September 26th, 2010

Avandia: Lessons Learned and Unanswered Questions

The following is republished from Pharmalot, a widely read site that provides commentary on the pharmaceutical industry and related litigation.

What should we make of the decisions on Avandia yesterday? There remains some controversy about the risk, but the concerns were sufficient, given the therapeutic alternatives, to bring about action. The Europeans decided to suspend sales of the drug, and the Americans opted to leave it on the market, albeit with tough restrictions. The company has announced it will no longer promote the drug, and the practical result in Europe and the US may be a lot more similar than the decisions at first appear. Usage will stop in Europe, and new use should virtually stop here. But is the story over? There are at least some issues worthy of consideration as we get to the end of the tale.

1. The Delay to Judgment: If the drug has a probable hazard that is sufficient to require severe restrictions in the US and suspension in Europe, then why did it take so long to reach a decision? The basic information about the drug has been around for years. No new trials indicated great risk — all we know could have been known a while ago. Moreover, why did it take more than two months in the US after the FDA advisory committee met (last July) and the vote was clearly signaling a concern to take action? In the interim, sales have been continuing, and patients may have assumed that no news is good news about the drug. We need a more-responsive FDA, one that moves with all deliberate speed — but with speed — particularly when there are life-threatening safety concerns.

And by the way, Avandia has been on the market since 1999 — aside from the recent delays — why did it take so long to assemble all the evidence? And what would have happened if Steve Nissen (who authored the 2007 meta-analysis declaring higher cardiovascular risk with Avandia) had not found the Avandia trial data? And what would have happened if (former New York Attorney General) Elliot Spitzer had not included the sharing of trial data in the settlement with Glaxo over Paxil? Why does it seem fortuitous that we are at this point?

2. The FDA Focus on New Users: Why does the FDA believe that the barriers to prescription in new users should be stronger than those for current users? There are no studies that indicate that the excess risk dissipates over time. Presumably those on the drug, whether new or long-standing, are exposed to the risk. It is not sufficient to determine if people are doing well on the drug since the adverse effect is a silent risk. It seems that those already on the drug should have to go through the same process as new users — and the recommendation should be to change the regimens as soon as possible if the guidance from the FDA is to be sensible. There is no basis for separating the recommendation for new users from those of current users. And if it should be the last option for new users, then it should be the same for current users.

3. The Feasibility of Applying the Restrictions: Can the provisions specified by the FDA be reliably applied? How will doctors ensure that patients are given the information about the risk and that they understand? Will the FDA supply tools? Who will monitor the prescribing? Given the challenges in guiding physician behavior, I was wondering how the program will be implemented. I am supposing that this approach is in effect now — and if I prescribe Avandia to a new user tomorrow, I am wondering what I need to do and what will happen to me if I do not do whatever I am supposed to do. And who is going to tell me what to do? And what about my colleagues who did not notice the announcement? I assume the FDA knows what they are doing, but it is not so simple to leave it on the market, institute restrictions, and expect them to be followed. The FDA has some experience with restrictions — there are roughly 30 drugs now carrying a Risk Evaluation and Mitigation Strategy. But I am not sure they have imposed such a program on a drug as widely prescribed as Avandia.

4. The Failure of the Surrogates: This episode is yet another example of how surrogate outcomes like blood sugar control can be misleading. Knowing how well a drug controls blood sugar, cholesterol, or blood pressure (or any other risk factor) is not enough to know what effect it has on people. Drugs that are better at controlling a risk factor like blood glucose may paradoxically increase risk — we have seen that before. Ask Bristol Myers, the makers of muraglitazar — great glucose control, but it increased cardiovascular risk.

