David's New Book

Thursday, June 16, 2016

Antibiotic Incentives - What's Missing?

In a word – training. I’m beginning to feel like a broken record.  I’ve been talking to various funding agencies about this need for 12 years now (1, 2, 3).  Either no one is home, or they think they have already addressed the problem, or they don’t believe there is a problem to address. 

Between mergers, acquisitions and frank abandonment of antibiotic research and development, there are precious few companies involved in the area anymore. While there has been an increase in funding for antibiotic discovery research in academia over the last decade, most academic researchers are poorly prepared to conduct this sort of research. At the same time, the committees that review grant proposals in the area are frequently made up, mostly, of the same academic researchers who are often unprepared to either judge or carry out the proposed research. Happily, at least during the years I was involved in reviewing proposals for the National Institutes of Health in the US, there were a few researchers from industry present who could help the committee understand the advantages and, more often, failings, of the proposals before us.  But we are a shrinking commodity. Many of us are older and retired. Many have moved on to areas of research outside of antibiotics  (you have to make a living after all).

Antibiotic discovery and development is a highly specialized endeavour.  It requires an understanding of a huge variety of topics and skills including clinical microbiology, epidemiology, biophysics, biochemistry, structural biology, pharmacology, pharmacokinetics, pharmacodynamics, animal testing, toxicology, chemical manufacturing, medical need, clinical infectious diseases and much more. While one does not have to have expertise in all these areas, you do have to have enough of an understanding to converse with the experts and to make judgements about how and whether to take compounds forward to the next step or not. This sort of breadth of knowledge and experience is found everyday within companies pursuing antibiotic discovery and development.  It is only rarely found in academia.

Where will our next generation of antibiotic hunters come from? I believe that they cannot come solely from academia as things stand today.  What I have been proposing for all these years is a training program of 3-12 months to take place within industry where all these skill sets can be found. For some reason (conflict of interest?), academia and therefore funding agencies seem unwilling to go forward with this sort of effort. Recently, a highly placed official from the NIH quipped that I should just fund these training programs out of my own pocket!  I just don't understand the reluctance here.

Who should be trained?  First – established researchers who are now or want to in the future conduct antibiotic discovery and development research. Next we should concentrate on post-doctoral training to give our new researchers the skills they need.  Finally, once we have trained mentors in place, we should focus on PhD candidates who want to make a career out of antibiotic research.

Who should fund this research?  We should!  Government should align with various companies still active in antibiotic research who have the appropriate skill sets to provide this training for academics. Private organizations such as Wellcome Trust and perhaps the Pew Charitable Trust could also take this on.



If we fail to act on this key area of need, we can offer all the incentives we want, but there will be no one left to take up the task of actually delivering the antibiotics we need.

Friday, June 3, 2016

Antibiotics - the Virtuous Cycle

I just returned from two days of DRIVE AB meetings in Amsterdam.  I am so excited that I couldn’t wait to get something in writing for the blog.

Two weeks ago, the O’Neill Commission (officially the Antimicrobial Resistance Review) released its final report.  If you haven’t read it – do it now! The report makes a number of very specific, key recommendations all of which make common sense.  They all fall under two general rubrics -
1.     Reduce the demand for antibiotics.
2.     Increase the supply of new antimicrobials active against resistant microorganisms.
These two are clearly conflicting – the paradox of the antibiotic market in a nutshell.  A new antibiotic hits the market and physicians don’t want to use it for fear of selecting for resistance too quickly. But this is what we must somehow achieve.

DRIVE AB is an effort to combat antibiotic resistance funded by the European Commission, the Innovative Medicines Initiative and EFPIA, the European version of PHRMA in the US.  DRIVE AB is founded on three principles – Access, Sustainability and Innovation. You can immediately see the similarity between the DRIVE AB goals and the O’Neill Commission report.  I look at DRIVE AB as the group that will provide more specific recommendations to various national and supranational authorities on how to implement the recommendations of the O’Neill Commission.

To me, the most exciting aspect of the DRIVE AB effort revolves around providing post-market incentives to pull companies into antibiotic R&D –a key recommendation of the O’Neill Commission.  Some have termed this de-linking with the idea that these incentive payments should alleviate the marketing pressure on the company to increase sales volumes and therefore to provoke a more rapid emergence of resistance. A significant upfront payment would address this need and resolve the paradox.  

Again – according to the O’Neill Commission - The reward would be given only based on societal priorities shaped by key medical needs. The CDC list of key resistance threats is a good starting point for these priorities. Payments should be free from political risk. The size of the reward should be linked to the value of the product to society (or to a given country). The payment would come soon after regulatory approval, but need not come all at once. Control for manufacturing, distribution, post-market research all should remain in the hands of the developer.

