Antimicrobials: resistant to pharma investment?
Antimicrobial resistance (AMR) is a spreading phenomenon that threatens to increase healthcare expenditure as previously treatable infections become significant sources of morbidity. Despite this looming crisis, the pipeline of antimicrobial drugs has dwindled greatly in recent years as low prices and the reservation of new products for later lines of therapy reduce the commercial return on investment in this area. In order to encourage pharmaceutical investment in the antimicrobial pipeline, significant commercial and regulatory barriers must be addressed. Governments must provide subsidies for the development of novel products, while regulators could ease the path to the market with the acceptance of smaller datasets and higher premiums for products addressing unmet needs.
On 18 October 2013, Datamonitor Healthcare attended the PharmAccess Leaders Forum at which several speakers discussed methods to improve the market access of infectious disease drugs and vaccines. There was a clear consensus that growing resistance to antimicrobial products represents a significant future healthcare burden, with Dr Kees De Joncheere, director of the essential medicines and health products department at the World Health Organization, describing the issue as "a sword that is likely to fall on us," making operations and transplants extremely high-risk practices and inflating the cost of healthcare as complications from infections become more frequent. Speakers identified the reasons why pharmaceutical companies have increasingly abandoned antimicrobial development and proposed possible solutions to increase investment in the pipeline.
Despite the ever-increasing threat to public health posed by AMR, the pipeline of novel antimicrobials remains thin. Indeed, the average number of new FDA approvals for anti-bacterial products during 2011–12 fell by 20% compared to 2003–10, while the average number of approvals of anti-fungal and anti-parasitic medicines fell by 43%. Dr Christopher-Paul Milne, director of research at the Tufts Center for the Study of Drug Development, also noted that of the 109 antibiotics in the pipeline, only 8% are in Phase III development, while over 80% are held by small and medium-sized enterprises (SMEs), which often lack the funds to advance compounds to late-stage trials.
The poor commercial viability of antimicrobial medicines once on the market has been the main driver of the reduction in pharma investment in the area over recent years. The first line of antibacterial treatment is highly genericized, and low payer tolerance of branded, higher-priced products makes competition within this section of the market exceptionally challenging. Furthermore, first-line antibiotic use is usually given before diagnosis of the causative pathogen and therefore novel targeted antimicrobial agents are reserved for use in later lines to minimize resistance generation. While a necessary contingency measure, unwillingness to use novel antibiotics results in low sales and is a major deterrent from investment in the antimicrobial pipeline.
Speakers suggested that more companies would be encouraged to invest in the antimicrobial pipeline if payers were willing to accept higher premiums for targeted antibiotics which provide superior benefit in well-defined patient populations. This is particularly important given that antimicrobials are usually given in short courses, leading to lower sales volumes. Dr Jan Posthumus, head of market access and market research at Basilea Pharmaceutica, noted a disparity in payer attitudes towards acute microbial infections and chronic conditions such as HIV and hepatitis C infection. While payers are willing to reimburse expensive antiviral medications for long-term use in the latter indications, there is surprising reluctance to accept higher premiums for short-term use of antibacterial products, even if they address unmet needs. Speakers at the forum suggested that surrogate endpoints such as reduced morbidity, reduction in the probability of transmission, and reduction in length of hospital stay could be used to differentiate new antimicrobials from currently marketed products and justify higher premiums. Transparency and clear communication of the parameters used by payers to compare new antimicrobials with existing products will also be essential in informing future clinical trial design.
Datamonitor Healthcare also expects that increasing government subsidies for the development of new antimicrobials and encouraging collaborations between pharma and academic institutions would boost investment in the antimicrobial pipeline by reducing the resources companies must allocate to preclinical R&D efforts. Such collaborative ventures could be particularly attractive to SMEs that have limited funds to invest, while also allowing health authorities to direct pipeline efforts onto addressing key unmet needs.
Speakers at the forum also proposed the easing of regulatory requirements to speed up approval of novel antimicrobials. First among the speakers' suggestions was the need for US and EU regulators to be willing to accept smaller datasets in cases of high unmet need. Microbial infections are often acute and patients infected with resistant pathogens usually have co-morbidities and can rapidly deteriorate. Combined with the requirement for sensitive diagnostic tests capable of identifying not only the species of pathogen, but the presence of resistance-associated mutations, enrolment of large numbers of patients in multiple Phase III trials is a slow and expensive process. Datamonitor Healthcare believes that investment in the antimicrobial pipeline could be boosted if regulators considered requests for approval based on a single Phase III study supported by several smaller Phase II studies.
The lack of investment in antimicrobial development is a result of conflicting interests between developers of novel products, and regulators and payers. Datamonitor Healthcare believes that increased government subsidies, higher tolerance of premiums for products that meet pre-defined clinical criteria, and the easing of regulatory requirements for new antimicrobial medicines will allow the interests of key stakeholders to be better aligned.