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Enforcement, IP protection keys to FDA innovation push

Many submitted public comments implored FDA to hold new dietary ingredient scofflaws accountable and to implement a confidential master file system.

The recent FDA meeting on innovation in dietary supplements highlighted potential tools to incentivize compliance with new dietary ingredient notification (NDIN) requirements and support development of novel ingredients and products, such as allowing master files and tweaking the interpretation of what qualifies as a “dietary ingredient.” But the industry has strongly advised the agency that any such tools would be pointless if enforcement remains lax and inconsistent.

“New tools and mechanisms will not result in significant change to the regulatory landscape without more rigorous enforcement,” warned the Council for Responsible Nutrition (CRN), in its submitted comments.

The agency’s May 16 public meeting on dietary supplement innovation was announced in an April 11 Federal Register notice that requested public comments through July 15.

“We understand that the public meeting and added comment period are part of the agency’s strategy to promulgate a final NDI guidance,” said the Natural Products Association (NPA), in its comments to FDA.

Thus, submitted comments from dietary supplement trade associations and prominent companies advised FDA to use its existing authority to enforce NDIN regulations and to include a master file as an option for such notifications to help protect intellectual property (IP) and foster innovation. Other key suggestions included suggested tweaks to FDA’s drug exclusion clause—a hot topic in this CBD-crazed market—and broadening of its application of the statutory definition of “dietary ingredient,” including for synthetic copies of botanical ingredients.

Act of Congress not needed

By far, the most common theme from industry comments was for FDA to establish a sound NDI enforcement plan to address low compliance trends.

“While much discussion has centered on asking Congress for new authorities, which is inconsistent with the present administration’s goals, where there is a commitment to remove two regulations with every one that is added, nothing that has been presented from the agency’s behalf has clearly demonstrated the metrics of compliance and where the actual gaps are regarding compliance,” posited Daniel Fabricant, Ph.D., president and CEO of the Natural Products Association (NPA), in submitted comments.

“There is a clear lack of meaningful and effective enforcement over NDIs,” wrote Najli Guthrie, president and CEO of KGK Science Inc., in the company’s submitted comments. “The industry perceives that there are no consequences for failure to comply with the NDI provision.”

Fabricant noted the always resource-challenged agency hasn’t publicly identified the tools that foster effective, but efficient, enforcement and oversight of NDI compliance.

A cyber warning letter program was recommended in KGK’s comments.

“There is no reason why FDA could not cast a wide net to noncompliant firms, by issuing untitled warning letters as part of an NDI blitz, based upon failure to demonstrate reasonable expectation of safety for dietary ingredients the agency believes to be ‘new’ or never sold in commerce prior to October 15, 1994,” Guthrie wrote. “KGK Science believes a similar untitled letter/cyber warning letter program could be adapted to identify ingredients the agency has determined to be new dietary ingredients.”

Both KGK and NPA suggested FDA consider the use of import bulletins and alerts to address non-compliance from foreign products.

 These measures “would signal a very serious message to the industry on adherence to federal statutory requirements,” Guthrie wrote.

In NPA’s comments, Fabricant asked ”if there is no enforcement against foreign NDI products that at a minimum have not presented their specifications to the FDA, why would a domestic firm ever see the NDI gate as a real priority to the agency?”

He noted some FDA personnel have said such imports are”technical adulteration” but not a priority, yet the agency issued such alerts for both androstenedione and kratom over technical adulteration and NDI non-compliance.

Master files for IP protection

A resounding complaint from industry submitters was over FDA’s lack of IP protection for innovative dietary supplement companies.

“Lack of IP protection has led some firms to use alternative safety review mechanisms not specifically designed for NDIs, such as the GRAS self-determination approach,” CRN wrote. “This approach addresses safety of new ingredients but does not require disclosure of intellectual property or proprietary data.”

FDA teased the use of a confidential master file in its 2016 draft guidance on NDIs but sought more input on the idea during its public innovation meeting.

In comments submitted for the innovation request, industry largely backed the concept of a master file for NDINs to foster innovation that would otherwise be unprotected.

“As described previously by CRN and others, the [master file] can house ingredient-specific confidential information and/or safety data, and can be used or cited (with permission) by subsequent notifiers,” CRN commented, noting the tool would streamline the collection and protection of data investments made by ingredient manufacturers. “Each [master file] should receive a unique file number and description, the contents of which should be protected as trade secrets.”

