Authors: Martha Powell, Future Science Group
We recently spoke about the ins and outs of funding and financing for antimicrobials with John Rex, Chief Medical Officer at F2G Limited (Manchester, UK), Expert-in-residence for the Wellcome Trust (London, UK) and Operating Partner at Advent Life Sciences (London, UK).
John has worked in drug development for over 30 years, 15 of those as an academic investigator and the last 15 from inside of regulated industry, and in this interview he shares his thoughts on the issues underlying antibiotic development, the recent DRIVE-AB report, and where we might be 10 years in the future.
What’s your assessment of the current drug pipelines for antifungal and antibacterial treatments?
The current antifungal and antibacterial pipelines are very thin. There are agents that are progressing, there are things that will be helpful; however, if you define innovation as novel mechanism, novel class, never seen before, there’s really very little true innovation in the current pipeline.
As another perspective on this, The Pew Trusts that has recently carried out a good pipeline survey and their conclusion is also that the pipeline is scarily thin. Also, relative to other areas, the total volume of work is much smaller – you’ll find hundreds of companies working on oncology projects but for antimicrobials we’re talking about tens of projects.
Why is there a need for new funding and financing approaches?
We speak about there being three problems with developing anti-infectives: they’re hard to discover, they’re hard to develop and the reimbursement is very poor.
I feel we’ve made good progress on the first two. For discovery, anti-infectives are still hard to discover but we’ve got grants and other kinds of push funding, and there are a number of companies now working towards high-innovation products. We just need high volumes of work to ensure at least some of them succeed – failure rates are high but the failure rate will be 100% if the effort is zero, that’s guaranteed.
In terms of development, we have made lots of improvements to the development pathways that are available to companies, and agencies have worked hard to think carefully about how we could make it possible to develop antimicrobials. So by-and-large the regulatory tools exist, there are still areas that we need to figure out, but we’ve solved a lot of problems and you’re seeing companies use new and improved regulatory tools.
So, the third problem is that of paying for drugs. For this, it’s helpful to think of antibacterial or antimicrobials as being like fire extinguishers or fire departments; infection proceeds quickly, as do fires, if you don’t have the tools to put out the fire the building burns down and if you don’t have the anti-infectives people will die.
Now, when you think about fire extinguishers and fire departments, we do not pay for these on a per fire basis. Rather, we have actually agreed as a community that we’ll invest in these to have them available, and we recognize the value they have in existence. However, we pay antimicrobials for as if they were ‘per fire’, and that is the essence of the fundamental problem. It’s also the case that when a new drug is invented you want to limit its use to people who really need it, so this new valuable agent exists that treats infections and allows you to safely do cancer care and minor surgery, but with limited use the reimbursement just isn’t there.
So we really have to think differently about incentive mechanisms for antibacterials and antifungals, and that’s been the focus of the DRIVE-AB project in Europe over the past several years, along with work by UK AMR Review and PAVE paper from the Duke-Margolis Center for Health Policy, all of which have all been focused on developing alternative business strategies and the rationale behind them.
Can you tell us about the DRIVE-AB program and its aims?
DRIVE-AB was part of the Innovative Medicines Initiative (IMI) a collaboration between the pharmaceutical industry and the European Commission. In 2011/12 an umbrella program called New Drugs 4 Bad Bugs (ND4BB) was created inside of IMI and to focus on AMR. ND4BB in turn created seven discrete projects, some were collaborations about drug discovery, some for drug development and one of them was about economics: DRIVE-AB.
DRIVE-AB comprised about 100 people who worked together for 3 years to talk about the language of access and stewardship, how you predict resistance and how you assess the value of an antibiotic, and those three ideas came together to create a basis for evaluating incentives.
DRIVE-AB critiqued about 40 different incentives and in the end selected 4 incentives as being most likely to be effective. It was a great project because, at the heart of it, it wasn’t limited to just one group – it had academics, the pharmaceutical industry, health-technology assessors, payers and governments. And by working together and teaching each other we’ve learned to appreciate the multiple views that are necessary and that’s what led to the insights and the language that came out of DRIVE-AB. So now there’s a group of 100 people who know this story and are familiar with the pros and cons of all the possible solutions. It’s exciting to now see that group fanning out and encouraging the next steps.
With regards to funding in industry what do you feel are the most promising strategies to address these challenges?
Well, I think they’re well summarized by the recent DRIVE-AB report, which as I’ve said highlighted four possible ideas as being the most likely to have impact. There are obviously no perfect incentives but there are incentives that are more likely to work, or more likely to be broadly applicable.
Of the four identified, there are two in the push category and two in the pull. In the push category, one is grants – that’s the obvious one – and on a global basis there’s currently approximately US $500 million going into antimicrobial R&D every year, DRIVE-AB suggested this should be increased to US $750 million, but what’s already being done is not bad!
