Here They Come!

It looks like the European and (with any luck) the US regulators will just about make it in time . . .maybe.  

An interesting news article just popped up from Edmonton, Canada where officials are investigating an outbreak of  Gram negative bacterial infections resistant to all of our most effective antibiotics.  These bacteria were introduced by a patient who had received medical care abroad, but who was not placed in isolation upon admission to the hospital in Edmonton.  The patient apparently died of her infection. Several other patients subsequently became infected. An investigation is ongoing and it made the local press and television.

Another  article  also caught my eye.  Dr. Huttner and colleagues examined the use of certain so-called last resort antibiotics between 2005 and 2010 within the 152 hospital VA system in the US.  They clearly showed an increasing use of polymyxin (up about 30%) and tigecycline (up over 5 fold) during the years of study.  Polymyxin is an antibiotic of questionable efficacy and is associated with frequent kidney and nerve toxicities.  Tigecycline (dear to my heart) is limited in the dose that can be used because of gastrointestinal intolerance and it has been shown to work poorly at recommended doses in very seriously ill intensive care unit patients. Nevertheless, both these antibiotics are on the upswing.  Why – because more and more patients are being infected by highly resistant Gram-negative pathogens – similar to those causing the outbreak that caught the news in Edmonton Canada.  For these infections, there are no other choices. 

There is hope.  There are antibiotics in the late stage pipeline that will address at least some of these pathogens – but unfortunately not all.  The question is – how quickly can they be brought forward?  That is the question that the regulators must decide and decide now.  And what about those pathogens for which there is little in the current late stage antibiotic pipeline?  There are some at earlier stages of development that might be useful.  How quickly can these be tested in infected patients?  Here again – regulators and sponsors will have to get together and move things along quickly. But the time for infeasible trial designs and a long FDA reboot process is over.  The time to act is NOW!

FDA REBOOT!!

In nothing less than a remarkable presentation to the Brookings Institution yesterday, Janet Woodcock, Director of CDER at FDA, stated that the FDA will reboot its approach to antibacterial development. Rachel Sherman, the Associate Director for Medical Policy at FDA remarked that Dr. Woodcock had said to her FDA colleagues that she would not preside over the demise of antibiotics – not on her watch! With these words, the non-FDA audience in the room – and I suspect some of the FDA audience both in the room and on the phones – were flabbergasted. During the last 15 years of interacting with the agency, this was the most positive, even exhilarating set of statements I have ever heard regarding antibacterial development from the FDA.  We have come a long way from the day when Bob Temple announced to a group from PhRMA back around 2000 that infectious diseases developers had been “getting away with murder for years.” 

Dr. Woodcock, in her presentation, reviewed how we had arrived at this point.  She emphasized the role of telethromycin (Ketek).  Safety concerns on a drug with a controversial and complicated history that was finally approved led to demands for “more rigor” in the clinical investigation of antibiotics – specifically around the non-inferiority trials that are always used as pivotal studies to support marketing approval for these drugs.  In their re-examination of non-inferiority trial designs, their search for justification for the margins used for these studies combined with concerns over the objectivity of the usual outcome measure – “cure” – led to tighter margins requiring higher patient numbers and new outcome measures. The new trial designs proposed in draft guidance were, mostly, simply infeasible.

In another surprising statement, Dr. Woodcock acknowledged in a way the loss of trust in the agency.  She stated that this reboot would not affect the FDA’s current agreements with sponsors on the design of ongoing trials.

What does this proposed reboot look like?  It is hard to say from the conversation during the daylong meeting.  But it is clear that the agency wants to focus on areas of unmet need – those patients where current therapy is inadequate in terms of efficacy or where efficacy is at least questionable and where toxicity may be an important consideration (e.g. colistin).  Dr. Woodcock mentioned the possibility of pathogen-specific studies instead of indication-specific ones.  She agreed that for these patients a tradeoff in certainty around the data vs. potentially efficacious and less toxic therapy would be worthwhile. The words “historical controls,” “natural history studies,” “Bayesian designs” and “orphan drug status” were all used.  Clearly, for these patients, everything is on the table for discussion.

