Last week, the United States Center for Disease Control (CDC) and Britain’s Chief Medical Officer issued separate warnings about the urgent problem of antibiotic resistance in infectious diseases. Given industry’s general lack of interest in developing new antibiotics to address this problem, the warnings indicate that a discussion is needed around which incentives and regulatory mechanisms might work to catalyze development programs and rehydrate the pipeline for these increasingly vital medicines.
Last Tuesday, the CDC reported that carbapenem-resistant Enterobacteriaceae (CRE) is spreading in inpatient medical institutions across the US, and called for enforcement precautions in these facilities to be implemented. UK Chief Medical Officer Sally Davies echoed such sentiments over the weekend by addressing antibiotic resistance as a worldwide problem needing urgent global action to fill the void in the antibiotic drug development gap. Methicillin-resistant Stapholococcus aureus, or MRSA, is highlighted as one such resistant organism wreaking havoc, causing more deaths annually in the US than HIV/AIDS.
Regulators, politicians and academics are working toward a solution to the antibiotic drug drought. Since it implemented the Generating Antibiotic Incentives Now (GAIN) Act last October, FDA has granted Qualified Infectious Disease Products (QIDP) status to a number of drugs, including most recently Cubist Pharmaceutical’s ceftolozane/tazobactam combination and Furiex Pharmaceutical’s avarofloxacin for their potential to combat particularly resistant pathogens, and also the latter’s ability to stifle a pathogen’s development of resistance. Under the GAIN Act, these new antibiotics gain certain developmental incentives, including priority review and Fast Track status, and, if approved by the FDA, a five-year extension of patent exclusivity on top of the Hatch-Waxman guarantees.
Beyond the GAIN act, there is a call to create an accelerated approval mechanism similar to that of orphan drugs. In 2012, the Infectious Disease Society of America (IDSA) proposed the Limited Population Antibacterial Drug (LPAD) pathway, with smaller, sleeker trial designs as a way of quickening the pace of antibiotic R&D and expediting the approval process. If implemented, LPAD would bring prices up on novel antibiotics, for the same reasons orphan drugs command a high price: to ensure manufacturers develop drugs for small populations in need of treatment, and reduce the cost burden associated with resistance, which exceeds costs of $26 billion in the US alone, according to IDSA. Higher prices for antibiotics would also promote careful use and safer prescribing practices among healthcare providers, to help prevent new drug resistance.
Steve Gilman, EVP of R&D and chief scientific officer of Cubist, explains: “If you’re providing a life-saving benefit that reduces length of hospital stay and cost, then you should have a pricing situation that fairly and equitably provides a return for the value created.” Also, smaller trial designs will allow drug companies to target patients with only the resistant infections as a way of demonstrating efficacy, while mitigating the risk of inducing resistance to the medicines being tested.
Last month, the FDA held a discussion panel in which it was brought up that LPAD has yet to establish meaningful clinical endpoints, and that the potential for these drugs to be used off-label is perhaps what caused this type of resistance in the first place. It was agreed that both considerations warrant further examination of the pathway. The IDSA points out that with effective stewardship programs, off-label use would be carefully scrutinized to ensure resistance is not developed. A recent Lancet Journal article discusses additional clinical trial designs as potential routes to expedited approval and access to antibacterial treatments.
Antibiotic resistance is also a global public health issue. The need for regulatory harmonization across markets is one that coincides with CMO Davies’ point that the effort to refill the antibiotic pipeline requires a global approach. However, if antibiotics are priced at a premium to spur development efforts from big pharma, drug-resistant infectious disease rates in poorer nations (case in point India, with its poor track record of easily accessible antibiotics, and where, coincidentally, MRSA rates are as high as 70% in certain regions) will continue to increase.
Moreover, financial incentives even within the US are shaky and few big pharma companies have expressed a renewed interest in antibiotic R&D. One of the latest examples is Roche’s Genentech partnering with RQx Pharmaceuticals to help fund their research efforts. The crux of the matter, as the Lancet article concludes, is that “we cannot force companies to do this work—rather, we need to persuade them to want to do it.”
Comment: What’s the best means of persuasion? Give your viewpoint.