The DRIVE AB group discussed several models for such post-market rewards of which I would like to highlight just two. The first is called an insurance type reward. (See Rex & Outterson) John Rex’s favourite way to explain this is to compare the payment required to our need for fire extinguishers and for firemen. We buy the extinguishers and place them strategically in our homes and businesses and we pay the salaries of our firemen and firewomen even though, happily, most of us never actually have a fire. Paying for an antibiotic that we don’t actually need today, but that we might desperately need tomorrow is similar – its insurance. In the example we discussed, a collar and cap model is used for insurance payments. A government of payer provides a developer with an annual payment up to some specific volume of courses of therapy. If this volume is exceeded (the collar), the payer must provide additional payments on a per course basis.  This volume though, is capped.  If the cap volume is exceeded, the payer would pay some discounted price for additional courses of therapy. From my understanding, some variation of this is likely to occur in a couple of EU countries as soon as this fall for antibiotics recently approved in Europe.

The other model we discussed is the market entry model. In this model, the developer is paid one or more payments upfront. As in the insurance license model, the developer has a number of obligations by contract including those relating to good stewardship.



The model I personally prefer is similar to the insurance license model but where the upfront payment is on the order of say $1B given over the first 3-4 years post-approval. But where the developer is still allowed to sell units at some capped price.  This price would be enough to encourage good stewardship at the level of the user and the company would still have to abide by their good stewardship contract with the payer. I envision that the cap would increase after the first 3-4 years such that by the end of the exclusivity period, all sales would be based on whatever price the developer was charging.  This provides several advantages.  It keeps the developer’s skin in the game – its motivating.  It provides for a potential upside beyond the initial payment – also very motivating. And it would encourage generic manufacturers to enter the market after the period of exclusivity has expired.  The key would be to make sure that principles of stewardship and responsible end user education are maintained while actual selling the product.

The reality is that for any innovative product education will be required.  That would probably occur via some sort of medical liaison group from the developer, but would not involve “sales” representatives.

Our discussion made clear that no one model would work for any one product for all regions and no one model would fit all products for any region.  We need a choice of different post-market incentives such that various regions can choose the one that best suits their needs.

One exciting result of these incentives is the virtuous cycle. Large pharmaceutical companies like Pfizer and J&J might be motivated enough to get back into antibiotic R&D. This means that there would be more private capital to invest in academic and biotech R&D – completing a virtuous cycle leading to an even more robust antibiotic pipeline for the future.


As John Rex noted several times during the meeting – such a meeting could not have occurred even one or two years ago.  Yet here we are – at the beginning of what could be a new world.

Wednesday, May 25, 2016

Antibiotics, Politics, UK, EU, USA



Well, the UK’s O’Neill Commission released its final report on tackling antibiotic resistance. This is a very detailed report looking at all sides of the problem and trying to take a global perspective. I won’t review it today – but you can read it yourselves.  There is a nice review in The Atlantic. 
I want to talk about the relationship between our public perceptions, priorities and policies and provide a contrast between the US and the UK in that regard. The UK, under Prime Minister David Cameron and Chief Medical Officer Dame Sally Davies, has undertaken the battle against antibiotic resistance in a public and committed way.  News articles and press releases are constant. The Review on Antibiotic Resistance (I call it the O’Neill Commission) was undertaken under UK leadership. The UK has made enormous strides in educating the public on the dangers of inappropriate antibiotic use and the consequences of resistance. The UK has established strong guidelines for the stewardship of antibiotics and has provided teeth to help make sure physicians comply with these guidelines.  They have also carried out extensive public education campaigns to try and decrease patient demand for antibiotics for inappropriate indications. These efforts have begun to bear fruit with a demonstrated decrease in antibiotic prescribing. Combined with the general strategy proposed by the AMR Review under O’Neill to incentivize the antibiotic pipeline, the UK program show us all a way forward – at least in general terms.

How does the US look compared to the UK? Does our Surgeon General call for antimicrobial stewardship or incentives for antibiotic discovery or development?  A look at his website shows no headliners for antibiotics at all.  A search for articles on antibiotics on the website turns up older documents from previous surgeon generals. Although there are one or two articles on the need to reduce inappropriate antibiotic use, there is nothing like what can be found in the UK.
What about the presidential campaign in the US. I was unable to find anything meaningful from any of the candidates on the problem of antibiotic resistance by searching on Google. A search of the candidates’ websites shows nothing specific about antibiotics.  Hillary Clinton has posted her thoughts on HIV-AIDS, but not on antibiotics and antibiotic resistance.  Neither Bernie nor Donald have anything to say.

How about the use of antibiotics in animals?  Europe including the UK have essentially banned the use of antibiotics in animal feed for the purpose of growth promotion. The UK is now considering other proscriptions such as against the use of certain antibiotic prophylactic regimes for poultry and other animals as has been done by certain other EU countries. In the US – we’re still working on gathering data.  Again our candidates are silent.

