiovascular safety information from large clinical trials of rosiglitazone new drug application 21071 Avandia® (rosiglitazone maleate) 9 Jun 2010.  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

7 Parks Mary H.  Inter-office background memo and draft questions for July 13 and 14, 2010 Advisory Committee Meeting for Avandia® (rosiglitazone).  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

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.

A Little Background on the Big Avandia Controversy

It should be understood that, in 2006, the Food and Drug Administration (FDA) had the results of a meta-analysis, performed by GlaxoSmithKline, which suggested possible increases in cardiovascular risks with rosiglitazone (Avandia, Avandamet, Avandaryl; GlaxoSmithKline),2 a year before Nissen and Wolski’s controversial article.1  In fact, the Food and Drug Administration (FDA) had requested patient-level data for these studies and was already conducting its own meta-analysis.2  The Food and Drug Administration’s meta-analysis included studies that were different from those used by Nissen and Wolskiand had occurred independently of Nissen and Wolski.

Most of the component studies in the Food and Drug Administration’s analysis were of less than six months duration–not very long for cardiovascular (“heart attack,” anginal chest pain, stroke, and sudden death) outcomes.  As with the group of studies included by Nissen and Wolski, none had been designed to evaluate cardiovascular risk, so they had lacked plans for studying cardiovascular events.  Instead, adverse events that were captured in case report forms had been classified using often vague terms (such as “chest pain,” without any laboratory or electrocardiogram (EKG) evidence that the heart was the cause).2  Without adjudication (tracking down and examining the appropriate original data), it is impossible to know what these reports really meant.  As noted in my December 18, 2013 post, “Steven Nissen and The Not-So-Great Avandia Controversy,” Nissen and Wolski did not do this; however, the Food and Drug Administration did.  When compared with placebo (an inactive lookalike), Avandia showed possible increases both in ischemic heart disease (“heart attacks” and anginal chest pain) and in ischemic heart disease plus strokes, but not when compared with active drugs.2  There was a possible increase in ischemic heart disease, but not ischemic heart disease plus strokes, in the combination of studies comparing Avandia either to placebos or to active drugs.2

So long as its results were compatible with his own, Dr. Nissen does not seem to have had any complaints with the Food and Drug Administration’s analyses.  As we will see in future posts, however, that changed, once its results no longer supported his agenda.  In spite of the glaring shortcomings in Nissen and Wolski’s meta-analyses,1,3 as compared both to another meta-analysis of the same data,4 published a mere five months after their first meta-analysis and to those of the Food and Drug Administration,2 Dr. Nissen has stubbornly clung to his conclusions.

Dr. Nissen has also viciously attacked the Food and Drug Administration for continuing with its planned evaluations of Avandia.  Why?  If it was only because he knew that his own conclusions would not be confirmed, why does he not seem to have ever lashed out at Diamond and others?4  The fact that his ongoing vitriol seems to be targeted against the Food and Drug Administration, but apparently not Diamond’s group, gives credence to speculations that Dr. Nissen fully expected Avandia to be his ticket to the top Food and Drug Administration position. Whether or not he ever sought a formal position, Dr. Nissen seems preoccupied with controlling the Food and Drug Administration.  At any rate, evidence will be reviewed that Dr. Nissen’s motives may be suspect on multiple levels.

© 2013 Myron Shank, M.D., Ph.D.

1 Nissen Steven E., Wolski Kathy.  Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes.  The New England Journal of Medicine 2007; 356:2457-2471.

2 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

3 Nissen Steven E., Wolski Kathy.  Rosiglitazone revisited:  an updated meta-analysis of risk for myocardial infarction and cardiovascular mortality.  Archives of Internal Medicine 2010; 170:1191-1201.

4 Diamond George A., Bax Leon, Kaul Sanjay.  Uncertain effects of rosiglitazone on the risk for myocardial infarction and cardiovascular death.  Annals of Internal Medicine 2007; 147:578-581.