Markey and Grassley as Brutus.

First, there was Ketek (telithromycin).  Then there was the spectacular FDA nosedive into gagaland as far as antibiotics are concerned. Now, the prestigious Government Accounting Office has issued a report on non-inferiority trials used in the approval of drugs by the FDA (http://www.gao.gov/new.items/d10798.pdf, http://www.reuters.com/article/idUSN276362720100827).  The report adds nothing new to the FDA’s guidance on non-inferiority trial design.  It does, however, clarify the mysterious influential group the FDA is seeking to pacify in their new guidance documents. The GAO, in turn, and I presume the congressmen who requested the report (Markey and Grassley), seem to have been speaking to those same statisticians who want us to run trials in community acquired pneumonia with 7500 to 200,000 patients so we can use mortality as an endpoint.  Such trials are impossible to run and even if they could be run, would take so long that the designs would be obsolete by the time they were completed. These are the same folks who want superiority trials or even placebo controlled trials when the designs are simply not feasible on planet earth.

If the congressmen wanted an objective, scientific opinion that would take all factors into account, including the future availability of antibiotics, they could have (read should have) asked the Institute of Medicine of the National Academy of Sciences.

In the wake of the Ketek scandal of 2006, congress piled-on on the FDA demanding answers as to how such a drug could have possibly been approved. For one view of this scandal, see David M Shlaes, Robert C Moellering. Telithromycin and the FDA: implications for the future. Feb 2008 The Lancet Infectious Diseases, Vol. 8 No. 2 pp 83-85. The results of this unnecessary scandal have been a loss of critical FDA personnel and a subsequent lack of leadership at the FDA, consistent interference in FDA’s efforts, especially in the critical area of clinical trials for new antibiotics, by congress, and constant and unpredictable waffling along with an antibiotic approval record that will leave our critical antibiotic pipeline in imminent danger for at least the next decade. While the congressmen try and make points with their constituencies, more and more companies abandon antibiotics research while more superbugs emerge to threaten our health.  What can we possibly be thinking?

Here are comments from various congressmen on the GAO report.

Senator Grassley said: “This study gives the FDA another reason to carefully consider its use of these sorts of trials when approving new drugs for the market. Every step should be taken to strengthen drug reviews done by the FDA for the consumers who rely on and benefit from life-saving and life-enhancing pharmaceutical drugs.”

“Non-inferiority trials are an essential tool for evaluating the safety and effectiveness of certain kinds of critically important drugs such as antibiotics—but they pose difficult scientific issues,” said Chairman Waxman. “I’m pleased to see that FDA’s March guidance clarified the standards for these trials. I hope FDA will work with industry and academics to address remaining issues on how and when to best conduct these trials. Although the pipeline for antibiotics is critically bare, no one benefits from ineffective drugs—and so I encourage FDA and industry to continue to collaborate to do everything possible to ensure that safe and effective antibiotics are developed.”

Rep. Dingell said: “This GAO report provides a very good assessment of the concerns related to the use of non-inferiority trials and the recent strides FDA has taken to address those concerns. Non-inferiority trials have a role in the drug review process. However, they must always be designed and interpreted in a way that clearly demonstrates a high level of safety and efficacy. I look forward to FDA’s continued progress in this regard. American consumers should have no doubts about the effectiveness of the drugs they consume.”

Rep. Markey said: “The GAO report shows that these so-called ‘non-inferiority’ trials have often proved to be an inferior means of reviewing the safety and efficacy of new drugs. While the FDA has made strides to improve evaluations relying on non-inferiority trial data, the GAO report highlights important limitations of non-inferiority trials. I will continue working to investigate and implement empirically sound changes to ensure that the FDA can protect the public’s health and that the drugs in our medicine cabinets have gone through a thorough test of their safety and effectiveness.”

These congressmen (especially Markey and Grassley) speak as if the trials that we have been carrying out for the last 5 decades did not assure either safety or efficacy.  Of course, this is not the case at all for antibiotics and I challenge the congressmen to demonstrate that we have approved inefficacious antibiotics with no more effect than placebo at least for serious infections over the last 50 years. I think that this will be hard to prove even for a number of so-called mild infections as well. But this argument is not about safety and efficacy really.  The argument is about how far we can or should go to prove to what level of certainty that drugs are safe and efficacious.  No drugs are 100% safe and no drugs, even antibiotics, work for all patients all the time. We have to find a way forward for antibiotics that provides us sufficient reassurance of safety and efficacy while at the same time providing for the realities of clinical trial conduct on the ground. There is a way forward, and many have pointed these options out to the FDA and congress, but their pleas seem to have met with a deaf ear. The GAO report gets us no further along these lines than we were as long as 10 years ago. 

All this political maneuvering puts our very lives at risk as we head into older age. As we age, we will be in greater danger of contact with hospitals with their antibiotic resistant bacterial pathogens like MRSA, multiply resistant Klebsiella that essentially cannot be treated, and now the NDM-1 superbug arriving on our shores from India. Everyone who does not want a new antibiotic active against these organisms raise their hands and vote for the congressmen listed above.

More on superbugs, the FDA and government later . . .