Multi-Ingredient Supplements Warrant Priority Safety Review - Whitehall Rep

Dietary supplements that combine numerous ingredients should be given high priority in a safety review framework being developed by an Institute of Medicine committee, a Whitehall-Robins representative said Oct. 11.

"Some of the products that are on the market today may have two, three, four, multiple botanical ingredients in them and, at some point, we need to address the potential for those ingredients for causing safety issues," said Senior Director-Regulatory Affairs & Toxicology Hulon McCain, PhD.

Speaking at a meeting in Washington, D.C., McCain also suggested the Food & Nutrition Board's Committee on the Framework for Evaluating the Safety of Dietary Supplements should give priority to "new" supplement ingredients, as well as older, single ingredients for which adverse events or case reports have raised concerns.

"If the signal is generated through AEs or through publications...to suggest there may be a safety issue, perhaps those individual ingredients should be pushed forward and evaluation should be conducted fairly early on," the Whitehall rep said.

Nutricia Senior VP-Scientific Affairs Susan Trimbo, PhD, agreed, suggesting the committee "focus on a short list of ingredients where perhaps there have been case reports."

Both industry execs said vitamins and minerals with a "long history of use" should receive low priority in the safety review framework.

"We don't have any real safety concerns with those, and we don't think the public does either," McCain asserted. "But if those ingredients are used at very high levels, then I think they should fall into the review process initially."

The Whitehall rep suggested the reviews be selective and based on available data. "They should not consist of a checklist of each individual type of safety data. They should consist of historical use from both domestic and foreign sources."

However, the relevance of historical use data may depend upon whether there are differences in current usage, he cautioned. "Any incidences in which the dosing recommendations or the dosing form would suggest dose escalation, that marketing history is of less value," McCain said.

The committee, created under a project sponsored by FDA's Center for Food Safety & Applied Nutrition, will develop a framework for categorizing and prioritizing supplement ingredients based on safety issues. The group also will determine how to best develop scientific reviews containing specifications for evaluating the safety of supplement ingredients and will establish at least six prototype reviews.

A proposed framework is expected 15 months after the project start, while prototype monographs are expected at the end of the two-year project. The committee first met in July (¹ (Also see "AHRQ Ephedra Evidence Report Targeted For August 2002 Release" - Pink Sheet, 13 Aug, 2001.)).

The IoM group convened the recent meeting to further clarify the project scope and hear stakeholder input on designing a framework.

CFSAN Office of Nutritional Products, Labeling & Dietary Supplements Director Christine Lewis, PhD, noted the center is seeking advice on how existing scientific, historical and anecdotal data that are "not always ideal" can be used to establish supplement safety concerns.

"What kind of data trump what kind of data? We, in essence, need guidance to weigh and balance the data that are available," Lewis said. "How do you deal with the fact that the mechanism of harm may be identified from the studies, but historical data show no problems? Does the scientific data body of evidence trump the lack of adverse events?"

Issues of product efficacy are beyond the committee's purview, Lewis stressed. "The issue here is not whether the ingredients are effective," she said. "The question is: 'Is something being marketed that causes harm?'"

Council for Responsible Nutrition VP-Scientific & Regulatory Affairs Annette Dickinson, PhD, disagreed with Lewis' assertion that the committee should not try to define what is meant by the Dietary Supplement Health & Education Act provision stating a supplement is unsafe if it presents "a significant or unreasonable risk of illness or injury."

"We would urge the committee to consider this issue of definition of what the safety standard is for dietary supplement ingredients. We would also suggest...the concept of unreasonable risk is open to an interpretation that would allow consideration of benefit as well as risks, and we hope the committee will consider this," Dickinson said.

CRN advocates the establishment of tolerable upper intake levels in assessing the safety of supplement ingredients. The group sponsored a Cantox Health Sciences International report that suggested a 90 mg per day safe upper limit for ephedrine alkaloids (² (Also see "Ephedra/AER Causality Link Not Possible - Cantox/CRN" - Pink Sheet, 1 Jan, 2001.)).

Consumer Healthcare Products Association Senior VP-Science & Technology William Soller, PhD, suggested the committee adopt a three-part Dietary Supplement Ingredient Safety Review program.

The first part would be a "reactive" component meant to "identify and evaluate emergent safety concerns, such as an interaction between a currently marketed dietary supplement and a new class of Rx products identified as a result of a newly published clinical trial," CHPA says in written comments. The DSISR also would include a prospective, post-marketing safety review of all marketed supplements.

Prioritization for both types of post-marketing reviews should be based on several overarching elements, including known toxicity, extent of exposure, severity of the adverse event, intended use and gaps in the data on safety issues, the association maintains.

Both the emergent and prospective post-marketing components would begin with an AER signal generator, such as well-designed, controlled, peer-reviewed clinical trials or a series of AE reports.

A CFSAN medical review would evaluate the strength of the AER signal and, if necessary, the center would issue a call for data, either directly to industry or via the Federal Register, but would allow companies to continue marketing the product in the interim.

CFSAN and the Food Advisory Committee's dietary supplement subcommittee would review any new data on risk assessment. Possible public health interventions that might follow include a label warning regarding drug and supplement interactions, Soller suggested.

The third DSISR component would be a prospective, pre-market safety review of new dietary ingredients. Although akin to the current 75-day pre-market notification program, the DSISR would better articulate the scope and extent of data needed to support marketing new ingredients, CHPA said.