David's New Book

Thursday, April 13, 2017

FDA Antimicrobial Drugs Advisory Committee Meeting

Today the FDA held an important Advisory Committee meeting to discuss approaches to the clinical development and approval of antibiotics designed for specific pathogens like Pseudomonas aeruginosa and Acientobacter baumanii. The meeting materials can be found here.  


(OK.  I gave up just after 3:30 pm – so I may have missed something really important).

Once again, the make-up of the committee left much to be desired.  There was no PK/PD person with expertise in antibacterial drugs on the panel.  It became obvious during the discussion that this was a serious omission. The safety expert came from a parasitology background and was obvious unfamiliar with antibacterial development. Lynn Marks, as the industry representative, was, mostly, quiet (I’m not being derogative here). One pleasant surprise was the consumer representative who seemed knowledgeable and asked relevant questions.

The meeting began with Ed Cox and Sumathi Nambiar reviewing prior recent FDA meetings examining this question. Both emphasized how difficult it has been to identify a means to develop these agents in the content of all our prior experience with antibacterial drugs. In particular, Sumathi noted the disadvantages of both the superiority approach and the NI approach to these agents. One issue that folks have with the superiority approach is that it is time limited.  That is, after the first one or two drugs, such trials will no longer be possible.

Robin Isaacs later presented the Entasis plan for a non-inferiority trial of their new B-lactamase inhibitor-sulbactam combination for the treatment of Acinetobacter infections. He also showed that about 60% of Acinetobacter globally are multiply antibiotic-resistant. Robin noted that the mortality of serious Acinetobacter infections like HABP/VABP and bacteremia approach 40% when treated with standard of care and 80% if untreated. Given the 40% number, he justifies an NI margin of 20% in an NI trial with 28 day all cause mortality as the endpoint. All the speakers noted that a rapid diagnostic only makes enrollment slightly easier and may limit the use of prior antibiotics.  Robin said that a rapid diagnostic was not necessary especially if up to 48 hours of prior therapy could be allowed. Entasis believes that such a trial, that would target geographic areas where Acinetobacter has a high incidence like Taiwan and Thailand.

The FDA presented information that had previously been shown by Polyphor regarding POL7080, an antibiotic targeting Pseudomonas aeruginosa specifically. Polyphor declined to present themselves (?). Their plan for a NI trial with a 10% NI margin suggested that they would have to enroll over 3000 patients to complete the trial.

For me, though, the highlight of the day was the Infectious Diseases Society presentation by Trish Perl. She suggested using validated external controls to bolster trial data.  Although Trish was not specific, this seems most likely to occur in the context of a superiority trial.  I have been saying this for years now.  By carrying out such a trial with a small number of patients where there is a 4:1 randomization to best available therapy, we can use the active controls to validate the external controls we have used. The FDA seems to be uncomfortable with external controls, but might be more comfortable with a validation plan as suggested by Trish and IDSA.

Another highlight was John Rex’s public comments. I paraphrase here. He suggests we will need four lines of evidence. Animal models.  PK in man. Safety profile. Some clinical data consistent with the above.  Stewardship guarantees lack of overuse. If we have no path – we’ll lurch from crisis to crisis. We live this now.  We lack drugs for some bugs. If the drug is available we can cautiously improve our understanding of the agent (given the limited data used for approval).

Mike Green asked about “provisional” approvals or conditional approvals – something that, without a surrogate endpoint, the FDA is unable to do under current law.  This is a topic we discussed at the pathogen-specific workshop last year. There we suggested that one could return to a product post-market if data warranted it. But we should be clear that the drug would be approved – not conditionally approved.  If at post-market follow-up a significant problem was identified, the drug could then be reviewed at another advisory committee and might then required label changes or might even have to be withdrawn.  This is obviously a cumbersome way to do this.  A change in regulations here would be welcome – but would apparently require legislation – an area where we are currently paralyzed.

Another issue that arose was the one of diagnostic accuracy – especially in patients with HABP/VABP. This is not like patients with cancer where we have a tissue diagnosis and we can even carry out receptor typing prior to initiating therapy. The problem is that if we enroll patients where our diagnostic accuracy is poor, the “noise” engenders a tendency for all outcomes to be the same. For me, this also raises the problem of mortality as the endpoint for this indication. We believe that 50% of this mortality is unrelated to the infection being studied.  This also will drive any trial towards the null.  For an NI trial this is good for the sponsor but not for the patient and physician.  For a superiority trial, this is not good for the drug and may result in non-approval of an efficacious agent. Jack Bennet emphasized this dilemma for us.

In answer to the questions posed by the FDA, a number of panel members supported the idea of using a clinical trials network.  There was general support for non-inferiority trials on the panel in contrast to many of the speakers in the public comment section. Many panel members wanted post-market evaluations to be an important component of the approval of pathogen-specific agents.

In conclusion, the consensus seems to be that we must go here.  There was also agreement that this is a tough problem and that the best we can achieve is some kind of “happy medium.”  But - “You won’t get a recipe from us.”