Ganley described in detail the extensive “toolkits” now available for characterizing an aerosol product, obtaining realistic performance data, simulating both deposition and local and systemic pharmacokinetics of the product in individual patients, and finally conducting an in silico clinical trial with simulated patients. All of the basic tools are available, he said, “The challenge for us as an industry is bringing all of these together into an integrated approach and putting these into files to start to get these generic approvals coming through.”
In response to a question about how close US regulators are to accepting the alternative approach, Ganley said that maybe he should defer to Bryan Newman who would be presenting the FDA’s viewpoint in the next talk; however, said that discussions at a recent workshop run by the Center for Research on Complex Generics (CRCG) and the FDA were productive and that he had found that “both industry and regulators are keen to make this approach work.”
Newman then presented his talk on “Design Considerations for Alternative Bioequivalence Approaches for Generic Orally Inhaled Drug Products” via livestream from the US. Noting that several generic inhaled products have successfully gained approval via the “weight of evidence” approach, he said that “The FDA acknowledges that this is not an easy task to accomplish” and reviewed challenges presented by required clinical endpoint studies, including inaccuracy and costly delays.
In describing how in vitro and in silico studies could potentially work together to provide an alternative approach to establishing BE, he emphasized that the types of alternative studies used would likely depend on the specific dosage form and formulation. Newman laid out the steps for an alternative approach to BE for solution MDIs, noted that more complex dosage forms like suspension MDIs and DPIs might require additional studies in an alternative approach, and described potential studies for alternative BE for both of those forms in detail. He also noted pressure on the FDA to provide more guidance on alternative approaches.
Acknowledging that designing alternative approaches for suspension MDIs and for DPIs “is a remaining challenge” and that validation would be necessary, Newman added that “in silico approaches could be useful in addressing some of these challenges.” In concluding, he promised, “I can say that developing these approaches for generic orally inhaled drug products is a top focus for FDA”; so, he said, “Stay tuned for future conference sessions and workshops to hear our latest guidance for these methods.” He also referred people to the recordings of the recent CRCG workshop, which are available on the workshop’s web site.
Regarding the in silico approaches, session chair Richard Dalby asked Newman, “You referred constantly to alternative approaches; but in the phase when you are trying to validate in silico or in vitro approaches with clinical data, are they really alternative, or is it additional work on top of clinical trials for at least the foreseeable future until you develop some confidence in these methods?”
Newman responded, “We do consider them alternatives just because we’ve had the weight of evidence approach for a while now, so it’s serving in place of these studies . . . you could use these studies as developmental tools, I think certainly a lot of characterization methods. The idea again is to build a better understanding of your product, so that’s obviously very valuable at the earlier stages just as it is when you are trying to detect product differences at the later stages, so I think these studies can perform either role so whether we define them as alternatives or not is just . . . I think it’s certainly something valuable for the industry if they are able to try to use something that is different from the comparative clinical endpoint study.”
