A “perspective” article in the April 3 edition of the New England Journal of Medicine (NEJM) is unrealistic and confusing, says the nonprofit American Botanical Council (ABC). In the editorial, Pieter A. Cohen, MD, assistant professor of medicine at the Harvard Medical School, calls for premarket approval of the safety of dietary supplements (referred to as “nutritional supplements”) before they can be sold. He also calls for a much more extensive adverse events reporting system for supplements.
Dr. Cohen comments on the current reporting systems for adverse events associated with dietary supplements. The case he makes for a reform of the current “woefully inadequate system for supplements” is in large part based on the numerous adverse event reports related to products containing unlabeled prescription drugs illegally masquerading as dietary supplements. The reporting system currently used by the FDA, MedWatch, includes an online portal for clinicians to voluntarily report adverse events associated with prescription and nonprescription drugs, medical devices, and dietary supplements. Manufacturers of dietary supplements have a mandatory obligation to report serious adverse events involving their products to the same system within 15 working days. Dr. Cohen views the system as inadequate, in particular for dietary supplements, due to the fact that products are “sold directly to consumers, often contain multiple active ingredients and are too often inaccurately labeled.”
He suggests the creation of a supplement response team including clinicians, toxicologists, pharmacologists, and chemists (but, apparently, no member with any specified expertise in dietary supplements). The team would be alerted immediately following an adverse event report and could give clinical advice to physicians, provide reports to the FDA, and analyze supplements for undeclared ingredients. He then concludes that even such a change would not prevent dangerous products from reaching consumers and that supplements should be required to undergo rigorous safety testing before marketing is allowed.
“ABC is sympathetic to Dr. Cohen’s concerns regarding public health problems associated with illegal drugs fraudulently sold as ‘supplements’ as well as his concerns about adulterated supplements that contain potentially toxic adulterants,” said Mark Blumenthal, founder and executive director of ABC. “We agree that prescription drugs that are illegally sold as dietary supplements are an obvious public safety concern and that these illegal products should not reach the hands of the consumer. In this regard, focusing on enhanced enforcement of currently existing laws and regulations would probably be more of a deterrent for manufacturers and marketers of fraudulent products than the proposed creation of a premarket approval system and an entire adverse event response team that focuses solely on dietary supplements.”
Blumenthal also noted that the illegal products containing prescription drugs and their analogs are made and marketed by people who have no respect for the law or industry self-regulatory initiatives. “Criminals who are currently intentionally breaking the law will not stop their illegal activities just because well-intentioned people might create new barriers to entry, i.e., premarket approval regarding the safety of the ingredients in their products. The criminals will continue to flout the law and the best interests of the public,” he added.
“While a quicker alert system for adverse event reports may be in the public interest, it is not sensible to restrict a proposed reporting system solely to dietary supplements, especially if it leaves responsible manufacturers out of the process,” said Rick Kingston, PharmD, president of regulatory and scientific affairs at SafetyCall International and clinical professor of pharmacy at the University of Minnesota.
“If the goal is to hold the unscrupulous companies responsible, healthcare professionals should report serious adverse events potentially associated with the use of a supplement to both the manufacturer and MedWatch,” Dr. Kingston continued. “Good companies will cooperate in the investigation of the report, and bad actors will ignore requests for assistance and also refuse to report the events themselves as currently required. If FDA knows a manufacturer was notified of an event, yet no report was made by the manufacturer to FDA, the Agency has the authority to take enforcement action which can include removal of potentially unsafe products.”
One of the most problematic aspects of Dr. Cohen’s article is the list of ingredients that appears to have been thrown together into a highly confusing and misleading table called “Examples of Potential Adverse Reactions to Legal Ingredients and Adulterants in Dietary Supplements.” For example, it is highly misleading to classify the controversial substances DMAA (1,3-dimethylamylamine), aegeline, phosphodiesterase inhibitors (sildenafil and analogues), galantamine, non-steroidal anti-inflammatory drugs (NSAIDs), stimulants (e.g., b-methylphenethylamine, N-a-diethylphenethylamine), sibutramine, and/or anabolic steroids as “supplement ingredients” as indicated in the subheader of the table, without a clear indication that these are adulterants and/or unapproved ingredients.
Further, according to Stefan Gafner, PhD, ABC’s Chief Science Officer, “it is inappropriate and misleading to list the highly regarded and safe herbs echinacea (Echinacea sp.), hawthorn (Crataegus sp.), and saw palmetto (Serenoa repens) in the same line as the prescription drug galantamine as agents that the table states may potentially cause nausea, vomiting, diarrhea and anorexia.” Dr. Gafner explained that in a systematic review of clinical trials on the safety of echinacea, Huntley et al. established an association between echinacea and allergic reactions but concluded that most clinical trials with echinacea reported similar incidences of adverse reactions for echinacea and placebo. He further noted that in a meta-analysis and systematic review of 24 and eight (respectively) clinical trials on preparations made with hawthorn, the authors concluded that hawthorn is well-tolerated. Adverse events were infrequent, usually mild, and reportedly similar to those associated with the placebo used in the trials. A meta-analysis of 21 saw palmetto clinical trials concluded that adverse effects in the saw palmetto groups were generally minor and similar to those of the placebo treatments as well. The same could be said for the associations between Asian ginseng (Panax ginseng) or hawthorn and the occurrence of palpitations, chest pain, tremor, anxiety or panic attacks, and hypertension.
Dr. Gafner noted that the above information on the safety of botanicals is summarized in the American Herbal Products Association’s Botanical Safety Handbook, 2nd ed., a highly reliable and authoritative reference, the consultation of which is helpful for any clinician who finds him or herself presented with an adverse event in which botanical dietary supplement involvement is suspected.
Blumenthal concluded, “Dr. Cohen is fully justified in his concern over adulterated products labeled as dietary supplements reaching consumers and causing injury, but, in our view, his solutions to address the problem may not be workable or realistic. The primary reason ABC started the ABC-AHP-NCNPR Botanical Adulterants Program is because there are people and companies that don’t play by the FDA’s GMP [good manufacturing practices] rules or the industry’s various attempts at self-regulation.”
The bottom line: ABC believes that neither a revamped adverse event reporting system just for supplements, nor the requirement of a premarket safety assessment for dietary supplements will deter unscrupulous manufacturers and marketers of fraudulent products from attempting to sell intentionally adulterated products, including illegal prescription drugs disguised as dietary supplements. What is needed is more robust enforcement on the part of the FDA, and fortunately, FDA has significantly increased such enforcement in this area in the past few years.