Tuesday, July 31, 2007

Secondary Endpoints, Opportunity Costs, Alternatives, Vioxx, Avandia, and Actos

There are few endpoints that can hold a candle to mortality as the end-all, be-all of clinical trials design, but two appear to be fit for the challenge, (at least according to past FDA decisions) - or are they? Blood Pressure lowering and glycemic control.

It is old news that Vioxx kills people, and does so utterly unnecessarily: alternative treatments are available that are generic, low cost, and have no toxicities that are demonstrably greater than Vioxx (despite Big Pharma inuendo to the contrary - you know, GI toxicity and the like).

(I am reminded of cognitive dissonance theory here - originally described by Alport, 1938; It has been demonstrated that folks who are more harshly hazed by a fraternity have greater allegence to it.....could this be one of the reasons why paying big bucks for a prescription NSAID with no demonstrable benefits over OTC generics leads to patient claims of superiority of the branded product?)

Well, the old news is still being published: http://content.nejm.org/cgi/content/full/357/4/360 .

The interesting thing to me about the Vioxx story is that with alternatives available (you know, Aleve, Mortin, and the like), and in relation to a "lifestyle drug," safety was not given greater weight. If your primary endpoint is mortality, you might allow an MI or two in your dataset (although you should report them). But when your endpoint is "confirmed clinical upper gastrointestinal events " (http://content.nejm.org/cgi/content/full/343/21/1520), perhaps closer attention ought to be paid to the side effects you have to pay in order to receive the benefits of the primary endopint. If no other NSAIDS were available to treat patients with crippling arthritis, that would be one thing (think IBS: Alosetron withdrawn and then reintroduced to the market because of lack of a suitable alternative; http://content.nejm.org/cgi/content/full/349/22/2136). But there were alternatives and this was a lifestyle drug....

And now we have the Avandia debacle, which, surprisingly, did not lead to a recommendation for withdrawl of this drug from teh US markey by the recent FDA advisiory panel (http://sciencenow.sciencemag.org/cgi/content/full/2007/730/1). Once again, it seems this decision, if made by a rational agent, would have given due consideration to whether there are alternative agents that might be used in place of Avandia if it were no longer available. Well, sure enough, in addition to metformin (think UKPDS), and insulin, and other oral hyopglycemics, lo and behold: Pioglitazone.


  1. My name is Tony Gomez and i would like to show you my personal experience with Vioxx.

    I am 56 years old. Have been on Vioxx for 2 years now. Everybody that works for the fda that oked this drug should be put in jail.

    I have experienced some of these side effects -
    heart attack hardening of the arteries and nerve damage in my feet

    I hope this information will be useful to others,
    Tony Gomez

  2. Sir - thank you for your comments. I am deeply regretful that you may have been harmed by this product. Thankfully, others will not be harmed in the future.

  3. In regard to my comments about paying more for something making you think it's better - I have become aware that this was not an original idea (like many of my "ideas") - see: http://papers.ssrn.com/sol3/papers.cfm?abstract_id=707541