At the same time, the FDA clearly would like to link these approvals with a label including a limitation of use.  It is here that things get dicey since it is not clear that they would have the authority to actually enforce such a label. This, I think, is the basis of their desire for the LPAD legislation now being considered in Congress. On the other hand, if such a drug were approved for such a narrow indication that only a few patients would be treated with the drug, the high price and perhaps even the spectrum of the drug would automatically enforce restricted use. This could easily be confirmed through a use registry. 

It also seemed to me that the agency was committing to reboot its entire approach to guidance for the more usual indications such as hospital acquired and community acquired pneumonia and others. The importance of this was emphasized by a number of other speakers during the meeting – notably Helen Boucher of the Infectious Diseases Society of America. To reboot industry, we need to have a way for all new antibiotics to get to the market – not just those that can treat very small populations of patients with specific types of resistant infections.  We need an armamentarium of antibiotics for the future since resistance is hard to predict and many of our antibiotics have been around for a long time and resistance to most is already increasing.

As in all things in regulated industry – the devil is in the details. And the details need to be worked out BEFORE guidance is released this time.  Towards that end, the FDA understands the need for competent external advice outside the usual advisory committee mechanism.  Their approach to getting this advice should be to use small FDA teams equipped with specific questions meeting with small groups of advisors (the Brookings meeting was too large to really get anything concrete done) in a non-formal setting.  The Brookings meeting was a good start to identifying the specific areas of inquiry.

For industry - For those companies planning to negotiate designs in Europe first – I think the FDA will be more open now.  Consider a simultaneous advice session.  In general, for those companies reconsidering antibiotic R&D – I believe that the US will be open for business – when I am not exactly sure.  The water is at least warming – but its not summer yet.

Culture Wars and Antibiotics

Two weeks ago, a well conceived article was published in Forbes. It discusses the problem of the lack of productivity of large pharma. The problem is very real.  Just look at the number of patent expirations threatening this industry and the state of their pipelines.  A great example is Pfizer – a company that is shrinking as fast as it can to offset their loss of revenue from Lipitor sales. Another good example is Astra-zeneca – a company that is also fighting loss of market exclusivity with layoffs. Obviously, a better way to deal with the problem is more productivity either from in-house research and development or from external sources. So why is this not happening? 

There are multiple causes for the poor productivity of the pharmaceutical industry overall.  These include scientific issues – its just plain getting harder to find new, safe and effective drugs.  Another contributor is the increasingly stringent and risky regulatory environment affecting products from obesity and diabetes therapies to antibiotics (don’t get me started!). But I think Bruce Booth, in his Forbes piece, has really hit on another underappreciated factor – the increasingly bureaucratic and metrics-driven approach to R&D within the pharmaceutical industry.

At Wyeth at one point, the Discovery group was asked to produce 15 clinical candidates per year (IND ready).  Did this increase their late stage pipeline? What do you think?  What it did, probably, was decrease the quality and increase the risk of the compounds entering phase I development. As described by Bruce Booth, Wyeth R&D was run by committee(s).  But each committee member had their own particular agenda.  Each functional area had their own constraints and concerns – work load, not wanting to be blamed for project failure, etc. So they would try and either block a project or at least make their reticence known to the committee so they could at least say, “I told you so” later.  In the industry, it is always easier to say NO at the beginning than it is to take a risk and support a potentially costly project that, 80% of the time, will fail anyway.

When you layer committees one on top of the other – business development, safety, R&D, the problems compound more often than they are solved. 

Bruce Booth’s solution is similar to one I have been pushing.  He would create geographically localized therapeutic area units with all the critical support required (I presume this is what he means) like toxicology, manufacturing, clinical development, regulatory, etc. He suggests giving them five years of budget and then leaving them alone.  The therapeutic areas would then report directly to the “top” (whatever that is) rather than to a committee. My suggestion has always been to shrink the companies altogether by giving each therapeutic area its own P&L.  That might be achieved by providing a budget (instead of profits) from the mother company or it might be (better) by allowing them to live within their P&L based on profits from revenues derived from marketed products. Essentially, what I am suggesting is taking the Centers of Excellence in Drug Discovery of Glaxo one giant step further towards independence from the leaky, unstable giant mother ship.  

I have said in multiple previous blogs that this would be a great strategy for improving the situation of antibiotics within the pharmaceutical industry.