On July 29, 2005, FDA received a Citizen Petition from Biostratum, Inc. Biostratum is the manufacturer of Pyridorin, which contains as its active ingredient a salt of pyridoxamine (i.e., a component of vitamin B6), and which is the subject of an Investigational New Drug Application (“IND”). Pyridorin is intended for therapeutic use to slow or prevent the progression of diabetic nephropathy, which develops in 25-40% of patients with type 1 or type 2 diabetes, and often progresses to end-stage renal disease.

Biostratum’s petition requested that FDA: (1) state in writing that dietary supplements containing pyridoxamine are adulterated; (2) exercise its enforcement authority by removing dietary supplements containing pyridoxamine from the U.S. market; and (3) place the Citizen Petition in a separate docket from that used for Premarket Notifications for New Dietary Ingredients (2004N-0454). FDA complied with the third request immediately, by placing the Citizen Petition in its own docket (2005P-0305, now 2005P-0259).

On January 12, 2009, FDA issued a response granting the petition in part and denying it. Most important, FDA effectively granted Biostratum’s first request by stating that products containing pyridoxamine, the active moiety of pyridoxamine dihydrochloride (Pyridorin), are excluded from the definition of dietary supplements. FDA denied Biostratum’s request for enforcement action against dietary supplements containing pyridoxamine, although that denial does not in any way guarantee that the agency will not pursue enforcement action of its own volition.

Statutory Background

Under DSHEA, the definition of “dietary supplement” was amended to exclude “an article that is approved as a new drug” or an article “authorized for investigation as a new drug…for which substantial clinical investigations have been instituted and for which the existence of such investigations has been public,” if the article in question was not “marketed as a dietary supplement or as a food” prior to approval or authorization for investigation as a new drug. (See 21 U.S.C. § 321(ff)(3)(B)). Therefore, under the DSHEA amendments a product is not a “dietary supplement” if: (1) it is an “article” approved as a new or investigational drug; and (2) it was not marketed as a dietary supplement prior to the drug approval.

FDA’s Reasoning on Pyridoxamine

Pyridoxamine as an “Article”: In Pharmanex v. Shalala (221 F.3d 1151 (10th Cir. 2000) (“Pharmanex II“)), the Circuit Court determined that an “article,” as used in the phrase “article approved as a new drug” could refer to either a finished drug product or any of the drug product’s active ingredients (Id. at 1159-60). Pharmanex argued that lovastatin, a component of red yeast rice, could not be an “article” because the lovastin was not a finished drug product and could not be independently approved as a new drug. Pharmanex also argued that the term “article” as used in the exclusionary clause was unambiguous.

However, the Tenth Circuit court rejected these arguments, determining instead that the term “article” was ambiguous, and that FDA’s interpretation of the term to include active ingredients was reasonable. Further, the Circuit Court reasoned that if “article” applied only to the finished drug product, dietary supplement manufacturers could evade the safety and efficacy requirements for new drugs and undermine incentives for drug development by marketing only the active ingredients of approved drugs. (See Pharmanex II, 221 F.3d at 1158-59.) Therefore, the term “article” was determined to apply equally to active ingredients and finished drug products.

FDA extends the Pharmanex decision’s reasoning with regard to active ingredients in finding that an active moiety is indeed an “article” for the purposes of DSHEA’s exclusionary clause. According to FDA, the principle underlying Pharmanex is that “substances that have been studied for a drug indication or have gained recognition in the marketplace as new drugs may not be incorporated into, or marketed as, dietary supplements” (FDA Response to Biostratum’s Citizen Petition, January 12, 2009). Therefore, because a dietary supplement with the same active moiety as an approved new drug would pose the same concerns as a supplement with the same active ingredient as a new drug, an active moiety should also fall within the term “article.” (See, id.)

