As we reach the crossroad that is FDA’s NDI guidance, let’s take a trip down regulatory lane to see how we got here.
“Be careful what you wish for because you might get it.” For many in the dietary supplement industry, this old adage is apropos. After more than a decade of the industry asking for clarification of the new dietary ingredient (NDI) provisions of the law, FDA finally issued guidance in July 2011.
When Congress enacted the Dietary Supplement Health and Education Act (DSHEA) in 1994, the new law prescribed that when manufacturers bring new dietary ingredients to market, they must file notifications with FDA with evidence that the ingredients are reasonably expected to be safe. Existing ingredients already in the market before the passage of DSHEA were presumed to be safe unless FDA demonstrated otherwise.
In the ensuing years (until 2011), FDA did not provide any guidance to manufacturers on what needs to be provided to meet the agency’s expectation of safety. Seventeen years later, FDA has objected to over 450 of those notices, while only “acknowledging” (i.e., without objection) 162 notifications. Clearly, the agency’s understanding of the hurdles in the NDI notification process has been different from the industry’s.
Under this circumstance, the dietary supplement industry began pressing for a document from FDA to clarify the NDI notification requirements of the law. Finally, at the insistence of Congress, FDA issued draft NDI notification guidance in July 2011. Having reviewed it, almost everyone in the industry is unhappy. To many, it seems a case of déjà vu.
For decades, FDA has taken actions that either overtly attempt to impose premarket approval on dietary supplements or seem to be covert attempts to do so. In the early 1970s, FDA proposed to restrict the potency of vitamins and minerals in supplements to 150% of the Recommended Dietary Allowance (RDA); levels above that would automatically redefine a supplement as a drug and require the agency’s premarket approval. FDA ignored the fact that even some unfortified conventional foods can contain many multiples of the RDA for certain nutrients (e.g., vitamin B12 in liver) and thus be far more “potent” than the vitamin supplements it sought to regulate. Consumers and the industry resisted, and Congress passed Section 411 (Rogers-Proxmire Amendment) to the Food, Drug & Cosmetic Act (FDCA), which specifies that FDA may not classify a supplement as a drug solely on the basis of potency.
Thwarted in that effort to call supplements unapproved new drugs, FDA next attempted to classify dietary supplements as unapproved new food additives, thereby imposing on particular dietary ingredients the same requirements for premarket approval as applied to chemicals that were added to food for non-nutritive reasons. At its extreme, FDA argued that because gelatin is regulated as food, any type of food (e.g., blackcurrant oil) contained in a gelatin capsule is thereby a food additive. The court struck down this attempt, saying, “The only justification for this Alice-in-Wonderland approach is to allow the FDA to make an end-run around the statutory scheme...” Congress then passed DSHEA, which states that dietary supplements shall not be regulated as food additives.
More recently, FDA was the sole sponsor of an Institute of Medicine (IOM) project and report titled, “Dietary Supplements: A Framework for Evaluating Safety.” The draft report included a table with unflattering comparisons of the regulatory framework for supplements with those for drugs and food additives, which do require premarket approval. Somehow, the draft failed to note that certain conventional food ingredients (self-declared Generally Recognized as Safe, or GRAS) have no requirement for premarket approval by FDA. Eventually the final copy of this report did include the comparison of supplements to self-declared GRAS ingredients, as well as food additives and drugs, but the bias toward premarket approval for supplements within the agency was apparent and lives on.
With this historical background in mind, we will now examine the recent NDI notification draft guidance (“the Draft Guidance”) as demonstration of how FDA once again seeks “to make an end-run around the statutory scheme...” and obtain pre-market review over at least a large portion of dietary supplement ingredients.
