From the Pew Charitable Trusts - 2

This is the second (longer than usual) installment from the meeting at Pew Charitable Trust, September 22, 2011. 

In this installment, I review discussions by the Infectious Diseases Society (Dave Gilbert and Helen Boucher), from John Rex of Astra-Zeneca and from Ed Cox of the FDA and others like Mark Goldberger (ex-FDA and currently at Abbot).

Both Dave Gilbert and Helen Boucher emphasized the growing medical need for new therapies to deal with resistant Gram-negative infections.  Both provided data, either from recent surveys of physicians, from the literature or from personal experience to demonstrate the relentless increase in the frequency of infections for which either the only antibiotics left for treatment were either carbapenems or polymyxins or nothing.  CDC data derived from their National Health Surveillance Network from 2009-10 showed that bloodstream infections caused by Enterobacteriaceae resistant to everything except carbapenems and polymyxins ranged from 4-16% and those resistant to ALL antibiotics were an astounding 2-12%.  Among Acinetobacter bacteremias, the numbers were an incredible 68 and 63%.  All these numbers are up from 2008 data.  The personal stories behind these numbers are nothing less than poignant.  The folks at Pew Charitable Trusts shared a film of the parents talking about the death of their son, a young military victim of one of these infections.

To answer this increasing medical need, the IDSA has documented a paltry 10 new antibiotics in the late stage pipeline and they have noted that none address those organisms resistant to all antibiotics (I presume they mean those carrying a metallo-beta-lactamase like NDM-1).   The approvals of new antibiotics continue their inexorable decline in spite of a rising number of drugs entering early development.

National, government-funded efforts to meet the scientific challenges associated with studying antibiotics for these severe infections are severely underfunded and will not even start until the last half of 2013.  According to IDSA this is too little too late!

Finally, regulatory challenges were reviewed.  IDSA notes that NO new drugs are currently being studied for hospital-acquired pneumonia where we expect that up to 20% of patients will die.  This is partly because of the general difficulty and expense of doing the trials, the high risk of studying drugs in such severely ill patients and finally, because there is no viable regulatory path forward for studying this disease in the US since the FDA trial design requirements are simply infeasible. The IDSA notes that even studies in community-acquired pneumonia have been made highly risky in the US given current guidance.  They suggest that the constant debate and revisions of guidance at the FDA create uncertainty in industry that only further discourages industry from continuing or entering or re-entering the antibiotics field.  

Ed Cox responded to these critiques by noting that the FDA is committed to providing feasible trial designs in their guidance.  But, in concrete terms, he only offered recent FNIH deliberations on the scientific justification and validation of new endpoints in trials of both skin infections and pneumonia.  He did not resolve areas of pneumonia trials that actually result in trial infeasibility such as making the analysis population in CABP trials the microbiologically documented population.  This requirement increases the trial population by 3-4 fold over what is normally the case rendering the design infeasible. The aspects of the hospital-acquired pneumonia guidance that make these trials infeasible are many and have been covered in previous blogs.

John Rex pointed out the incredible paradox of the discovery and then development-regulatory processes.  These processes take a good deal of time.  We need to anticipate resistance problems 10-15 years before they occur.  If this timeline could be shortened we could actually respond to resistance more quickly.  A great example was the outbreak of vancomycin-resistant enterococcal infection that started in 1989.  Our first drugs for treatment of these infections were approved 10 years later – and that was quick!

John noted the following –

•21 CFR 314.126 (US Code of Federal Regulations)

–“Reports of adequate and well-controlled [clinical]¹ investigations provide the primary basis for determining whether there is ‘substantial evidence’ to support the claims of effectiveness for new drugs.”

•Important implications

–Preclinical data are usually insufficient alone²

–Adequate & well-controlled clinical data are required

–Confirmation via more than 1 trial is desired: investigations

–FDA has flexibility:³ Other confirmatory evidence may be acceptable at FDA’s discretion in support of an adequate and well-controlled trial

This has been stated by others, including Mark Goldberger when he occupied Ed Cox’s position (essentially) at the FDA over a decade ago now.  In fact, at the Pew meeting Mark reiterated that the FDA has the statutory flexibility to find new paradigms for antibiotic development for severe and life threatening infections. John Rex raised the idea of progressive approval or conditional approval based on a more limited data set.  This is similar to arguments made by the Manhattan Institute back in 2005-6 to the Office of the Commissioner of the FDA.  This would be feasible – if only we could agree on a way forward.  One way would be organism-specific approaches backed by sound scientific preclinical and clinical data (PK in appropriate sites like ELF and appropriate populations like ICU patients, and preclinical and clinical PK/PD or pharmacometrics).  These might then be combined with more limited trials in more standard clinical indications such as intraabdominal or other infections. The conditional approval would then be validated by ongoing studies and safety registries. These paradigms already exist for a number of other therapeutic areas within FDA. The FDA has the flexibility to make this happen. 

Why is it not happening?  For that – we have no answer. But we better come up with SOMETHING soon.  If not, the vision I shared with you in my last blog, and that I stated at the Pew meeting, will surely come to pass.