I guess it will not surprise anyone to hear that, when it comes to directly challenging the FDA, pharmaceutical companies, large and small, are wimps. I have spoken to a number of companies over the last two weeks and no one is willing to be clear and honest with the agency. They will tell me that the trials called for in recent FDA guidance are infeasible or at best on the edge. But they will not be clear with the agency. You can find all the submissions to the docket at regulations.gov.
Astra-Zeneca states “trials of this size may not be feasible in a reasonable time frame.” They further suggest that the trials required by the guidance (in this case in VABP) “could hinder the pursuit of further research in this area of high medical need.”
The Pfizer submission, from a company that just abandoned the entire area of antibiotics, is a complete wimp-out. GSK talks about how the design is challenging and risky.
PhRMA was more open in their response to the FDA.
PhRMA goes on further to note that the FDA’s double discounting of the treatment effect to establish the NI margin is overly conservative and not scientifically based. But instead of simply saying that the approach is not acceptable, they ask the agency to clarify its rationale for the discounting. Is this diplomacy or what exactly?
Perhaps the best and most compelling submission comes from Johnson & Johnson. J&J has also essentially abandoned antibiotic discovery research but they continue to try and develop and market doripenem. They describe their ongoing attempt to carry out a study for doripenem.
Our concerns regarding the feasibility of conducting studies that adhere to the recommendations in this guidance are based on our recent experience conducting several studies in HABP/VABP patients and more specifically the challenges we are encountering with recruitment into an ongoing Phase 3 study in patients with VABP (DORI-NOS-3008). Study DORI-NOS-3008 is a double blind, randomized, multi-center comparator controlled Phase 3 safety and efficacy study that implements many of the principles proposed in this draft guidance document. Eligible patients must be hospitalized for at least 5 days, on mechanical ventilation for ≥48 hours, have a chest radiograph consistent with pneumonia, have a fever/hypothermia or WBC count indicative of systemic infection, have a CPIS ≥6, an APACHE II Score >8 and <35, and a bronchoalveolar lavage (BAL) or mini-BAL performed at baseline from which at least one bacterial pathogen must be isolated from culture at ≥104 CFU/mL. Patients are excluded if they receive >24 hours of prior antibiotic therapy (before the first dose of study drug) for the current episode of VAP. The use of adjunctive aminoglycoside therapy is only permitted at initiation of study drug therapy as empiric adjunctive therapy for infections suspected to be caused by a carbapenem-resistant gram-negative pathogen. The adjunctive aminoglycoside must be discontinued by 72 hours unless a pathogen is isolated from the baseline lower respiratory tract (LRT) specimen that is resistant to the comparator, and presumably the investigational agent also. The first patient was enrolled into this study April 1, 2008 and as of February 15, 2011 only 272 patients have been enrolled (approximately 100 pts/year). A total of 128 sites have been initiated and had study drug shipped. However 89 sites have been closed due to lack of enrollment. Of the 39 sites that remain open, only 22 sites recruited 1 or more subjects in 2010. Given the enrollment challenges, the feasibility of completing this study and providing data in a relevant timeframe is currently under evaluation. In addition, given the very sick and complex patient population, the limited number of patients with VABP, the small numbers of patients enrolled per site, and the complexity of study design, there are very high costs per patient enrolled into these trials (much higher than costs we are aware of in other indications). Therefore, the feasibility of recovering the costs for conducting this and future HABP/VABP studies is low, and potentially warrants re-assessment of the feasibility of initiating development programs for new antibacterial agents.
But lets be clear. There is NO WAY any of these companies or any other will be able to carry out the trials called for in this guidance. Why can’t someone from industry say just that? The agency needs to hear it from someone other than Brad Spellberg and me.
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