Image via WikipediaYesterday was a big day for news on the antibiotics front. The Infectious Diseases Society of America (IDSA) presented testimony to support reauthorization of the Prescription Drug User Fee Act (PDUFA) whereby certain incentives for antibiotic R&D would be included. Their testimony and press release are provided here by links.
To me, by far, the most important aspect of their testimony and the subject of the press release is FDA reform. They clearly point out, in no uncertain terms, that the lack of feasible trial designs to meet FDA requirements is undermining our ability to bring forward new and needed antibiotics. The entire quote from this section of the IDSA testimony is shown below.
One solution proposed by IDSA is a good one, but one that, in my view, will still have very limited applicability to expanding our antibiotic pipeline. They propose a pathway they call “Special Population, Limited Use (SPLU).” This hearkens back to Mark Goldberger’s 2002 call for trials showing high quality but low quantity. In fact, this idea has been discussed both within and outside the FDA for at least the last decade. It would involve invoking subparts E and/or H of the FDA regulations to allow exactly this – approval of drugs targeting limited populations with high medical need. In the case of antibiotics, this would be those patients with serious infections caused by pathogens resistant to either all approved antibiotics or all but two last line agents such as say tigecycline and colistin - where we don’t know that either will work in such infections anyway. These antibiotics would be restricted to very limited use only in those targeted populations. A high price could assure that there would not be much off-label use.
The advantage of the IDSA initiative is that it gets the FDA talking seriously about this approach – something they have failed to do since Mark Goldberger. Another very positive aspect is that it may provide a pathway for some new antibiotics. I can only think of two possible candidates for this approach today. One is the Pseudomonas-specific antibacterial peptide from Polyphor. A second would be if some company ever decided to develop a combination of a monobactam plus a beta-lactamase inhibitor similar to avibactam that could be used to treat infections with most metallo-beta-lactamase producing organisms including NDM-1.
Even for these examples – the devil will be in the details.
Here is what Janet Woodcock said – “A company might be able to test a product on 400 patients rather than 8,000 to get it on the market. But it could only be used for a very limited group of patients with life-threatening antibiotic-resistant infections for which other medications are not available, not widely for off-label uses.” But of course no antibiotic is ever studied in 8000 patients to begin with (or almost never) and enrolling 400 patients with serious infections with MBL-producing strains will be next to impossible in any kind of reasonable time frame. Other questions include that of the indication. Can one enroll patients with infections at any site including the urinary tract? Will UTI patients be excluded? Is it OK to lump skin and soft tissue infections with pneumonia as might be required to study patients with Acinetobacter infection? Is mortality the endpoint or is it cure (I believe mortality will be very challenging and highly confounded as an endpoint).
For other antibiotics with broader spectrum or targeting more general populations will this “new” pathway allow for more rapid entry to market? I’m not sure. For example, is it much faster to develop it for these rare infections and get an early approval, begin to accrue revenues and then study the drug for a broader indicaton? In that case, you would start out at a very high price then lose both your pricing advantage and the SPLU designation after approval for a more traditional indication like UTI or intra-abdominal infection for example. I am not convinced that the timelines fit here and that this makes any sense - hence my belief that SPLU will benefit a very small number of drugs.
Another aspect yet to be determined is the NPV for the companies for an SPLU drug. Clearly the price could be high, but will the number of patients treated provide a return on investment under these circumstances? I would need the help of a marketing person to sort this out and I will seek such help and provide a follow-up to this blog soon. At the end of the day – large pharma may be willing to forgo profits for an SPLU antibiotic.
In conclusion – this is an important initiative by the IDSA. I am skeptical that the FDA will be able to make even this key initiative feasible on planet earth. I believe that if the FDA can make this approach feasible, it will only benefit a very few new antibiotics – but that would still be a very positive step. Finally, I think the jury is out on return on investment – but this may be less important to large pharma in this case.
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