Has the US really done nothing?  No.  President Obama has been more engaged in the problem of antibiotic resistance than any other US President in history. A number of important initiatives have been established under his watch. These include a report from his Council of Advisors on Science and Technology and a subsequent plan for implementing many of the suggestions from that report.  There has even been an increase in funding for NIH and BARDA to support these plans. Our regulatory agency has made great strides in providing feasible pathways for the development of new antibiotics, but they still lag behind Europe in that regard. The CDC website is replete with information, but we are just beginning to carry out surveillance for antibiotic use and we do not have the kind of teeth that UK and Europe do to alter prescribing habits. There has been nothing like the attention given to antibiotic resistance in the UK and in Europe. There is little discussion in the US of the kind of post-market incentives that will be so important going forward.

I am supposed to head to Amsterdam next week to attend a meeting of Drive-AB – the EU-funded effort to actually find ways to implement the strategies being promulgated by the O’Neill Commission. In thinking about this meeting, I am of two minds.  I am disappointed that the US is not more of a leader in this area.  But I also agree with President Obama (and, help me, Donald Trump) that Europe needs to do more to pull its own weight. 

Historically, the US has accounted for about 50% of the total pharmaceutical market.  As of 2013, it still accounted for over 40%.  That’s one country – 40% of the world dollar volume in prescription drug sales.  If you look at sales of new drugs, the US is responsible for 55% of sales.  When translated into pharmaceutical company profits, the US still dominates.  Since these sales are, to a certain extent, rolled back into research and development, one could conclude that the US has been subsidizing global pharmaceutical R&D for decades.

So I look forward to incentives for antibiotic R&D coming, to a large extent, from Europe!





Tuesday, May 17, 2016

Solving Antibiotic Resistance - The Longitude Prize

Guest Blogger Tamar Ghosh




The Longitude Prize is the UK’s biggest science prize, a 5-year challenge with a £10 million prize fund, and a 300 year legacy.  It commemorates the anniversary of the Longitude Act of 1714, the first British challenge prize, which offered the public £20,000 to solve one of the biggest global problems of the time, determining longitude at sea.  It was eventually solved when a little-known carpenter, John Harrison, invented the first marine chronometer, H4, surprising the establishment which expected a solution to come from the field of  astronomy,.  This early achievement demonstrated an early principle of prizes that we have seen time and again: if you create a public challenge, of reputation and profile, a far wider group of innovators are likely to get involved in finding solutions to the problem.


 In 2014, this new Longitude Prize, instigated by the Astronomer Royal in the UK, Lord Martin Rees, was launched after a public vote that selected resistance to antibiotics as the equivalent global issue to be resolved.  It aims to conserve antibiotics for future generations, revolutionising global healthcare. It is looking to award one prize of £8m to a team that can develop a transformative, accurate, affordable, rapid, point of care diagnostic test that is easy to use, anywhere in the world. The Prize is being developed by Nesta, supported by Innovate UK, and is open to entrants from any country.  This global Prize has the support of the UK Prime Minister and will be awarded by the Longitude Committee chaired by Lord Martin Rees and including Dame Sally Davies, Baron Peter Piot and Professor Jeremy Farrar, among other luminaries.


So far we have 130 teams working on ideas from 29 countries, however we want to ensure the Prize is helping as many teams as possible enter the Prize from a range of countries, sectors and disciplines, and through new collaborations.  We already have a mix of entries from industry large and small, academia, individuals and many collaborations. However, we want to make sure everyone who is able to take part can do so, and to address some of the concerns we hear from current teams who have hit a barrier in the development of their ideas.

For this reason, on Monday 16th May we launched the Longitude Prize Discovery Awards.

These are small seed grants to help individuals or teams to further develop their ideas to win the Prize, hopefully enticing more of the greatest minds across the world to take part.  The total current fund for the Discovery Awards is just over £200,000.  From this total pot we will look to make grants of around £10,000, rising to maximum of £25,000 for exceptional ideas.  These are small grants and our teams tell us they are likely to use these to access labs for testing, evaluating the feasibility of their test in communities, securing expertise to help them to develop a business plan, or acquiring new specimens to develop their concept. We want to make as many awards as possible, and these may be very early stage ideas coming from very different areas of science. The current awards are being funded by GSK and by the Biotechnology Industry Research Assistance Council (BIRAC) in India. We hope the awards will attract more entries from the UK and around the world.

Dame Sally Davies, Chief Medical Officer for England, has said of these Awards: “I'm delighted to see the launch of the Discovery Awards, providing support for teams that have great ideas to be further developed. We need the best minds in the UK and around the world to work on this and find us all a diagnostic that will help reduce the misuse of antibiotics.”

Applications for a Discovery Award can be submitted from 6pm BST 16th May until midnight on the 26th August BST, and awardees will be announced in late November.   

Applicants need to demonstrate that their overall idea is in the scope of the prize and that the activity they are putting forward for funding is feasible and will help them to move forward with their idea.  Some of the teams working on ideas have told us that by winning a Discovery Award they may be able to access far higher levels of funding, through reaching proof of concept or through credibility attached to this. .

We hope this will help us to broaden the range of innovators and innovations into the race, so we can make sure the equivalent of the present day John (and Jane) Harrisons do get involved.