Regulatory Comments to Docket Number FDA-2011-D-0376; Draft Guidance for Industry: “Dietary Supplements: New Dietary Ingredient Notifications and Related Issues”; 81 Federal Register 53486-53490 (12 August 2016).
Background:
The Dietary Supplement Health and Education Act of 1994 granted FDA the authority to develop a premarket gate for any new dietary ingredients that came to the market after October 15, 1994. Any dietary ingredients that were already sold in interstate commerce would be grandfathered and not subject to the NDI provision in DSHEA. Any dietary ingredients sold after October 15, 1994 would be considered a “new” dietary ingredient as it was never before in commerce. Manufacturers and distributors must submit a New Dietary Ingredient dossier to FDA which contains the basis for reasonable expectation of safety. FDA did not submit guidance on new dietary ingredients to provide greater clarity to the industry and answer their questions until July 2011. It was not until the Food Safety Modernization Act (FSMA), signed into law January 4, 2011, required FDA to issue draft guidance to industry on this topic within the first 180 days that the NDI draft guidance became a reality. Backlash from the first NDI Draft guidance resulted in FDA delaying the NDI guidance re-draft for five more years. The NDI guidance re-draft was submitted by FDA in August 2016. NPA drafted comments to extend the deadline for the NDI guidance re-draft, and this was accepted by the agency. This allowed NPA time to draft a 98-page rebuttal to their 102-page guidance document.
Issue:
The NDI dossier should contain identity and safety information unique to a company’s dietary ingredient. FDA’s reliance on Generally Recognized as Safe (GRAS) status to enable NDI’s to be used in dietary supplement products with different safety standards applying has contributed toward the blurring of this statutory wall Congress had intended between conventional foods and dietary supplements. Whether NDI or GRAS, substances added to foods must be “safe,” but an important consideration centers on the different safety standards that apply for new dietary ingredients and GRAS substances. The “lesser” safety standard where the NDI does not present a significant or unreasonable risk of illness or injury applies for the components in dietary supplements, but food additives and GRAS substances must meet the “higher” statutory standard of reasonable certainty of no harm under the intended use conditions. FDA has offered little in the way of making a distinction between these two safety standards. FDA’s July 2011 NDI draft guidance, followed by the agency’s announcement in December 2014 to include dietary ingredients and supplements in the FDA Redbook, a guidebook historically used to evaluate safety of food and color additives, and finally the release of the latest revised NDI draft guidance in August 2016 only perpetuates the industry belief that FDA would evaluate NDI’s under the lens of food additives and GRAS substances.
- FDA continues to blur the distinction between dietary supplements and conventional food ingredients in their testing recommendations.
- FDA should rewrite the toxicology sections in the revised guidance and not link NDI safety to food additive testing protocols and study designs in the Redbook.
- FDA should avoid referencing testing protocols and study designs created for food and color additives in NDI draft guidance.
- FDA’s suggested toxicological assessments in the NDI re-draft are akin to the OFAS Redbook to address safety guidelines for food additives.
- FDA should accept NPA’s safe harbor list of pre-DSHEA ingredients.
- FDA should not require product-specific submissions.
- FDA should acknowledge live microbials used in foods and in food fermentation as grandfathered, pre-DSHEA dietary ingredients not requiring an NDI notification.
- NPA recommends a decision tree for grandfathering live microbial ingredients.
- FDA should clarify the status of microbial ingredients as dietary ingredients and evaluate them on a case-by-case basis.
o Identity of the culture media and fermentation process is not germane to discussion of live microbial ingredient safety in an NDI notification. - FDA’s guidance re-draft contradicts itself on the topic of esterification.
- FDA’s reliance on a list of processes that do not lead to a chemically altered ingredient from the Congressional Statement of Agreement is not reasonable.
- FDA’s attempt to treat synthetic copies of botanical constituents differently from other ingredients has no basis in the law and is unreasonable.
- FDA’s interpretation of 201(ff)(1)(E) imposes unreasonable regulatory barriers to bring novel dietary ingredients to market.
- FDA should open a comment period for developing an illustrative list of processes that do not lead to a new “chemically altered entity
- The draft guidance should provide criteria for identifying a “chemically altered” ingredient.
- FDA should reevaluate the status of synthetic constituents of botanicals as dietary ingredients.
- FDA should adopt the term “dietary substance” as established in case law.
- FDA has held the position that there is no difference between natural and artificial ingredients in terms of safety.
- Vinpocetine fits under 201(ff)(1)(E) and (F) of the FFDCA as a synthetic copy of a botanical constituent.
- Background on Vinpocetine
- Regulatory Status of Vinpocetine in the U.S.
- Vinpocetine Fits Under 201(ff)(1)(F) in Addition to 201(ff)(1)(E) of the FFDCA.
- FDA Wrote “NDL” Letters in Response to NDI Notifications for Other Ingredients in 1999
- NPA Supports that Vinpocetine is Lawfully Marketed in the U.S. and Possesses Sufficient Historical Use.
- FDA’s Decision to Tentatively Conclude Vinpocetine is Not a Dietary Ingredient is Inconsistent with the Statute.
- FDA has no statutory authority to re-evaluate vinpocetine’s regulatory status as a dietary ingredient through an administrative proceeding after it has been acknowledged without comment.
- FDA Failed to Submit an Economic Impact Analysis to the Office of Management and Budget Regarding this Cost to the Industry and Regulatory Alternatives
- NPA applauds FDA’s decision to allow a company to reference the safety information provided in a previously submitted notification through the allowance of an NDI Master File.
- FDA should provide a separate guidance on what is required when submitting a NDI Master File.
- Evidence for marketing of a dietary ingredient pre-DSHEA should include any “dietary substance” as outlined in 201(ff)(1)(E) case law discussed previously and include ingredients used in foreign countries.
- FDA should reevaluate the status of synthetic constituents as dietary ingredients.
- FDA should clarify the NDI filing implications of ingredient activity as opposed to concentration.
- FDA should clarify the 75-day review period.
- FDA should clarify what constitutes investigation as a new drug.
- FDA needs to submit an impact analysis of both their capacity to handle an influx of NDI notifications and the significant economic cost burden to industry based upon the ramifications contained in this revised draft guidance.
- FDA should take measures to protect intellectual property and prevent “piggybacking” while exercising enforcement discretion to remove NDIs posing a safety concern.
Action:
The current NDI guidance re-draft requires an entire rewrite as there are many problems with the document.
