INSIDER Law
Drug Clause in DSHEA May Cause Death of Dietary Ingredient Vinpocetine

Drug Clause in DSHEA May Cause Death of Dietary Ingredient Vinpocetine

<p>FDA&#8217;s tentative conclusion that vinpocetine cannot be sold in dietary supplements surprised the industry and drew strong critique since the agency had received five safety-related notifications on the ingredient without any objections.</p>

In an unexpected move that has drawn censure from the industry, FDA has tentatively concluded an ingredient that has been on the market since the late 1990s cannot be sold in dietary supplements.

In a notice in the Federal Register, FDA is requesting comments on its tentative determination that vinpocetine is not a dietary ingredient and is excluded under federal law from the definition of a dietary supplement because, in part, it was authorized for investigation in the United States as a new drug.

The ingredient is fairly popular and has been sold by the likes of General Nutrition Corp. (GNC) and The Vitamin Shoppe. Vinpocetine is present in more than 340 dietary supplement brands and has been marketed as a drug in countries outside the United States, according to researchers from Harvard Medical School and the University of Mississippi.

FDA’s tentative conclusion surprised the dietary supplement industry. Although FDA has received five safety-related premarket NDI (new dietary ingredient) notifications on vinpocetine dating back to 1997, the agency has never instituted action to remove the ingredient from the dietary supplement market.

The five notices were submitted by Amrion Inc. in 1997, GNC in 1999, Leiner Health Products in 1998 and 1999 and Pharmavite Corp. in 1999, according to an FDA webpage. (All five notices on vinpocetine are available through the American Herbal Products Association (AHPA) NDI Database).

The companies, some of which have been acquired since FDA received the notices, did not respond to requests for comment. FDA never objected to any of the NDI notifications, according to industry representatives and the Federal Register notice.

The first NDI notification, dated June 27, 1997, was submitted to FDA by Amrion. That was the same month and year The New York Times reported Whole Foods Market agreed to acquire Amrion for $146 million in stock.

Industry Reacts Strongly to Tentative Determination

Daniel Fabricant, Ph.D., executive director and CEO of the Natural Products Association (NPA), described FDA’s recent notice as a “form of double jeopardy." “This sets a very bad precedent and is no environment to conduct business in," declared Fabricant, FDA’s former director of the Division of Dietary Supplement Programs, in a statement.

Steve Mister, president and CEO of the Council for Responsible Nutrition (CRN), was equally critical of the agency. Responding to FDA’s tentative conclusion that vinpocetine isn’t a dietary ingredient, Mister asserted in a phone interview, “Well, you had five times to tell us that and you didn’t."

It appears “FDA thinks it can change its mind whenever it wants," Mister said. “That it can approve something and then come back and take it away from the industry after companies have invested in the research, invested in the marketing, making it a viable product."

During a Sept. 8 workshop hosted by the United Natural Products Alliance (UNPA) and to discuss 2016 draft NDI guidance issued last month by FDA, an FDA official, Cara Welch, Ph.D., stressed the agency’s determination in the Federal Register is only tentative and FDA is not taking enforcement action against marketers of vinpocetine. Welch is senior advisor to FDA’s Office of Dietary Supplement Programs.

“The problem is … a document of that sort puts a brand holder and a retailer in a very awkward position," observed Loren Israelsen, president of UNPA, in concluding remarks during the workshop. (The audio/synchronized PPT presentations from UNPA’s NDI Guidance Workshop will be available later this week at unpa.com/store).

He said the industry is questioning the stability of the NDI notification structure.

“If you go through the trouble and spend all the money to have an acknowledged NDI, and then there’s these uncertainties that leave you wondering if we’re still good," Israelsen remarked. “Did we make a good investment? That is a fair question from a business perspective."

Safety Concerns Questioned

Some industry sources said they were unaware of acute safety concerns related to vinpocetine in dietary supplements. Marianna Naum, an FDA spokeswoman, said the agency has received 81 adverse event reports (AERs) associated with products containing the ingredient since 2004, and one of the reports related to a death.

“Adverse event reports involving a particular ingredient do not necessarily show that the ingredient caused the event, however, especially for products that contain several different dietary ingredients," she cautioned in an emailed statement.

FDA couldn’t provide more specific details on the AERs, citing the need to submit a Freedom of Information Act request.

Stefan Gafner, Ph.D., chief science officer of the American Botanical Council (ABC), a nonprofit research organization, said vinpocetine doesn’t present significant safety concerns when it’s used at the appropriate dosage. He described the proper dosage as typically 5 to 10 milligrams (mg) three times per day.

