On Oct. 16, Wisconsin-based research and development company Quincy Bioscience—whose Prevagen supplement is a fast-growing retail brand in the cognitive health sector—received a warning letter from the U.S. Food and Drug Administration (FDA) citing a suite of infractions, including unapproved drug claims, failure to disclose serious adverse events, and use of an active ingredient that is allegedly not a dietary substance. The warning could have implications for the broader brain health market—a budding supplement segment that has undergone little scrutiny to date.
According to the warning letter, FDA had investigated Quincy’s headquarters and warehouse facility in the fall of 2011 and discussed the company’s use of disease claims on its website and promotional materials. Though Quincy’s president Mark Underwood responded in January 2012 that the company was taking corrective action, a recent online investigation by FDA revealed that the company’s marketing and testimonials still used claims that Prevagen has a therapeutic effect on such diseases as brain cell death, Alzheimer’s and dementia.
Mr. Underwood was unable to comment at the time of publication.
Neither IND nor NDI
Furthermore, FDA alleged in its letter that Quincy was conducting clinical trials on Prevagen’s active ingredient—the synthesized molecule apoaequorin—for treatment or prevention of various diseases and that the product is therefore an unapproved drug. The Food, Drug & Cosmetic Act, Section 301(ll), requires that companies submit investigational new drug (IND) applications for substances undergoing drug-like clinical trials.
According to FDA’s website, “Section 301(ll) … prohibits the interstate shipment of foods containing an added drug or a biological product that has been the subject of substantial clinical investigations, the existence of which has been made public.” By performing “substantial clinical investigations” with therapeutic endpoints on a substance without dietary ingredient status, Quincy defaulted Prevagen into drug status.
“If a manufacturer didn’t do an NDI notification, and significant clinical trials were instituted and made public before the dietary supplement was marketed, the FDA could opine that the ingredient is an unapproved drug because the NDI notification hadn't been filed,” said John Endres, chief scientific officer at research consultancy AIBMR.
It’s a curious dilemma for the supplement industry that substantial research on new ingredients cannot be initiated before the product is ready for market. And if the ingredient is produced synthetically, the stakes are even higher.
“I went down exactly this road for a client of mine—the ingredient was homotaurine,” said Marc Ullman, of New York law firm Ullman, Shapiro & Ullman. Originally seeking a new drug approval (NDA), but having failed to make it past phase 3 of clinical trials, Canadian biotech firm Ovos Natural Health tried to take its homotaurine ingredient into the supplement market.
“You can petition FDA to allow your NDA into the food supply,” said Ullman, “but FDA declined to even address the substance of the petition we filed because they said that, while the product homotaurine is found in kelp, [Ovos’s homotaurine] can’t be a dietary ingredient because it’s synthetic.” FDA rejected Ovos’s bid in February 2011. It is out of the U.S. market but is currently sold as a dietary ingredient in Canada.
The debate over synthetics in dietary supplements has become especially heated in the last few years, and was one of several major points of argument between industry and FDA over the agency’s 2011 NDI draft guidance. Specifically pertaining to botanicals and plant-based ingredients, FDA takes the position that synthetic forms of these nutrients are not dietary ingredients as defined by the Dietary Supplement Health & Education Act (DSHEA). Industry argues that these substances are nature identical.
“They first took this position with ephedrine alkaloids,” said Ullman, “and the industry made the political decision not to fight it because ephedra was nasty.” He added, “The only way [FDA’s stance on synthetic botanicals] will change is through litigation.”
Steve Mister, president and CEO of the Council for Responsible Nutrition (CRN) is more optimistic. In a recent letter to FDA, CRN asked the agency to reverse its position on synthetic botanicals, arguing that it is contrary to the intent of DSHEA, is not scientifically justified and stands in contrast to precedent.
“We think that a combination of a really sound legal argument—which is what we’ve crafted in our letter—and a lot of political pressure gives the agency the opportunity to resolve this issue before litigation or legislation,” Mister said. “There is an alternative—you could ask Congress to step in and amend the law.”
Quincy Bioscience's problems are a bit removed from the issue of botanicals because apoaequorin is a synthesized form of a protein found in jellyfish. “Jellyfish isn’t a plant, so it does not fit nicely into the nature identical botanical debate,” said Mister. But assuming this jellyfish protein is somehow part of the diet, and Quincy can prove their synthesized version is identical to the natural one, NDI status may be within reach.
A setback for the brain space?
Brain health is a strong up-and-comer in the condition-specific supplement market, and, with its strong investment in clinical research, Prevagen appeared to have a leg up on the competition. Could the warning letter send ripples through the rest of the brain space?
Prevagen has many human clinical trials (perhaps too many?) to its credit showing its benefits for memory and cognition. But because Quincy Bioscience initiated, published and marketed these trials before an NDI notification on apoaequorin, it invited a knock from FDA.
Ullman said that discussing research plans with counsel before launching trials can prevent a large number of potential road blocks. Ultimately, overblown health claims tend to lead FDA to a company’s door, and it’s best to have the house in order when they arrive.
“Is this going to screw up cognition products? I don’t think so,” AIBMR’s Endres said. “Not if you go through the proper channels to establish that the ingredient is reasonably expected to be safe for its intended use and submit an NDI notification to FDA.”
Quincy also failed to report serious adverse events to FDA, some of which required hospitalization. That combined with its NDI issues, over-marketing and drug-like trials prompted the warning letter. “I don’t think it’s a cognitive function problem—I think this is regulatory compliance problem and meeting the definition of a dietary ingredient issue.”