You Don’t Change Horses in Mid-Stream: Product-Specific Guidances

May 7, 2019By Sara W. Koblitz

As you may have noticed, FDA recently unveiled a new website.  As part of this redesign, FDA “enhanced” the Product-Specific Guidances (“PSG”) for Generic Drug Development web page.  The “enhanced” version of the website includes new database and search function features, export features, and paginated search results.  The new search functions will allow users to perform text searches of PSGs by active ingredient, by Reference Listed Drug application number, or Reference Standard application number and will allow further filtration of search results.  Of course, the guidances are still available to browse alphabetically rather than search (and there are 1685 of them for your reading pleasure).

As exciting as the new website is, FDA really buried the lead when it announced the new website.  In response to common complaints from industry, FDA has adopted a new resource for PSGs, a dynamic web page entitled “Upcoming Product-Specific Guidances for Complex Generic Drug Product Development.”  This web page contains a list of PSGs for complex generic products that are currently under development or for a which a revision is planned in the next year.  The list reflects FDA’s efforts to be transparent regarding plans for development and revision of PSGs so that sponsors can be aware of what is in the pipeline and discuss with FDA the appropriate testing as necessary.

Generic manufacturers have found that FDA’s bioequivalence recommendations for a given product may have changed during development of a generic.  Sometimes, these recommendations change after a product has been submitted but before FDA has completed its review, requiring sponsors to perform additional studies after submission.  In fact, this situation has occurred enough that Congress carved out an exception from the 180-day exclusivity tentative approval forfeiture provisions for it.  As Brian McCormick, Vice President & Chief Regulatory Counsel Teva Pharmaceuticals USA, Inc. explained during the Incentivizing Generic Competition Panel at FDLI’s Annual Conference last week, such changes to bioequivalence requirements “midstream” can throw off the years of planning that goes into large ANDA development programs and may have ripple effects in the development of other ANDA products in the pipeline.  To paraphrase Wag the Dog (and Abraham Lincoln): You don’t change horses in midstream.

While obviously no one advocates for the approval of a generic product with a less than robust demonstration of bioequivalence, transparency in the publication and the revision of these guidances would go a long way to alleviate some industry complaints.  To that end, FDA’s list of planned PSG revisions announces the PSGs in development, as well as those under revision in the next year, so that sponsors can plan accordingly.  According to Dr. Robert Lionberger, Director of FDA’s Office of Research and Standards, the intent of this list is to provide the notice and transparency that industry seeks to alleviate surprises that may arise after an application is submitted.  FDA is aware of the issue and is therefore attempting to be more open with sponsors about changes in the pipeline.

The PSG list information includes the active ingredient(s), route of administration and dosage form, and RLD application number.  Additionally, the PSGs undergoing revision are also assigned a “planned revision category.”  The revision categories are “Major Revisions,” “Minor Revisions,” and “Editorial Revisions.”  “Major Revisions” are defined as the revision of PSGs to include additional bioequivalence studies or evidence recommended to support FDA approval.  “Minor Revisions” are any revisions not considered major, including the removal of certain studies, providing alternative and less burdensome approaches to currently recommended studies, to add information on newly approved strengths of the RLD, or to make other recommendations that would not result in the requirement of a new bioequivalence study.  “Editorial Revisions” are non-substantive changes, updates of external references, corrections of grammatical issues, and changes to formatting.

This new system isn’t perfect.  Some companies rely on these PSGs years in advance of submitting an ANDA, so notice of new bioequivalence requirements only a year in advance might not be a panacea.  Further, the list only covers “complex” generics, and if there are any changes to PSGs for more basic generics, sponsors may not have the same transparency.  But there is little doubt that the Agency’s efforts to remediate at least some of the generic industry’s complaints in this area provides at least a bit of relief to sponsors.  We’ll have to see how well FDA keeps this list updated and how helpful this list actually is given how early some companies start development of new generics.  But if nothing else, FDA’s continued work to make the generic development process easier and more accessible demonstrates that the agency’s commitment to generic competition has not waned in the post-Commissioner Gottlieb era.