Generic Firms Want Looser Bioequivalence, But Change May Be Difficult For FDA

Sponsors contend that changes to bioequivalence guidances in the middle of a review cycle have delayed approvals; FDA says rule changes might be difficult because of existing regulations.

Generic sponsors are requesting that the US FDA review and approve abbreviated new drug applications (ANDAs) using existing standards even when a relevant bioequivalence guidance is changed in the middle of the review process so long as the change does not involve safety and efficacy of the product.

"Over the years, FDA continues to change the goalposts, and what may have been acceptable in the past with approved ANDAs is no longer the standard for many applications that were submitted years ago," Scott Tomsky, vice president of North America regulatory affairs at Teva Pharmaceutical Industries Ltd., said July 18 at the agency's Hatch-Waxman public meeting.

"Approved products are often not required to meet the improvised requirements, while unapproved applications, which met the requirements at the time of submission, and matched those applications that have been approved, are now penalized as a result of these new standard."

As a result of changes to guidances, generic companies are also forced to conduct extra testing and manufacture extra batches of product, in addition to dealing with complete response letters and multiple review cycles, all of which delay approval of competitive generics, Tomsky said.

Teva vice president of global generic clinical product development Gregg DeRosa specifically pointed to a 2016 draft guidance on assessing adhesion to transdermal delivery systems and topical patches. The guidance has "drastically changed the dynamic of measuring transdermal adhesion," DeRosa said. (See sidebar for story.)

DeRosa also noted that changes to product-specific guidances have also been problematic, as they completely redefine submission requirements and delay generic entry.

"When we are actually submitting applications for those products, we are utilizing the guidance being given at the time," DeRosa said. "And so we are designing our entire bioequivalence program based on that guidance. So we submitted it, it sits with the agency for a year or two, and then all of a sudden there is a new guidance, and that guidance changes the paradigm completely."

Candis Edwards, senior vice president of clinical regulatory affairs at Amneal Pharmaceuticals LLC, echoed Teva's concerns.

"Changes occur during mid-cycle review and they can definitely impact the approvability of the ANDA," Edwards said.

Although presenters didn't provide data on how frequently this happens, the problem appears to be big enough for presenters to spend large chunks of their presentation time discussing the matter.

Administrative Policy Changes Requested

While several of the presenters throughout the meeting were calling for solutions on a variety of subjects outside of FDA's purview, the generic sponsors called for specific agency action on how to approach bioequivalence study changes during mid-cycle review.

Edwards called for an administrative policy "that will allow review and approval of studies conducted under preexisting requirements when changes to the requirements were made mid-cycle, and the changes do not impact safety or efficacy of the product."

She said such changes that shouldn't hinder a review cycle could include changes to a guidance regarding a clinical trial design.

DeRosa took Edwards' suggestion a step further. He suggested generic companies could conduct postmarketing commitments to comply with guidances as scientific knowledge evolves, noting that "it is very difficult for us to have designed an entire program based on guidance that now no longer really is enforced."

Unclear How FDA Will Proceed

Changing the rules, however, might not be so easy for FDA.

Maryll Toufanian, deputy director of the Office of Generic Drug Policy, noted that bioequivalence regulations require that the agency use the agency use "the most accurate, sensitive, and reproducible method" in evaluating bioequivalence.

In responding to Tomsky's presentation, she asked for an analysis on how to judge bioequivalence of a product after a guidance has changed mid-review cycle that is in the context of regulatory and statutory requirements.