Thursday, January 31, 2019

The UK Plan

The United Kingdom recently released a 5-year and a 20-year plan for combatting antimicrobial resistance.  These are both worth a careful read – especially if you are interested in efforts on stewardship and research support. (I sent several emails to colleagues within and outside the UK querying them on details on the UK plan, but have had no replies.  The workings of the UK team seem to be shrouded in secrecy.)

Buried in the forward to the 5-year plan is this –

We are leading the way in testing solutions that will address our global failure to incentivise the development of new antimicrobials and alternative treatments. We will test a new model that will de-link the payments made to companies from the volumes of antibiotics sold, basing the payment on a NICE led assessment of the value of the medicines and supporting good stewardship.

There is a great deal in that paragraph – most of which I find opaque. The idea of testing solutions to incentivize the development of new approaches to anti-infective therapies comes from the AMR Review headed by Lord O’Neill and recently reiterated in a blog post by him. The idea is to develop a global consortium to assemble the funding required for such a pull incentive. In their 5-year plan, the UK seems to be saying that they will “test” a model based on “value” of a new medicine to the health care of the nation. The first question is, how can one test an incentive that will surely not be an incentive since it will be unlikely to provide for global value to healthcare. The second question is, how will they determine “value.” And finally, where will the money come from?  If the money comes from an already underfunded NHS, how much money can this possibly be? 

What is “value” in this case?  Is it determined by things like decreased mortality, decreased length of hospital stay, decreased time of disability, increased quality life years,  . . . ? If it is any of these, how will that be determined since this is not usually a robust part of our modern non-inferiority trials that are used to approve antibacterial products? Would we then turn to historical data – either contemporary observational studies, NHS data mining or data from the preantibiotic era? We await further information from the UK in this regard. 

The UK population is around 66 million, the US is about 350 million and Europe is close to 500 million. Saying nothing about Asia and Africa, this makes the UK represent less than 8% of the population of the developed world. Let’s say, for argument’s sake, that the value of a new antibiotic on a global scale is on the order of $2 billion.  Would the UK share then be $160 million? Regardless of how this is calculated, the plan by the UK seems to assure that the pull incentive they alone would provide would not be enough to pull anyone anywhere.  

From a more positive perspective, perhaps their plan is to provide a method to determine value and come up for a number that would hypothetically be the UK share of some global incentive.  Then, their idea is to lead the world to a value based incentive where the cost would be shared among nations or regions. I think this is what they mean by “test.” 

This would be a valuable endeavor, but would probably not provide a significant pull incentive within 2019, which is the time frame many experts believe is critical to saving our antibacterial infrastructure and hence our pipeline of new products from oblivion. 

We all agree that an incentive that provides companies for a reasonable return on their investment in anti-infective therapeutics is an absolute requirement at this point. Such an incentive should, logically, to one extent or another, decrease the reliance of companies on price and sales volume and will thus also support good stewardship for these new products. Given the current urgency, I strongly believe that our default position for 2019 is to provide a market entry reward (prize if you like) to be awarded for the approval of a high priority antibiotic (as defined by CDC or WHO) on the basis of a contractual agreement with the company involved to guarantee access, manufacturing and distribution and to decide on pricing etc. Other approaches, such as the one being undertaken by the UK, will take too much time, but could inform the market entry reward at a later time. 

Tuesday, January 22, 2019

Musings on Penicillin - Can we Learn From History?

Lately, I’ve been thinking about new approaches to antibacterial therapy. But I keep going back to some old family history. It was 1944.  My father was completing his internship year in New York City. That summer, he took on additional work as a physician for a childrens’ camp in Connecticut. My aunt, who suffered from type I diabetes, came to visit.  Her parents thought the fresh air and activity would help. Soon after arriving, she developed a staphylococcal breast abscess. My father tried treating her with sulfonamides, but her condition deteriorated rapidly.  She was hospitalized in Manhattan delirious with positive blood cultures. The family gathered, arriving from Chicago, thinking she would not survive. My father knew that penicillin was available for use in our troops fighting overseas and he had heard that the army would supply the drug for emergency use through public health offices around the country.  He called the public health commissioner for the City of New York and was able to obtain penicillin for my aunt.  With intravenous penicillin, she recovered rapidly. She lived another 25 years before succumbing to cardiovascular disease complicating her diabetes.

