Dogma says that a compound used for a nutrition, such as a vitamin, cannot be a drug. Such dogma prevents the development of many good drugs. The FDA just approved vitamin C – ascorbic acid as a drug. Read on to learn how this came about. Afterward, challenge yourself to think about other situations where ‘common knowledge’ prevents innovation.

There is often confusion regarding the regulatory difference between dietary supplements and drug products. An understanding of these distinctions could potentially change the product development strategy and the subsequent regulatory oversight, marketing opportunities, and labeling claims for a product.

Dietary Supplements Are Not Drugs

According to the Dietary Supplement Health and Education Act (DSHEA) of 1994, a dietary supplement is defined as a product taken by mouth (i.e., as a tablet, capsule, powder, softgel, gelcap, or liquid form) that contains a dietary ingredient intended to supplement the diet. These ingredients include vitamins, minerals, herb/botanicals, amino acids, and substances such as enzymes, microbial probiotics, and metabolites. Unlike drugs, dietary supplements are considered safe until proven unsafe. Dietary supplements are not under strict regulation by the FDA and the burden of proof of safety and effectiveness before the supplement hits the market lies solely with the manufacturers and distributors. However, manufacturers are still required to produce quality products. Manufacturers must ensure that the supplements do not contain contaminants or impurities and are accurately labeled according to current Good Manufacturing Practice.

The FDA only has the authorization to regulate the safety of supplements in specific contexts. This includes notifying the FDA if a supplement contains a new ingredient not previously recognized as a food substance (unless it was sold as a supplement before DSHEA went into effect). The manufacturer must provide reasonable assurance that the ingredient does not present a significant or unreasonable risk of illness or injury. However, the FDA will only review this notification, not approve, and only for safety, not effectiveness. In addition, the FDA can remove dietary supplements from the market if they are found to be unsafe or if the product claims are false and misleading.

Case Study: Vitamin C as an Approved Treatment for Scurvy

Q: Did you hear about the pirate suffering from scurvy?

A: His attempts to cure it were fruitless!

There are ways to develop a product that turn what could be a dietary supplement into a regulated drug. On 2 October 2017, Ascor^® (ascorbic acid injection for intravenous use) was approved for short‑term (up to one week) treatment of scurvy in adult and pediatric patients age 5 months and older (NDA 209112; McGuff Pharmaceuticals, Inc.). Ascorbic acid, or vitamin C, is not endogenously produced and human exposure depends upon external dietary sources such as fruits and vegetables. Scurvy occurs after ascorbic acid has been eliminated from the diet for at least 3 months and the body’s pool falls below a critical threshold. Scurvy is an orphan disease in the US and most commonly affects those who are malnourished, homeless, or refugees (and, in the 15^th and 16^th centuries, sailors and pirates, as vitamin C‑rich foods would spoil during long sea voyages).

Ascor is meant for a population for whom oral administration is not possible, insufficient, or contraindicated. Since it is not orally ingested, Ascor is not considered a dietary supplement. The product labeling specifically states that Ascor is not indicated for treatment of vitamin C deficiency that is not associated with signs and symptoms of scurvy, further distancing the product from any nutritional claims.

Ascor is the first single moiety ascorbic acid drug approved for the US market. Ascorbic acid was previously approved in multiple fixed‑dose combination products (FDCPs) as an osmotic laxative for colon cleansing or as an injectable maintenance supplement for those receiving parenteral nutrition. These products circumvented the dietary supplement label through the route of administration (non‑oral) or non‑nutritional claims (laxative).

Not only is Ascor a unique case of a vitamin drug product, it was also approved under our favorite type of regulatory submission pathway, 505(b)(2). It is not clear whether a listed drug was used, but this is unlikely given that all possibilities were FDCPs containing no fewer than six active pharmaceutical ingredients, complicating any safety information within the labels. Although the Summary Basis of Approval is not yet available, it is reasonable to assume that the literature was heavily relied upon for the approval of Ascor due to the historical use of vitamin C (or its food sources) as the sole treatment for scurvy. In fact, the label makes multiple references to data in the published literature. Furthermore, information in the label suggests that only a single Sponsor‑conducted pharmacokinetic study in eight patients was necessary for approval.

Finally, Ascor was classified as a Type 7 NDA- that is, an NDA for a drug product that contains an active moiety that has not been previously approved in an application, but has been marketed in the US. While the circumstances surrounding this classification are not clear in this particular instance, there are positive implications for McGuff Pharmaceuticals if there are other similar unapproved ascorbic acid products on the market. If this is the case, the FDA will typically allow a grace period of approximately one year from the date of this approval before it will initiate enforcement action (eg, seizure or injunction) against these unapproved products. After this grace period expires, and while Sponsors are seeking approval for these similar products, McGuff Pharmaceuticals will have a period of de facto market exclusivity. In general, the hope is that this period of exclusivity will provide an incentive to be the first to obtain approval to market a previously unapproved drug (see Guidance for FDA Staff and Industry: Marketed Unapproved Drugs).

Conclusion

Walking the fine line between a dietary supplement and a drug can be tricky. Unsure of which category your product falls under, or how to propose a vitamin as a drug product? Premier Consulting can provide an assessment of your product and help facilitate interactions with the Agency regarding the development program. To learn more about how Premier Consulting can help, contact us.