To a regulatory and compliance professional, FDA citations are a part of the landscape. Granted, no one welcomes such a situation, but ensuring regulatory compliance is the core of what we do on a daily basis. While the foundation of compliance requirements within our profession is black and white, in terms of how we must proceed with developing a regulatory strategy and employing risk management, much of what we bring to the table is in the gray zone. So the FDA’s distinct shift to flexing its enforcement muscles should be central to any regulatory and compliance strategy under discussion today.
Earlier this year the FDA made its new philosophy on enforcement clear when it announced its intention to push for an increase in the use of criminal misdemeanor prosecutions of “responsible corporate officials.”1 This change in enforcement policy means that executives in the pharmaceutical, medical device, and other FDA-regulated industries may be targeted for criminal charges under the Food, Drug, and Cosmetic Act (FDCA).
Two landmark U.S. Supreme Court cases underlie this new position, United States v. Dotterweich and United States v. Park. As a result of these two cases, a corporate official can be convicted of a misdemeanor violation of the FDCA without personally engaging in wrong doing, or even knowing about another person’s violation of the statute, provided the official had the responsibility or authority to prevent or correct the FDCA violation, but failed to do so.
Senior management accountability has always been the cornerstone of a well-designed pharmaceutical Quality Management System (QMS). At a minimum, the lead quality professional was always held accountable for the quality practices of the organization, but fully compliant QMS’ are able to demonstrate a broad level of accountability across the organization. However, this new doctrine by FDA departs from standard principles of criminal law by imposing strict criminal liability on a person who has neither engaged in misconduct nor exhibited criminal intent. Under this new philosophy executives convicted of misdemeanor violations of the FDCA can face imprisonment and substantial fines.
The driver behind such a public shift in dogma by the FDA Commissioner may be a critical internal report by the Government Accountability Office that criticized the FDA’s oversight of their Office of Criminal Investigations. The Commissioner further indicated that senior leadership within the FDA had recommended that the agency “increase the appropriate use of misdemeanor prosecutions, as a valuable enforcement tool, to hold responsible corporate officials accountable.”
There is additional evidence that the agency has adopted a much tougher stance on enforcement. Through the Freedom of Information Act (FOI), it is possible to get redacted copies of all FDA regulatory warning letters. Evaluating the language and tone of these documents reveals a clear trend toward stronger language and more definitive deficiency assessments. Phrases which refer to the FDA’s concern regarding the level of understanding the firm has of their product, or evidence of a firm’s failure to provide a complete explanation of the non-conformance are indicative of a higher bar being set by the agency. The most telling element that backs up their new tougher stance is that the FDA has tightened inspection-to-warning time, halved the time allowed for manufacturers to respond to warnings, and taken a pass on legal reviews prior to sending warning letters.
From a regulatory and compliance perspective the dilemma is how to adequately manage risk within this changing ideological framework. The agency’s desire to step up enforcement sends a message to industry that a higher level of compliance sensibility will need to be evident during its surveillance audits if an organization wants to maintain business as usual. In spite of this, the factors which delineate minor, major, critical, and criminal are now more blurred than ever. The FDA has stated in internal communications that it has established criteria for evaluating whether nonconformance episodes warrant escalation to misdemeanor enforcement but they have not shared this with the rest of industry. So once again we are being held accountable to a standard which we do not fully understand. This raises a number of questions for pharmaceutical leadership:
- Under the FDA’s new policies, will misdemeanor prosecutions of executives be limited to the most serious cases or will executives face criminal charges in cases without such aggravating conditions?
- Will the FDA adhere to its “prior notice” policy and seek criminal sanctions against a person only when a prior warning or other type of notice can be shown?
- Will the FDA afford executives an opportunity to be heard prior to referring matters to the Department of Justice?
One trend that is taking hold is the concept of continuous manufacturing. Continuous manufacturing equipment and process development have been simmering in the background for many years. Today the technology exists to make it a viable path forward for manufacturing. At the November 2010 AAPS meeting, FDA’s Christine Moore, Ph.D., Deputy Director for Science and Policy for CDER’s Office of New Drug Quality Assessment came right out and said the FDA is all for continuous manufacturing, because it is consistent with more modern manufacturing and consistent with the basic philosophy of ICH Q8. She stated that since manufacturing is continuous, it would be up to the manufacturer to define and defend its definition of a batch or lot. It could be based on time, manufacturing equipment cycles, raw material feedstock, etc., as long as it was defensible. Second, she indicated it would most likely require the additional application of chemometric modeling, e.g. multivariate analysis, as a surrogate for conventional sampling and testing offering up the Real Time Release Testing that has long been the promise of PAT. Finally she framed all this with the following statement “there are ‘no regulatory hurdles’ for industry to implement continuous practices,” she said, although providing a caveat: “There is a lack of experience [within and without FDA]; therefore we really need to work together as we move forward with these approaches. We recommend frequent and early conversations with our organization.” 2
Anyone who has been involved in a product program that employs the concepts of ICH Q8, Q9, or PAT knows the uncertainty and complexity associated with each regulatory and compliance decision made. Taking chances is a direct by-product of the FDA’s new risk based philosophy. I am sure that the FDA’s new, tougher position on non-conformance will send a message to industry and to Congress that it is ready, able, and equipped to regulate and protect the public. However, it is difficult to predict what impact the specter of criminal prosecution may have in terms of stifling innovation. There is no doubt the agency needs to prove it has the mettle to get the job done. The question is, at what cost?
- “FDA Recommends Increased Criminal Prosecutions of Responsible Corporate Officials; Important Questions Left Unanswered” Ropes and Gray, March 2010
- Thomas, P. “Continuous Manufacturing in Pharma: Beginning to Snowball?” Pharma QbD, www.pharmaqbd.com, Nov. 2010