FDA also relies on its past statutory interpretations in extending the definition of “article” to include an active moiety. FDA cites the FDCA’s exclusivity provisions for Orphan Drugs, under which seven years of marketing exclusivity are granted to the first orphan drug to be approved for use in a given orphan disease or condition. FDA has interpreted this exclusivity provision to prohibit approval of another drug for the same orphan use that has the same active moiety as the protected drug. FDA has also interpreted the term “drug” to mean “active moiety” under provisions allowing an extension of marketing exclusivity to manufacturers of drugs who test their products in children. In this way, FDA has applied pediatric marketing exclusivity to entire lines of drug products containing a single active moiety, where the moiety has been tested in children. Finally, under the Hatch-Waxman Marketing Exclusivity for New Drugs, FDA has interpreted “active ingredient” to mean active moiety, for the purposes of determining whether a drug product contains a “new chemical entity.” The longest exclusivity period under Hatch-Waxman is given to drugs with different active moieties than those already approved.

Pyridoxamine as an Investigational Drug: FDA’s response finds that pyridoxamine had indeed gained authorization from FDA as an investigational drug in September, 1999, and was the subject of “substantial clinical investigations.” Moreover, the agency found that those clinical investigations had been made public through Biostratum’s press releases. The completion of three Phase II clinical trials constituted “substantial clinical investigations.” Therefore FDA concluded that pyridoxamine had been authorized for investigation as a new drug since September 1, 1999.

Marketing of Pyridoxamine as a Dietary Supplement or Food Before Drug Approval: FDA again relies on one of the Pharmanex cases, Pharmanex III, to explain the precise meaning of “marketed as a dietary supplement or as a food.” According to that case, in order to have been “marketed as a dietary supplement or as food” prior to drug approval, the article must not only have been present in food or supplements marketed prior to drug approval, but the article itself must have been marketed. (See Pharmanex III, 2001 WL 741419 (D.Utah 2001). As justification for its position, FDA reasons that “[t]o argue that the mere presence of a substance in the diet preserves dietary supplement status would mean that even a few molecules of a substance never before recognized as therapeutically beneficial would, if present in some food, defeat any incentives for pharmaceutical manufacturers to develop such a substance into a new drug” (FDA Response to Biostratum Citizen Petition, January 12, 2009).

FDA also sets a high evidentiary standard for demonstrating prior marketing of an article as a supplement or food. The agency makes clear that affidavits alone will not suffice to demonstrate that pyridoxamine, or vitamin B6, was specifically marketed as a component of foods like Brewer’s yeast, frozen fish, milk, eggs, beef, chicken and pork, prior to its approval as an investigational drug. In addition, FDA refuses to accept industry-sponsored lists of “grandfathered” ingredients as reliable evidence. Rather, historical documentation, such as business records, is required to show that the levels of pyridoxamine in a food or supplement product were independently touted. As no such records were produced during the comment period on Biostratum’s citizen petition, FDA concludes that pyridoxamine was NOT marketed as a dietary supplement or food prior to its approval as an investigational drug.

FDA’s Enforcement Discretion: In one respect, FDA’s response appears timid. Specifically, while it is true that FDA’s official position is that pyridoxamine is not a dietary ingredient and is subject to enforcement action as an unapproved new drug, the agency did not take enforcement action or say specifically that dietary supplement products containing pyridoxamine are adulterated. Rather, FDA stated that it was not necessary to find the dietary supplement containing pyridoxamine adulterated and a Citizen Petition was not the appropriate venue to discuss enforcement actions. Thus, the agency may take action against pyridoxamine products that violate the [FDCA], as with any other product under its jurisdiction, but it does leave some ambiguity as to whether the agency is confident it could prevail if an enforcement action is taken. Indeed, given the relative safety of pyridoxamine, one must wonder whether it would be high on FDA’s current enforcement agenda.

Takeaways for Industry

The pyridoxamine decision presents some issues for dietary supplement manufacturers. First, it emphasizes the necessity of not only being aware of the history of your ingredients, but being prepared to substantiate that history through documentation. Industry-sponsored lists of “grandfathered” ingredients are not officially recognized by FDA, and cannot be relied upon to show that a particular substance was marketed prior to approval as a drug or investigational drug.

If FDA believes that a dietary ingredient was marketed after its approval of a new drug or after substantial public clinical investigation pursuant to an IND, the company will need substantial proof such as catalog copy, old labels, and possibly bill of laidings to prove it was marketed before the IND application was filed or before clinical investigations of that ingredient began—a task that in practice may be extremely difficult.

This decision also raises the issue of what FDA considers to be a new dietary ingredient. Clearly, reliance on the industry lists will not be sufficient to support an ingredient’s status as an “old” dietary ingredient.