“I do know that protecting consumer safety, protecting the public health is our top priority, but it’s also very important to us that we ensure the product identity, integrity and quality of products that are on the market," said Welch during the UNPA workshop while responding to questions on the vinpocetine notice.

FDA Describes Vinpocetine as ‘Synthetic Compound’

In the Federal Register notice, FDA specified two reasons vinpocetine cannot be sold in a dietary supplement. First, the agency tentatively concluded vinpocetine is not a dietary ingredient. FDA noted vinpocetine isn’t a botanical or constituent of a botanical. Instead, FDA characterized vinpocetine as a “synthetic compound" that can be formed synthetically from vincamine, which the agency described as “an alkaloid found in the Vinca minor plant." FDA also said vinpocetine can be derived from “tabersonine, an alkaloid found in Voacanga seeds."

Gafner of ABC indicated the manner in which vinpocetine is made is unusual.

“However, what exactly is regarded as a ‘natural product’ is a matter of debate," he said in an emailed statement. “Natural products are almost always subject to some type of processing, and the extent of processing that still can be considered to provide a natural product is not clear.

“I don’t think that vinpocetine fits within the idea people have of an herbal ingredient," Gafner added. “Herbal ingredients in dietary supplements are typically powdered herbs, or those ingredients obtained from an herbal raw material by extraction, distillation, fermentation, etc. that may or may not [have] been further purified to a certain degree."

Responding to FDA’s tentative conclusion, industry insiders were quick to point out FDA reviewed five NDI notifications on vinpocetine without objecting to its status as a dietary ingredient.

“FDA is objecting in 2016 that this ingredient is synthetic, but one has to assume that when the five new dietary ingredient notifications were submitted back in the 1990s, there was detailed information as to how this ingredient was manufactured," observed Steven Shapiro, of counsel to the law firm Rivkin Radler LLP, who has decades of experience in food and drug regulatory matters. “So FDA had the opportunity not once or twice but five times to say that a synthetic ingredient cannot be a dietary ingredient and [the agency] did not."

Federal Register Notice Follows Letter from U.S. Senator

FDA’s notice in the Federal Register was published approximately one year after Sen. Claire McCaskill (D-Missouri) wrote to the agency, requesting copies of NDI notifications on the ingredients vinpocetine and picamilon as well as AERs associated with either ingredient. In her Oct. 6, 2015 letter to then FDA Acting Commissioner Stephen Ostroff, M.D., the senator described the two ingredients as “synthetic or semisynthetic substances."

McCaskill’s letter referenced a study by researchers from Harvard Medical School and the University of Mississippi’s National Center for Natural Products Research, School of Pharmacy, who examined the sale of vinpocetine in dietary supplements. While describing vinpocetine as a pharmaceutical drug that has never been approved by FDA in the United States, the researchers also noted the substance has been “prescribed in Germany, Russia, China and other countries at dosages from 5 to 40 mg for acute stroke and cognitive impairment."

In the Federal Register notice, FDA tentatively determined vinpocetine is excluded from the definition of a dietary supplement because it was authorized for investigation as a new drug and had been subject to substantial clinical investigations that had been instituted and publicized. The investigational new drug (IND) exclusionary provision was written into the 1994 Dietary Supplement Health and Education Act (DSHEA).

“It’s good news that the FDA is aiming to take stock of the scientific work of third-party researchers," said McCaskill, a ranking member of the Senate’s Special Committee on Aging, in an emailed statement. “That said, the fact remains that oversight of the dietary supplements that Americans take every day remains alarmingly inadequate. We cannot and should not wait around for outside research or tragedy in this space to spur us to action, and I look forward to working with the FDA to improve the health and safety of all American consumers."

FDA Cites 1981 Authorization as Investigational New Drug

Citing records on file in its Center for Drug Evaluation and Research, FDA noted vinpocetine was authorized as an IND in 1981. FDA referenced an April 15, 1986 article in The Los Angeles Times. FDA had approved clinical trials by Ayerst Laboratories, and the trials concentrated on treatments of patients with a brain disorder known as multiple-infarct dementia, the newspaper reported.

In order for the IND exclusionary provision in DSHEA to apply—preventing vinpocetine from being sold in dietary supplements—the ingredient must have been “authorized for investigation as a new drug." Moreover, “substantial clinical investigations" on vinpocetine must have been instituted. Finally, the investigations must have been “made public." The exclusionary clause doesn’t apply if vinpocetine was marketed as a food or dietary supplement prior to the drug authorization.

