Antibacterial Drugs: FDA Panel To Explore Approval Path For Single-Species Agents
Executive Summary
US agency’s advisory committee will weigh the pros and cons of five possible development and regulatory pathways, with a specific focus on animal models.
The US FDA is calling on its Antimicrobial Drugs Advisory Committee to assess the potential use of five different development and regulatory pathways for antibacterial drugs targeting a single species of bacteria.
Sponsors have expressed interest in developing antibacterial drugs and monoclonal antibodies with activity against a single bacterial species that infrequently causes infection, but several hurdles exist in comparison with regular drug development, FDA said in briefing documents released ahead of the panel’s April 13 meeting.
"Drug products that target a single bacterial species that infrequently causes infections may be candidates for LPAD because of the inherently limited population … and greater uncertainty regarding the benefit-risk profile.” – FDA
A clinical development program can be challenging if the target pathogens occur infrequently at any body site of infection and the effect size is roughly the same as for other antibacterial drugs, the agency said.
The advisory committee will discuss the pros and cons of five different pathways: non-inferiority trials; superiority trials; accelerated approval using surrogate endpoints; approval based on the animal rule; and the limited population pathway.
Low Frequency But Urgent Treatment
The agency has held several prior meetings on the topic of drug development targeting a single species of bacteria, including a two-day session in July 2016 to discuss developing antibacterial drugs for patients with unmet needs.
FDA also convened a March 1 meeting on animal models for antibacterial drugs. (Also see "Antibacterial Development: Industry Cautious About Role Of Animal Models" - Pink Sheet, 8 Mar, 2017.)
At that meeting, Entasis Therapeutics Chief Medical Officer Robin Isaacs discussed challenges in the development of the company's beta-lactamase inhibitor sulbactam-ETX2514, a pathogen-specific drug to treat Acinetobacter baumannii (A. baumannii) infections. Isaacs noted that A. baumannii infections represent only about 2% of hospitalized gram-negative infections and patients are often in intensive care units.
"This is essentially a problem of studying a low frequency event for which therapy must be initiated urgently/emergently and the first doses of treatment are very important in determining outcomes," FDA’s briefing documents state.
The A. baumannii and Pseudomonas aeruginosa (P. aeruginosa) species of bacteria will serve as the framework for the advisory committee’s discussion.
Noninferiority Vs. Superiority
Of the development pathways up for discussion, non-inferiority trials are regarded as the most feasible option available.
FDA said there are circumstances in which it would consider a single non-inferiority (NI) trial to be acceptable that uses a wider non-inferiority margin than would typically be used for a standard development program.
The margin may be even larger if the trial is limited to a single species of interest "provided that the data supporting NI margin justification are available," FDA said. "In this case, it may be acceptable to choose an NI margin equal to the estimated treatment effect."
There are drawbacks to non-inferiority trials, however, including uncertainty about a treatment effect. A non-inferiority trial may be impractical to conduct if the active control has only been shown to have a small or inconsistent treatment effect.
Additionally, the use of prior effective therapies "can confound the assessment of the effect of an investigational drug," FDA said.
Sponsors generally are not willing to conduct superiority trials with antibacterial drugs due to feasibility and ethical concerns, FDA said.
It generally is not considered acceptable to conduct placebo-controlled studies in cases where an available treatment exists to prevent serious harm, and there are limited opportunities to demonstrate superiority as new therapeutic options become available.
Drug Concentration As A Surrogate Endpoint
As for the issue of surrogate endpoints, FDA said it has considered allowing the use of microbiologic endpoints but that, at the present time, it does not consider them appropriate for acute infectious diseases.
The timing of the microbiologic endpoint is usually concurrent with, or at least close to, that of the clinical endpoint, and treatment effects on these endpoints have not always translated into effects on clinical outcomes, FDA said.
Potential limitations of using plasma or infection site drug concentrations as a surrogate include differences between healthy volunteers and infected patients.
While FDA is considering the use of test drug concentrations in plasma and/or infection sites as a surrogate, there are limitations with this approach that would need to be discussed, including potential drug concentration differences between healthy volunteers and infected patients.
"If approval under subpart H is considered using plasma/infection site drug concentrations, further discussion will be needed regarding the design of the trial in which the efficacy of the drug based on the surrogate will be assessed as well as the design of the postmarketing trial to verify and confirm the drug’s clinical benefit," the briefing documents state.
Diving Deeper Into The Animal Rule
The agency also asks the committee to weigh in with specific suggestions regarding the animal rule.
FDA seeks input on the types of information from animal models that might be useful to assess efficacy of an investigational agent. This includes: types of animal models and appropriate endpoints, clinical use of products where efficacy was demonstrated in animal models, and types of clinical data that would be helpful in addition to efficacy data from the animal models.
FDA's animal rule was created in 2002 to allow drug makers to demonstrate efficacy when it is unethical or infeasible to conduct controlled clinical trials. The agency may approve a drug on the basis of adequate and well-controlled animal studies when the results show the product is reasonably likely to produce clinical benefit in humans. (Also see "Where is US FDA's overdue 'animal rule' guidance for drugs?" - Pink Sheet, 27 Feb, 2015.)
The animal rule has been seldom used over the past decade. Johnson & Johnson and GlaxoSmithKline PLC both received approvals in 2012 based on animal models, for the treatment of plague with Levaquin (levofloxacin) and the anthrax antitoxin raxibacumab, respectively.
The rule sets forth four criteria manufacturers must demonstrate in animal models for FDA to rely on their findings for efficacy in humans:
- A well-understood pathophysiological mechanism of the toxicity of the substance and its prevention or substantial reduction by the product;
- A demonstrated effect in more than one animal species expected to react with a response predictive for humans, unless the effect is demonstrated in a single animal species that represents a sufficiently well-characterized animal model for predicting response in humans;
- An animal study endpoint that is clearly related to the desired benefit in humans; and
- Data on the kinetics and pharmacodynamics of the product that allow for selection of an effective dose in humans.
A Role For LPAD?
The 21st Century Cures Act’s limited population pathway provision for certain antimicrobial drugs also looks to be a point of discussion at the meeting.
The provision, often referred to as LPAD, provides FDA with the flexibility to approve antimicrobial drugs based on a limited population if the drug treats a life-threatening infection.
Experts believe the limited population pathway will incentivize the development of infectious disease drugs that would impact small, specific populations by codifying the removal of regulatory barriers.
"Drug products that target a single bacterial species that infrequently causes infections may be candidates for LPAD because of the inherently limited population of patients for whom the drug is intended and greater uncertainty regarding the benefit-risk profile of the drug that may follow from the development approaches described above," the briefing documents state.