FDA and Pathogen Specific Antibiotics

As I promised in my blog on FDA, Roche and Polyphor, I met by telephone with the FDA today (Ed Cox, Sumathi Nambiar).   I began by reminding them of my experience at IDSA at the origin of the last blog.  Specifically, many people both from academia and from industry were complaining that there was no existing pathway for approval of a pathogen specific drug at FDA currently.  Various folks said that the FDA was insisting on some “inferential” (read statistically significant) data to support an approval for a new antibiotic.  But we all know that for rare pathogens like Pseudomonas aeruginosa and Acinetobacter baumanni, there are not enough patient numbers to fulfill this requirement.

For example, lets say that you have a new antibiotic active only against Acinetobacter and no other bacteria. To show that your drug provides an advantage of currently available therapy, you target patients likely to have infections caused by resistant Acinetobacter.  Such infections might be pneumonia, urinary tract or skin infections. As such, you will probably have to treat at least 300 patients to end up with about 30 resistant Acineotbacter infections in your trial.  Such a trial will take at least 18-24 months (the longest reasonable time to spend on a enrolling a trial). And, lets say that standard therapy of patients with pneumonia, urinary tract infection and skin infections provides a clinical response in about 50% of such patients. You hope that your drug will bring the response rate up to 70-80% for a 20-30% improvement over standard therapy. We didn’t even get into the idea of stratifying patients by site of infection – but I’m not sure it would be necessary. To power the study to achieve statistical significance would require studying 100-250 patients with the desired infections – clearly not feasible in a two-year period – to say nothing of the expense involved.

It is clear to me, and to FDA, that these trials will be externally controlled.  Historical controls like retrospective but contemporaneous chart reviews or prospective observational studies where inclusion and exclusion criteria are similar to those used to enroll patients in the treatment trial would be acceptable.  Another approach would be to use pharmacometric data (I think) if robust data were available. The FDA agreed that external controls are OK.  This is not the problem for them.

In general, the FDA understands that they do not have a clear pathway at the moment for such drugs. They have always preferred to have enough data such that statistical significance at P less than 0.05 in a two-sided test was possible. They understand that for these pathogens, this will not be possible in any reasonable time frame.  What they need is a way to approve such drugs given their current regulatory constraints.

I mentioned orphan drugs where I thought that there would be examples where non-significant data would be used for approvals.  Ed corrected me.  He had just studied many such approvals and found that the P values were highly significant for most of these drugs.  The diseases tend to be chronic.  Enrollment seems not to be a problem.  And the effect size is very large making the trial size requirement fairly small.

I suggested that for a pathogen specific antibiotic they accept studies not powered at the 0.05 level, but rather that they accept more statistical trends (P of less than 0.1 for example). This could only occur in the presence of a very substantial PK/PD package including a strong dose-justification rationale. In the case of such an approval, the label would specify use is approved only for those patients with few or no alternatives. There would be a post-approval commitment for the sponsor to continue gathering data to try and provide a more substantial inferential argument.  In the case that this was not achieved, that is, with greater numbers of patients the new therapy could not be shown to be statistically superior to standard of care, both the FDA and the sponsor would have to rethink. This solution is fallible since standard of care might change in the interim making continuing study difficult or even impossible. Both the FDA and the sponsor would have to be willing to accept this risk.

Ed reminded me that I had proposed something very similar back in 2005-6 during a project I carried out with the Manhattan Institute.  I had totally forgotten about this proposal, but it was very similar to what I have proposed above.

Ed asked if I thought that rapid diagnostics would provide a way forward here.  I said – not tomorrow.  For this to be helpful, the diagnostic would have to be “point of care” and CLIA-waived.  I don’t think we are anywhere near something like that for Gram-negative infections today.

I am sure that there are other ways to approach this problem as well.  Ed told me that the FDA has been working hard on this internally, and in fact had spent virtually the entire day today on the subject.  He also told me that he has presented this as a problem to the President’s Advisory Council on Combating Antibiotic Resistance and asked for their help here.

