Antibiotics - Limited Use, High Price and Stewardship

I must apologize for being a little tardy in writing the blog.  I wanted to wait until the last of three important meetings had taken place before writing.   Warning – this is an unusually long blog.

 The three meetings in question were the

·      A New Pathway for Antibiotic Innovation: Exploring Drug Development for Limited Populations,” on January 31^st at Pew Charitable Trust.

·       Public Hearing: February 4, 2013 Creating an Alternative Approval Pathway for Certain Drugs Intended to Address Unmet Medical Need.

·      “Incentives for Change: Addressing the Challenges in Antibacterial Drug Development” on Wednesday, February 27 at the Brookings Institution.

I did not attend the FDA public hearings believing that much of what was discussed would have been covered at the Pew meeting where I was a rapporteur.  The Pew meeting was perhaps the most important one for me.  The highlight of the meeting was the presence of various payers including a consultant who works closely with medicare.  The agenda first attempted to define IDSA’s proposed Limited Population Antibiotic Development (LPAD) pathway for approval for antibiotics effective in patients where resistance (or other circumstances such as drug allergies) results in few or no other available options for therapy.  This development pathway would be similar to that proposed by PhRMA called tier C development. Here, very limited clinical studies in patients with serious infections caused by highly resistant pathogens would be carried out.  These studies would demonstrate, in probably only a few patients, that the new antibiotic could cure such infections.  Such data would be bolstered by other evidence such as in vitro studies, animal studies of efficacy and pharmacokinetic and pharmacodynamics data all supporting the proposed use of the new antibiotic.  The approval would be a limited one covering the use of the new product only in the kinds of patients studied. Such a pathway would be less expensive and might be more rapid that the usual pathway for an antibiotic.  Further, for some drugs such as one only active against Pseudomonas aeruginosa for example, such a pathway would be the only feasible way forward to approval. 

While most experts at the Pew meeting agreed that it would be beneficial to have LPAD inscribed in law by legislation, there was considerable disagreement as to whether, from a statutory point of view, the FDA did not already have the authority to institute such a pathway without legislation. 

One aspect of the discussion that I found particularly interesting was that around stewardship and empiric therapy.  I believe that this is an area that deserves further thought.  But basically, in clinical use, antibiotics are used mostly empirically – 80% of use in today’s hospitals is empiric.  That is, when a physician prescribes the antibiotic in the hospital, he/she is responding to a patient’s need for treatment but without knowing the pathogen causing the infection and sometimes not knowing the origin of the infection (urinary tract, respiratory tract,  etc).  For an LPAD product, in hospitals or in particular units like intensive care units, where highly resistant organisms are common, physicians might choose to treat seriously ill patients with the LKPAD agent empirically.   What frequency does such resistance have to achieve to alter physician behavior?  I’m guessing that occurs as you start to get to levels of 10% and higher.  But – as we are about to discuss, these drugs will be EXPENSIVE.  So stewardship takes on a critical role here – not only in terms of preserving the utility of these precious new antibiotics but also in saving our healthcare dollars. 

This gets us into a discussion of what stewardship is as was raised at the Brookings meeting.  The fact is that there are very few studies of the effect of stewardship on patient outcomes like length of stay in hospital, readmission rates, resistance rates and mortality that have any controls other than sort of a before and after intervention approach.   Virtually all studies agree that stewardship lowers pharmacy costs and does not harm patients.  But better, controlled studies are desperately needed (are you listening NIH?). 

When the Pew examined the populations that might be treated with various types of LPAD-approved antibiotics, in order for companies to make some reasonable return on investment, they tried to estimate (with the help of Lew Barrett – see his previous blog on this) the price that would be required.  The estimates ranged from $2000 per course for a drug that had relatively broad use to $20-30,00 per course for a drug that would specifically target resistant Pseudomonas for example. These price estimates were reviewed by payers.  Given the amounts they now pay for oncology drugs that often add little real benefit for patients, payers were happy to pay these prices for a potentially life-saving therapy.  So – not only were there no heart attacks among the payers – but they basically embraced the concept. They all wanted to see data showing that the drugs did provide value such a decreased length of stay, less time on ventilators, lower readmission rates etc.  But all agreed that this approach of limited use and high reimbursement makes sense.  They all also hesitated about the empiric therapy aspect.  Medicare is kind of a special case that I won’t go into here – but such an approach is ultimately feasible for medicare as well.  A question that was raised at the Brookings was how such a product should be implemented from the payer point of view.  Some suggested that prior approval might be the way to go.  I dislike that since it might delay therapy.  I would rather pre-qualify hospitals to use a drug based on active and effective stewardship programs. 

So I understand how the high price strategy might work in the US and Europe.  I do not understand how this translates to the rapidly growing markets of the emerging economies like India, China and a number of others.  Is there anyone out there willing to take this on in either a comment or a guest blog?

The Brookings meeting discussed strategies to de-link reimbursement from volume of use.  Most of the suggestions revolved around various ways of providing a government funded guaranteed market with a number of methods to pay for this. I won’t be able to go into the details of the discussion here – you’ll have to wait for the summary on the Brookings website.  But – my conclusion about all such plans is, GET REAL.  Has anyone been looking at what is going on in Washington lately?  I believe that the only form of de-linking that is currently feasible is price and therefore market based.