The Antibiotic Pipeline Dilemma
A short summary of the current dilemma with antibiotic development. Others, including the World Health Organization and Infectious Diseases Society of America, have expressed this issue more elegantly and in greater detail (click on the links to check out), but it bears repeating:
- Drug discovery is tough. Discovering or creating a new (i.e. novel class of antibiotics) antibiotic is increasingly difficult, because the “easy targets” (folate pathway, cell wall components, ribosome, DNA gyrase, etc.) have all been attained in past generations of antibiotic development. It therefore becomes ever more costly and complicated to discover a new class of antibiotics – as an example, the process to develop teixobactin (article behind a paywall) was actually incredibly laborious and time-consuming.
- Drug development (the process to bring a newly discovered and promising compound to market) is costly. A new study from the Tufts Center for the Study of Drug Development estimates that the process will often exceed 10 years, and costs approximately USD 2.6 billion. This includes both the actual costs of development, as well as the time costs (expected returns that investors forego during the time taken to develop the drug).
- Regulatory hurdles for antibiotics are uniquely complex. Prof Brad Spellberg (currently chief medical officer of LAC+USC) gave a nice example of this in his article for the Alliance for the Prudent Use of Antibiotics (APUA) newsletter in 2012, comparing antibiotics with antifungals. Antifungals are approved for “invasive candidiasis” and/or “invasive aspergillosis” – the prescribing doctor has to figure out on his/her own that echinocandins (one of the newer classes of antifungal drugs) do not penetrate the urinary tract or eye (relatively common sites of invasive Candida spp. infections) well, and may fail when used to treat infections at these sites. Antibiotics however, have to be approved for each specific type of infection (i.e. chest infection or pneumonia, soft tissue infection, bloodstream infection, etc. all require their own indication), even if caused by the same bacterium, which is costly. This is intrinsically not a bad thing, as it increases patient safety, but it does increase the bar and the costs for drug development of antibiotics, and reduces the return on investment for antibiotics. Although in clinical practice, it is an open secret that doctors will prescribe antibiotics outside of what they are approved for (i.e. off-label use).
- Antibiotics are not profitable. The return on investment is low for antibiotics relative to other types of drugs such as antihypertensives, diabetic drugs, or cancer drugs.
- Antibiotics are mainly prescribed in short courses (7 days on average – compared to years or even lifelong for antihypertensives or anti-cholesterol medications), and the public expectation is for antibiotics to be cheap (although the pharmaceutical industry have been pushing up the prices of new antibiotics over time, they don’t approach anywhere near the prices of cancer drugs) and safe in terms of the side-effect profile (especially when compared to cancer drugs again, where expectations are much lower).
- The most effective antibiotics for the treatment of infections are currently generics, and they are extremely difficult to improve upon in terms of cost-effectiveness, achieving cure rates of better than 90% for all but the most severe infections.
- Perhaps worst of all – from the view of the pharmaceutical industry – is that the first thing that happens when an antibiotic is launched is that its use gets restricted by infectious diseases physicians like myself for the purposes of “judicious prescription”.
These factors combine to make antibiotic development extremely unattractive to most pharmaceutical companies. A monograph by Adrian Towse and Priya Sharma from the Office of Health Economics in UK (Incentives for R&D for New Antimicrobial Drugs – behind a pay wall) published in 2011 claimed that the net present value of an antibiotic at discovery to a drug company is negative USD50 million. Small wonder that despite the increasing “unmet need” for new antibiotics, there has been – and still is – market failure.
What can be done to improve the situation? The vast majority of suggestions by global experts relate to policies that will encourage the pharmaceutical industry to develop new antibiotics, whereas the rest comprise initiatives (including increased research funding) to spur antibiotic discovery and innovation by both academia and the private sector. Economic “pull” and “push” incentives are now being brought into play because moral arguments or outrage will not result in new antibiotics. A couple of well-researched write-ups on potential policy initiatives can be found here and here and here. Some of the “pull” and “push” incentives include:
- Public-private partnerships to reduce the risks of antibiotic development by sharing costs and expertise between the pharmaceutical industry, government, academia and possibly philanthropic organisations.
- Tax breaks and extended exclusivity periods to increase the potential returns for antibiotics that are commercialised.
- Options market for antibiotics. I find this difficult to explain, since I don’t understand options well, but the paper is here. But it goes hand in hand with market guarantees, which has been used successfully to stimulate development of vaccines and “orphan drugs”.
- Priority review vouchers. This is perhaps the most interesting suggestion, which I first learned during the WEF 2015 discussion on “End of Antibiotics”, also alluded to in an earlier post. Essentially, if a pharmaceutical company develops and achieves FDA approval for a treatment for an “orphan” or “neglected” disease, it is awarded a transferable “priority review voucher” that can be sold or used for another of its potential “blockbuster” cancer or antihypertensive (as an example) drug. The more rapid review (priority review) and therefore more rapid market access (estimated to be 6 months faster than a standard review) may result in a few hundred million USD extra revenue for the company, This idea was first proposed by researchers from Duke University in 2006.
- Regulatory reform. Mainly to streamline and hasten the process for approval of new antibiotics.
Some of the above has already been implemented. For example, the GAIN (Generating Antibiotics Incentives Now) Act, passed into law by the U.S. Congress in 2012 (it is not always gridlocked!), guarantees 5 extra years of market exclusivity and priority FDA review for new antibiotics targeting qualifying pathogens (a long list that includes Acinetobacter spp., Enterobacteriaceae, and other organisms such as Mycobacterium tuberculosis and Helicobacter pylori).
It will probably take a combination of these incentives and policies, along with increased research funding in both public and private sectors for antibiotic discovery, to spur innovation in antibiotic development. In the meantime, we will have to struggle with a rising tide of antibiotic-resistant bacteria, in particular extremely drug-resistant and carbapenem-resistant Gram-negative bacteria.