“Health Canada’s Natural and Nonprescription Health Products Directorate (NNHPD) uses a [master file] system as well to protect proprietary information,” said KGK Science Inc., in its submitted comments. “FDA should also require the listing of NDI notification numbers on the label similar to how Canada does with Natural Product Numbers (NPNs).”

In its submitted comments, the American Herbal Products Association (AHPA) stressed the importance of assurances from FDA that it would consider the data in such master files as protected trade secrets to be undisclosed except for as directed by the original NDIN submitter (via licensing, for instance).

However, AHPA recommended FDA issue a targeted guidance to establish a master file system for NDINs. It suggested two other key areas ripe for such targeted guidance include areas of common non-compliance, such as ingredient identification and broad conditions of use.

AHPA’s comments, composed by its president Michael McGuffin and its general counsel Will Woodlee, noted other industry trade associations have promoted the idea of targeted guidance for non-controversial issues, rather than areas of legal interpretation.

Expand agency’s scope of ‘dietary ingredient’

A major point of differentiation between industry and agency is on interpretation of the Dietary Supplement Health and Education Act of 1994 (DSHEA) as to what qualifies as a dietary ingredient.

Both AHPA and CRN highlighted the issue with synthetic copies of botanical ingredients. They said federal law allowed for synthetic copies of dietary ingredients as long as they are chemically equivalent to their nature-derived counterpart.

CRN’s comments, composed by its scientific and regulatory affairs leaders Andrew Shao, Ph.D., interim senior vice president, and Haiuyen Nguyen, senior director, highlighted FDA’s inconsistency with synthetics, as the agency’s draft NDI guidance excluded synthetic botanicals from the definition of a dietary ingredient while acknowledging DSHEA-listed dietary ingredients—including vitamins, minerals and amino acids—were still acceptable in supplements despite being synthetically made.

“Congress made no reference to the source of dietary ingredients as being natural or synthetic, nor did Congress specify that only some of these categories of dietary ingredients may be produced synthetically while others must only come from natural sources,” Shao and Nguyen wrote. “CRN recommends that chemical equivalence (including consideration of stereochemistry, if applicable), rather than the source of the ingredient, should be the determining factor in whether or not a synthetic copy of a botanical constituent is a dietary ingredient.”

In addition to echoing the calls for allowance of synthetic botanicals, AHPA asked FDA to revise its dietary supplement “drug exclusion clause” (21 U.S.C. § 321(ff)(3)(B)), an issue facing popular ingredients such as CBD. AHPA argued that requiring a dietary ingredient to be marketed before the date an investigational new drug (IND) application goes into effect is an interpretation of the statute that stifles dietary supplement innovation and is not in line with congressional intent.

“For example, under FDA’s interpretation, a dietary supplement manufacturer could develop and market a product in compliance with the FD&CA [Federal Food, Drug & Cosmetic Act] while the existence of an IND is maintained by FDA and the IND sponsor as confidential,” AHPA wrote. “Upon the publication of information about substantial clinical investigations conducted under the previously confidential IND, FDA could assert that the manufacturer may no longer market the product as a dietary supplement because the company introduced the product after the effective date of the previously confidential IND.”

Loosen the claims reins

There were several requests for FDA to revise or define its stance on certain claims for dietary supplements.

AHPA’s comments included a call for FDA to follow FTC’s lead on traditional use claims to allow such claims to be made, even in cases lacking required scientific evidence, as long as marketers lawfully describe the claim in a way that consumers understand the sole basis for the claim is historical or traditional use.

“AHPA firmly believes that such a revision in FDA’s position would support responsible innovation in dietary supplements as more supplement marketers would use the revised guidance requested here to bring accurately labeled and traditionally used products to the market,” McGuffin and Woodlee stated. “Establishment of clear guidance on use of substantiated traditional use claims for dietary supplements would also preserve and strengthen FDA’s ability to efficiently and effectively enforce the substantiation requirements for such claims by setting a clear standard for their appropriate use.”

AHPA also implored the agency to establish a rulemaking on the use of “natural” and “healthy,” including variations such as made from natural and 100% natural.

“Defining these terms and establishing clear regulatory criteria that must be met to use these terms in dietary supplement labeling would support responsible innovation for products that are, in fact, natural and healthy, and may motivate supplement companies to produce and market dietary ingredients and supplements that meet such definitions,” AHPA reasoned.

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