The product in question, branded as Limbrel, is marketed for the “dietary management of the metabolic processes of osteoarthritis.” The product, which is available in two dosages and two formulations—with and without zinc—is prescribed by doctors to help manage the pain and joint discomfort experienced by osteoarthritis sufferers. The product is reportedly used as an alternative to NSAIDs and opiods, in cases where patients have other underlying issues that preclude the use of these pain relief medications or in cases where they prefer to avoid opiods altogether. The product is based on dietary ingredients extracted from two botanicals—catechin (derived from Acacia catechu, a thorny tree species used in Ayurvedic preparations) and baicalin (derived from Scutellaria baicalensis, an herb that is used in TCM).
FDA cites 194 AERs
The agency first put Primus on notice that it had concerns about Limbrel, which has been on the market for more than a decade, in November. The agency said it had received 194 adverse event reports on the product over an almost ten-year period, which included instances of drug-induced liver injury (DILI), pancreatitis, and hypersensitivity pneumonitis (HP), or an inflammation of the lung tissue. The agency said that, “Any of these conditions can present in patients with varying degrees of severity, ranging from mild to life-threatening. These conditions may go unnoticed by the patient until symptoms develop that require hospitalization, such as respiratory failure.”
Call for FOIA requests
Primus CEO, JD Weir, said the company acknowledged the agency’s concerns at that time and posted a safety warning for health care practitioners about the product on its website. Weir said all of the information the company had from its own adverse event reports data (some AERs could go directly to FDA and not be included in the company’s own records) indicated the possible side effects of the product were mild and in the few cases where patients had reacted adversely, those conditions resolved quickly after the use of product was ended. Weir said in trying to more fully understand the agency’s concerns, Primus requested copies of the 194 reports FDA had mentioned, but was told that they could only be obtained via a Freedom of Information Act request. The company put in the FOIA request in November and received the 194 reports on Tuesday and had just begun its own evaluation of them, Weir said. The company was also told that a FOIA request was necessary to get a look at FDA’s HHE, or Health Hazard Evaluation, the formal process by which it determined that the recall was necessary. At publication time, Weir said FDA had yet to act on that second request.
In mid December FDA sent a letter requesting the recall of Limbrel. In that letter FDA acknowledged Primus’s posting of the safety warning and its agreement to cease signing up new patients but said that did not address the products currently on the market. And yesterday, FDA agents visited Primus’s facility in Scottsdale, AZ to review information such as inventory records related to the recall.
“We’ve been in business since 2001 and we launched our first medical food in 2004, which was Limbrel. We’ve had consistently over the years the same kinds of adverse events and we have reported the serious adverse events to FDA since the beginning. We investigate every of these both with the patient and the physician. We are very serious about safety,” Weir told NutraIngredients-USA.
Weir said his company has had a number of interactions with FDA concerning Limbrel. That included a discussion revolving around one of its clinical trials and whether the study design called for the product to have an Investigational New Drug application on file.
“We have cooperated with FDA all the way through. We always have. We helped create the first medical foods description,” he said.
Outside of medical foods description
In the December letter, FDA took the stance that Limbrel did not meet the definition of a medical food and that the claims made on the product made it an unapproved drug. “FDA is not aware of any distinctive nutritional requirements for individuals with osteoarthritis,” the letter stated.
Ever since the agency issued a guidance on medical foods in 2013, it has taken an increasingly restrictive view of the category. The agency’s reading of the foundational Orphan Drug Act language led it to conclude that in diseases that cause sufferers have specific deficiency state, or if they have an identifiable problem with a nutrient requiring a specially formulated food, such as is the case with phenylketonuria, then a medical food is appropriate. In phenylketonuria, an inborn error of metabolism, babies are born without the ability to metabolize the amino acid phenylalanine, and require specially formulated foods in which that substance has been eliminated. Even if the dietary ingredients in the products could benefit consumers with certain health indications, unless the product addresses a specific disease-related nutritional issue, it should be marketed as a medical food, the agency has said. This view was underlined in a warning letter sent to category leader Metagenics in 2013 that coincided with the release of the draft guidance and two more later that year.
Disagreement on agency’s stance
Some industry stakeholders disagree with FDA’s restrictive view.
“In FDA’s reading of the law there would be only two categories of medical foods: those for phenylketonuria and clinical rehydration products. That’s not what the law says,” said Dan Fabricant, PhD, CEO and executive director of the Natural Products Association. (Full disclosure: Primus is an NPA member.)
Fabricant said FDA’s strategy seemed over the top in the case of Primus, given that the AERs the agency mentioned were accrued over a ten year period with no apparent spike in the frequency or severity of reports. He contrasted the situation with his experience while at FDA in managing the recall on OxyElite Pro, a product made by USP Labs that included the ingredient aegeline. In that instance, cases of severe liver injury, included some that progressed to the need for liver transplants, started to show up quickly, indicating an acute public health concern. Fabricant said that as far as he can tell, there is no similar concern with Limbrel.
“What is the strength of these cases? Is there a temporal relationship that could be established, like there was with Hydroxycut or with aegeline? I don’t think there has been a spike in the AERs on this product,” Fabricant said.
“It appears that if the agency doesn’t want to classify the product as a medical food, then they want to move it over into being an unapproved drug. It’s not as if Primus is putting drug ingredients into the product. The agency’s issue then is with claims. That could be fixed fairly simply,” he said.
As of publication time, FDA had not responded to a request for comment.