Pull Incentives and AMR - Is Europe up to the Task?

 I have been saying for years that for a pull incentive to actually function as an incentive, it must be large enough to motivate investors and large pharma to get back into antibiotic R&D. This will take a $2 (to $4) billion commitment for each priority drug approved regardless of how this goal is achieved. This could be a market entry reward, a transferable patent exclusivity reward (still my favorite), an antibiotic susceptibility bonus, a subscription payment regardless of use, etc. 

 

Years ago, DRIVE-AB, a European effort looking at potential incentives for antibiotic R&D suggested that countries “pilot” various models.  In fact, several countries are now doing just that.  France has had a DRG carve out for certain hospital antibiotics for years.  Germany just introduced such a carve out last year.  Has this increased the market for antibiotics in either country?  I don’t think so. Sweden is piloting a subscription model – but the money committed is not publicly available.  The UK (no longer part of Europe) is also piloting a subscription model committing up to  £10 million per year for up to 10 years per product.  It is claimed that this will constitute the UK’s fair share of the overall antibiotic market in terms of their commitment to a subscription type pull incentive. Of course – that is only meaningful if many other countries join since the UK accounts for something like 3% of the total market. But what does “pilot” mean exactly.  What is the endpoint?  How will we judge success or failure? Is success defined by the sponsor somehow in terms of market increase? And how would that be defined?  Is success defined by the national authority in terms of value of therapy?  What if the country has very few resistant infections like Sweden?  How will they define “value?” I admit that, at the time, sitting in the DRIVE-AB conference room in the Netherlands, I did not understand this concept – and I still don’t.

The other issue is that each country picks different antibiotics for its incentive. That just dilutes the market and makes no sense. 

In my view, the goal of a pull incentive is to provide a significant return on investment for companies who pursue antibiotic R&D and succeed. This, in turn, will motivate investors to invest in the area. No matter how I look at this problem, it seems like the only way that such a large pull incentive will come to pass is if a region or country takes a leadership position and provides an incentive that will work globally.  Once that occurs, we can work to bring other countries on board.  But until then, I think we are stuck in incentive purgatory. The Table below shows the 2017 (pre-Brexit, pre-Covid) GDPs of Western countries and Europe including the UK, Sweden and Germany. Clearly either Europe as Europe or the US are the best positioned to offer such an incentive just based on the size of their respective economies. 

 

 

GDP by country

 

Country/Region 2017 (Trillion USD) USA                19.5 Europe (pre Brexit) 13.0 UK                          2.6 Sweden                  0.5 Germany                  3.7

 

This brings me to a discussion of the possibility that Europe will take on this task. And every time I think about this, I go back to Flora Lewis’ book, Europe, A Tapestry of Nations. And there is no better example of the contemporary issues facing Europe’s ability to bring together its national authorities than their botched approach to providing covid vaccine for their population.  This problem has been analyzed in detail by Politico Europe and their analysis should be a wake-up call to all in Europe as to the continuing shortcomings of the alliance. According to the article, Europe was late coming to the table.  They even supplanted an alliance of four national authorities who had already begun negotiations for vaccines for their countries to restart negotiations for Europe. This resulted in further delay.  Then they negotiated a price well below what the US, Israel and others were paying – which may have dropped them further down the priority list for vaccine suppliers.  This is to say nothing of their clear preference for Europe-based vaccine companies like Sanofi that ultimately were unable to provide any supply in time. Then there were delays in approvals based on delayed applications to the European regulatory authority by sponsors (a frequent event since the US is a bigger market).  Even though Europe was quicker to approve than the US once having received the submissions, the delay based on delayed submssions was still present. Then there was continued bickering among the diverse national authorities in Europe.  Hungary, for example, recently approved and is administering Russia’s Sputnik and China’s Sinopharm vaccines. 

The recent experience of biotech attempting to market their new antibiotics in Europe is also cause for serious concern.  In at least two cases, the European regulators insisted on post-market commitments that would have been more costly than the total potential market in the region. Neither drug was ultimately marketed in the region. 

All this makes me less than optimistic about Europe’s ability to get a true pull incentive for antibiotic R&D together in any reasonable time frame. So – that brings us back to the US. The United States, in my view, is the only country capable of pulling this off. We have the PASTEUR Act on the table – which I think would work (given clarification around a number of questions). I think it is there where we need to focus our efforts. 

 

 

Covid vaccines compared to AMR

 

I never dreamed this would be possible. Of course, so many things are possible today that I thought were impossible that I’m almost embarrassed to admit it (but I have no pride). Twenty-five years ago I thought that an immunologic approach to cancer would never work because cancer cells are, after all, self. My excuse is that I am neither an immunologist nor an oncologist and many of my oncologist friends agreed with me. But to think that one could go from the SARS-COV-2 viral nucleic acid sequence to a marketed vaccine in less than a year – I’m sorry – but that was science fiction, Star Wars, warp speed. Plus – mRNA instead of a killed virus or protein or conjugate antigen?  mRNA – the epitome of instability? Come on!

 

Beyond the technology though, there was the desire, based on a lethal danger to the population posed by a pandemic virus, to get to this goal of a vaccine that is safe and effective and that can be distributed in record time. To accomplish this required an enormous investment in manufacturing – at risk. This investment came either from government (us taxpayers), from private industry (large and small) or from both.  And, at the end, governments are paying for the final product – although some vaccines are being sold at cost (not for profit). This plan required a strong will, a strength of steel, and an organization and expertise that we have rarely seen anywhere before. It’s almost enough to give one confidence in government again – since without government intervention, this could not have happened.  The plan also should make us stand in awe and gratitude for the extraordinary efforts of the pharmaceutical industry and their scientists and clinicians and their partners and stakeholders without whom this would never have happened. The industry should no longer be viewed as evil incarnate!

