Part 2: "IT'S A NIGHTMARE": After the Avandia debacle, is history about to repeat itself?

"It was really a sham"

By —— Bio and Archives--August 19, 2014

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Part 1: “I was in a coma for four days
Part 2: “It was really a sham
Part 3: “My quality of life shot

Hot on the heels of the Avandia debacle, is history about to repeat itself?


Last December an FDA advisory committee voted 13-1 to approve marketing of dapagliflozin, a new diabetes drug developed jointly by pharmaceutical giants AstraZeneca and Bristol-Myers Squibb. (Bristol-Myers Squibb has since sold its stake in the drug to AstraZeneca). Dapagliflozin had already been approved the previous year by the European counterpart of the FDA, the European Medicines Agency, and is currently being marketed under the trade name Forxiga. In the United States, the drug is known as Farxiga.

Diabetes is an excess of blood sugar, or glucose. Individuals with type 1 diabetes suffer from an deficiency of insulin, a naturally-occurring protein which enables cells to take up glucose from the bloodstream. In individuals with type 2 diabetes, insulin levels may be normal or even elevated, but the ability of cells to take up glucose us overwhelmed—a phenomenon known as insulin resistance. Over 90% of diabetics have type 2 diabetes. Physical inactivity, unhealthy diet, obesity, smoking, and excess alcohol consumption are all known to increase the risk of type 2 diabetes. Complications of either type of diabetes include heart attack, strokes, limb amputations, and kidney failure.

Diabetes is a huge and growing problem, no doubt about that. Diabetes-related conditions account for one-tenth of all US healthcare spending. By 2050, the number of Americans afflicted with type 2 diabetes is expected to exceed 29 million. A press release by AstraZeneca quoted Doctor John Wilding, Professor of Medicine at the University Hospital Aintree, as saying “The approval of FORXIGA represents a significant advance in the treatment of type 2 diabetes.”

Dapagliflozin is the first of a new class of diabetes drugs which work by inhibiting the action of Sodium Glucose Transporter 2, a protein embedded in the membrane of the epithelial cells lining the kidney tubules which normally serves to resorb glucose from the urine back into the bloodstream. Patients taking this drug eliminate excess glucose in the urine—as much as 70 grams of glucose per day. Several more drugs of this class are already in the pipeline.

What these drugs have not been shown to do is to enable the people taking them to avoid premature death or any of the other complications of diabetes. That may sound like an astonishing statement, but that sort of thing is just business as usual for the drug companies and those charged with regulating them. Since the 1990’s, the FDA has allowed the use of “surrogate endpoints” such as reduction in blood sugar levels to serve as the basis of approval for new drugs. A 2011 report by the Institute of Safe Medication Practices stated “The underlying issue in diabetes treatment has remained unchanged since 1970; drugs that lower blood sugar or increase insulin secretion have never been proven to reduce the risk of heart attack and stroke and some agents appear to increase it.”

Indeed. The medical literature is replete with examples of drugs that produced “favorable” outcomes in terms of blood sugar, blood pressure, cholesterol levels, or red blood cell count, but which had unfortunate side effects comes for the people who took them, like killing them. In the case of dapagliflozin, storm clouds are gathering on the horizon already. An FDA briefing document from 2010 sounded a worrisome note: “It was determined that the number of breast and bladder cancers in the dapagliflozin-treated group exceeded the expected number of cases in the general type-2 diabetes population.”

A double-blind, placebo-controlled study, the DECLARE trial, that will assess the effect of dapagliflozin on the rates of heart attack, stroke, and death, is slated for completion in 2019. Again, this may sound astonishing ‚Äì shouldn’t the safety and effectiveness of a drug be determined before it is put on the market, rather than after? Let us quote from once more from the ISMP report: “Because the risks (and health benefits) become apparent only over many years’ time, pre-approval testing is simply too short to determine whether the drugs’ benefit-risk balance is favorable. Nevertheless, the FDA and others feared that truly rigorous long-term testing were required, the time and costs of developing new agents for diabetes might become prohibitive.”

