Bar association panel rebukes FDA over NDI enforcement

The panel was part of a New York Bar Association online event that took place on Friday. The presentation was moderated by lawyer Marc Ullman, attorney at Rivkin Radler. Also in attendance were Mark LeDoux, CEO of contract manufacturer Natural Alternatives International (and a lawyer himself), and attorney Kevin Bell, of Arnall Golden Gregory.

The purpose of the panel was to elucidate the current state of affairs regarding the Novel Food Ingredient provision of the Dietary Supplement Health and Education Act (DSHEA). Under this law, developers of ingredients that have entered the market since the DSHEA went into effect on October 15, 1994 must submit a dossier to the United States Food and Drug Administration that proves that the ingredient can reasonably be considered safe. Acquired ingredients, the so-called Old Dietary Ingredients (ODI), carry a presumption of safety.

Carnosyn’s case study shows problems with the NDI process

The panel used the example of NAI’s proprietary ingredient beta-alanine, branded as Carnosyn, as a case study of how, in their view, the NDI provision went off the rails.

The FDA first issued draft guidelines for how the NDI process should work over a decade ago. Industry stakeholders had many questions and concerns about this document. The pushback, which featured prominent members of Congress, was strident enough that the FDA withdrew the guidelines and reissued them in revised form several years later.

The updated project did not satisfy all critics. But there has been little progress since then as other issues, such as the global pandemic and the booming CBD market, have captured attention.

How wide is the NDI Security Umbrella?

A key question is whether the information in a successful NDIN, in which the FDA agrees with the safety conclusion, applies only to that manufacturer’s ingredient or can be interpreted more broadly. In other words, does the NDIN that NAI filed for Carnosyn mean that only Carnosyn is safe, or that all of the beta-alanine ingredients are?

Ullman said he’s been involved in this debate almost since the beginning, when in 2011 he represented Mitsubishi Gas Chemical and its ingredient PQQ, which has a successful NDIN on file. He was unable to get the FDA to take enforcement action against distributors of other PQQ ingredients who had not filed NDINs.

“In May 2014, I wrote a review with the title ‘The FDA is broken.’ If I was doing an update, the title would be “The FDA is still down.”Ulman said.

Ullman said he had a similar experience representing a client who brought an astaxanthin ingredient to market.

“As the market grew for their ingredient, they faced serious competition from companies marketing counterfeit ingredients of uncertain provenance,” Ulman said.

In one case, Ullman said the FDA rejected NDIN due to questions raised in toxicity studies. But the FDA later approved a GRAS notification on the same ingredient.

“It’s as if everything that happened on the NDI side never happened,”Ulman said. “There is a serious silo problem at the FDA.”

Millions spent on the development of Carnosyn

LeDoux pointed to his company’s Carnosyn ingredient development history as an example of ongoing issues. He said NAI funded much of the early research done in England and elsewhere into the ingredient’s ability to buffer lactic acid and improve performance by allowing athletes to push harder for longer. The ingredient has also shown benefits in improving sarcopenia in the elderly. NAI then licensed the patents on the ingredient.

LeDoux said that between preliminary research, human clinical trials, and building the case for a successful NDIN, NAI spent millions of dollars on Carnosyn.

“We have chosen to submit a very extensive dossier. We did a very comprehensive analysis,” he said.

All the pieces were in place to recoup this investment by collecting the Carnosyn royalties, all of which were based on the proven safety of the ingredient.

“Then we were mystified when we found that there was quite a bit of material from other parts of the world, mainly China. Some of that was made from recombinant strains of e coli,”said LeDoux.

“If you are using bacteria extracted from feces, someone had better demonstrate that the product is safe for human consumption. To my knowledge, no such submission has been made.said LeDoux.

NAI defended its patents in court, but LeDoux said it was an uphill battle.

“60% to 70% of the beta-alanine imported into this country does not belong to us and much of it is made through the e coli process. The agency responsible for securing the border against tampered goods just seems absent without leave”,said LeDoux.

Bell said he represented NAI on the issue in meetings with the FDA and sent a letter to the agency about it. The result was not what the company was looking for.

FDA: no safety issues observed

Cara Welch, PhD, then acting director of the FDA’s Office of Dietary Supplement Programs, responded to NAI’s concerns by a letter dated April 28, 2021​​. In it, she said the FDA questioned whether beta-alanine required filing an NDIN in the first place. Additionally, she wondered if the other beta-alanine ingredients on the market really posed a threat to public safety.

“While we recognize that manufacturing differences could potentially change the safety and suitability of the ingredient for certain conditions of use, or even change the identity of the ingredient, the FDA is not aware that any such differences are at issue here”,Welch wrote.

“To the extent you have specific evidence of particular security risks or other evidence of tampering, we welcome the opportunity to review this information. However, speculation about differences in the manufacturing process or on potential contaminants are generally not sufficient to warrant enforcement action,”she added.

“In the end, I had to ask, what do you get out of all these meetings? Is it the norm, that someone has to die?Bell asked.

Bell alleged that NAI provided information to the FDA about the nature of other beta-alanine ingredients on the market. He said this was met with responses that the information was insufficient or, in other cases, that NAI had buried the Agency under a mountain of paper.

“It’s really discouraging. We are trying to do the right thing under the laws that have been imposed on us. The FDA has created a situation in which there is simply no incentive,” he said.

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