I hope for all our sakes that we find a way forward – and soon.  Pathogen specific drugs are coming and they will be good for the microbiome , good for patients and good for us as a society. Apparently the ball is in the court of the President’s Council for now . . . .

The Antimicrobial Resistance Congress - Meeting Notes

On Monday and Tuesday, I chaired the World Antimicrobial Resistance Congress – a meeting organized by Terrapinn. The meeting was small,  with about 120 attendees, and the topics covered everything from various aspects of antibacterial discovery to policy and regulatory initiatives. I would like to take this opportunity just to share a few highlights from the meeting.

There were several key presentations from various funding agencies including BARDA, NIH, IMI and the Wellcome Trust.  With the exception of the Trust, it was abundantly clear to everyone that without additional funding, the efforts of these agencies to go beyond their current funding levels or even to maintain them will be threatened.   The funding from these agencies goes to everything from early discovery all the way through phase III clinical development and has been very important for academia and both small and large pharma in the pursuit of new antibiotics.  Any diminution or even an inability to expand these efforts would be a terrible tragedy. 

Several non-antibiotic approaches were discussed including antibodies, peptides and virulence.  Some are being examined for prevention while others are thought of as adjunctive therapy.  All of these approaches will mean superiority trials. How to set control levels of response within these trials then became a topic of conversation.  More later.

Diagnostics, both rapid and not, were discussed by FDA. On the more usual antimicrobial susceptibility testing devices, it is clear that the delays in availability of these devices after antibiotic launch is not being well addressed by FDA.  Until this occurs, the delays will continue to impede acceptance of new antibiotics by end users – not a good state of affairs with continuing increases in resistant infections.This will require some sort of preliminary breakpoint from FDA that would allow device manufacturers to begin their process prior to approval. Everyone will have to work at risk.  Will this ever occur???

Stava Epstein gave a wonderful and elegant talk on the iCHIP. There was nothing really new in his talk, but it was exciting to hear him speak about this wonderful new technology that may revolutionize the way we look for new drugs.

Dr. Sumathi Nambiar provided a discussion on the QDIP designation and on market authorization for products to treat resistant infections.  In the latter portion of her talk, she admitted that the FDA remains somewhat lost on how to proceed in pathogen specific trials. She noted that the FDA prefers a hybrid approach with non-inferiority trials plus some additional data on activity against resistant infections.

Later, Dr. Nambiar was roped (my fault) into a panel discussion where the topic of an orphan drug designation for such unmet needs antibiotics was raised. As I discussed in a previous blog, the orphan drugs group is still back in the 1990s of antibiotic development.  They only think in terms of broad clinical indications like urinary tract infection, pneumonia, etc. In this thinking, the affected populations are much too large to be considered for orphan drug status (200,000 individuals or less in the US). But a pathogen specific indication where the drug is indicated only for those with few or no alternatives (4500-7500 per year in the US for carbapenem-resistant Enterobacteriaceae for example) has not been considered even though this is addressed by the unmet needs guidance both in the EU and in the US. As a result of this discussion, Dr Nambiar agreed to raise this issue with her FDA colleagues.  We await, once again, further developments.

Finally, the economics of the antibiotic markets was broached by Kevin Outterson and Barrett Thornhill.  The proposals for so-called de-linking, where there would be an attempt by governments to provide a guaranteed return on investment for companies pursuing antibiotics for resistant pathogens seem to be in limbo in the US since we have no congress.  In Europe there is hope that such an approach will bear fruit – but whether that will occur soon or with the usual tectonic EU speed is hard to predict. The precise method of implementation of such payments also remains nebulous.  These discussions reminded everyone that, at the end of the day, to progress, we need money.  And, especially in the US congress, that remains a dirty word.

FDA, Roche, Polyphor.