That’s the kind of thinking that led GlaxoSmithKline’s blockbuster diabetes drug Avandia to be put on the market without adequate long-term safety data. Severe restrictions were subsequently placed on its use after Doctor Steve Nissen of the Cleveland Clinic analyzed GSK’s own data and concluded that of thousands of people unnecessarily suffered heart attacks as a result of its use. In 2012, GlaxoSmithKline paid out a whopping $3 billion to settle criminal and civil claims for a variety of unlawful business practices including withholding safety data about Avandia, the largest settlement of its kind in history.

Astonishingly, just last November, the FDA lifted most of the restrictions on Avandia, on the basis of recommendations made the previous June by an FDA advisory panel, the RECOD Steering Committee. The panel in turn based its recommendations on a reanalysis, or “re-adjudication,” of the data from the RECORD trial, which had been funded by GlaxoSmithKline at the behest of the European Medicines Agency. The re-adjudication, which was also funded by GSK, was conducted by a group of researchers at Duke University headed by Doctor Kenneth Mahaffey.

In a blistering commentary in Forbes.com, Dr. Nissen noted that the RECORD trial had already been reviewed by Doctor Tom Marcianak of the FDA and found to be, in Nissen’s words, “totally unreliable.” By then fewer than 3000 people in the United States were taking Avandia, GlaxoSmithKline’s patent on the drug had already expired, and the company had not asked for any changes to the restrictions. So why did the FDA, in the middle of the sequester, convene a 2-day meeting for a drug almost nobody uses anymore?

Dr. Nissen suggested a reason. In a telephone interview he stated “This was much more about the FDA than about the drug. They were terribly embarrassed by the revelations that they had known about the problems with Avandia for a long time before they told the public. So they really wanted to make the problem go away and they carefully orchestrated it to lift the restrictions but nobody’s being fooled.

“First of all, the RECORD trial was completely open-label and unblinded. I mean, open-label to the extent that the company and the CRO actually knew when [adverse] events were coming in who was getting the Avandia and who was getting the non-Avandia therapies. What Marciniak’s investigation showed was that the decision on which events to refer for adjudication showed selective reporting of events for adjudication. Now the adjudicators can be completely unbiased, but if the events are not being referred to them, then obviously they can’t do a job with a high degree of intellectual integrity. What happened with the re-adjudication was that the same people—the company—decided which events to send to Duke for re-adjudication. Of course they got the same result. It wasn’t independent. They didn’t go back to the original source data from the sites. They simply used the files supplied by GlaxoSmithKline. So it was really a sham to call it re-adjudication when they really are using the exact same files the company used originally.”

By the way, the Duke Medicine News and Communications website notes that several of the authors of the re-adjudication study have personally received money from GlaxoSmithKline. Dr. Mahaffey’s university salary is paid, in part, by a research grant from GSK, as is that of fellow study author Doctor L. Kristin Newby. Dr. Michel Komajda reports payment for service on a “speaker’s bureau” for GSK, and Dr. John McMurray notes that GSK paid for his travel and accommodation for the RECORD steering committee and also paid Duke for the time he spent as a committee member. (For the record, Dr.Nissen stated that while he does many clinical trials for the drug companies, he has a strict rule that he will not accept any remuneration from them.)

Is it any wonder health care costs are soaring?

List of Sources

1. Steve Nissen, personal interview 6 March 2014.

2. Alisha Martin, .(JavaScript must be enabled to view this email address).

3. Bristol-Myers Squibb 2013. FDA Advisory Committee Recommends the Investigational SGLT2 Inhibitor Dapagliflozin for the Treatment of Type 2 Diabetes in Adults. December 12 2013. Retrieved 11 January 2014.