5. Will We Have Another Avandia? Finally, will we learn anything and change anything from watching the misdeeds of the company? There were dirty tricks and lack of transparency, episodes of intimidation of critics, and denial of responsibility. The Senate Finance Committee exposed individuals and the company, and the reports made for interesting reading. But how can we move forward in a way that such shenanigans can be avoided? In the end, the story is as much about Glaxo and the profession of medicine as it is about Avandia. And I fear that the culture has not changed — reputations seem to have survived intact, and the beat goes on. Profits were made: the sales of Avandia were extended by the misdeeds, and billions of dollars in revenues were preserved for a long time, even as many were likely exposed to risks that could have been avoided with a different regimen. Remember that a strong majority of the FDA advisory committee in 2007 agreed that Avandia increased the risk of heart attacks. What truly needs to be remedied is how we all work together to get the best information to the public. Needed studies must be done in a timely way so we can equip clinicians and their patients with the evidence that allows them to make the best choices.

4 Responses to “Avandia: Lessons Learned and Unanswered Questions”

  1. Jeoffry Gordon, MD, MPH says:

    Thanks for enumerating all the defects in this regulatory process. Our pharmaceutical surveillance system looks like Swiss cheese.I am a family doc with 40 years of experience and I can remember when there was an “ethical pharmaceutical” industry. No more, commercial and market values rule the day – spreading in subtle ways even to the most prestigious journals and the FDA.You have to keep your wits about you and actively search for pharmaceutical information. Take the TZDs – a great class of drugs: I stopped prescribing Rezulin when the original series on liver deaths came out in the LA TIMES. Since there was a good and equivalent alternative (ACTOS)I have not prescribed AVANDIA in all most three years.Concerned physicians have to take responsibility back from this limp system.

    Competing interests pertaining specifically to this post, comment, or both:

  2. Louis Krut, MB.ChB. MD says:

    Dr. Krumholz:
    Someone once said: All it takes for evil to triumph is that good men remain silent. You probably know that quote and it is, philosophically, more complex than at first appears, but thank you for speaking out.
    Physicians must recognize that we live according to the values in our society. I’m not certain we ever were particularly exceptional professionals, but we certainly are not that now. Regrettably it is unlikely we will change before the value system in our society changes in a way some of us might prefer, but that too is not a choice as obvious as it initially might seem. There are however some mimimal criteria that should be acceptable guidelines and those should include the end of our collusion in corrupt behaviour. It just struck me that was too was easier to put down than it is likely to be defined in a way that will win widespread acceptance. There really would be no difficulty in defining what is corrupt if we had the kind of common background that would still allow one to say: “I cannot define what it is but I know it when I see it.” Again a loose quote but we will not all recognize the same thing for what it is. In the end we are dependent on those whom we put in place to govern our lives. The best we can do for our professioin in this regard is to ensure that individuals who are honest, or who can be enticed to be so, run the FDA. That again is philosophically complex but if we cannot agree on what honesty means we shall continue to feed our patients, and ourselves, compounds that do much more good for Big Pharma than they do for the ingesters. Well, do we allow our profession to slither along in the way it has been going or should we pose Hamlet’s question: “Whether it is nobler in the mind to bear the slings and arrows . . . .”
    Hope this will encourage some to disengage, however briefly, from the standard “fail safe” mode that preserves us, and think it time to act.

    Competing interests pertaining specifically to this post, comment, or both:

  3. robin motz, M.D., Ph.D. says:

    But we are never consistent about drug risks. Does anyone still care about the studies that showed that sulfonylureas increased cardiac morbidity and mortality? Or what about the fact that soon after the Delaney clause was added, saccharin was shown to cause tumors in mouse bladders, and saccharin was immediately made an exception to the Delaney clause?

  4. Venkatesan Sangareddi, MD.DM says:


    Avandia is not the only issue we face. We experience such new drugs every day. It needs to be emphasized that our brain often perceives only drugs can have side effects. The fact is every investigation, procedure, device, surgery, or for that matter any decision we make in the bed side has a potential to trigger a chain of untoward incidents. Reducing such events is the only aim of modern medicine ! (First do no harm !)

    The health care providers should realize how important their thought processes are, as these thoughts ultimately reach the patients as drugs and devices.

    Most of the medical care providers are rapidly losing the ability to think rationally.

    Please spare a few moments for the patients (Also!) in your board rooms.

    Allow me to link to related posts from my blog:

    When truths are silent . . .Evil takes over

    Herd behavior in medical profession