I just returned from the annual Infectious Diseases Society of American (IDSA) meeting in San Diego where I gave a presentation entitled, “New Regulatory Pathways” for antibiotic development. As I entered the convention center on Thursday morning, I ran into a senior academic member of  IDSA.  “I’m looking forward to your talk.” He said. “Do you know what is going on at FDA?  They are not allowing companies to pursue pathogen specific antibiotic trials even though this is clearly part of their published guidance.” Since I have retired, I had no idea what he was talking about.

The talk I gave was relatively optimistic.  I said that based on the FDA reboot of 2012, their new guidance documents and their recent approval of ceftazidime-avibactam based primarily on phase II data, regulatory pathways appeared to be functioning well. One sponsor asked a question regarding the use of pathogen-specific pathways and how that could be accomplished.  I had covered that in my presentation – but I said that since POL7080 from Polyphor, an antibiotic only active against Pseudomonas, would have to follow such a path, we would have our answer very soon.

After the seminar, a clinician from Roche-Genetech approached me to inform me that Roche had returned POL7080 to Polyphor. She explained that part of the problem was that they could not reach an agreement with FDA on a feasible pathogen-specific trial design to develop the drug.  When I enquired as to what happened in Europe, she said that EMA was enthusiastic about their proposal. Their proposal, as she explained it, was to carry out a retrospective study of patients with infections at a variety of sites (mainly pneumonia and urinary tract I presumed) caused by highly resistant Pseudomonas.  The point of the study would be to determine the response rate to standard of care therapy.  This response rate would then be the control rate used to construct a superiority trial of POL7080 in such patients. Patients would be entered into the retrospective study based on the proposed inclusion and exclusion criteria that would be used in the later, open-label trial of POL7080 to treat these infections. This kind of approach is included in guidance both from FDA and EMA.

As I said, apparently the regulatory problem with FDA was only a part of the reason the drug was given back to Polyphor – but it was the first explanation offered by the clinician who approached me.

Later, a second company related an identical story for a completely different antibiotic and a virtually identical design proposal.  The FDA turned them down while Europe was enthusiastic.

My response to all this was what it was during the FDA craziness preceding the 2012 reboot.  Do your trials under the aegis of the EMA and present the FDA with a fait accompli.  

 So – no – I have no idea what is going on at FDA.  But I did just get a response to an email I sent to FDA.  They would like to chat - so I promise a follow-up to this story.

Antimicrobial Agents and Chemotherapy - Vindicated!

Today’s blog is a lesson in history recalling an era of journal elitism among universities, scientists and funding agencies that, I am sure, still exists to some extent today. During my years as a young assistant professor, as I was starting to apply for grants, I was told that publishing in “important, high impact” journals was as important as the publication itself. I was even given a list of journals preferred by the university promotions committee and by funding agencies like the National Institutes of Health in the US.  Does this sound familiar to anyone out there?

My chosen field of research, however, was antimicrobial resistance.  That was a very poor choice in the 1970s and 80s since the NIH believed that such research should be funded by the pharmaceutical industry (what were they thinking?). Complicating my choice was the dearth of journals available to publish my research. One of the best and most appropriate journals for this research was Antimicrobial Agents and Chemotherapy published by the American Society for Microbiology. When I looked down the list of “important” journals provided by my university – AAC was nowhere to be found. 

I admit that when I first began my career, I didn’t even know about this priority list of journals.  I was more interested in my research and getting my data published. But as I began to apply for more grant funding and for promotion in the university, the journal list suddenly loomed before me. I had been publishing in a variety of journals including those for clinical medicine, epidemiology, clinical microbiology and later, more and more, in AAC.  None of those journals were on “the list.” My department chairman approached me about this. Publishing in the “higher priority” journals would be more likely to convince funding and promotions committees.

I listened.  I began to try and publish in Journal of Biological Chemistry, J Biochem, Biochim Biophys Acta, J Bacteriol, J Med Chem, Chemistry, etc.  These were on the list. I guess it worked since I was promoted and was able to obtain grant funding. But I still published a fair number of papers in AAC since it was, for much of my work, the most appropriate journal. Not only that, but I felt that for the microbiology of resistance, there really was no better journal out there.  For the discovery of new antimicrobial agents, again, AAC was an important outlet since, unlike the chemistry journals, AAC insisted on key, relevant biological information. 

