The foundational regulation of the dietary supplement industry, the Dietary Supplement Health and Education Act, includes an amendment (See 21 U.S.C. [section] 321(ff)(3)(B) that excludes ingredients that have first been investigated as drugs from the definition of legal dietary ingredients. It’s a clause that has been invoked only rarely.
Clause meant to protect market for pharmaceuticals
Most dietary ingredients used in supplements, even those that have come on the market since DSHEA, are substances that are rarely patentable in and of themselves, and thus not very attractive to drug developers. But the legislative intent was to protect the market for those companies that sought even so to go ahead with the expensive and lengthy process of developing a drug. Even if a composition of matter patent might not be suitable, a developer could get some degree of market exclusivity by invoking the exclusionary clause.
An early example of such a move was pyridoxamine, for which an Investigational New Drug Application was filed in 1999 by a company called Biostratum Inc. The company called its pyridoxamine drug Pyridorin. It was developing it as a treatment to prevent the progression of diabetic neuropathy, which develops in 25% to 40% of patients suffering from Type 1 or Type 2 diabetes. It can often progress to end stage renal disease.
Biostratum filed a petition in 2005 for the ingredient to be taken off the list of legal dietary ingredients because of the IND exclusion. In 2009, FDA agreed, at least in part, with Biostratum’s petition. At the time, CRN said it was 'disappointed' with that decision, because of a disagreement over whether pyridoxamine should have been grandfathered in under DHSEA.
In its most recent comments, CRN delves into the notion of whether the exclusionary clause, once invoked, means the ingredient is off limits forever. Biostratum apparently ran out of funds years ago along the long development road, and the Pyridorin effort ended in 2016.
CRN filed the comments recently in support of a petition filed in November of last year to have pyridoxamine reclassified as a legal dietary ingredient. That petition was filed by a company called Vi Guard Health Inc.
Steve Mister, president and CEO of CRN, said that the pyridoxamine issue was one that escaped the attention of much of the industry at the time.
“CRN was one of the few entities that filed comments on that decision. We argued that it has been on the market prior to 1994. We were able to show that it was on our ODI list,” Mister told NutraIngredients-USA.
An IND shouldn’t be carved in stone
The core of CRN’s argument in the current comments is this: “CRN agrees with the petitioner that the prior marketing clause was intended to create fairness for pharmaceutical companies that intend to bring an article to market as a new drug and have invested in substantial clinical investigations in the process and that this protection should only be necessary and appropriate so long as the article is still in the drug development process. Under certain circumstances, this prior marketing clause should no longer apply, such as when all INDs for the article have been permanently terminated, and thus, no longer in effect.”
CRN argues in the comments, which were signed by Mister and Haiuyen Nguyen, senior director of scientific and regulatory affairs, that FDA has the power to rescind an IND on various grounds, “[I]including when the sponsor fails to submit an accurate annual report of the investigations in accordance with 21 CFR 312.33 or when the IND has been on inactive status for five years or more.”
Further, CRN noted that Vi Guard Health had submitted evidence that the Biostratum IND had been withdrawn and all investigations had ceased.
Mister said CRN is still convinced that it was right in 2005 that the initial exclusion should not have been granted.
“So long as pyridoxamine meets all requirements under the statute, it should be lawfully marketed in or as a dietary supplement in the United States. CRN persists in its position, espoused in its 2005 comments (FDA-2005-P-0259), that pyridoxamine was indeed marketed as a dietary supplement prior to 1999, and indeed, even prior to October 15, 1994, making it an “old dietary ingredient,” which would not be subject to the requirements of new dietary ingredients in 21 U.S.C. §350b,” CRN’s comments state.
Question extends beyond just pyridoxamine
Mister said the issue of whether drug investigations can keep dietary ingredients off the market is one that more stakeholders in the dietary supplement industry should pay attention to. It forms the basis of the argument that drug maker Amarin is using to try to get some high concentrate forms of fish oils declared as illegal dietary ingredients. That question also hinges on whether these ethyl ester forms could be called Old Dietary Ingredients.
It points to a broader issue of whether an agreed-upon list of these ingredients can be assembled. When DSHEA was enacted, CRN and other stakeholders assembled lists of what was on the market in 1994. FDA did not accord official recognition to any of those lists at that time, but signaled in its latest version of the NDI draft guidance a willingness to work on the issue, though little official action has been taken since then.
“The current leadership at FDA is starting to realize that the farther we get in time away from 1994 the harder it will be for anyone to prove what was on the market back then. I think there is some sense now that we need to capture that moment in time before it is too late,” Mister said.