A biotech company in Texas that has researched its product to treat COVID-19 faces obstacles over its plans to market “Oleandrin” as a bulk dietary ingredient for use in dietary supplement products.

In response to a new dietary ingredient notification (NDIN) submitted by Phoenix Biotechnology Inc., an FDA official in the Office of Dietary Supplement Programs (ODSP) stated Oleandrin is excluded from the definition of a dietary supplement because, essentially, it was first studied as a drug.

The irony is that FDA cited drug trials by the same company that wants to market Oleandrin as a supplement—Phoenix Biotechnology. Oleandrin is a molecule extracted from the Nerium oleander plant.

“Based on available information, FDA has concluded that ‘Oleandrin’ has been 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 made public,” Jennifer Dooren, an FDA spokesperson, said in an email.

For example, Dooren referenced a Phoenix Biotechnology webpage, where the San Antonio-based company highlighted “encouraging” results from Phase I and Phase II clinical trials to study the effect of its product, PBI-05204, on cancer patients. Another link she provided was published research of a Phase II study of PBI-05204 analyzing 38 patients with pancreatic cancer.

Twenty-six years ago, in passing landmark legislation to promote access to dietary supplements, Congress sought to preserve incentives to research new drugs for the potential treatment of diseases. Under a provision in the Dietary Supplement Health and Education Act of 1994 (DSHEA), which amended the Federal Food, Drug & Cosmetic Act (FDCA), an ingredient or "article" cannot be marketed in a dietary supplement if it was first authorized for investigation as a new drug and the subject of substantial clinical investigations made public and instituted.

Will Woodlee, a food and drug lawyer, said he read nothing in the statute that would give the holder of an investigational new drug (IND), such as Phoenix Biotechnology, the right to waive the above provision in the law. Woodlee, who serves as general counsel to the American Herbal Products Association (AHPA), granted a phone interview in August before FDA’s letter to Phoenix Biotechnology was publicly released.

“It doesn’t matter whether the IND holder or the sponsor of the investigation wants to now market the article as a supplement,” said Woodlee, a partner in Washington, D.C., with Kleinfeld Kaplan & Becker LLP.

In response to warning letters, some companies have argued the “concept of ‘substantial clinical investigations’ isn’t well defined and may not be as easy a test to meet as FDA has suggested it is—that a single Phase II clinical investigation may not rise to that level,” Woodlee observed. “But I think that’s an open question for the courts to decide at some later date.”

Phoenix Biotechnology could overcome the hurdle identified by FDA by establishing Oleandrin was marketed in a food or supplement before it was authorized for investigation as a new drug; or the secretary of the U.S. Department of Health and Human Services (HHS) could issue a regulation, finding Oleandrin is lawful to be marketed in a supplement.

According to FDA, it’s not aware of any evidence that Oleandrin was marketed as a food or supplement before it was authorized for investigation as a new drug.

In an emailed response to questions for this story, a member of Phoenix Biotechnology’s board of directors, Rick Matos, Ph.D., said, “The determination of IND preclusion is fact specific but still subject to interpretation.”

“We are working with our attorneys and the FDA to obtain further clarification on this objection and determine how best to proceed,” added Matos, who according to his biography has more than 32 years of experience in the pharmaceutical arena as a researcher, patent practitioner and consultant. “We believe a case might be made that our dietary supplement should not be subject to IND preclusion.”

Safety concerns

The IND preclusion is not the only barrier facing Phoenix Biotechnology in its quest to market Oleandrin as an ingredient in a supplement.

“We also note that, even if ‘Oleandrin’ was not excluded from the definition of dietary supplement, the agency has significant concerns about the evidence included in your submission as a basis for concluding that a dietary supplement containing ‘Oleandrin’ will reasonably be expected to be safe under the conditions of use described in your notification,” Ali Abdel-Rahman, Ph.D., director of ODSP’s evaluation and research staff, wrote in FDA’s response to the NDIN.

The notification to FDA referenced a history of medicinal use of Nerium oleander extracts and clinical and pre-clinical studies of N. oleander preparations. In FDA phase I and II human clinical trials for a cancer application, Oleandrin was shown to be safe, Andrew Whitney, director and vice chairman of Phoenix Biotechnology, said in a previous interview with Natural Products Insider.

But according to Abdel-Rahman, the company’s submission to FDA failed to “provide sufficient information to establish that the information that you rely on as evidence of safety is qualitatively and quantitatively related to the ingredient, when used under the proposed conditions of use, as indicated in your submission.

“Furthermore, studies performed in advanced cancer patients generally cannot establish the safety of your ingredient in its intended population of normal healthy adults, and you did not provide any information to indicate that such extrapolation between different populations would be scientifically valid,” Abdel-Rahman added.

In a follow-up call with FDA, the agency suggested to Phoenix Biotechnology that the safety data provided in the NDIN failed to meet “formal requirements, because it was based upon safety data for PBI-05204, and not based upon a determination of safety for our dietary ingredient when used under the conditions described in the notification (or the package labeling),” according to Matos.

FDA officials “indicated we should obtain safety data for the dietary ingredient in a toxicity study in rodents,” he added. “We will be obtaining the data they requested.”

During an Oval Office meeting in July, Oleandrin was promoted to President Donald Trump—with the backing of MyPillow CEO Mike Lindell and Housing and Urban Development Secretary Ben Carson, the news website AXIOS reported. The article fueled a series of additional news reports, including a testy exchange between Lindell and CNN’s Anderson Cooper during an interview.

Botanical experts warned oleander is dangerous and can even cause death. "With respect to oleander, all parts of the plant are highly toxic, dangerous and life-threatening when ingested," Mark Blumenthal, founder and executive director of the American Botanical Council (ABC), a nonprofit, international member-based organization, said in a consumer advisory.

While Whitney acknowledged eating an oleander plant from someone’s back yard could be extremely toxic, he and Matos stressed the company’s extract is safe, based on human oncological trials.

“Oleandrin (in PBI-05204) has already been safely administered orally to humans in clinical trials at doses that are about 15-fold higher than proposed under the recommended conditions of use (daily serving) for our dietary supplement,” Matos said.