Companies seeking an indication for an antimicrobial agent to treat resistant pathogens could rely mostly on pharmacokinetic and pharmacodynamic studies, FDA said.

CDER Lead Medical Officer for Antimicrobial Drug Development & Resistance Initiatives John Powers, MD, outlined a development process at a Nov. 19 workshop on antimicrobial resistance in Rockville, Md.

First, companies would need to "demonstrate that your drug is effective in the disease where that resistant pathogen is most likely to be found," Powers said.

"The second thing would then be to come in with some minimal amount of clinical data supplemented by PK/PD eradication of organisms at various body sites and use that information to support the resistance claims," Powers said.

An FDA working group is developing an exposure-response database for antibiotics from information in drug applications in order to expedite future drug development.

The working group, chaired by CDER Division of Pharmaceutical Evaluation III Pharmacologist Francis Pelsor, is considering whether a PK/PD index derived from plasma can predict outcome at the infection site.

"And if the answer is indeed yes, then is the magnitude of the index also the same at the site of infection as it is in the plasma?" CDER Office of Clinical Pharmacology & Biopharmaceutics Pharmacologist Phil Colangelo, PhD, asked the workshop.

At the American Association of Pharmaceutical Scientists annual meeting in Toronto, Canada, CDER Division of Special Pathogens & Immunologic Drug Products Medical Team Leader Edward Cox, MD, said that a limited clinical program focused on Phase II could allow commercialization of drugs that might not be developed otherwise because of toxicity concerns.

"The Phase II studies may actually provide or contribute important information to the database with regards as to how the drug fares with regard to safety and efficacy," Cox said Nov. 12.

"And the Phase III program would be a smaller program, seeking a limited range of indications...predominantly more serious infections....An agent that would...be developed in this fashion might be one where the risk-benefit ratio for the drug, based on either potential toxicities, or toxicities of the drug, would not be appropriate for a broader development program."

Drugs approved under such a limited development program would likely be subject to the restricted distribution provisions of Subpart H's accelerated approval regs, Cox said.

"The key here is the risk-benefit ratio that's achieved in the smaller safety database. Potential toxicities or uncertainties with regards to toxicity should be offset by the greater benefit that the drug would bring to bear, given that it's used for the treatment of only serious infections. And these serious infections may include resistant pathogens for which there is a limited number of available therapeutic options," Cox observed.

If the product being studied is I.V.-only with some toxicities or difficult to administer, "in fact then it's probably not that big an issue, because the drug's use will be somewhat limited," Office of Drug Evaluation IV Director Mark Goldberger, MD, said at the Rockville workshop.

"So I think that that is another option, but one has to look very carefully at product labeling, and very carefully about whether there needs to be any limitation at all in how the drug might be made available because we are then trying to do something on the barest amount of data possible in terms of understanding how well the drug performs as an antimicrobial, what we know in terms of the safety."

"If it's a clear unmet medical need, it's a serious illness, we've got no other alternative therapies. One therapy with a lot of resistance [may be] a trade-off for those patients, the drug that may not have safety fully characterized....It doesn't mean you'd want to use it for instance on every patient that came in with pneumonia. And that's the kind of concern that would somehow need to be addressed," Goldberger said.

Because "it's difficult to enroll sufficient numbers of patients with the resistant pathogen of interest" in clinical trials, a more limited approach could "increase the feasibility of completing clinical studies for agents that might be pursuing a much more limited range of indications," Cox said.

FDA also is encouraging slightly broader "focused" development plans in addition to the "limited" strategy relying mostly on PK/PD.

Goldberger gave an example for companies interested in studying a product for community acquired pneumonia, hospital acquired pneumonia, intra-abdominal infection and complicated skin.

Firms could conduct two trials in community acquired pneumonia (since it is "probably the easiest" indication to study) and one trial in each of the other indications.

"If one were comfortable about PK/PD across those different indications, one might easily be able to synthesize those four studies into getting all the indications, all four indications," Goldberger said.

"And if you were able to capture, say a significant number of resistant organisms, say a resistant enterococcus out of the complicated skin, a few out the hospital acquired pneumonia, more out of the intra-abdominal, you might ultimately be able to glean that, perhaps supported by some small, if you had done it, open-label study, as a more efficient way of doing a development program."

By conducting these studies, "you're fundamentally beginning to show that across a broad range of seriously ill patients, the drug can perform well. And that helps you with the idea that even though there may be some differences in the resistant organisms, you've at least got a handle that this is a drug that you're comfortable using to treat severely ill patients."

"And then I think your overall comfort level goes up, as opposed to simply getting an indication that may be less challenging, and then trying to do everything else with a small open label study that has a mish mash of patients. That would be at least, ideally, the kind of perspective that we would sort of have."

For resistance claims, "it may be necessary to provide...a larger body of evidence to support the activity of the in-class resistance claim," such as a beta-lactam to treat penicillin-resistant streptococcus, than an out-of-class, such as a fluoroquinolone for the same claim, Cox said. A new in-class agent could "be affected by the resistance mechanism that's being sought."

FDA is considering how to include data from non-traditional development programs in a product's labeling. "How could we get information in labeling that showed a relatively small study with a favorable microbiologic profile but clinical data that was harder to interpret perhaps as a result of the amount of data that was actually available or the amount of patients studied," Goldberger said.

"There were several approaches floated in terms of just being able to put such information in the labeling, you know, sort of leaving it to clinicians to use this information as they thought best," he said. "I proposed one alternative which was ultimately you would get what we call a second-line indication."

FDA has proposed eliminating in vitro susceptibility data from labeling because it might inappropriately imply efficacy.

The Pharmaceutical Researchers & Manufacturers of America and the Infectious Diseases Society of America, which co-sponsored the workshop with FDA, support including in vitro data in labeling as a guide to clinicians (¹ Also see "Antibiotic In Vitro Data Needed In Labeling For Appropriate Use, PhRMA Says" - Pink Sheet, 16 July, 2001., p. 8).

PhRMA is asking FDA to issue a guidance on developing treatments for resistant pathogens.

GlaxoSmithKline Director-Strategic Microbiology James Poupard, PhD, a member of PhRMA's Antibiotics Working Group, said "realistic FDA guidelines to secure labeling claims for agents to treat infections caused by resistant pathogens" are needed. "There's a need for inclusion of that information on the label describing the benefit of the new agents, particularly how to differentiate from those existing agents, to provide incentives for the companies."

GSK VP-Regulatory Affairs David Cochetto, PhD, said, "I know the division is interested and has in fact probably started in this direction...I think I would reduce uncertainty in the minds of sponsors."

At the workshop, PhRMA also urged FDA to create a list of resistant pathogens to encourage development of treatments ("² [A#00640470012], p. 18).

Antibiotic Indications For Resistant Pathogens Could Rely On PK/PD – FDA

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