Issue link: https://www.e-digitaleditions.com/i/845331
32D July 2017 Tablets & Capsules The FDA does allow a confidential NDI master file, which is similar to what is sometimes included in a new drug application. The master file should contain an ingre- dient's "manufacturing, specifications, and other identity information," which a company can authorize others to reference in their notifications. When filing an NDI, an OLD should ask its manufacturer for the master file to save time and money on safety research. Action on NDINs The FDA's 2016 NDI draft Guidance states that 5,560 new dietary supplements enter the market every year and that more than 55,660 dietary supplements are on the market. Considering that only 4,000 dietary supplements were on the market in 1994, it's odd that the FDA has evaluated only 750 NDIs as of December 2014. Since a goal of the draft Guidance "is to improve the rate of com- pliance with the NDI notification requirement," the Agency may begin by looking for manufacturers who should have filed NDINs [2]. In fact, in March 2016, the FDA sent warning letters to companies that used Acacia rigidula leaves or bark in their dietary supplement prod- ucts. See the sidebar. According to Couch, bigger manufacturers are filing now. Manufacturers with smaller staffs and fewer resources could have some difficulties filing NDINs, as they often require years of study development, literature reviews, and tens of thousands of dollars. Even when a company has thoroughly prepared, the FDA may ask for more evidence of an ingredient's safety. The American Herbal Products Association reports that from November 2015 to October 2016 the FDA had no comments on only 25 percent of the NDINs it reviewed [4]. The GRAS alternative Designating an ingredient as Generally Recognized as Safe (GRAS) is another way manufacturers can demon- strate the safety of ingredients used in dietary ingredients. Often, these are ingredients widely used in conventional foods. If a company can obtain GRAS designation for an ingredient, that ingredient can also be used in dietary sup- plements as long as it isn't further chemically altered. The steps required to gain GRAS designation are simi- lar to those of an NDIN and the process costs about the same. GRAS has also been on the books longer, so more people understand the submission process. The draft Guidance and GRAS guidelines differ slightly, however, in how they address safety. The Guidance requires evi- dence that an ingredient have a "reasonable expectation of safety" under the proposed conditions of use of the dietary supplement, whereas GRAS requires proof of a "reasonable certainty that no harm will result" from the proposed use. The difference could make it easier for manufacturers to use the GRAS approach to get their ingredients or products on the market [2, 5]. The only drawback to the GRAS route is speed. Under GRAS, the FDA has 180 days to respond, while the NDIN approach requires a response within 75 days. Regardless of whether you submit an NDI or GRAS notification, the process is challenging, and whether you succeed depends largely on citing studies that show a rea- sonable expectation of safety under conditions of use and/or the recommendations on the product's label. Impact on innovation During the comment period for the August 2016 draft Guidance, many manufacturers and other stakeholders expressed concerns about the broad definition of NDIs and the impact it would have on the industry. Dan Fabricant, chief executive officer and executive director of the Natural Products Association, said that the draft Guidance creates an economic burden that "could harm small businesses and create a chilling effect on innova- tion, and lead to fewer submissions from legitimate firms, while encouraging fly-by-night companies to operate through NDI 'piggybacking' until they are caught" [6]. Considering that it took 5 years for the Agency to pub- lish a revised draft, it may be a while before a Guidance on NDIs is finalized. Until then, dietary supplement manufacturers should exercise caution. T&C Case study: Acacia rigidula warning letters In March 2016, the FDA sent six warning letters to dietary supplement manufacturers about their use of Acacia rigidula leaves or bark as a dietary supplement ingredient [1]. Extracts of A. rigidula are purported to have weight-loss benefits. The FDA letters said that there was no evidence that A. rigidula had been used as a dietary supplement before 1994, no evidence of its presence in the food supply, no history that suggested a likelihood of safety, and no NDI submissions by the manufacturers. Thus, it deemed products containing the ingredient adulterated and told the manufacturers to cease distribution of the products. They were also told to inform the FDA within 15 days of receiving the letters what they planned to do about the products on the market. The letters also stated that the Agency was concerned that A. rigidula contained amphetamine-like substances and cited the FDA's analysis of 21 dietary supplement samples, which showed that nine had been spiked with a synthetic compound, beta-methylphenethylamime (BMPEA). In 2015, the FDA sent warning letters to man- ufacturers that listed BMPEA as an active ingredient in their products [2]. References 1. Acacia Rigula in Dietary Supplements. FDA, March 2016. Online. Accessed May 3, 2017. 2. BMPEA in Dietary Supplements. FDA, April 2015. Online. Accessed May 3, 2017.