An attorney with FDA regulatory expertise stressed all the factors above must be satisfied in order for the exclusionary clause in DSHEA to kick in.

“You can file an IND and do nothing, which doesn’t get you anywhere," observed A. Wes Siegner, Jr., a director of the law firm Hyman, Phelps & McNamara PC, in a phone interview. “You can publicize that FDA filed an IND and do nothing. That doesn’t trigger the exclusionary clause."

“If all of those factors are present … the story is FDA made a mistake 20 years ago when they filed the NDI, and it’s excluded by statute from being in a dietary ingredient," Siegner said. “If that’s not the case, then I think we have a fight about whether this is appropriate or not, and I would say it’s not.

“There either is or is not an IND," the lawyer continued in the interview. “It either is or isn’t the same ingredient and either is or isn’t public."

The more difficult question, he indicated, is whether such clinical studies were “substantial."

“FDA is now pointing to research … that was published in 1986," observed Mister of CRN, whose members make vinpocetine and sell finished products containing the ingredient. “If that’s correct, they were certainly aware of that research every time somebody filed an NDI, and they didn’t object to it."

Israelsen noted many dietary ingredients have been sold as drugs in foreign countries.

“If this is a trigger point, that causes us great concern, especially if it’s a look-back into acknowledged NDIs," he said.

Pieter Cohen, M.D., a physician at Cambridge Health Alliance in Somerville, Massachusetts, and assistant professor of medicine at Harvard Medical School, supports FDA’s recent notice in the Federal Register. He is one of the researchers who studied vinpocetine in dietary supplements last year.

“I would hope we would all agree that DSHEA is not designed as a back door to introduce drugs onto the U.S. market, and that’s really my concern," he said in a phone interview.

“Here, we have a situation where instead of what the consumer might suspect would be a natural product, something found in nature or extracted from a natural botanical … what we are seeing in these products are a pharmaceutical drug that’s prescribed or used in other countries like China and Russia," Cohen said. “I don’t think any consumer would want to be in a situation where they are shopping for a botanical and end up taking a Chinese drug."

Former FDA Official: Tentative Conclusion Not Unprecedented

The notifications that FDA received on vinpocetine were in the early years of implementation of the NDI provision in the law, observed Vasilios (“Bill") Frankos, Ph.D., a former FDA dietary supplement official and Herbalife Ltd.’s senior vice president of global regulatory compliance and product safety.

“I think what FDA has done is what I would have done while I was at the agency, which is to periodically review the status of NDIs," Frankos said in a phone interview. “In fact, FDA has a history of periodically looking at [the] status of NDIs because they are not regulations. They are purely notifications, and FDA has always retained the right to revisit the notification if new information becomes available to them."

Frankos noted FDA’s tentative conclusion on the status of vinpocetine isn’t unprecedented. For instance, he referenced a 2005 citizen petition that was filed with FDA by BioStratum, Inc. requesting the agency remove supplements containing the ingredient pyridoxamine from U.S. interstate commerce.

BioStratum stated the ingredient was the subject of an IND application that was filed with FDA in July 1999 as a potential therapeutic agent for use to slow or prevent the progression of diabetic nephropathy in patients with certain types of diabetes. However, unlike the case with vinpocetine, the petition alleged pyridoxamine had never been the subject on an NDI notification.

While the supplement industry argued pyridoxamine was a grandfathered dietary ingredient that was exempt from an NDI filing, FDA eventually ruled products containing the ingredient were not dietary supplements and couldn’t be marketed as such products. As Hyman, Phelps & McNamara observed in a 2009 blog, FDA found the ingredient met the IND triggers in DSHEA and there was no independent evidence that could be verified that pyridoxamine was marketed previously as a food or supplement.

Cohen, whose 2015 research may have contributed to FDA reexamining its position on vinpocetine, said FDA would send a strong message by maintaining its tentative conclusion that vinpocetine can’t be sold in dietary supplements.

“If the FDA stands firm here, then that is exactly the signal that the administration has to send to all companies to say, ‘We will not permit any drugs to be sold as supplements, even when we made mistakes in the past,’" he said. “And that’s a powerful message that needs to get out to everyone in this industry."

Steve Myers contributed reporting for this article.

Editor's Note: Interested in learning more about what’s happening at FDA around dietary supplements? Join FDA’s Cara Welch, Ph.D., senior advisor to the Office of Dietary Supplement Programs in the SupplySide West Featured Speaker session on Thursday, Oct. 6, at SupplySide West 2016.

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