The FDA Increases Clinical Trial Design Stringency and Costs Companies Abandon Antibiotic Research

In 1999, I was working at Wyeth Pharmaceuticals. Wyeth had discovered a new chemical series of tetracycline derivatives that was active against a variety of resistant bacteria including those resistant to the tetracyclines. We were getting ready to enter the last (and most expensive) stage of clinical trials prior to submitting our request for marketing approval. We followed the FDA guidelines in designing our trials. They allowed us to set the statistical stringency of the study, within limits, according to the size of the trial. Therefore, as the trial size got smaller, the stringency would be lower. In our discussions with the FDA, it became clear that they were going to require trials of a size and cost that was unprecedented for antibiotics being developed to treat patients in hospitals. The FDA was concerned that the kind of clinical trials used for approval of antibiotics in the past were not sufficiently robust. In these trials, since using a placebo is generally thought to be unethical, we compare the new, experimental antibiotic with an older, proven antibiotic. But, since the older, comparator antibiotics (after the sulfonamides and penicillin) had never been compared to placebo (no active therapy) the FDA felt that there was a chance that new products might slip to a point of being ineffective. The issue is a statistical one (but has little to do with life as we know it!). When you compare two products in a trial, the two are compared statistically. This being the case - you can't really do an equivalence trial since to prove that two drugs are statistically equal requires an infinitely high number of patients. For antibiotics, you also would be hard pressed to do a superiority trial since the antibiotics work so well that proving superiority also requires a very high number of patients. It would also be hard to recruit patients into a trial where you know that the patient has a pathogen resistant to say the comparator antibiotic but not the new one given that the patient would have a random chance of receiving either drug. Therefore, all antibiotics since the 1950s have been studied in a so-called non-inferiority trial. In this sort of trial, you must accept some limit on the chance that the new drug is inferior to the standard approved therapy used as a comparator. That statistical margin is the problem. The tighter the margin, the more patients are required for the trial. In the past, as I noted above, margins were deliberately set to keep trials at a reasonable size. These margins, usually set somewhere between 10 and 20%, were acceptable to the FDA. 15% was a commonly used margin. That is, for seriously ill patients, the FDA would accept the possibility that the new treatment might be up 15-20% worse than the comparator. So, over time, in the worst case scenario for every drug, if one were 15% worse than the other and than that one became the comparator for the next and so on, the new antibiotics could end up being no better than nothing at all. Those of us actually treating patients with infections were always puzzled by this worry since we knew from the evidence of our own eyes that the antibiotics were effective for most serious infections. The FDA wanted us to reduce that margin to 10%. When you compare the patient numbers for the two circumstances, the 10% margin required more than twice the patients (and therefore about twice the cost) compared to the 15% margin. Remember, we are talking about a theoretic maximum difference between the two drugs, not the actual difference. So, while scientifically, it might be preferable to narrow this margin (why not to 5 or 2 or 1%?), the trials were going to cost more, expose more patients to an experimental drug and were going to take longer to perform. The time until the new therapy would be available to patients would be longer and the time to market for the new therapy would be more distant.

We presented the result of our discussions with FDA to Wyeth's senior management. When they saw the estimated costs for the FDA-proposed trials and the increase in time required, they balked. Our management was concerned that it would take too long for us to recoup the trial costs or that we might never recoup them. They put the entire program on hold.

We worked with Pharmaceutical Research and Manufacturers of America (PhRMA, the pharmaceutical trade and lobbying group) and with the Infectious Diseases Society of America representing infectious diseases physicians to open a public discussion with the FDA in hopes of salvaging our potentially important new antibiotic and to keep open opportunities for the development of other new antibiotics. A series of workshops with all three, FDA, PhRMA and the Infectious Diseases Society were held during 2000 and 2002 to address FDA concerns. The result of these discussions was that the FDA did not make any blanket decision covering all antibiotics, but agreed to evaluate trial designs on a case-by-case basis.

In further discussions with Wyeth the FDA allowed Wyeth to proceed with 15% margins and tigecycline was developed and finally approved in 2005. Wyeth as it turns out, was one of the last companies to be allowed to use a 15% margin - almost everyone else since then has had to use a 10% margin for most indications.

Between 2000 and 2002, Roche, Lilly, Bristol-Myers Squibb and even Wyeth all announced they would discontinue research in antibiotics. Many more would follow closely on their heals. There are many reasons for this as we will discuss in Chapter 6, but one of the reasons certainly was the uncertainty around the FDA's clinical trial requirements and a feeling among many in industry that the agency was actually hostile to antibiotics in general.

One of the requests industry and the Infectious Diseases Society made to FDA in 2000 was that the agency modernize their guidance for the development of antibiotics so at least companies would know what kind of trials they would have to conduct to obtain approval. Since then, the agency has actually released a number of new draft guidance documents. The good news is that industry knows what it has to do. The bad news is that, frequently, they can't do it.

The first new guidance released indicated that all the old guidance documents on trial design for antibiotics were no longer considered valid by the agency. Next, the agency required a justification for the statistical margin that was to be used in proposed comparative trials. I think this was a way of getting sponsors to help FDA in doing some literature research in this area. The idea is that to define this margin, you have to define the benefit that the antibiotic would have compared to placebo. Since placebo controlled trials have not been done since the sulfonamides and penicillin, this gets to be a bit difficult.

With their advisory committee and in public, the FDA began to examine the issue of antibiotics used for mild infections like sinusitis, bronchitis and otitis (middle ear infections). The issue for these infections is that they frequently are caused by viruses and not bacteria and therefore would not respond to antibiotics in any case. This leads to much of the unnecessary use of antibiotics which in turn probably leads to antibiotic resistance. The other question is that even when bacteria cause these types of infections, will they get better without treatment? Will serious complications arise without antibiotic treatment? How do we know that antibiotics even work? The scientific literature is very conflicted on this subject. The area of mild infections is directly related to the agency's basic concern about comparative trials where a placebo is not used. How do we know that the standard or comparator antibiotic is better than no antibiotic?

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