Exclusivity = Innovation = Clinical benefit: Who decides?

By Ed Allera - Chairman of The 505(b)(2) Platform

​In our “Exclusivity Under Attack” article published in August 2019, we discussed the U.S. District Court for the District of Columbia’s opinion in Braeburn Inc. v. FDA, holding that FDA’s use of “innovation” in determining exclusivity under §505(b)(2) of the Federal Food, Drug, and Cosmetic Act (FFDCA) was too broad.  The court remanded the matter to the Agency to more clearly frame the definition.  This issue arose because multiple §505(b)(2) new drug applications (NDAs) were filed for variations of buprenorphine delivery, and some applications were blocked by market exclusivity granted by FDA to previously-approved competing products.
In late November 2019, FDA quietly responded to the plaintiff, Braeburn, Inc., in a decision that was not highly publicized but that nonetheless has significant ramifications for exclusivity decisions not only for §505(b)(2) NDAs, but also for orphan drugs and other novel products such as combination products and gene therapies.  In its response to Braeburn, FDA defined “exclusivity” in terms of clinical benefit to a patient population that is studied in a clinical trial.  Based upon FDA’s response to Braeburn, the central question becomes:  What unique clinical question about the safety and effectiveness of the active moiety is answered, for the first time, by the clinical trials that were conducted for—and are essential to—the application’s approval?
FDA’s conclusion is that exclusivity is available when there is no other data available to support the application; in other words, exclusivity does not apply to aspects of the drug product for which the clinical investigations that were conducted were not essential.  According to FDA, as the number of applications for therapeutic improvements in the active moiety increases, the exclusivity that is available to sponsors of these incremental advances becomes more limited and usually narrower in scope.
In its decision, the Agency emphasized the fact-specific nature of exclusivity determinations.  Clinical trials must address clinically meaningful differences that are unique (i.e., previously unanswered questions of clinical relevance).  Thus, clinical safety benefits must be unique to the product that is the subject of the §505(b)(2) NDA.  Accordingly, there is a relationship between the scope of exclusivity awarded and the changes to the product that required new clinical investigations which were essential for approval. 
However, FDA also noted that the context-specific nature of exclusivity decisions may create divergent results across different therapeutic areas.  A product change may be considered an innovation in one therapeutic area, but not in another therapeutic area if clinical trials would be unnecessary to approve the change.  Moreover, sponsors must recognize that changes to warnings or other risk information on a drug label must be included in generic drug labeling as well; therefore, such changes do not qualify for exclusivity.
Because FDA’s exclusivity decisions are fact-specific, it is difficult to rely upon a previous FDA exclusivity decision in a new situation—particularly as the industry continues to develop new technologies, combination products, and digital products.  FDA’s evaluation of what is known about a previously-approved drug product, combined with new clinical evidence generated by clinical investigations of another drug product containing the same active moiety, presents what we call “the clinical benefit dilemma”:

• What data and outcome is considered clinically relevant?
• What new question is being answered for the first time, particularly when competition already exists?
• Who determines what qualifies as clinical benefit?  This is a particularly hot topic in the oncology and orphan drug areas, as evidenced by ongoing public dialogue about the scope of clinical benefit and expanded access, as well as Oncologic Drugs Advisory Committee (ODAC) discussions.
• As technology advancements are made and we gain more knowledge about cellular mechanisms of action, will clinical benefit look different in the future—and who will decide?

It is important to recognize that FDA is neither a hydra nor a monolith.  The Center for Drug Evaluation and Research (CDER) is composed of many divisions and offices, including the Oncology Center of Excellence; the Office of Combination Products; the Office of Orphan Products Development; the Office of Pediatric Therapeutics; and the Office of Women’s Health.  Each one of these divisions and offices takes a different approach in determining what constitutes clinical benefit.  Opinions vary, and some reviewing divisions are more open-minded than others.  It is important to recognize these differences, along with the fact that every division and office believes that it is the ultimate decision maker.  Although often true, sponsors must be aware that FDA may consult the CDER Exclusivity Board, while the Office of Chief Counsel will have the final say in the most competitive, contentious, and economically-significant situations.
Because of the economic ramifications involved in many of these decisions, the courts often become entangled in these legal decisions.  However, the courts do not realistically appreciate the scientific nuances or practical aspects involved in drug development.  Courts look for FDA to make reasonable decisions, and they are becoming more cautious about providing FDA with unfettered discretion.  To this end, at least two current U.S. Supreme Court Justices have discussed revisiting the Chevron standard of review, which for decades has given great deference to Agency decisions.
Where do these recent developments leave industry?  While congressional groundwork has started on “21st Century Cures 2.0” and the 2022 user fee re-authorization bill, we are entering a new era of patient activism.  In this new era, the concepts of clinical benefit and clinical relevance are quickly becoming the 21st century equivalent to the 20th century standard of adequate and well-controlled clinical investigations.  Drug development no longer is only about showing efficacy and safety of a product.  It now requires that sponsors demonstrate product value.  Sponsors would be wise to take all of these facts into account when developing their drug products and when seeking exclusivity for their §505(b)(2) NDA.