If you love something, set it free. If it comes back and bites you, then it’s time to make a change. So maybe that’s not exactly the words of Sting’s 1985 hit song, but that’s what is happening today with what was once an obscure provision of the Dietary Supplement Health and Education Act (DSHEA). Section 201(ff)(3)(B) of the Food Drug & Cosmetic (FD&C) Act (codified at 21 USC 321(ff)(3)(B))—sometimes called the “drug preclusion provision”—is increasingly used to prevent or remove safe and legitimate dietary ingredients from the market. It’s time to change that.
After the FD&C Act enumerates the types of ingredients a dietary supplement must contain, the preclusion provision states that a dietary supplement may not include an article that has already been approved as a new drug, or an article authorized for investigation as a new drug for which substantial clinical investigations have been instituted and made public, prior to its being marketed as a dietary supplement.
This provision sets up a race between drugs and supplements that use the same article as an ingredient: if the supplement is already marketed prior to the entrance of the drug, the two products must coexist in the market (e.g., omega 3s, niacin and Vitamin D, that all currently can be found as supplements and as prescription drugs). But if the drug arrives first—either by entering the market as a drug or having been studied in a clinical investigation—the drug gets a monopoly on the article.
This provision was inserted into DSHEA to satisfy a Congressman concerned that companies might choose to market a substance as a supplement after a competitor spends years conducting expensive pharmaceutical research and frustrate the incentives for drug investigation and development.
For the first five years under DSHEA, the provision went largely unnoticed. However, it attracted attention in the notable case Pharmanex v. Shalala when FDA announced that red yeast rice could not be marketed for its monacolin (lovastatin) content because prescription drugs containing statins were already in the market before the company began promoting red yeast rice for its monacolin. In a decision from the U.S. Court of Appeals, Tenth Circuit, the court held that monacolin was precluded from being marketed as a supplement. However, red yeast rice could continue to be sold with its naturally occurring levels as monacolin so long as those levels were not manipulated or standardized to achieve a specific dosage or marketed for those levels. Note the court never considered the issue of safety of the supplement; rather, the debate was about providing sufficient economic incentives to foster pharmaceutical research.
Then in 2009, FDA removed pyridoxamine (a form of Vitamin B6) from the supplement market when it invoked the preclusion provision and asserted that there was no evidence the article was marketed as a supplement prior to the commencement of clinical trials for the ingredient as a drug. Otherwise, little attention was paid to the implications of drug preclusion at the expense of supplements.
Fast forward to 2019 and the legislation to remove cannabidiol (CBD) from the Controlled Substances Schedules—the 2018 Farm Bill (passed in December of that year) removed hemp with THC content below .3% from the schedules. FDA quickly invoked 201(ff)(3)(B) to argue that, nevertheless, CBD is precluded from being a dietary ingredient because of the prior approval of Epidiolex as a drug. This artificial hurdle has frustrated mainstream retailers from selling ingestible CBD products for over two years.
FDA again invoked the preclusion again last summer, this time to attack the legal sale of N-acetyl-l-cysteine (NAC) and issued warning letters invoking a drug approval for an inhalable version of NAC going back to 1963. FDA asserted that the preclusion provision enacted in 1994 has retroactive effect to prevent supplements containing an ingredient that was investigated long before the innovation protections of section 201 even existed. The agency has ignored differences in delivery form (inhaled versus ingested), different dosage levels, and vastly different indications to attempt to remove a longstanding safe and popular ingredient from the supplement market. Unfortunately, other dietary ingredients in the market today, and more potential ones in the future, could be precluded just like CBD and NAC.
The law does provide an escape hatch. The end of the drug preclusion provision states, “…unless the Secretary [of Health and Human Services], in the Secretary’s discretion, has issued a regulation, after notice and comment, finding that the article would be lawful under this chapter.” The agency has an opportunity to resolve these conflicts when they arise with a rulemaking that grants an exception to the statutory race to market. So even if the “article” is the same for both drug and supplement—and there are good reasons why they are not the same—FDA could fix the problem. Unfortunately, FDA has never exercised this authority and seems reluctant to do so now for either NAC or CBD.
It’s important to remember that safety is not the issue in these cases; it’s a purely economic argument to preserve the financial incentives to conduct drug research. Does the statute contemplate that safety should even be a consideration? It does not instruct FDA how to determine that the article “would be lawful under this chapter.” If it is possible to label and market the article as a supplement without posing a significant and unreasonable risk of injury or illness, is that sufficient? If it was first marketed as a supplement after 1994, under an new dietary ingredient (NDI) notification, is it enough to show the ingredient is reasonably expected to be safe? Or that it is marketed for a different indication than its pharmaceutical counterpart?
All this points to the need for a reexamination of the preclusion provision. FDA could issue guidance on this topic, but absent that, Congress needs to revise this section of the statute. This race to market should not protect pharmaceutical interests at the cost of denying consumers access to effective supplements that may address common health conditions.
This issue will arise more and more often as drug firms eye longstanding supplement ingredients for their potential therapeutic effects and want to “clear the decks” of any supplements on the market that might undercut their ability to charge more for the drug version. Think about NAC: you can purchase a 600 mg NAC supplement for under 33 cents per serving. A 200-count bottle may sell for less than just the typical $20 co-pay of a prescription drug. If you thought NAC also has a therapeutic effect for COVID patients, you’d want to corner the market too.
The provision should not hand over legitimate dietary ingredients because a clinical trial investigated a disease endpoint years ago. The industry needs clarity and balance given that the motivation for the provision is an economic one to protect Big Pharma’s investments and incentives to do drug research—supplement innovation and research should matter too.
We’re in a real predicament now, and it’s time to resolve it before we lose any more safe and beneficial ingredients in the name of pharmaceutical innovation.
Steve Mister is president and CEO for the Council for Responsible Nutrition.