Section 413 of the FDCA was added by DSHEA and created a requirement for NDI notification. This Section provides that a “new dietary ingredient” is “a dietary ingredient that was not marketed in the United States before October 15, 1994,” the date of enactment of DSHEA. It also provides that a dietary supplement that contains an NDI will not be deemed adulterated if it meets one of two conditions: the supplement contains only dietary ingredients which have been present in the food supply as articles used for food in a form in which the food has not been chemically altered, or the manufacturer has appropriate information that a supplement containing the NDI is reasonably expected to be safe.
In other words, even if the ingredient is new to a dietary supplement, if it was already used as an article of food in essentially the same form, the supplement is not adulterated on that basis. No notice to FDA is required in this circumstance. Alternatively, the supplement containing an NDI will not be considered adulterated if “[t]here is a history of use or other evidence of safety establishing that the dietary ingredient when used under the conditions recommended or suggested in the labeling of the dietary supplement will reasonably be expected to be safe.” In this case, the manufacturer or distributor must, at least 75 days before marketing the ingredient, provide FDA with “information, including any citation to published articles, which is the basis on which the manufacturer or distributor has concluded that a dietary supplement containing such dietary ingredient will reasonably be expected to be safe.”
And thus, the controversy began.
Soon after 1994, the supplement trade associations assembled “grandfathered” lists, attempting to preserve a snapshot of what ingredients had indeed been marketed prior to the enactment of DSHEA and thus were exempt from the NDI notification requirements. Admittedly, the associations did not accumulate independent evidence at the time, but they relied on the veracity of their memberships to recreate the pre-1994 marketplace. After all, the new statute did not specify that the burden of proving a particular ingredient was marketed pre-DSHEA would be placed on the industry any more than it placed the burden of proving an ingredient was not marketed pre-DSHEA on FDA. What evidence would be required to provide proof of presence in the market before DSHEA was passed?
The industry’s first clue of FDA’s interpretation occurred in 2006 when the agency declared that pyridoxamine was no longer a dietary ingredient under a separate provision of the FDCA (21 U.S.C. 321(ff)(3)(B)(ii)). The issue was whether pyridoxamine was marketed as a supplement prior to the filing of an investigational new drug application for its potential therapeutic uses. Interestingly, pyridoxamine occurs in the exact same chemical form in foods that have not been chemically modified. The Council for Responsible Nutrition (CRN) introduced its grandfathered list as evidence. FDA rejected the list and accompanying affidavit of CRN’s former president, saying that original documentation in the form of catalogs, sales receipts, or invoices was required. Now in the Draft Guidance, FDA has formalized that opinion stating it believes the burden lies solely on industry to prove an ingredient’s pre-1994 history, and objective forms of evidence are necessary.
The passage of time makes FDA’s viewpoint all the more problematic. In the intervening years since DSHEA was enacted, many company records have been destroyed or failed to make the conversion into readily searchable computerized records. Paper files, microfiche, and even film may be no longer accessible and would require manual search, page by page. Additionally, companies that have arisen in the post-DSHEA boom of the industry may not have any pre-1994 records, even for ingredients that have been in the marketplace for decades. One wonders, if such a company were to file an NDI notification for an ingredient, would that notification serve as evidence to FDA that the ingredient is “new” for other manufacturers, who if asked could produce old records demonstrating the ingredient’s long history of use?
This insistence by FDA on physical records can be explained by FDA’s dissatisfaction with the very concept of a “grandfathered” status altogether. Under that doctrine, FDA is charged with proving that pre-DSHEA ingredients are unsafe in order to remove them from the market, unlike most other regulatory categories that FDA oversees in which the manufacturer must bear the burden of proof of safety before getting products to market. By placing insurmountable burdens on the industry to prove this status, FDA can effectively shrink the universe of “grandfathered” ingredients and can thereby require manufacturers to seek NDI notifications on more ingredients. As will be seen later, if the NDI process for those now “new” ingredients can be elevated by Guidance to a premarket approval system, the agency will have made the end-run around the statutory scheme-at least for those ingredients.
