Is GRAS the cure for the high rate of NDI rejections?

George Burdock, PhD, president and founder of the Burdock Group, lays out the interplay between GRAS and NDI regulations and the level of safety data needed under current conditions to ensure a successful NDI notification.

For several years, Burdock Group has advised its clients wishing to submit a New Dietary Ingredient Notification (NDIN) that a generally recognized as safe (GRAS) determination and GRAS notification might be the optimal route for a subsequent trouble-free NDIN submission. Why?

Look at the numbers—in 2005, even after the NDIN process had been in place for a decade, the failure rate was nearly 70 percent. One would think that when a process had been around for that long, things would have stabilized—more notifications would succeed than would fail. In contrast, over an equivalent period of time, the GRAS failure rate has been fairly low, even counting the voluntary withdrawals.

How did this high rejection rate for NDINs happen? A review shows that those NDINs that successfully made it through the process mirrored the scientific rigor of a GRAS determination. DSHEA intended that NDIs should be held to lower threshold of scientific proof of safety, characterized as being a “reasonable expectation of no harm.”

This is a far cry from the standard for food ingredients (including GRAS ingredients), which is a “reasonable certainty of no harm.” However, FDA apparently sees these different standards as a distinction without a difference. FDA staffers have expressed frustration with a regulatory structure that allows ingredients to be on the market with different levels of safety.

But, it is not a matter of the safety of the substance, it is the degree of certainty of that safety. Congress has had experience in delineating different degrees of certainty. Prior to the 1958 Amendment to the Food Drug and Cosmetic Act, the standard of safety for a food ingredient was complete certainty and absolute harmlessness at any dose. Congress and the courts wisely set aside “complete” and “absolute” as a thresholds for the safety of food ingredients because they were both impractical and unachievable. They settled instead for the more pragmatic wording “reasonable certainty of no harm.”

Why Congress lowered the threshold for safety

So what’s the justification for requiring a lower threshold for evidence of safety for a supplement ingredient? The rationale lies in the idea that we have no choice when it comes to eating food, so food must have a presumption of safety. On the other hand, consuming a dietary supplement is voluntary. And because it’s voluntary, there is an assumption of some risk on the part of the consumer. Therefore, as Congress saw it, in order to get more ready access to dietary supplements, the consumer had to make three concessions:

  1. Dietary supplement consumption must always be a voluntary act and therefore supplement ingredients cannot be added to food (because of the lower threshold of evidence for safety for the supplement ingredient).
  2. Supplements must always be in a container clearly labeled as a supplement and not be presented as if it they are food.
  3. Dosing instructions must be on the label (including recommended daily dose and any restrictions such as for adults or not for women of child bearing age).

In exchange for these tacit concessions, Congress lowered the evidence threshold for safety (not the safety threshold) and abandoned the pre-market approval concept.

But even with the clearly discernible lower threshold for evidentiary support of safety, rejection of NDINs has been high. In many cases this is not without justification. Some notifications are rejected for not meeting the evidence standard, making it clear that some submitters have little experience in constructing a persuasive scientific argument for safety. Others have been rejected for purely administrative mistakes, such as lack of proper label information for dose/supplement consumption, improper or inadequate description of the ingredient (whether a chemical or botanical source), un-translated foreign language documentation, statements considered drug claims, and the like.

Reasons for high NDIN rejection rate

The root of the problem is two-fold.

First, FDA set the bar too high. It may have done so as the result of the law that allows inexperienced persons to make the declaration of safety. Some large dietary supplement ingredient manufacturers have the same degree of resources as food companies and have qualified personnel who can make a safety determination. But most of these companies lack those resources, so the declaration of safety is left to inexperienced, under-qualified people.

If the law had stipulated a process similar to the GRAS process, in which a submitting company must assemble a panel to assess the data, a panel made up of “experts qualified by scientific training and experience to evaluate its safety,” the situation might be different today.

Second, FDA failed to supply guidelines as how to manage the process (such as indicating that all scientific information has been considered and inclusion of a discussion of all information, both affirmative and conflicting). It is apparent that experienced help could have avoided many of the problems associated with administrative errors and many issues associated with lack of a cogent argument for safety.

Submitting a successful NDIN

We believe that for any successful NDIN, the petitioner must meet the “burden of proof” as well as the “burden of persuasion.” The burden of proof involves a thorough discussion of all of the evidence supporting safety—direct, indirect and antithetical—and the evidence must be relevant, not anecdotal, conjectural or speculative.

Further, because no clear guidelines have been provided regarding what is required to demonstrate the “reasonable expectation” of no harm, there remains a great deal of subjectivity in the approval process and we believe that more than one NDIN has been rejected because of this subjectivity.

Therefore, because the facts cannot always speak for themselves, a successful NDIN must also meet the burden of persuasion by telling a good story about the safety data, building what we at the Burdock Group call a “theory of approvability,” giving FDA a margin of comfort.

George Burdock, PhD, is president and founder of Burdock Group.

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