New questions have arisen concerning the approval of substances as dietary supplements which may have first been the subject of an approved investigational new drug (IND) and which may have also been the subject of a substantial clinical investigation. Logically, the pertinent section of the Dietary Supplement Health and Education Act (DSHEA) is §201(ff), often referred to as the “exclusionary clause” and defines a dietary supplement (Portions of the statute that are not relevant to this discussion have been redacted.):
(ff) The term “dietary supplement”… (3) does -… (B) not include -…
(ii) an article authorized for investigation as a new drug, antibiotic, or biological for which substantial clinical investigations have been instituted and for which the existence of such investigations has been made public, which was not before such approval, certification, licensing, or authorization marketed as a dietary supplement or as a food unless the Secretary, in the Secretary’s discretion, has issued a regulation, after notice and comment, finding that the article would be lawful under this chapter.
To give an example of how this clause has been applied in the past, the pharmaceutical company Biostratum, l filed a citizen petition (permitted under 21 CFR 10.30) in 2005, to request that pyridoxamine (one of the two active forms of vitamin B6) be disqualified as a dietary supplement. The basis for the petition was that pyridoxamine had been the subject of an IND application for diabetic kidney disease filed in 1999. The petition was made in response to internet sales of pyridoxamine that began after the IND was submitted. Ultimately, the FDA decided in favor of Biostratum’s petition in 2009 with the result that pyridoxamine cannot be legally sold in the US as a dietary supplement.
FDA’s rationale was based on two primary considerations:
- Although pyridoxamine is naturally present in foods such as yeast, milk and beef, the substance was not sold as a food nor was it sold as a dietary supplement prior to the enactment of DSHEA in 1994. On the basis of the first finding, pyridoxamine could have qualified as a dietary supplement, but on the basis of the latter finding, pyridoxamine could not be “grandfathered” in as a dietary supplement.
- Because the internet sales of pyridoxamine as a dietary supplement occurred after Biostratum’s IND submission and after the completion of Phase II clinical trials, pyridoxamine had, therefore, been made the subject of an IND for which substantial clinical investigations had taken place and for which the existence of such investigations had been made public. Therefore, with these considerations, pyridoxamine could not be introduced and sold as a “new” dietary supplement.
To give an example of a current case to which a similar rationale might be applied, the Canadian firm Ovos Natural Health submitted a new dietary ingredient (NDI) application in 2009 for a substance (homotaurine, an amino acid derived from seaweed) that had been the subject of a discontinued IND (Tan Sheet, July 27, 2009). Ovus’s intended use of homotaurine is the sale of homotaurine as cognitive support supplement “Vivamind”. Although homotaurine’s safety was not an issue, Ovos’ parent company, Bellus Health, chose not to proceed with IND approval and opted to withdraw their application, because the results of a 78-week phase III study in patients having mild-to-moderate Alzheimer’s disease were not deemed sufficiently significant for a drug (Tan Sheet, July 27, 2009). During the study, cognitive function was shown to improve by 33% versus control at 12 months and hippocampus brain volume was shown to be preserved by 68% versus control at 18 months (Tan Sheet, July 27, 2009).
FDA’s rationale could take a similar tract for homotaurine as it did for pyridoxamine:
- Although homotaurine is naturally present in the red alga Rhodoglossum japonicum, there is no evidence that this algal species has been sold as a food prior to the enactment of DSHEA in 1994. It is also known that homotaurine has not been sold as a dietary supplement prior to 1994. With these considerations, homotaurine could not be “grandfathered” in as a dietary supplement.
- There were no sales of homotaurine as a dietary supplement prior to Bellus Health’s IND application or prior to the Phase II clinical trials. Homotaurine has, therefore, been made the subject of an IND for which substantial clinical investigations have taken place and for which the existence of such investigations had been made public.
Because these considerations are similar to the pyridoxamine case, it would be reasonable for FDA to rule that homotaurine could not be introduced and sold as a “new” dietary supplement. However, these considerations are not identical to the pyridoxamine case, because the clinical studies have been discontinued and pursuit of an IND abandoned. Therefore, in the absence of an on-going inquiry into the safety and effectiveness of a substance as a drug, what sort of conditions must be met such that the substance can be pursued as a dietary supplement or is homotaurine forever precluded as a candidate dietary supplement? The single possibility for resurrection of homotaurine may be for the Commissioner to exempt homotaurine from the exclusionary clause.