The value of playing it safe

Better science improves the likelihood of success in the markplace, whether for a dietary supplements ingredient or a food ingredient. Jim Griffiths, PhD, posits that ?GRAS is greener? because it avoids the pitfalls of the ?reasonable certainty? safety standard

The Dietary Supplement Health and Education Act of 1994 established mandatory safety requirements for dietary supplements; however, a distinction was made between dietary ingredients marketed prior to Oct 15, 1994 (?grandfathered?) and anything since (a new dietary ingredient, or NDI).

For NDIs, the Food and Drug Administration requires the manufacturer and/or marketer to notify the agency 75 days prior to the introduction of the ingredient with sufficient data to substantiate its safety. The specific language used to describe this level of safety was deliberately different from the language the agency uses for food ingredients.

DSHEA was intended to give the consumer the ability to purchase dietary supplements, for whatever perceived benefit the consumer wished to derive. Congress, in enacting DSHEA, required the consumer assume some responsibility for his or her own safety by maintaining proper use and dosage regimen of the NDI. In exchange, the manufacturer and/or marketer was obliged with a less-onerous safety data standard, codified as ?reasonable expectation of safety?,1 ie, when consumed according to label directions, the NDI will reasonably be expected to be safe.

On the other hand, ingredients added to food, whether via the rigorous FDA food additive petition processes or via GRAS determination, must be demonstrated at a higher safety standard, the ?reasonable certainty of no harm? standard.2

However, it appears from recent FDA actions that reasonable expectation vs reasonable certainty is a ?distinction without a difference? and because all substances offered for consumption must be safe, all substances must, in principle, meet the same standard.

This position contradicts the FDA?s past actions; the best example of which is the sweetener stevia. The FDA has held that current safety information does not support food ingredients use, but stevia is permitted by the FDA as a dietary supplement — this action is an obvious nod to the two-tiered standard of safety.

However, reasonable expectation does not end with the two-tiered standard; there is also a difference in the degree of rigor with which safety is demonstrated. The demonstration of safety of a food ingredient (a food additive or GRAS substance) is often quite voluminous in terms of testing and data interpretation because a food ingredient must have no risk at its intended intake levels.

On the other hand, demonstration of the safety of NDIs usually requires less mandatory supporting data and greater latitude in data interpretation. Clearly, while Congress has always held the safety of the public as a primary concern, Congress intended that the FDA use a more flexible, less stringent standard for its assessment of the safety of NDIs than that which it uses for food additives (including GRAS substances).

The theory by which Congress supported this rationale is that the consumer can choose to take a dietary supplement based on his or her belief that it will fulfil a perceived benefit. The choice to take dietary supplements allows reasoned judgment to consume, and therefore assumption of some risk. This choice is in contrast to a food ingredient, which is added by a manufacturer, and the consumer has, theoretically, no choice in the consumption of a substance that has become a part of the food. The volunteerism of consumption in foods is subject to some choice, however, as the result of the ingredients statement on the label; for example, if the consumer does not want to ingest preservatives or artificial sweeteners, he or she can always purchase another brand.

The NDI ?success? story
Between October 1994 and June 2003, 238 NDI submissions were submitted to the FDA?s Office of Nutritional Products, Labeling and Dietary Supplements. It has been shown that 59 per cent were rejected and the rejection rate for botanicals was higher still at 70 per cent. The FDA has cited several reasons for objecting to these submissions, including: mismatches between the marketed and tested ingredient; use of therapeutic language, ie, ingredient is represented for mitigation of a disease state; use of food language, ie, ingredient is represented as a traditional food; clinical studies have been done via nonoral routes; and lack of sufficient safety data.

The FDA does not provide a concise list of sufficient safety data it would find to be persuasive, it only indicates that safety must be demonstrated to the ?reasonable expectation? of no harm standard.

However, the extraordinarily high ?objection? rate is a form of paternalism and abrogates the bargain with the public; namely, a lower standard of safety for an assumption of risk. This is not to say that some ?objections? are not well founded; some new dietary ingredients notifications have rightfully been faulted, as the submitter has the misguided assumption that a lower safety standard means no safety standard.

The core of the issue is simply that the regulatory agency equates ?expectation? to ?certainty,? and thus negating or at least diminishing the distinction between the two standards of safety. The agency ?expects? the NDI notifier to be ?certain? of the safety of the ingredient, and this mindset is not likely to change. The agency must err on the side of conservative safety, as recent escapades with legend drugs, such as Vioxx and Celebrex, as well as adverse effects and publicity on kava kava and ephedra, lessen the chances that the FDA will cede more safety decisions to the general public.

Further validating the FDA?s fears is the fact dietary supplements seem to be natural magnets for consumers with the philosophy that ?if one is good, two are really good and a handful must be even better.?

Therefore, for all intents and purposes, the agency view is that ?expectation? equals ?certainty,? and a safety package submitted to the less data-intensive, less-onerous DSHEA standard is likely to be just a coin-toss on approval.

Go the extra mile
One proposal that would put control of the safety process, and in reality, the ultimate decision back into the hands of the supplements manufacturer or marketer would be to ?opt out? of the DSHEA program and review the new dietary ingredient to the level of a food ingredient through a GRAS determination. This route adds an increase in time and expense to prepare a safety dossier to the ?reasonable certainty? safety standard, and does involve high-powered and highly visible external ?experts.? The GRAS route does, however, remove the highly visible ?red flag? and potentially bad publicity from a denied DSHEA 75-day notice, and the time and cost for resubmissions when attempting to ameliorate the agency?s rejections.

The manufacturer and/or marketer can orchestrate the GRAS process, often through an experienced consulting group, in developing the safety dossier, and relating the expected consumption (exposure) to the available safety data. If there is insufficient safety data, the manufacturer and/or marketer can develop the appropriate toxicology data. While development of this data is potentially expensive, a method for maintaining its proprietary nature is often possible via tight production specifications and proprietary manufacturing processes.

A GRAS dossier is usually developed spelling out the technical or functional effect; however, for a dietary supplement for which physiological efficacy would be an inappropriate technical effect, a use stating simply that the proposed GRAS ingredient is solely for those seeking to add more of that ingredient to their diet has been a successful strategy for several manufacturers.

Another immediate benefit to subjecting a dietary supplements ingredient to the GRAS process is that when successfully accomplished, the supplements ingredient is also available for inclusion in food products. This makes transition from the supplements aisle to the grocery aisle seamless.

Further, this shifting of the burden of decision making outside the agency relieves the FDA of interpreting which safety standard to apply, and more effectively addresses the manufacturer?s and/or marketer?s concerns that the threshold for their product safety — ?due diligence? — has been met.

Although undertaking extra work and expense is usually not justified in a highly competitive free-market economy, there is a time, and perhaps this is one instance, when absorbing these costs may yield the expected benefit of not becoming one of the 59 per cent unsuccessful NDI notifications, but being one of the many successful GRAS ingredients being used in the supplements and food industries. Time-to-market may actually be cheaper and quicker by avoiding the flawed ?express lane.?

Jim Griffiths, PhD, DABT, Cbiol, FIBiol, is director of toxicology at the Burdock Group, a regulatory, safety and efficacy consultancy based in Florida and Washington, DC. Respond: [email protected] All correspondence will be forwarded to the author.

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