DRIVE-AB also recommended that there be the creation of a strategy that they called a ‘pipeline coordinator’. The concept is that the funders globally should make themselves mutually aware – we don’t want everyone to fund the same things but with awareness we might discover gaps or places where more emphasis might be needed. It would be mutually informative and a group that may emerge as the critical pipeline coordinator is the G20’s Antimicrobial Innovation Hub that was created as a consequence of the recent meeting in Berlin.
The two pull are ideas about how we can pay differently for an antibiotic. For innovative new antibiotics DRIVE-AB recommends the implementation of an idea called the market entry reward. The notion here is that if you register an antibiotic that meets certain features you receive some form of payment, probably spread out over several years, that is independent of the volume of use of the drug. You’re still permitted to sell the drug but part of the presumption is that sales will be limited, that you’ll agree not to aggressively pursue marketing, and that you’ll agree to appropriate access.
So this market entry reward is designed to take the pressure off the sales side and ensure you actually get a return on your investment for the valuable thing that you’ve created – even though we hope it mostly just sits on the shelf in the hospital to be admired each day as you walk in! But just as with the fire extinguisher next to it you’re actually using it because you’re relying on its existence, it makes you’re hospital safe it means that if someone gets in trouble you have a tool to save their life.
The other pull incentive that’s recommended by DRIVE-AB is for older, generic drugs. Unfortunately you find that valuable generic drugs are often not available because nobody makes them and if there’s limited sales of a drug you’re not going to get somebody making it – it’s the same problem as with the innovative drug but at the far end.
For example, if you wanted to prescribe benzylpenicillin, a useful drug from the WHO Essential Medicines List, you might not be able to get it due to lack of supply. That doesn’t make a lot of sense – we’ve got appropriate generic drugs and some of them have nice features, like being narrow spectrum, so why wouldn’t you want those available?
The fix is that it needs to be worthwhile for some manufacturers to make them, and this is the idea behind the long-term continuity model. Countries might band together and agree with a manufacturer that if they make the drug for the next 10 years, those countries promise to buy it – then if they need it they have it and if they don’t use it we’ll cheer for the people who didn’t get infected but we’ll be glad that we had it all the way along.
So those are the four ideas DRIVE-AB has put forward and I think those are great ideas. They’ve been exhaustively tested and the language behind them has been developed, which didn’t exist 3 or 4 years ago.
And do you think developing world would have a different approach to tackling antimicrobial resistance?
No, not really. There is a start point for managing antimicrobial resistance that’s before drugs, and that’s about being aware that part of the reason we’re troubled with antibiotics is that they’re so good you can use them as a substitute for infrastructure.
Rather than providing clean food, clean water, and good sanitation you can treat the infections that result – the antibiotics are a patch for underlying problems. If you look at infection rates over time historically they started coming down in the early 1900s, well before antibiotics were widespread, and that was due to improvements in sanitation. So part of the WHO Global Action Plan is about tending to the basics first, and then layering the other things on top.
How important are other aspects of controlling antimicrobial resistance, such as infection control and surveillance?
An ounce of prevention is worth a pound of cure – it’s just so much better to prevent. It’s really clear that good process makes a big difference in terms of the emergence of infections and the spread of resistance – you do things right and you’re better off. Resistance ultimately will develop even if you’re using the antibiotic absolutely correctly but using it incorrectly makes it worse.
Thinking about the process of developing new antibiotic agents – how important is clinical trial design?
Clinical trial design is absolutely fundamental to this area. The big advance we’ve had over the past 5 years or so has been our understanding of which infections are most amenable to high-quality studies in an organized way. We’ve had to come to grips with the fact that in anti-infective development we can’t routinely do the kind of superiority studies for new drugs that you’d do for a for migraine or hypertension, for example.
In chronic diseases, where leaving the disease untreated for a few days or weeks is not a big deal, you can easily require new agents to have superior activity to existing agents, but in anti-infectives you can’t do that. Serious infections kill people and we must always offer everybody a good effective therapy if one exists, not doing so is unethical. In addition, as you begin to invent new, effective therapies there’s less and less room for you to demonstrate clinical superiority.
We’ve had to learn how to develop drugs despite the fact that we can’t routinely do superiority studies. We have to use an alternative design called non-inferiority, and this is a harder design to implement correctly – it’s easy to implement badly, it’s hard to do it correctly. However, we’ve put a lot of effort into coming up with strategies, guidance and tools to tell researchers how to implement non-inferiority studies correctly and that’s worked very well.
Finally, where do you see the field/hope to see the field in 10 years’ time?
Well I think we’re all looking for a robust, diverse pipeline of interesting innovative products that are appropriately incentivized by some pull incentives – that’s the essence of everything we need right now. We want diversity, we want innovation, and we want the products that really stand out not to be used and yet be rewarded: that’s that business tension we have to fix.
I’m very hopeful that we’re going to see some activity at country level in different parts of the world where credible pull incentives get put together and I think that would change the whole area dramatically!
John is a physician and drug developer with ~30 years of development and policy experience focused on antimicrobial agents. See http://amr.solutions for further details.