 During the bad old days of the FDA meltdown (starting around 2000, accelerating in 2006 and reversed by 2012), we used to speculate whether penicillin could even be developed and approved today. I think that for intravenous penicillin in 1945 the answer is a resounding yes.  But for oral penicillin – the answer is maybe. For oral penicillin, what clinical indication could one study?  The requirements to study very severe skin and soft tissue infections might preclude the use of an oral drug.  Clinical trials in pneumonia might work, though. For streptococcal pharyngitis, the FDA guidance has been withdrawn. Then, imagine if we did not know about the frequency of hypersensitivity reactions to penicillins (as we might not have known in 1944-5).  After marketing penicillin we realize that about 1 in 7000 treated patients develop a serious allergic reaction and death occurs in 1 in 67,000 to 1 in 70,000 treated patients (Idsoe O, Guthe T, Sillcox RR, de Weck AL. Nature and extent of penicillin side-reactions with particular reference to fatalities from anaphylactic shock. Bull World Health Organ 1968; 38: 159–88 – see this link).  What would happen then? I presume that intravenous penicillin approved for serious infections would remain approved with some warning label. But oral penicillin would probably be restricted to the treatment of pneumonia and approval withdrawn for other indications. 

One question I have asked my friends at FDA is – how was penicillin approved in 1945?  I don’t yet have a clear answer.   Apparently this information is very hard to find – especially in the midst of our current government shutdown.  But I believe that we will find that the approval of penicillin was based on published papers including experiences such as I described above.  In that case, this is, in part, like approving a drug based on external controls where all clinicians can agree that the treatment effect is very large.  I also think that this is a principle we should consider today for new therapies that have obvious dramatic ameliorative effects in otherwise deadly circumstances.  Case examples can be found among patients treated for severe, antibiotic-resistant  sepsis with custom-designed bacteriophage cocktails (e.g. Development and Use of Personalized Bacteriophage-Based Therapeutic Cocktails To Treat a Patient with a Disseminated Resistant Acinetobacter baumannii Infection. Schooley RT, Biswas B, Gill JJ, Hernandez-Morales A, Lancaster J, Lessor L, Barr JJ, Reed SL, Rohwer F, Benler S, Segall AM, Taplitz R, Smith DM, Kerr K, Kumaraswamy M, Nizet V, Lin L, McCauley MD, Strathdee SA, Benson CA, Pope RK, Leroux BM, Picel AC, Mateczun AJ, Cilwa KE, Regeimbal JM, Estrella LA, Wolfe DM, Henry MS, Quinones J, Salka S, Bishop-Lilly KA, Young R, Hamilton T. Antimicrob Agents Chemother. 2017 Sep 22;61(10). pii: e00954-17. doi: 10.1128/AAC.00954-17 – see this link).  This case example is complicated by the use of concomitant antibiotics and the emergence of bacteriophage resistance during therapy.  And these sorts of complicating issues may also undermine our belief that the miraculous clinical improvement seen in this case was due to the bacteriophage therapy.  Treatment today is so much more complicated that it was in 1944-5. Nevertheless, those taking care of the patient in this example remain convinced that bacteriophage therapy was in large part responsible for this patient’s survival just as my father was sure that penicillin cured my aunt. 

Another observation from my musings is that whatever the new therapy is that we contemplate, its clinical effect must be dramatic and measurable in a way that convinces clinicians (and regulators) that it is a valuable addition to our treatment paradigm. This remains our challenge. Would it also be a challenge for penicillin if it were to be developed today as one of the first antibiotics? 

(I apologize if it seems like these considerations are circular and go on forever - but I thought I would share anyway).