Industry wants to launch another weapon in the effort to speed antibacterials to market for drug-resistant bacteria – approval based on pre-clinical efficacy data and limited demonstration of clinical activity.

The new evidentiary standard is part of a four-tiered regulatory framework for antibiotics proposed by members of the Pharmaceutical Research and Manufacturers of America Working Group on Antibiotics in an article published online Jan. 15 in The Lancet Infectious Diseases.

The aim is to facilitate antibiotic development in areas of unmet need and address an anemic pipeline that industry, physicians and regulators have been grappling with for several years Also see "Financial Incentives Seen As A Path To Resurgence Of Antibiotics" - Pink Sheet, 26 April, 2010..

The proposal would complement the economic incentives created by the Generating Antibiotic Incentives Now (GAIN) provisions of the FDA Safety and Innovation Act by allowing manufacturers to cut development costs and market a paying product more quickly. FDA in December began the process to identify pathogens that should be the target of compounds that can qualify for an extra five years of marketing under GAIN ([A#14121218002]).

There is no absolute need for new legislative authority to implement this four-tier framework, although it could be helpful, John Rex, AstraZeneca PLC Head of Infection, Global Medicines Development, said in an interview. Rex is corresponding author on the article.

Orphan drugs, which are aimed at very small numbers of patients with a clear unmet need, are a model for approving therapies with limited data, he noted. Because rare infections do not involve a predictable number of patients and those numbers can change, industry felt there needed to be new language for the antibiotics space, he explained. “But notionally, there’s a lot of similarity between the two, so you can say that the agency has a lot of experience with approving in that zone.”

Four Degrees Of Data

The industry approach adds two levels of evidentiary standards between the need for two randomized controlled Phase III trials that support an indication for a specific disease, which is considered to be Tier A, and approvals based on the Animal Rule, which is Tier D.

Approval without a randomized controlled trial would be Tier C, intended for drugs that treat drug-resistant infections found in a limited patient population and constituting an unmet medical need. The indication would be to treat a list of studied infections when proven or strongly suspected to be caused by susceptible strains of specific pathogens. Labeling would state that since data is limited, the antibiotic “should be used only in situations where it is known or suspected that other alternatives are less suitable.”

As an example of needed data, the article suggests that for a drug to treat Pseudomonas aeruginosa, the supporting evidence could include a prospective, randomized, open-label study comparing the drug to best available therapy, an open-label companion study and observational data from subjects receiving inactive or inappropriate therapy for the same infections.

A second new level of evidence, Tier B, would be used for drugs that are narrow-spectrum, such as those approved in Tier C, but also have activity against more common bacteria. In this case, a single Phase III randomized controlled trial, backed by a Tier-C type clinical package, could support approval. The indication would be to treat the more common infection, as well as a list of studied infections that are proven or strongly suspected to be caused by specified susceptible strains of pathogens. Labeling would carry the same caveat as a Tier C approval.

Case-By-Case Justification

The article does not lay out when each tier is appropriate. That categorization would be “driven by the magnitude of the unmet medical need with subsequent consideration to the strength of the preclinical data and clinical trial feasibility,” the authors note.

Those criteria, in turn, will be determined as industry and regulators work through the process, Rex said. “We had felt like that was something that would always be adjudicated on a case-by-case basis and that it would change. The definition of unmet need would evolve as our tools to make diagnoses evolve, as new drugs hopefully become available,” he said.

“We felt that it was difficult to actually write down a hard, fast set of rules other than to say, the story would need to make sense in the context at that time.”

A sponsor will have to make the case in the drug’s regulatory package, showing there is an unmet need, more data cannot be generated in a reasonable time and the drug has a positive risk/benefit profile based on the submitted data, Rex suggested. “All that will need to come together and will need to pass the face validity test.”

Rex said he expects sponsors would begin evaluating the pathway with regulators as they get into designing Phase II and III programs.

Labeling Must Communicate “Areas Of Residual Uncertainty”

An important component of Tier B and C approvals will be labeling since they will require less data. Since less is known about Tier B and Tier C drugs, “there is greater need for informative labeling that clearly communicates areas of residual uncertainty,” the authors point out, noting that specialist guidance could be helpful in this area.

If an indication is supported by a Phase III trial, as in Tier B or label expansion, the PK and PD and clinical data from Tier C investigations remain valuable information, according to the article. This allows prescribers to make informed choices and supports antibiotic stewardship, the article says.

“It’s going to be important that the labeling information correctly addresses the challenge of describing the boundaries of our knowledge and how to make a logical extrapolation for body sites that cannot ever really be studied,” Rex explained. “The label should provide as much information as possible to help the ID [infectious diseases] doctor when he or she is stuck at the limits of our knowledge.”

Guidance Addendum Already Released In Europe

The industry proposal comes as FDA plans a public hearing Feb. 4-5 to discuss approving drugs for limited populations based on smaller and more rapid trials than could be conducted in a broader set of patients ([A#14130114004]). That approval pathway stems from an Infectious Diseases Society of America proposal for a Limited Population Antibacterial Drug (LPAD) approval process Also see "FDA Exploring Limited-Use Approvals For Antibiotics Based On Small Development Programs" - Pink Sheet, 7 March, 2012..

The four-tier approach is not the same thing, Rex said. But “LPAD as a notion could help everybody get comfortable with the risk/benefit tradeoff that is inherent in Tier B, and in particular Tier C.”

A limited-use pathway could be useful for antibiotics, he said. But, he added that industry doesn’t want action on antibiotics to get bogged down by a broader conversation.

Drug companies are pushing their proposal in both Europe and the U.S. The European Medicines Agency issued an addendum to its antibiotic guidance in mid-2012 that describes an idea that looks like Tier B and alludes to an idea that looks like Tier C, Rex said.

Under GAIN, FDA is working on new guidance with regard to developing antibiotics for specific pathogens rather than diseases, he noted. Since there is interest by both agencies in global harmonization, there is hope policy will emerge that “permits developers to do a globally harmonized program that picks up the essence of Tier B or Tier C as appropriate for an agent and is accessible to both agencies.”

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