Commissioner of Food and Drugs Dr. Robert Califf has raised at least two major issues that he hopes to address in his current tenure. The first is obvious – combatting the pervasive misinformation that is a cancer that affects all healthcare, especially pandemic-related issues. Unfortunately, this cancer continues to metastasize, and it requires ongoing outreach and education. That it is a topic for another day. His second issue, improving evidence generation, is more subtle, and for those in the regulated industry, more virulent. Here we address the scope of the second issue and provide four recommendations for combatting the problem.
The Problem of Substandard Clinical Trials
A major element of the need to improve evidence generation has arisen from the pandemic. This element has created an internal agency acronym within the Center for Drug Evaluation and Research (CDER), SCT’s, to describe the problem. In polite company the problem is described as Substandard Clinical Trials. In private they are called Sh***y Clinical Trials. SCT’s are bad enough, but they have generated even worse progeny – SFP’s (Sh***y Foreign Protocols). CDER is not a monolith. Each reviewing division is its own silo and has its own issues. For an issue to reach the Commissioner’s level – and to be a priority – the problem has to be pervasive and serious throughout CDER. And to the Commissioner and senior CDER officials it is.
The pandemic generated an explosion of Investigational New Drug Applications (INDs) – approximately 400 INDs, according to CDER’s reports, attempting to deal with aspects of COVID-19. Dr. Janet Woodcock, Principal Deputy Commissioner, has repeatedly commented that only 6% were designed to produce any meaningful results. The INDs were reviewed for safety only. This approach, of course, is consistent with traditional FDA policy and practice, as well as the law. The agency does not know an applicant’s clinical development strategy for approval of its drug product. Therefore, as long as the IND does not present an unacceptable risk to patients, the applicant is permitted to proceed with the study. As the pandemic unfolded, the agency was pragmatic in permitting these studies to be opened in hope that some would eventually produce data of clinical value. It appears that 94% produced nothing tangible, and it is not clear how much the other 6% produced. Tragically, however, the wave of IND’s created something worse. The tsunami created a toxic environment not only for the companies involved with these studies, most of which were for supplemental NDAs or new §505(b)(2) applications. They have poisoned the environment for the milieu from a CDER perspective. And the skepticism is growing.
SCT’s and SFP’s have poisoned the environment because a vast amount of agency resources are being consumed reviewing substandard submissions. These reviews not only waste agency resources, but divert resources and time that can be better focused on dealing with products that could potentially improve the public health. Some of these studies are also linked with misinformation which increases the problems for the agency logarithmically. Further the time sink must be considered an impediment to the agency meeting its user fee goals.
Although the vast majority of the SCTs and SFPs have been in the value-added space, i.e. §505 (b)(2)’s and supplemental NDAs, the problem is growing. The Office of Oncology Excellence has complained about this phenomenon, and the Office of Generic Drugs is now concerned.
Potential Causes of the SCT’s and SFP’s
Applicants are dumping half-baked data on the agency for what may be numerous reasons. Some hypothesize that the applicants hope that the agency will teach applicants how to create quality submissions – a quest for free consulting services. Still others suggest a deeper level of naivete. The naifs somehow hope the substandard submissions will lead to approvals. A third hypothesis is that these applicants arrogantly have no clue how bad the protocols are and how substandard the data that will be produced by these protocols will be. Whatever the reasons, we have been told that applicants are now filing without advice from experienced experts and consultants or worse. Even worse, we have been told applicants are filing applications contrary to the advice from experts not to submit these substandard applications – the regulatory equivalent of walking out of the hospital Against Medical Advice (AMA).
Many of these submissions are by applicants who are new to the clinical development segment of the pharma industry – either without prior experience or whose experience is solely in the generic space. Some may file due to intracompany pressure. Others may file due to naivete, ineptitude, or arrogance. All lead nowhere or into a death spiral.
These submissions despoil the reputation of the applicants. As a matter of human nature, their future submissions will face increased skepticism if not derision at the agency. And these SCTs and SFPs have a ripple effect that tarnishes the reputations of all involved.
Removing the scarlet letters that submitting SCTs and SFPs will be imprint on your reputation is far more to accomplish than creating a good initial impression. Therefore, the best strategy is to start with quality. We recommend using the OODA loop of decision making, which originated with fighter pilots during the Korean War: Observe, Orient, Decide, and Act. According to the originator, Col. John Boyd, the concept applies to situations analogous to drug development where one has a continuous cycle of observe, orient, decide, and act. Of course, you do not want to get killed or critically wounded in the first skirmish, which is even worse than being toxically branded as substandard submitter.
Your observations must be comprehensive. You must view the full theater of conflict. To accomplish this task, you must research the area exhaustively, looking at all related product development in your area and related areas. FDA will be aware of them. You must be too. Too many submissions fail to consider the historic market and its evolution. What don’t I know, or see, which is of equal importance to all of the other factors?
Your orientation is critical. What experience do you have with this reviewing division? What is the division’s reputation? How has it treated analogous products? What is your relative position to other products in the area? For many applicants their product is their child – flawless with no issues. Unfortunately, this unique child does not exist. Each reviewing division has its own biases, nuances, blind spots, and peculiarities. Learn about them just as you would learn about all of your child’s teachers, coaches and playmates.
There is no one simple, single decision in the value added drug development space. Every decision leads to multiple follow-up decisions and steps. Your observations and orientation must give you the perspective to help you make each subsequent decision, and you must continue to observe and orientate. Do I need help? How costly will the assistance be? Who can help? How do you select the correct help? How do you deal with competing input from multiple sources?
Finally, you must act, and inaction is an action, as former Deputy Commissioner Sherwin Gardner used to say. You can agonize over decisions, but in the OODA process you may get knocked out of the air if you ponder too much. As the late John Wooden, legendary UCLA basketball coach said, “be quick, but don’t hurry.” Our experience shows that companies are often as siloed as any bureaucracy. They forgot or ignore their access to other valuable assets, e.g. internal colleagues, members of their Board of Directors and Scientific Advisory Boards, who can help guide them or direct them to other experts, consultants and lawyers. Use them.
We’ll discuss this and many other topics impacting in-house attorneys and corporate practitioners at the Buchanan Life Sciences Product Portfolio Optimization Summit on September 28. Click here to earn more about the program and register.