Where does novel antibiotics R&D stand among other pharmaceutical products: an industrial perspective?

It is clear from the breadth of topics covered in this supplement that antibiotic resistance continues to emerge and cause increasingly complex clinical problems. Thus, it may be surprising that the impetus for research and development by the pharmaceutical industry in this area is generally lacking and diminishing. Recent calls for action by the Infectious Diseases Society of America have specifically named the species we must focus our efforts toward [1]. Indeed, some of these species are discussed in this supplement; however, in contrast to these increasingly desperate pleas for help has been the continued withdrawal of the larger pharmaceutical companies from these efforts. Companies such as Aventis, Lilly, Bristol-Myers Squibb, Roche, GlaxoSmithKline and Procter & Gamble are among the notably experienced who have left the field, while others have retained much reduced research efforts (e.g., Bayer and Merck). It has largely been the mid-sized to smaller companies who have carried the torch of antibacterial research, including Cubist, Theravance, Vicuron, Cerexa and Protez. However, with the exception of Cubist, each of these companies has needed external financial support to take their candidate agents to the next stage of submission or eventual approval. This need for significant quantities of cash to carry potential agents from the preclinical to the new drug-application stage is a deterrent to both large and small companies. It is the evaluation of the various risks along the development pathway that balances the estimated US$1.7 billion cost with the chance of success or failure [2].

Currently, this ‘tipping point’ is potentially more negative than positive, as more safety hurdles are placed along the development path (e.g., the recent mandate of thorough corrected QT interval evaluations for all drug classes [101]), and regulatory requirements for specific indications became increasingly uncertain (e.g., the continuing uncertainty from the US FDA regarding the ‘true benefit of antibacterials in certain respiratory tract infections, upon which one can base a sample-size estimation’ [102]).

Another factor that can ‘tip the decision’ is market analysis in terms of potential use and cash value of the drug in a specific indication. Antibiotics are, essentially, considered commodity drugs by many formulary organizations. Indeed, they welcome the opportunity to replace established branded drugs with generics, regardless of the indication and the proven equivalence or not. Indeed, in some situations, it is almost impossible to prove bioequivalence owing to the site of infection and drug action (e.g., oral vancomycin and the GI tract).

In addition to this market-value consideration, there are two other significant forces that impact this analysis; generally, antibacterials are priced quite conservatively, as demonstrated by Falagas et al., who showed that in a basket of recently approved classes of drugs, antibacterials came fifth out of 11 classes in terms of average cost per course of therapy [3]. Second, there are increasing efforts to reduce antibiotic prescribing either in the form of antibiotic-stewardship programs [4] or national health authorities, demanding significant reduction in prescribing for respiratory tract infections.

The latter has been attempted before but with some interesting consequences. Between 1994 and 1996, the UK government introduced strenuous efforts to reduce antibiotic use at the primary-care level by enforcing draconian controls, often at the individual physician level. However, analysis of the annual mortality rates due to pneumonia or influenza over this period, and a similar period 2 years later without the draconian controls, showed that as medical doctors reduced their antibiotic prescribing for respiratory tract infections, the death rates due to pneumonia increased, but that when they were allowed to prescribe less fearfully, the mortality rate dropped [5]. Thus, it seems reasonable to ask that such significant instruction should be accompanied by appropriate education. In this situation, it would appear not to have been the case.

Thus, we have at least two significant efforts to reduce antibiotic prescribing, usually for valid reasons; although, from the accounting aspect, this simply means an even lower return on the company’s investment of US$1.7 billion.

Accompanying these simple economics with improved pharmacological knowledge, enabling researchers to develop once-daily drugs administered over 5 days or fewer compared with previous courses of one or two tablets taken three-times daily for at least 10 days, means that, with only five tablets, companies are trying to recoup their investments. However, the next question would be: who is willing to pay 20–30-times more for this new effective medication? Generally, in today’s economy-conscious market, no one. So, to the original question – where do novel antibiotics stand?

There are several small biotechnology firms with some exciting candidate agents, such as Achaogen with their new aminoglycosides and Theravance with their novel hybrid molecules, along with other technologies from MPEX, Kalbio and others, all of which look very promising at this early stage. However, it is the resources required to move these exciting potential novel candidates from preclinical/Phase I to the ‘heavy-lifting’ of Phases II and III that are daunting to many larger companies and investors in light of the increasing challenges of research and development. These challenges include regulatory risks, increased safety monitoring (both preapproval and now, increasingly, postapproval) and heightened ethical scrutiny of clinical trials leading to more complex enrollment criteria and, thus, longer study periods; and, once approved, more stringent economic hurdles are to be overcome, especially in Europe where each country has its own reimbursement criteria.

Indeed, as the Infectious Disease Society of America has stated so eloquently, we do have ‘bad bugs but no drugs’; however, do we have what it takes to address the ‘tipping point of antibiotic development?’ Currently, the weight of evidence is behind the bugs, and they are winning.

Financial & competing interests disclosure

G Tillotson is an employee of Viropharma Inc. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.