Product Failure Is Not Process Failure

The FDA must never be flexible. Flexibility is for losers. Flexibility makes the regulatory process look like a wet noodle, lacking rhyme, reason, and predictability. Flexibility doesn’t instill confidence in an increasingly high-risk developmental environment. What the FDA must be is “nimble.” It’s a distinction with a difference.

Regulatory Nimbleness understands and respects the need for process. Undefined and anecdotal “flexibility” can easily lead to regulatory pandemonium. Nimbleness must enhance progress through process, not result in entropy. New approaches require well-considered rules because, as Victor Hugo reminds us, “Where the disposal of time is surrendered merely to the chance of incidence, chaos will soon reign.” Flexibility bends rules. Nimbleness reads between the lines. Nimbleness looks to the spirit of the FDA’s mission. Experts are nimble.

Witness the agency’s recent experience with Relyvrio (for amyotrophic lateral sclerosis). Approved after an almost unheard of second advisory committee vote and over the objections of many on the divisional review team, the product flamed out (there is no subtler way to put it) in a comprehensive Phase IV study. Not surprisingly (but still disappointingly), the ossified standard bearers of the regulatory status quo took the opportunity to claim the failure of the product was proof positive that the FDA’s progressive approach to 21^st century regulatory science was a failed experiment. They’re 100% wrong. Product failure is not process failure, and those who chose to link the two only show the paucity of their understanding of how drug regulation works.

As Steve Usdin argues in his recent commentary, ALS disappointment should not close the door on patients, “New regulatory approaches are sorely needed for rare disease drugs. They need to reflect scientific consensus, and to be applied via a well-reasoned and consistent decision-making framework. One-off moves make the drug development process unpredictable for both patients and companies and are all too likely to backfire.”

There is FDA Draft Guidance and Final Guidance, but what we increasingly need is nimble guidance. If the Relyvrio failure along with the successes of Duchenne muscular dystrophy, Friedreich's ataxia, idiopathic pulmonary fibrosis, and Alzheimer's disease medicines (yes – Alzheimer’s disease!) teaches us anything, it's that guidance (both capitalized and lower case) is a two-way street. Good ideas, new ideas, challenging ideas aren’t the sole remit of those inside the walls of White Oak. “Not invented here” has no place in drug development or review.

Don’t fix the blame, fix the problem. Traditionally, the FDA hasn’t been a terrific intra-mural player. In order to accelerate and sharpen the agency’s regulatory nimbleness, this must change.

Advancing biomarkers via more regular partnerships with industry and academia is, of itself, a biomarker of FDA’s recognition that it needs to be a better team player. The agency should be applauded for its collaboration with the Critical Path Institute (in biomarker consortia development), as well as their EMA partnership to facilitate collaborative review of drug development tool qualification. But the echo of past applause fades away quickly, and silence shouldn’t be allowed to fill the vacuum. The Relyvrio story and the continued debate over accelerated approvals are a clarion call to hasten biomarker development, including:

• Maximizing Expert Resources: FDA needs adequate resources to provide advice and oversee review and decision-making. One solution is to partner with an external entity (an Intramural Biomarker Consortium-IBC) to develop early advice and serve as an expert sounding board for nascent biomarker efforts. The IBC could be a required or voluntary resource in the review process, especially for initial data package reviews. This approach would allow FDA staff to focus on their primary role of product review and regulatory oversight.
• Refined Evidentiary Considerations: The product development and research community should collaborate to support FDA in developing a framework for the proper level of evidentiary substantiation required for qualification and the criteria used to evaluate them – such that FDA can issue guidance -standards which do not exist today. The IBC could be charged with overseeing relevant workshops and the drafting of initial guidance documents (consistent with FDA’s Good Guidance Practice recommendations and provided FDA is actively participating and has final approval).
• Qualification Plan: FDA should clarify the components of individual qualification plans and judge submitted data packages against them. Decisions not to qualify a proposed biomarker for a particular context should be accompanied by an explanation of the evidentiary gaps between the agreed plan and the submitted qualification package. IBC could work with biomarker developers to build these plans and perform initial data package reviews.
• Enhance Learning:  Give FDA the authority to share information about biomarker qualification programs that are being advanced through collaborative efforts. Much can be learned by reviewing successes and failures across ongoing biomarker programs and would inform the broader research community to enable refined evidentiary standards.
• Timeliness: FDA must clarify and communicate timelines for the qualification process to foster predictability and encourage participation. Such resources could be provided via the PDUFA process.

FDA can further solidify its place squarely in the center of the innovation ecosystem by fostering collaborative alliances with all stakeholders, enhancing qualification planning, sharing developmental endeavors, and clarifying standards.

The system is working. Now the entire developmental/regulatory ecosystem (including patient groups) must collaborate to make it better.

FDA be nimble. FDA be quick. FDA jump over the bureaucratic schtick.