A white paper published on behalf of the Infectious Diseases Society of America, or IDSA, outlined new trial designs for the timely development and approval of narrow-spectrum antibacterial agents, which researchers say are “critically needed” as resistance to current drugs continues to rise.
According to Helen W. Boucher, MD, FACP, FIDSA, director of the infectious diseases fellowship program at Tufts Medical Center and associate professor of medicine at Tufts University School of Medicine, and colleagues, an estimated 700,000 people die each year from infections caused by multidrug-resistant pathogens, and millions experience serious complications of these infections.
Helen W. Boucher
“For these patients, the threat of a post-antibiotic era is already a devastating reality,” they wrote. “Left unchecked, annual deaths attributable to [antimicrobial resistance] are estimated to reach 10 million by 2050, outpacing cancer, diabetes, diarrheal diseases, and automobile accidents.”
Adding to the global threat is the recent emergence of two genes with resistance to colistin — a last-resort antibiotic. This development further underscores the need for antimicrobial research and development, the authors wrote.
New antimicrobial agents are typically studied in noninferiority trials that focus on one site of infection. However, Boucher and colleagues noted that noninferiority and superiority trial designs are not always optimal and often impracticable given the few number of patients with life-threatening infections.
“It is undesirable at a population level to be able to show superiority of a new antibacterial drug when that depends on studying appreciable numbers of patients infected with a pathogen resistant to the current standard of care,” they wrote. “We never want the current public health crisis of antimicrobial resistance to expand such that we lack effective treatment options in such a large number of patients that we can readily conduct such clinical trials.”
In the paper, Boucher and colleagues presented new trial designs involving very small clinical datasets for drugs targeting specific bacteria, particularly highly resistant gram-negative pathogens such as Pseudomonas aeruginosa, Acinetobacter and Klebsiella spp. Such trials are now authorized through the new regulatory paradigm known as the Limited Population Antimicrobial Drug (LPAD) pathway, a component of the 21st Century Cures Act that was signed into law on Dec. 13, 2016. In addition to allowing for smaller, more efficient and feasible trials, the LPAD pathway includes safeguards promoting appropriate use of agents that gain approval, according to the researchers.
Specific elements of clinical trial designs outlined in the paper include:
- pharmacokinetic/pharmacodynamic-based dosing regimen selection from pre-clinical and in vitro models;
- confirmation of targeted drug exposure in relevant patient populations, including children, indicated by pharmacokinetic data from healthy volunteers, infected patients being treated with other active agents, and treated patients;
- confirmation of regimen efficacy in a range of animal models;
- validated external controls; and
- very small clinical datasets, possibly with pooled data from multiple body sites.
Boucher and colleagues emphasized the importance of ensuring limited and appropriate use of newly approved drugs through antibiotic stewardship practices. They also recommended that the drug labels clearly state the intended use of the drugs and include information on the pharmacology of the drug at all studied body sites and effectiveness data, when available, at less common sites of infection.
“Finally, to succeed in a sustained fashion and return to a robust and vibrant, diverse antimicrobial development pipeline, we must engage the larger group of stakeholders and make push and pull incentives work in order to address economic barriers to antimicrobial drug development. This will require a path forward that is unique and pragmatic,” they concluded. “Not finding such a pathway would force future patients and physicians to accept even greater degrees of uncertainty as antibiotic resistance continues to emerge and threaten public health. Such a course is unacceptable to our patients and future generations.” – by Stephanie Viguers
Boucher HW, et al. J Infect Dis. 2017;doi:10.1093/infdis/jix211.
Disclosures: Boucher reports being a consultant to Actelion and the National Institute of Allergy and Infectious Diseases. Please see the full paper for a list of all other authors’ relevant financial disclosures.