 

Compare and contrast. Antibiotic resistant infections have been killing people since the dawn of the antibiotic era. According to the CDC, the use of seat belts saved 13,000 lives in 2009. Compared to the 460,000 Americans killed by covid in this past year, 13,000 seems like a small number.  Does that mean we should forget about wearing seat belts? Again, according to the CDC, antibiotic resistant infections and C. difficile kill 48,000 Americans every year. And most of us think this is a significant underestimate. Should we now relax since this number is almost 10- fold lower than the covid losses to date? Should any sense of urgency to save these lives be somehow lessened because of covid?  Or should we rather look at this lesson from covid and apply it to lethal antibiotic resistant infections? How would we do that?

 

First, although a vaccine approach to the prevention of resistant bacterial infections is a great idea, and one that has worked for a few selected bacterial infections, I don’t think that we are at the same place with this problem as we were for certain viruses and mRNA technology. We will need other approaches focusing on therapy. It takes us 10-20 years to go from an idea to a new antibiotic.  We could shorten that time by doing more at risk as we did for covid. We could also do a better job of delaying the increase in resistance by doing a better job of restricting antibiotic use to cases where it is really necessary both in humans, plants, fish and other animals. But because even appropriate antibiotic use will ultimately lead to resistance, we still must find new approaches to the treatment of resistant infections.  My personal opinion is that this will most likely involve new antibiotics or new inhibitors of resistance (like B-lactamase inhibitors). But right now, our pipeline is in a disastrous state and any companies still working in the space are facing economic oblivion. One risk we must take is the use of financial incentives to make up for the broken marketplace that is driving investors out of the antibacterial space. Compared to the cost of warp speed for covid at $18 billion, the fix for the antibiotic marketplace would probably be more like $2 billion per new product.  If we awarded one or two new products per year, we’re talking $20 billion over five years maximum.  In any case, I don’t think our current pipeline would get us to 10 approved products in five years at least in terms of our key priorities.  So, new antibiotics for resistant infections – a fire sale! Why can’t we see this?

 

Let’s talk about Europe for just a minute.  Will Europe and its disparate national authorities have learned the lesson of pricing for new products from its experience with covid vaccines?  Will they have learned that their regulatory approach leaves something to be desired when it comes to considerations of feasibility in their demands for new data? Will Europe be left behind again as they have been for covid vaccines if (my lips to God’s ear) the US establishes a market incentive for new antibacterial products? 

 

We need to learn from this pandemic and apply these lessons to our approach to fighting antibiotic resistant infections – and we need to do it urgently!

 

 

 

 

AMR - a Holistic Approach

 

A very important report on the state of antibiotic use and resistance globally has just been release by The Center for Disease Dynamics, Economics & Policy (CDDEP).  Before delving into this topic, I want to explain my long absence from my blog.  I have been ill but am rapidly recovering and am now ready to continue thinking and writing about AMR. 

 

 The report focuses on the relationship between antibiotic use and resistance with a tool that provides an index or score for a given country.  A number of countries are included as examples in a digital dashboard. This tool and dashboard will be helpful for national and international agencies to evaluate and develop policies to address problems of resistance.  The report also notes that among some LMICs, there is a clear issue of access such that patients suffer and die from simple lack of antimicrobial therapy or vaccines more than from resistant infections. A webinar by CDDEP with Ramanan Laxminarayan and Dame Sally Davies and others discussing the report is also available. 

 

While I cannot agree more wholeheartedly that a greater understanding of the “you use it, you lose it” law of antimicrobial resistance is important, it is not the whole story.  As implied, even carefully monitored and appropriate use of antibiotics will still select for resistant variants within microbial populations. There are many examples of this from our experience in hospitals with strong antimicrobial stewardship policies, even given the fact that these hospitals exist within a larger global community. What this means is that, even if we alter our policies and focus our antimicrobial use in animals and in humans to only what is needed, we will still face the problem of resistance.  It is likely that under those circumstances resistance will evolve and grow more slowly – but it is still going to be inevitable. 

 

Therefore, in a holistic approach to resistance, we have to anticipate resistance even to our last line antibiotics. This means that our current antibiotics will yield to resistance over time and that we will need new antibiotics (or possibly other approaches) to deal with these resistant infections. And today, we are nowhere near ready for that eventuality given the perilous state of our antimicrobial pipeline. 

 

Our pipeline depends on the ability of sponsors (for profit or not) to discover, develop, manufacture and distribute new, effective drugs for the treatment of resistant infections. While there is more and more support for discovery and early development, and even some new support for late-stage development, without an ability to manufacture and distribute these putative new products globally, the entire endeavor collapses like a house of cards. And that is exactly what has been happening over the last decade. The clear evidence for this is in the bankruptcy of multiple small companies who engaged in the commercialization of new antibiotics active against resistant infections. To compound this, a number of sponsors have been unable to market their new antibiotics in Europe given burdensome and expensive regulatory requirements or inadequate national pricing proposals. Even if, as some argue, that these products deserved their fate, private investment in antibiotics is getting more and more difficult. 

 

Recent economic analyses by John Rex and Kevin Krause at a meeting of the National Academies (see links here) shed some light on the costs of commercialization – and they are considerable. The problem is that we know what we must do to address the problem.  We have to pay! While some countries (e.g. UK) are trying this by an effort to “pay their share” – this is clearly insufficient by itself. Either we need a more global approach, or some country or region must take a leadership position and provide much more than their “share.” I’m looking at you US and EU! 

 

Without addressing this other end of the AMR problem, our inadequate pipeline, stewardship will only delay the inevitable.