FDA has also used the Draft Guidance to further convert still other “grandfathered” ingredients into “new” ones by declaring them to be “chemically altered.” Recall that the law exempts from the notification process ingredients which “have been present in the food supply as an article used for food in a form in which the food has not been chemically altered.” In the sparse official legislative history that accompanied DSHEA, Congress did not define “chemically altered” but instead offered specific examples of what is not included in the definition, stating “chemically altered does not include” the following physical modifications: minor loss of volatile components, dehydration, lyophilization, milling, tincture or solution in water, slurry, powder, or solid in suspension. However, FDA’s Draft Guidance now interprets that list as an exhaustive enumeration of the only manufacturing processes that do not result in chemical alteration, which is like saying that the statement “Good house pets do not include lions, tigers, and bears” is an assertion that all other animals should be considered domesticated.
More troubling than FDA’s literal misreading of the law are the implications that follow. FDA’s expansive reading of “chemically altered” means that many processes developed and employed since 1994 unwittingly have made longstanding ingredients into NDIs-in FDA’s view. For example, supercritical CO2 extraction, routinely used today for many botanicals, automatically results in a new dietary ingredient according to FDA, as do many other extracting agents. However, several of the permissible processes in Congress’s exempted list also result in an increased concentration of an ingredient; it follows that the resulting ingredient with higher concentration should not automatically be defined as “chemically altered.” Yet, the Draft Guidance would convert many innovations of ingredient refinement of the past 17 years into impediments to marketing because they would trigger the NDI burdens. Thus, FDA’s position can be explained as freezing manufacturing methods of existing ingredients in time in 1994. If FDA creates disincentives for innovation within the supplement industry, that will winnow the product development platform, constrict the application of new technology, and perform an end-run on the statute.
For decades, U.S. laws have regulated drugs on a product-specific basis, and food, including dietary supplements, on an ingredient basis. Following this U.S. precedent, a large proportion of countries, regional authorities such as the European Commission (EC) and the Association of South East Asian Nations (ASEAN), and the international Codex Alimentarius regulate supplements as a subcategory of foods and impose ingredient-specific (but not product-specific) requirements. Inline with that history, Section 413 of DSHEA specifies that new dietary ingredients-not new dietary supplement products-must reasonably be expected to be safe. Neither the law nor FDA’s 1997 regulation on NDI premarket notification (21 CFR 190.6) make any mention of premarket notification for a new dietary supplement product. Indeed, DSHEA’s only reference to a finished product in the context of NDIs concerns evaluating the safety of the ingredient under the conditions recommended or suggested in the labeling of the finished supplement; it does not imply that each product must be subject to review. As further evidence of the original understanding of the law, in 1997, FDA predicted the filing of about 12 NDI notifications annually, one for each of the 12 new ingredients it expected to enter the market each year.
However, in the Draft Guidance, FDA now takes a different view. The agency proclaims that each new product containing an NDI must have a separate notification. FDA has stated that it has received an average of 55 notifications per year over the last several years, but that falls far short of the number of dietary supplements products that it presumes to enter the market each year containing an NDI-and FDA wants an NDI notification for each one. Even if the product combines an NDI with a longstanding “grandfathered” ingredient, FDA wants the manufacturer to file a notification separate from the notice filed for the single ingredient. There is no statutory basis for this misinterpretation of Section 413, and it substantially raises the costs and burden of making even minor changes to product formulations that the dynamic supplement marketplace demands. In addition, it reassigns the burden of developing the safety dossier for new ingredients from the ingredient suppliers to the finished-product manufacturers on a product-by-product basis.
FDA’s attempt to apply the premarket notification for new dietary ingredients to most new dietary supplement products, however, is misguided and unnecessary, as well as beyond the law. In the years since DSHEA was enacted, the industry has enjoyed an enviable safety record, as illustrated by the comparatively low number of serious adverse event reports filed for these products, even among ones with NDIs in them.
