By: Johnel Lagabon and George A. Burdock, Ph.D.
In the process of compiling a GRAS dossier, often so much emphasis is placed on showcasing the safety data that communicating the rationale behind the conclusion of safety becomes an afterthought. This lack of a convincing rationale can have disastrous results, ranging from prolonged review times by regulators to a request for conduct of additional studies to “tie up loose ends” or one more study to respond to a rhetorical hypothesis that a logical presentation would have made unnecessary. At Burdock Group, we believe that a GRAS dossier should be a narrative of safe use that not only has the requisite scientific data to support safe use but also communicates the logic of the findings effectively. In other words, you must not only meet the Burden of Proof (i.e., the rigor of the data supporting the safety of the substance), but, equally important (and often forgotten), the Burden of Persuasion (i.e., effectively communicating the logic of your conclusion).
Multiple Priorities, One Dossier: Address Everyone’s Concerns
To meet the Burden of Persuasion, it is important to consider the priorities and perspectives of your audiences, as it will allow you to address their concerns. In the case of a GRAS, the audiences include industry professionals, Expert Panelists, regulators and even an interested public (once your GRAS notification is finally posted on the FDA website). But threading the needle to address all these audiences with a single document, requires agility focus and, while each GRAS dossier is different, each in the audience will have its own priority when reviewing a dossier. For example, industry professionals are most impressed with the pragmatism of the type of studies performed and how these studies address gaps in the literature. Expert Panelists prioritize the rigor of the science; that is, that the scientific studies were carried out in a well-controlled manner, the studies are reproducible and the concept and outcome of each study fits together like a jigsaw puzzle to tell the story of the safety of the substance. On the other hand, Regulators are concerned with addressing the key elements of a GRAS and, ensuring your scientific conclusions are consistent with mainstream science or an explanation of why not? For the lay public, the dossier cannot be over-laden with jargon or impossible to understand technical narratives, and while the layperson will accommodate some technical terms as needed, overuse will be seen as deliberate and sinister obfuscation of “right to know” information. The bottom line is that understanding a person’s expectations and priorities is arguably the most important part of writing a GRAS. At the end of the day, there is but one dossier and it must address the priorities of each audience, without unnecessarily going over the head of one nor condescending to another. To meet the Burden of Persuasion, you must address everyone’s concerns in a logical, concise, even-handed manner without overly technical terms or blather.
Simple Explanations for Complex concepts are Most effective but Require a Unique Set of Skills
The purpose of a GRAS is to show that an ingredient is safe for its intended use. While this sounds simple, the concepts necessary to explain why an ingredient is safe can be complex and difficult to follow. To address this dilemma, the dossier author must ensure that the logic behind the evidence used to support safe use is communicated in a manner that is clear, dispositive and most of all – understandable. The goal when describing the supporting evidence must have a logic that is understood by all parties. Ironically, simplifying complex concepts can be anything but simple. Albert Einstein once remarked, “If you can’t explain it simply, you don’t understand it well enough”. In the case of GRAS, it is necessary not only have the scientific qualifications in the field of Toxicology to comprehend and understand the data, but also have the experience to successfully communicate the safety of a substance. In understandable terms, the writer of the GRAS must think as both a translator and a teacher, translating the meaning the science and breaking the concepts into more easily understood logic. Ultimately, the GRAS must be a self-explanatory, stand-alone document.
In a perfect world, the author of a GRAS would have both the scientific background and relevant experience in communication to multiple audiences however, there are very few individuals with such backgrounds, creating a dilemma.1 Because of this dilemma, many dossiers are written by unqualified individuals and/or are written by multiple individuals that stitch together a narrative like Dr. Frankenstein with his monster. While it is difficult for unqualified individuals to find consistent success with GRAS, the latter team-based approach can sometimes find success, due to the shared expertise of multiple contributors. However, having separate contributors with differing sets of expertise can sometimes lead to large gaps in the logic resulting in a serious miscommunication. Therefore, in order to most effectively communicate and provide a solid explanation of the complex concepts, it is important to work with individuals with the right combination of the scientific expertise, regulatory experience and communication skills.
Credibility Gains the Trust of the Reviewer
Because the concept of GRAS is not well understood by the public i.e., food regulation via “qualified experts”2 and that suspect abuses of the concept, there are many who are distrustful of GRAS as they feel that the process allows too much room for unscrupulous individuals to wrongfully claim an ingredient as “Generally Recognized as Safe” for the sake of personal or professional gain. Unfortunately, there is some element of truth in this perception and there are a few bad actors who take advantage of this system. Because of this frangible trust, it is important to maintain the trust of the reviewer by protecting the credibility of the argument and the process. One way to add credibility to the dossier is to conduct internal peer review where a qualified colleague will review the logic of the argument and identify flaws that need to be examined. In this way, the peer review process accounts for the natural bias of an individual toward their own conclusions and adds another level of credibility to the dossier.
Furthermore, while the purpose of a GRAS is to show safety of an ingredient by showing supporting scientific literature and a commitment by the dossier author of his/her belief in the safety hypothesis by avoiding passive voice or “weasel words”. The audience will realize that you will have inherent interest to support your hypothesis of safe use, but showing blatant favor compromises your credibility. Further, it is important not to dismiss antithetical findings out-of-hand, with rancor or as irrelevant, but to address them as you would a friend with a bad idea.
Facts do not speak for themselves; they are tools used to communicate ideas. In order to have a successful GRAS dossier, you cannot rely solely on scientific data, you must create a narrative of safe use that communicates the logic of safe use effectively. It is only in this way that one can meet both the Burden of Proof and the Burden of Persuasion – something we do at Burdock Group on a daily basis.
Society of Toxicology
Federal Register (2016) Substances Generally Recognized as Safe, I. A. History of FDA’s Approach to the GRAS Provision of the FD&C Act.