Are You Going to the Guidance?

The FDA’s Center for Veterinary Medicine (CVM) recently published its list of “Guidances Under Development for 2014.” When I read descriptions of the 32 pending guidances, I wondered how CVM decided when a new guidance was needed. I then realized that, although I had been following FDA guidances for 30+ years, first on the human and now on the veterinary side, I knew little about the FDA’s history, the development of its regulations, or what prompts the issuance of a new guidance. Dr. Susanne Junod’s 2013 publication, “FDA and Clinical Drug Trials: A Short History” was very helpful.

The story starts in 1938 with passage of the Food, Drug, and Cosmetic Act (FDCA) which created basic regulations but little development guidance. In 1962, the Drug Amendments to the FDCA were passed, but they also lacked specific guidelines. Then, when the FDA was charged with evaluating the efficacy of all drugs approved before 1962, many were deemed less than acceptable. This called for additional regulation and specific standards for new product development.

During the 1970s, the FDA issued an array of regulations aimed at improving pharmaceutical efficacy. Unfortunately, many of these new rules were ambiguous or inconsistent with other regulations. Sponsors often felt obligated to contact the FDA for interpretations of the regulations before investing too many resources in a new product. The demand for such regulatory clarification soon became onerous for the FDA.

In September 1975, the Federal Register published a statement noting that the “present administrative practices and procedures of the Food and Drug Administration are largely uncodified…(and many) of these practices and procedures have been developed over the years on an ad hoc basis…without systematically integrating them into the agency’s overall practices and procedures… (and many) of the agency’s practices and procedures have not been written down in any… regulation.” The Commissioner of Food and Drugs recommended a (thorough review) of agency practices and procedures to “codify existing requirements, establish new requirements… and conform present regulations so that practices and procedures will be applied consistently throughout the agency.” (40 Federal Register 40682, 40682- 83, 1975)

But how were these new codes communicated? Initially, the FDA presented them at various industry conferences which was not the most effective method. For example, if a company’s executives did not attend a particular conference, they might not learn about new guidelines discussed at that gathering. Moreover, the fact that these early documents merely reported the FDA’s non-binding interpretations of various regulations further clouded the regulatory landscape.

The issue came to a head in 1995, when an industry trade group filed a Citizen Petition requesting that the FDA “control the initiation, development, and issuance of guidance documents by written procedures that assure the appropriate level of meaningful public participation.” This petition eventually led to a Congressional Oversight Committee hearing on FDA enforcement standards. In 1997, the FDA Modernization Act was passed which required the FDA to publish a regulation specifying its policies and procedures for the development, issuance, and use of guidance documents. The resulting Good Guidance Practices (GGP) regulation did not eliminate all of the uncertainty surrounding many FDA regulations but it did point toward greater clarity in the future.

A “guidance document” may relate to (a) the processing, content, or approval of new product submissions, (b) the design, production, or testing of a regulated product, (c) the agency’s policy on or regulatory approach to an issue, or (d) inspection procedures or enforcement policies. Guidance documents may be directed at sponsors, FDA staff, or the public. There are two “levels” of guidance documents: Level 1 documents are directed at sponsors and Level 2 documents are directed at all other audiences.

I asked Stephen Sundlof, DVM, PhD, who was director of CVM in 1994-2008, how a new guidance, like the ones currently under development for 2014, is created. He explained that, if several entities request clarification of a particular matter, the FDA will often issue a guidance document. However, a guidance document is not the same as a regulation, and it does not bind the FDA to a particular position. It merely gives the FDA’s “current thinking” on the issue. Dr. Sundlof noted, though, that most regulated entities strive to follow guidances because they believe such adherence to be in their longterm interest.

Since the FDA solicits public input during the guidance development process, it is in the industry’s long-term interest to actively participate. If everyone contributes to the 32 guidances under development for this year, the regulatory picture will brighten even further.

Acknowledgment. I thank Stephen Sundlof, DVM, PhD, Senior Vice President for Regulatory Affairs at Kindred Biosciences, Inc., for his generous personal insights.