Tuesday, August 28, 2012
The NIH recently reported an outbreak at the NIH hospitals where 11 patients died with infection caused by a KPC carbapenemase producing Klebsiella resistant to virtually all antibiotics. The outbreak was finally uncovered by DNA sequencing of all Klebsiella strains isolated either as part of the infection or from patients who were just carriers. This was an enormous effort but it did allow physicians and epidemiologists at the hospital to track the infection to help stem its spread. The story was picked up by several news outlets after its publication last week. This in turn led to the inevitable question – where are the new antibiotics we need to treat these infections?
This last question led to several subsequent reports including one from the Washington Post and a segment of the Diane Rehm show on NPR public radio. While most of the time on the Diane Rehm show was dedicated to understanding the outbreak, there was a brief segment on exploring where the new antibiotics are or are not. I was interviewed along with Ed Cox. I tried to make points around the difficulties with discovering new antibiotics, with the marketplace, with industry consolidation and with companies just dropping out of antibiotic R&D altogether. But I only got to 2-3 of these. Ed pointed out how the FDA is looking at accelerated and higher risk pathways for new products for these very resistant infections. I know that Ed also understands that we have to have feasible pathways for traditional development as well – but he didn’t get a chance to go there either.
At the same time, a Financial Times article highlighted how many pharmaceutical companies are negotiating their trial designs for registration of antibiotics for the market in Europe putting the FDA in second place. This emphasizes the risk that the US is running. If trial designs are negotiated in Europe where the development pathway for antibiotics remains reasonable and feasible (see my last blog on this), the US will be left in a take it or leave it position when these trials are completed. None of us want to be in that position. This is such a turnaround from the 1990s when EU was the conservative and more difficult regulatory agency and the FDA was more approachable and tried to make sure trials were feasible. But EU never got to the point where the FDA is now – requiring infeasible trials with endpoints that many physicians believe are clinically irrelevant and that I think are unnecessary.
Hopefully the FDA will act quickly to provide feasible and reasonable trial design paradigms for antibiotic approval here in the US. The fastest way for the FDA to accomplish this would be to rescind all previous guidance (again) and to harmonize with EU. Then they can slowly evolve away from that position if needed. But this strategy would give the industry, patients and physicians an immediate pathway forward that would be global. What is wrong with that idea? Why can’t we just do that? I hope to ask that question at the Brookings Institution in a couple of days.
Wednesday, August 22, 2012
article just published in the Canadian Medical Association Journal suggests that, at least among patients older than 65 years of age, serious liver toxicity occurs at a rate of 7.98-8.62 per 100,000 patients treated with levofloxacin and moxifloxacin respectively compared with 6.44 per 100,000 for cefuroxime, a B-lactam usually considered to be safe. But clarithromycin, a macrolide, a class known to be associated with rare toxic liver reactions, had a rate of 3.95 per 100,000 patients treated in this large Canadian study. Of course these rates are low overall – about 10 fold lower than the rates of fatal aplastic anemia we used to see with chloramphenicol (for those of you who remember back that far).
But more fascinating to me is that the rates of serious liver toxicity associated with these fluoroquinolones are all higher by several fold than the rate estimated for telithromycin (Ketek) liver toxicity. There the rates were calculated (this link requires a subscription or payment) to be about .5-1 in 100,00 patients treated. You remember Ketek – the scandal that resulted in the FDA virtually halting antibiotic development in the US (at least in most indications). I should note that the methods used in the fluoroquinolone study and that used for the FDA studies are not the same. Nevertheless, these data support the contention that Ketek was no more toxic than many other antibiotics already approved for indications like sinusitis, bronchitis and otitis. But approval for use in these indications was withdrawn for Ketek – but not for any of the generic antibiotics or even any of the other branded antibiotics like levofloxacin even though some were as toxic as Ketek. What will now happen to levofloxacin and moxifloxacin? My guess – nothing – not even relabeling. Ketek was just in the wrong place at the wrong time and served as a focal point for congressional anger and frustration with what they apparently saw as a flawed antibiotic development process in the US. Of course, what this led us to is a paralyzed development process for antibiotics in the US that the FDA now says has to be entirely rebooted. I think Ketek was good in a way for making us examine some of the principles upon which our process is based. But Ketek also engendered action on the part of regulators without consideration for the consequences. We are all now paying for these decisions in antibiotic R&D that has shrunk and continues to shrink based on PhRMA’s correct view of the increased regulatory risk (in the US) in spite of rising levels of resistance and increasing numbers of untreatable infections in the US and abroad. This is a price that we will continue to pay with interest for several years.
Should we withdraw our withdrawal of Ketek?
Sunday, August 12, 2012
As I mentioned in my last blog, I was recently invited to participate in another meeting with the FDA at the Brookings Institution. At the last meeting (summarized in a previous blog) Janet Woodcock made the extraordinary admission that the FDA would have to reboot in order to get antibiotic development out of the cellar in the US.
In this installment, I would like to explore a feasible way forward for hospital acquired and ventilator associated pneumonia. The FDA guidance for these indications currently suggests designs where the endpoint is mortality and where patients are precluded from receiving prior antibiotics. These designs have been discussed several times in this blog and are completely infeasible and in many ways not at all real world (over 80% of ICU patients receive antibiotics for e.g.).
Ventilator-associated pneumonia is a particularly problematic indication because of great controversy around diagnostic accuracy and the fact that the disease incidence is shrinking making these patients difficult to find for enrollment in clinical trials. Adding to the difficulty are US rules suggesting that nosocomial infections might not be reimbursed by Medicare that, in turn, provide a disincentive to actually make an official diagnosis in the chart of hospital-acquired pneumonia.
Many studies suggest that antibiotics for this indication have a treatment effect of 40-60%. When looking at mortality, but more importantly for our purposes, even when looking at clinical outcome via pharmcometrics these numbers hold up. In spite of this, the FDA has proposed a 10% non-inferiority margin within the microbiologically documented population and the EMA proposes a 12.5% margin. The patient numbers required by these margins, even when looking at clinical outcome as an endpoint, may be difficult to achieve today. But the treatment effect numbers suggest that in a clinical trial setting, we can think about non-inferiority margins of 15-20% that still retain at least 50% of the treatment effect. This range of margin would almost certainly bring these trials within the range of feasible patient numbers.
So here is a proposed design with trial numbers that might be required (note that for a combined HAP/VAP trial at least 30% of patients would be required to have VAP).
Patients would be allowed up to 24 hours of prior antibiotic within 72 hours of enrollment in the trail (as per EMA). Patients who had failed prior therapy (predefined in protocol) would be allowed to enroll regardless of the time course of the prior failing antibiotic.
Endpoint - clinical response at test of cure.
Endpoint - clinical response at test of cure.
Analysis population – ITT and modified ITT (per protocol).
Non-inferiority margin – 17%. For a trial with a 60% treatment success rate, 90% power and 70% evaluability rate, 500 patients would be required per trial or 1000 for two trials.
Option for a single trial – using support from a previous trial in severely ill (PORT III-IV) trial in community acquired pneumonia, a single trial in HAP/VAP would suffice for approval. For a 17% NI margin as noted above but at 80% power, the trial population would be 750 patients total.
This proposal harmonizes, to a large extent, the FDA and EMA proposed addendum. I have increased the non-inferiority margin above that suggested by EMA to account for both the very large treatment effect of antibiotics for this indication including that seen for an endpoint of clinical outcome, and to allow for increased feasibility at a time when the disease incidence and therefore patient availability are decreasing.