The FDA Should Withdraw Penicillin

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  • 07/19/2006

According the NY Times today, David Graham who is to rational evaluation of the risks and benefits of medicine what Hezbollah is to advancement of peace in the Middle East, called for the withdrawal of Ketek based on the fact that others in the FDA’s infectious disease division relied on post market data from Europe submitted by the company. That’s pretty funny considering Graham has called for the removal of Crestor, Celebrex, Accutane, Rice Krispies and tap water based on post market data.

Graham is not alone is his obsessive pursuit of Ketek. He is joined by an FDA staffer who wondered in a memo whether the risk of liver failure was worth one less ear infection in regards to a Ketek trial. Well, as I wrote before, if that is the benchmark, we shouldn’t give anyone tylenol for a fever.

“David Shlaes, an expert in infectious disease and antibiotic research with the development of a new medicine under his belt has sent this email to me in response to the recent articles about Ketek’s “dangers”

Recent press reports on the development, approval and subsesquent reports of toxicity of the antibiotic Ketek have me concerned. … The implicit (if not explicit) message was that the evil pharmaceutical company submitted flawed data to the FDA who, admitting the study was flawed, still approved the drug in spite of serious safety concerns. Now patients are dying because of the greed of Sanofi and incompetence or worse at the FDA.

.. Ketek, an antibiotic developed by Aventis, now Sanofi-Aventis, was reviewed by the FDA in 2001. They noted safety concerns, partly around the potential for liver toxicity, and requested additional safety data. Aventis then carried out an extremely large study of over 24,000 patients using more than 1800 different investigators worldwide. This was the study (no. 3014) where the FDA noted that the study was so flawed that they could not rely upon its data. Nevertheless, the FDA noted that in the post-marketing experience with Ketek worldwide during the intervening years until 2003, almost 4 million courses of therapy had been prescribed with no clear safety concern, plus there was a general lack of a safety signal in the 24,000 patients in the flawed study. Therefore, the FDA approved the antibiotic.

FDA conducted a thorough review of adverse events related to Ketek in the post-market setting. They were able to identify 12 cases of acute liver failure of which four were fatal among 10 million prescriptions. There were 23 cases of liver toxicity overall in the data set. As a result of these findings, the FDA approved label for Ketek has been changed to note in bold letters the possibility of severe liver toxicity â a reasonable approach based on the data.

Congress, specifically representatives Markey and Waxman, both democrats, and Senator Charles Grassley, a republican, have sent inquiries to the FDA regarding the approval of Ketek. Apparently, they believe that Ketek should never have been approved, and that the FDAâs approach to the entire problem has been flawed. Some have demanded that Ketek be withdrawn.

I would like to try and put all this in some perspective. To me, Ketekâs story is one of risk and benefit and the risk tolerance of American society and the FDA. Let us take an old reliable antibiotic or even two or three â penicillin, amoxicillin and augmentin. These antibiotics are very closely related, generic, inexpensive and are taken by many more millions of patients, including and especially children, than take Ketek. Augmentin, a combination of two penicillin-like drugs, had peak year sales of well over $2B at one point and may be the biggest blockbuster antibiotic in the history of the pharmaceutical industry. Penicillin is thought by most physicians to be the most safe and effective antibiotic ever to be developed and marketed. Yet the penicillin drugs can be expected to cause a fatal allergic reaction once in every 35-100,000 courses of therapy. Therefore, among the 10 million courses of therapy as surveyed for Ketek and for which 4 fatal cases of liver toxicity were identified, we could expect 100 to 285 deaths if the prescriptions had been for any of these penicillin drugs. In the FDA approved labeling for the penicillin drugs, the possibility of serious or even fatal allergic reactions is noted, just like the possibility of liver toxicity is noted in the Ketek label. Aspirin probably causes 7,000 deaths and 76,000 hospitalizations a year in the United Sates.

I wonder if, given our concern over Ketek, penicillin would even make it to the marketplace today, or if it were approved, whether it would be withdrawn shortly afterwards as reports of fatal anaphylactic reactions started to arrive at the FDA. Could we register asprin? Or, would we rely on the information already included in the approved product label noting a risk of rare but serious allergic reactions? Is Ketek different from penicillin? Would there be congressional hearings pillorying the FDA for approving or not forcing the withdrawal of penicillin?

I think its time for all of us, the press, Congress and the American public to take a step back from this brink â for the brink it is. More large pharmaceutical companies have halted their antibiotic research efforts than the number that still continue working in the area. Among a large number of reasons for this pullback is the increasing stringency and cost of clinical trials required for registration â of which Ketek is an example. If we want to have continued new and beneficial therapies from the pharmaceutical industry, in particular, if we want to have new antibiotics that fight infections resistant to the old antibiotics, we need come to a realistic understanding of the risk we are willing to accept.”


Center for Medicine in the Public Interest is a nonprofit, non-partisan organization promoting innovative solutions that advance medical progress, reduce health disparities, extend life and make health care more affordable, preventive and patient-centered. CMPI also provides the public, policymakers and the media a reliable source of independent scientific analysis on issues ranging from personalized medicine, food and drug safety, health care reform and comparative effectiveness.

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