Products with new combinations of ingredients do not create new ingredients subject to notification but only constitute new products. However, if FDA’s interpretation of this issue were to stand, then it will have achieved a product-by-product review of new dietary supplements, something inline with its regime for drugs-yet another end-run on DSHEA.
An Insurmountable Safety Standard
Perhaps the artful but thinly-veiled manner in which FDA has attempted to recharacterize so much of what is and isn’t a new dietary ingredient and therefore subject to NDI notification would not be so burdensome for the industry if the standard of review FDA proposes was not so onerous and was more closely aligned with what the statute envisioned. But alas, the scientific burdens FDA would inflict on manufacturers to demonstrate safety to FDA’s satisfaction are yet another example of an attempt to rewrite DSHEA. Indeed, if FDA’s course succeeds, the NDI notification process will look so indistinguishable from the food-additive review that Congress and the courts rejected in the early 1990s that FDA will achieve what it tried-and failed-to obtain long ago. The NDI notification will become a de facto food-additive evaluation.
To make this point, compare the following safety standards and corresponding evidence requirements:
As illustrated, the safety standards for food additives for removal from market are “reasonable certainty of no harm” for entry into the market and “may render injurious.” In comparison, the statutory safety standards for new dietary ingredients in dietary supplements is “reasonably expected to be safe” to enter the market and “significant or unreasonable risk of injury or illness” for removal. Clearly, the standards for food additives are more comprehensive, more demanding, and less accepting of risk than those for new dietary ingredients. Another disturbing aspect of the Draft Guidance is its repeated references to The Redbook as the authority for the various safety studies FDA would demand for NDIs. The Redbook, of course, is the official compilation of requirements for establishing the safety of food additives. If the food-additives standard is applied in NDI notifications, the data requirements would include tests for in vitro toxicity, short-term effects on animals, mutagenicity, teratogenicity, carcinogenicity, etc. Most of these tests are suitable for new food additives intended for use as preservatives, fungicides, etc., but are less appropriate for nutrients that are specifically ingested for their biological effects.
Recently, in the context of the Draft Guidance, FDA has referred to its ephedra decision in 2004 in which it utilized a risk-benefit analysis to demonstrate that the ingredient posed “a significant or unreasonable risk” to public health in removing it from the market. Agency personnel have even suggested that such an examination of the potential benefits of a dietary ingredient may need to be applied in the NDI notification to offset any perceived risks that may arise. In this assertion, FDA overlooks where the underlying burdens of proof must lie. Under DSHEA, even if the agency may employ a risk-benefit analysis to meets its burden to prove an ingredient is not safe and should be removed from the market, that analysis has no place, according to the FDCA, in the manufacturers’ burden of demonstrating a reasonable expectation of safety in order for an ingredient to enter the market.
The proposed premarket notification scheme contemplated by FDA would allow it to possibly request additional data, ad infinitum, before it makes a decision, re-setting the 75-day clock each time it seeks more information. Instead, if a company believes it has a reasonable expectation of safety, it is legally incumbent on FDA to agree-or disagree-and then allow the manufacturer to make the decision on whether to go to market, even over FDA’s objection. FDA is then free to pursue an enforcement action under the adulteration provisions if it finds evidence that the ingredient is unsafe. The views presented by FDA in the Draft Guidance distort the process and tilt the balance in its favor by imposing a de facto premarket authorization scheme.
The Draft Guidance on NDI notifications is an overreach that goes well beyond the law and practical need. First of all, the Draft Guidance employs a number of tactics to make as many “grandfathered” ingredients as possible into “new ingredients.” Then, FDA’s reinterpretation of DSHEA to apply requirements to dietary supplement products, rather than ingredients, is simply untenable. Once it has ensnared all these products into the NDI regimen, it would impose a standard for demonstrating safety that was designed for food additives, a standard Congress never intended for dietary supplement ingredients to meet. If FDA is able to impose these procedures on new dietary ingredients, it will finally succeed in its unrelenting attempts to impose drug-like premarket approval on a broad range of dietary supplements.