4. AstraZeneca 2012. FORXIGATM (Dapagliflozin) Now Approved in the European Union for Treatment of Type 2 Diabetes. Wednesday November 14 2012. Retrieved 11 January 2014.

5. Simpson, S.D. 2013. Bristol Myers Squibb and AstraZeneca: A Big Break-Up in the Diabetes Space. Motley Fool December 21 2013. Retrieved 24 March 2014.

6.American Diabetes Association 2003. Economic costs of diabetes in 2002. Diabetes Care 26:917-932.

7.Boyle, J.P. et al. 2001. Projection of diabetes burden through 2050. Diabetes Care 24:1936-1940.

8. US Department of Health and Human Services 2007. Guidance for Industry: Clinical trial Endpoints for the Approval of Cancer Drugs and Biologics.. Retrieved 12 January 2014.

9. Institute for Safe Medication Practices 2010. QuarterWatch: 2010 Quarter 3: Monitoring MedWatch Reports. May 19 2011. Retrieved 11 January 2014.

10. Furberg, C.D. et al. 1995. Nifedipine: Dose-related increase in mortality in patients with coronary heart disease. Circulation 92:1326-1331.

11. Berenson, A. 2008. The evidence gap: For widely used drug, the question of usefulness is still lingering. New York Times September 1 2008.

12. Sharp, K. 2012. Blood Feud: Blowing the Whistle on One of the Deadliest Prescription Drugs Ever. Dutton.

13. FDA 2011. FDA Briefing Document: NDA 202293: Dapafloglitazone Tablets, 5 mg and 10 mg.

14. Nissen, S.E. and K. Wolski 2007. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. NEJM 356:2457-2471.

15. Nissen, S.E. and K. Wolski 2010. Rosiglitazone revisited. Archives of Internal Medicine 170:1191-1201.

16. FDA 2010. FDA Briefing Document: Advisory Committee Meeting for NDA 21071 Avandia (Rosiglitazone Maleate) July 13 and 14, 2010. Retrieved 12 January 2014.

17. Claggett, B. and Lee-Jen Wei 2011. Analytical issues regarding rosiglitazone meta-analysis. Archives of Internal Medicine 171:179-180.

18. Nissen, S.E. and K. Wolski 2011. Reply. Archives of Internal Medicine 171:180.

19. FDA 2011. FDA Drug Safety Communication: Updated risk evaluation and mitigation strategy (REMS) to restrict access to rosiglitazone-containing medicines including Avandia, Avandamet, and Avandaryl. Retrieved 1 March 2014.

20. FDA 2011. FDA Drug Safety Communication: Reminder to healthcare providers and patients to enroll in the Avandia-rosiglitazone medicines access program. Retrieved 1 March 2014.

21. Department of Justice 2012. GlaxoSmithKline to plead guilty and pay $3 billion to reolve fraud allegations and failure to report safety data.  Retrieved 1 March 2014.

22. FDA 2013. FDA Drug Safety Communication: FDA requires removal of some prescribing and dispensing restrictions for rosiglitazone-containing diabetes medicines.  Retrieved 1 March 2014.

23. Nissen, S.E. 2013. The hidden agenda behind the FDA’s new Avandia hearings. Retrieved 1 March 2014.

24. Lopes, R.D. et al. 2013. Methodology of a reevaluation of cardiovascular outcomes in the RECORD trial: Study design and conduct. American Heart Journal 166-208-216.

25. Duke Medicine News and Communications 2013. Re-Analysis of diabetes drug finds no higher heart attack risk. Retrieved 1 March 2014.

26. Herper, M. 2013. Avandia vote ends an era of drug safety scandals..Retrieved 1 March 2014.

Patrick D Hahn -- Bio and Archives | Comments

Patrick D Hahn is an Affiliate Professor of Biology at Loyola University Maryland and a free-lance writer. His writing has also appeared in Biology-Online, Loyola Magazine,Popular Archaeology, Natural News,Canada Free Press, and the Baltimore Sun.

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