Perspective

IDSA outlines trial designs for development of antibacterial agents

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 Boucher
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

Reference:

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.

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 Boucher
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

Reference:

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.

    Perspective
    WIlliam Powderly

    William Powderly

    • IDSA has a multiprong approach against the public health threat of antimicrobial resistance that starts with prevention, antimicrobial stewardship and rapid diagnosis of bacterial infections. For quite some time, we have also focused on the lack of innovation in developing new agents for patients with resistant organisms, particularly those with multidrug-resistant gram-negative infections.

      The traditional pathways have made it very difficult and expensive to pursue innovative drug development. This white paper was developed to focus attention on a different way to approach the problem, and it represents the perspectives of people involved in the investigative side and industry side of drug development. In it, we encourage the development of drugs that have relatively narrow spectrums with indications not for pneumonia, for example, but rather for targeting either a single pathogen, a group of pathogens that share a resistance mechanism, or perhaps a very localized infection.

      When we reach a point of having new drugs, we hope that stewardship programs across the country, which are now becoming increasingly mandated, will mature and develop to a point where there is more rational and appropriate use of antibiotics. IDSA is exploring important policy questions with interested stakeholders and partners on how we can ensure that the pharmaceutical industry will receive a return for investing in these drugs, but also guarantee that the drugs will not be widely used and develop resistance rapidly.

      Overall, this paper is very important in terms of creating a discussion. We hope that it is widely reviewed and commented on, but in particular, we hope this paper will help the FDA in its thinking around how it will model the drug development and regulatory framework for new antibiotics.

      • William Powderly, MD, FIDSA
      • IDSA President
        Co-director, division of infectious diseases
        Washington University
    • Disclosures: Powderly reports serving on advisory boards for Gilead Sciences and Merck.