Yesterday, through my AAC editorial duties, I learned that two of the three papers cited by the Nobel Committee in awarding the Nobel Prize in Medicine this year were AAC papers (http://dx.doi.org/10.1128/AAC.15.3.361, http://dx.doi.org/10.1128/AAC.15.3.372).  So much for academic elitism!

Drugs, Patents, Prices and Politics

There have been a number of articles in the press recently about drug patents and pricing.  Much of the recent furor stems from the move by Turing Pharmaceuticals’ CEO Martin Shkreli to increase the price of pyremthamine, an ancient, generic antibiotic used to treat certain rare infections, 5000% from $13.50 to $750 per pill.  Hilary Clinton and others have vowed to take action. The public in the US firmly believes that the pharmaceutical industry is evil incarnate and that it takes advantage of its monopoly positions (see next paragraph) to gouge the public on drug pricing.

Another recent article from the Upshot in the NY Times states that the patent system discourages companies from pursuing potentially promising new therapies because of their inability to patent the inventions for one reason or another.  The patents are linked to pricing in some cases (but definitely not for pyrimethamine) since it is the patent that provides market exclusivity, and hence profit potential for the innovator.

Neither of these beliefs is correct and they display an incredible lack of understanding of the pharmaceutical industry by both politicians and the public.  While the ability of a single manufacturer of an essential generic drug to blackmail public health by threatening to halt manufacturing is a clear example of gouging, it is the government itself that is to blame for allowing this potential to exist at all. Generic drugs that are deemed as essential for public health, like penicillin and, in this case, pyrimethamine, should never be allowed to rest in the hands of just one single manufacturer.  The government should provide for subsidies to establish competing manufacturing facilities to prevent this sort of blackmail.

The other major cause of high prices is, in fact, medical need. It is clear that the cost of the new Gilead antiviral drugs to treat Hepatitis C is justified based on the cost savings to society for curing this terrible infection that causes liver failure, liver transplantation and death when untreated. Even in this case, though, we can probably bring the price down somewhat.

As it stands now, about 50% or so of pharmaceutical industry profits come from a single country – the US of A. Why?  Because we are one of the only countries in the world that does not have a national drug price negotiation strategy – that’s why.  Is that good for the pharmaceutical business?  Are you kidding?  Do we pay a higher price for drugs than everyone else in the world? Do we in fact subsidize pharmaceutical innovation for the rest of the world?  Of course! What would happen to drug prices in the US if Medicare, Medicaid and the Veterans Administration plus all other federally funded healthcare facilities could negotiate a single price for every drug they buy?  What do you think?  Of course, the industry cries, "foul!" "That would be socialist."  If you don’t like that form of socialism, than you should just shut up about drug prices. Its what every other country does and they pay lower prices than we do.  Will this decrease investment in innovation?  Possibly - but I'm not convinced and I'm willing to do the experiment. 

The patent system has nothing to do with preventing new, effective drugs from coming to market – at least as far as I know from my own experience. That this might be so is an assumption that previously patented drugs might serve some new but not patentable purpose.  But that is a big assumption that, again to my knowledge, is not based on scientific fact.  In fact, many of today's antiviral drugs were patented back inn the 1960s, but they have been patented for new uses within the past decade. 

The patent system has everything to do with providing a reward for innovation and the investment required to bring the innovation to market.  In the Upshot article, development costs ranging from $140 million to over $2 billion are quoted.  The lower figures come from costs of actual clinical development of a single molecule.  But consider this.  A minimum of ninety-five per-cent of everything begun in a pharmaceutical or academic laboratory will never even make it to clinical trials.  Of the 5% that make it into tests in people, 80% will fail.  So for every drug that actually makes it to market, there is a ton of molecules that failed.  And someone somehow has to pay those sunk costs. That’s where the $2 billion and rising figure comes from.

People who have no idea what they are talking about should either get informed or, at the very least, shut up.