David's New Book

Tuesday, February 5, 2013

Antibiotics - You Get What You Pay For!

There has been a good deal of discussion in the news lately – especially from the UK and Europe – on the increasing danger of antibiotic resistance.  In a statement towards the end of last year and again more recently, Dame Sally Davies, the Chief Medical Officer for England, said that the coming apocalypse is the lack of effective antibiotics.  She said that this could make routine medical care like surgery untenable for a large number of patients.  A recent paper from the CDC seems to underline this point demonstrating a clear increase in incidence of carbapenem-resistant Klebsiella (CRKP) infections over the last decade. On the other hand, I think talk of a coming apocalypse is probably hyperbole that makes good news but not necessarily good sense.  A better way to look at this is that antibiotic resistance is becoming more and more of a public health threat that we ignore at our peril.  In the case of CRKP, the rate has increased from about 5 to 11%.  This is a doubling and should make us all quake in our boots – but it is not 100%.  Further, there are antibiotics in our late stage pipeline today that will address this threat.  They include various antibiotics combined with avibactam or MK7655, both novel Beta-lactamase inhibitors that inhibit the resistance making the organisms susceptible once again.

But most authorities agree that in spite of the promise of our late stage pipeline, the threat is that this pipeline is not nearly as robust as it needs to be.  Some of these pipeline products may yet fail during development.  Many resistant organisms are still left out.  So what can be done to supplement our faltering antibiotic armamentarium for our future and that of our children?

Antibiotics are special.  They are jewels that we must preserve.  They are the only drug class (with a very few exceptions) that actually cures disease in a matter of days. We must value them as such.  Society, and I mean the global society, has to see this as it applies to new drugs to treat highly resistant infections. Since these new products will only be used by relatively small numbers of patients, they will have to be priced such that companies can still recoup their return on investment and maybe even, excuse my French, make a profit.  Prices from $2000 to $30,000 per course have been considered.  One problem with this approach is that of empiric therapy.  80% of antibiotics are started in hospitals without knowledge of the infecting organism and sometimes without knowledge of the site of infection.  But obviously, with such expensive drugs, empiric use will have to somehow be very controlled and well justified.  This is all good because with limited use, these new jewels will be preserved and protected to some extent from the inevitable emergence of resistance. How will this play out in the emerging economies like India, Indonesia, Singapore, Malaysia, China and others? This is a commercial question that must be answered at some point soon.

Another possibility would be to have the government(s) guarantee the market for such products by purchasing and distributing them as necessary and alleviating the need for companies to actually “market” their products.  At risk of sounding heretical – in this I think the market ought to be allowed to choose.  In fact, there are a number of products in the pipeline with overlapping utility.  Which should be chosen?  Each hospital ought to be able to make this choice depending on its own needs.  I’m not sure the government can fulfill this market function without essentially providing guaranteed markets for all these products. Having worked for the Veterans Administration for sixteen years, I think I can remember 3 years when we had a budget on time.  This does not bode well for government being the sole market for needed new antibiotics.

Secondly, we as a global society have to provide a regulatory pathway for the development of such products recognizing that their limited use will require limited studies and therefore some higher risk on the safety side.  Less data equals more risk. So, which would you choose – limited numbers of effective antibiotics for your next bout of pneumonia acquired in the hospital or limited safety data on an antibiotic that is likely to cure your infection? Such an approach is already being considered and even applied both in the EU and the US.  The LPAD (Limited Population Antibiotic Development) proposal of IDSA is one example.  Another is NEWDIGS.  NEWDIGS focuses on adaptive approvals and release to market.  It is very reminiscent of a proposal made by the Manhattan Institute to FDA a number of years ago.  Here, a drug would first be developed for a limited population with high unmet need (sound familiar?) and would be approved for such based on small trials and limited data.  More trials and more data would allow approval for larger more general populations.  I would anticipate that pricing would reflect this evolution. NEWDIGS is not yet focusing on antibiotics – but of course it should do so.

So – let’s try and get what we pay for!