My name is Dr. Anna Mazzucco. Thank you for the opportunity to speak today on behalf of the National Center for Health Research. After completing my Ph.D. at Harvard Medical School, I conducted research at the National Institutes of Health before joining the Center’s staff. Those are the perspectives I bring today.
Our research center conducts research, analyzes data in the research literature, and then explains the evidence of risks and benefits to health professionals, patients, and policymakers. Our president is on the Board of Directors of the Alliance for a Stronger FDA, which is a nonprofit dedicated to increasing the FDA’s budget, so that it can do its job well. Our organization does not accept funding from pharmaceutical companies, and therefore I have no conflicts of interest.
We are all concerned about the growing problem of antibiotic resistance. We want to ensure effective treatment options for those with serious infections. However, ineffective antibiotics actually worsen our situation by increasing antibiotic resistance. They also expose patients to unnecessary risks, with no chance for benefit, and delay effective treatment. For these reasons, we must be sure that antibiotics are adequately studied and demonstrate clear safety and efficacy before being used.
With these considerations in mind, we are gravely concerned about the minimal evidence being presented here today. You are asked to consider a new drug based on preliminary data from a recently unblinded phase III trial for only one of the three indications being sought. The remaining phase III trials are either ongoing or still being analyzed. We urge the committee to clearly recommend that the FDA wait until these trials have been completed and further analysis has been done before making any recommendations regarding approval.
Although preliminary, the phase III trial data on complex intra-abdominal infections (cIAI) showed that patients who had moderate renal impairment at baseline (MRIB) had a lower clinical cure rate when treated with CAZ-AVI + MTZ compared to meropenem. Of even greater concern, 8 deaths were observed in the CAZ-AVI + MTZ group versus only 3 deaths in the comparator. Not surprisingly, the sponsor believes that this safety signal and the lack of efficacy are unlikely to be related to the study drug. However, that claim is not based on conclusive evidence. The size of this subgroup is too small to make a conclusion, which the sponsor has acknowledged. Furthermore, the agency has not yet reviewed this data, making any conclusions inappropriate.
But even after the FDA reviews the data, the samples are too small to draw the conclusion that this new drug is safe or effective.
The FDA has stated that the sponsor’s pooled meta-analysis from the literature has several uncertainties and should only be used as additional supportive evidence. We strongly agree. The only other evidence we have is from two small phase II trials, which the FDA has stated were not analyzed in a formal statistical manner and had no pre-specified hypotheses. Instead, the results of these trials were summarized descriptively.
The totality of this evidence is not sufficient for informed decision-making. While I personally would not seek an antibiotic with a higher death rate, it would make sense for the panel to strongly urge the FDA to wait until all the phase III trials have been completed and the agency has fully reviewed the data before making a decision.
We have carefully reviewed the agency’s regulatory approach regarding this drug combination and the section 505(b)(2) pathway as described in the background material. The FDA background document states that “the contribution of avibactam will be demonstrated by in vitro studies, animal models of infection and with limited clinical data. Safety of avibactam will be determined from Phase 1 studies of avibactam alone and phase 1 and 2 studies of CAZ-AVI.” We are alarmed that the agency would consider this new combination entity on such limited data. In fact, in the 1970 Upjohn versus Finch court case it was determined that for “…combination drugs purported to have advantages exceeding those of the components, there must be adequate, well-controlled data documenting the claimed advantages.” That type of evidence is NOT presented here.
Although I am a scientist, I also want to speak on behalf of patients today. Patients care about antibiotics that make them feel better sooner and save their lives. Animal and in vitro studies cannot ensure either. Furthermore, as stated before, antibiotics are unique among drugs in that ineffective antibiotics can worsen a patient’s condition and also create new problems. There are numerous unfortunate examples of antibiotics that were approved and subsequently withdrawn from the market due to safety concerns. In fact, the withdrawal rate of antibiotics over the last three decades was triple that of other drug classes, with 26 out of 61 antibiotics approved during that time being subsequently withdrawn.
We strongly urge the committee to ask for completion of the remaining phase III trials and the agency’s review before making any recommendations about approval.
Thank you for the opportunity to address the panel today.
- 422 F.2d 944; 1970 U.S. App. LEXIS 10524.
- Outterson, K., Powers, J. H., Seoane-Vazquez, E., Rodriguez-Monguio, R. and Kesselheim, A. S. (2013), Approval and Withdrawal of New Antibiotics and Other Antiinfectives in the U.S., 1980–2009. The Journal of Law, Medicine & Ethics, 41: 688–696.