Getting Smart about Antibiotics

Getting Smart about Antibiotics

02.06.13 | By Sascha Haverfield

Facilitating Increased Antibiotic Development with Existing Regulatory Frameworks

Antibiotics are an essential tool in modern medicine. Pre-antibiotic era mortality rates approached 80% for infectious diseases such as complicated ear infection, blood infection and cholera.

Resistance to antibiotics is an unavoidable, naturally occurring process and the number of multi-drug resistant strains of bacteria is increasing. The Centers for Disease Control and Prevention found that the proportion of staph infections that are resistant to at least one commonly used antibiotic has risen from 3% to 60% since 1980.

Antibiotic resistant infections come with a substantial cost both in terms of lives lost and dollars spent. 99,000 Americans die each year from a bacterial infection acquired during a hospital stay - more than die from HIV/AIDS. Post-surgery patients with multi-drug resistant strains of bacteria face 11 times higher risk of death than patients without infection and patients with multi-drug resistant infections average over $40,000 in additional hospital charges. According to the Agency for Healthcare Research and Quality, septicemia (blood infection) was the single most expensive condition treated in U.S. hospitals in 2009 with a cost of nearly $15.4 billion.

The number of antibiotics approved in the U.S. has been steadily decreasing in the past two decades and the pipeline for new antibiotics is alarmingly slim. In 2009, there were 16 antibiotics in development, none of which had activity against bacteria known to be resistant to all available antibiotics. Two years later, only 10 antibiotics were in clinical development and none of those have activity against bacteria known to be resistant to all available antibiotics.

As discussed in a peer-reviewed article published online in Lancet Infectious Diseases last month, the decline in antibiotic approvals reflects a gap in the current regulatory approval paradigm for antibiotics that needs to be addressed. The traditional regulatory paradigm depends on the availability of a lot of people with the target illness. From a public health perspective, it is unwise and irresponsible to wait until there are a lot of patients with a life-threatening, infectious disease.

What can be done to encourage the development of innovative, safe and effective antibiotics? The good news is that existing regulatory frameworks at the Food and Drug Administration (FDA) are sufficiently flexible, if fully utilized, to permit streamlined development of antibiotics for serious and life-threatening infections.

Traditional registration programs depend on the ready availability of a significant number of patients with the target pathogen in a specific organ. The Animal Rule, a regulatory pathway for the approval of medicines that treat or prevent serious or life-threatening conditions caused by exposure to lethal or permanently disabling toxic substances, is only appropriate in limited, clearly defined circumstances.

What is needed is guidance to define a middle path within the existing, sufficiently flexible regulatory framework to enable the development of antibiotics to treat infections caused by resistant pathogens while the pathogens are still relatively rare and therefore challenging, if not impossible, to study in traditional, large clinical trials. This middle path would permit the proactive development and approval of novel antibiotics for serious or life-threatening infections before a public health crisis emerges.

The additional good news is that the FDA recently announced the formation of an internal task force to develop and revise guidance to support the development of new antibiotic drugs.

The FDA should prioritize the clarification of this middle path with guidance for industry that defines how the totality of preclinical and clinical data can be better utilized to inform antibiotic development and in regulatory decision making. This includes guidance to facilitate pathogen-specific (rather than body-site specific) and feasible studies, the acceptance of efficacy data from preclinical studies as a strong predictor of efficacy of an antibiotic in humans, acceptance of clinical trial designs that incorporate prior knowledge of efficacy to streamline clinical development, and guidance that improves the feasibility of traditional Phase III clinical trials and increases real-world applicability of study results.

There is universal agreement on the urgent need to develop effective new antibiotics. Clear guidance from the FDA on this middle path would provide regulatory clarity and help to facilitate a robust and sustainable discovery and development infrastructure for new antibiotics for patients.

PhRMA and our member companies are pleased to be working collaboratively with the FDA and other stakeholders to overcome the hurdles to developing new antibiotics for the patients who desperately need them.

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