The dietary supplement market in the United States has substantially and consistently expanded over the past two decades. The market saw increases of 5.5% in 2007, 7.5% in 2009, and 7% in 2012, raising annual sales to $11.5 billion.1 This number reached $23 billion in 2017, with more than an estimated 85,000 supplement products currently available in the U.S. marketplace.2 Consumers of these products can be found in every age group, with average use across all age groups at around 52%.3
Unfortunately, the dietary supplement market also has been associated with fraudulent claims and deficient quality standards that have endangered the well-being of many consumers. Both patients and health care providers frequently report misconceptions about the safety and marketing of dietary supplements. Several surveys of health care professionals and patients have established that many people incorrectly believe the Food and Drug Administration (FDA) approves dietary supplements based on safety data, efficacy data, or both.4–7 In addition, oncologists report rarely discussing the use of dietary supplements with their patients, despite a concern that the products may impact the efficacy of chemotherapy.8 And despite high rates of self-reported use of dietary supplements, a retrospective review demonstrated that providers rarely asked about use or documented use in the patient chart upon hospital admission.9 It is crucial for health care professionals to gain a better understanding of the risks associated with dietary supplements and to develop strict policies with which to protect hospitalized patients.
Dietary Supplement Regulation in the U.S.
The passage of the Dietary Supplement Health and Education Act (DSHEA) in 1994, which came about after substantial lobbying from celebrities and dietary supplement manufacturers, is often cited as the impetus for growth of the dietary supplement market. It allowed for reduced oversight and restrictions upon any product classified as a dietary supplement (Table 1). In fact, it places the onus of evaluating safety, efficacy, and quality on the manufacturer, but it does not require the manufacturer to provide evidence of this information to any regulating body prior to releasing the product to market.10 This leaves the FDA positioned in a reactive role; regulation of these products can come only after adverse events have already occurred.
|Table 1 Dietary supplement ingredients as defined by the FDA with commonly encountered examples|
|Dietary Supplement Ingredients||Examples|
|Vitamins||Vitamins A, B, D, E, K; ascorbic acid|
|Minerals||Selenium, zinc, copper, magnesium|
|Herbs||Kava, ginseng, ginger|
|Botanicals||Chamomile, lavender, black cohosh|
|Amino acids||Glutamine, arginine, glycine, citrulline|
|Enzymes||Lactase, papain (papaya), protease, lipase|
|Organ tissues||Raw testicle, raw hypothalamus|
|Glandulars||Bovine colostrum, dried thyroid extract|
The inadequate quality of many of these products received a significant amount of attention in the years following the passage of DSHEA. One of the more infamous incidents was the recall of all ephedra-containing products in response to over 900 reports of health events and deaths.11 The inconsistent and irregular alkaloid composition of marketed ephedra products was later identified as one of the major contributors to this rampant health risk.12 A number of other products were also reported to contain inappropriate quantities of the labeled ingredient, adulteration with prescription products, or contamination with an array of unlabeled chemicals. These included some of the most commonly purchased dietary supplements, such as kava, ginseng, feverfew, and dehydroepiandrosterone.13–15
In response to these concerns, Congress passed an amendment to DSHEA in 2007 that established standards for dietary supplement good manufacturing practices (GMPs) as described in Title 21, Part 111 of the Code of Federal Regulations (21CFR111).16 While the law technically requires all dietary supplement manufacturers to register with the FDA and abide by these statutes, the finances and personnel required to enforce this requirement are lacking. Thus, the legislation has resulted in a general misconception that all dietary supplements have reproducible quality, as well as freedom from adulteration, misbranding, and contamination. This has only been advanced by leaders in the natural products industry, touting claims that “…manufacturers must adhere to strict current GMP, requiring identity, potency, and contaminant testing on all ingredients…, only use ingredients that are federally sanctioned, [and] not add pharmaceutical ingredients, including steroids.”17
Dietary Supplement Production Quality Control
Adulteration and Misbranding
Unfortunately, evidence for a continued lack of quality in the industry is easily identified in a review of the FDA alerts related to misbranded and tainted products. The FDA recalled 90 products that were adulterated with drugs in 2017. The majority of these products contained phosphodiesterase-5 inhibitors, claiming to naturally treat erectile dysfunction. Sibutramine, a medication that was withdrawn from the market due to an increased risk of serious cardiovascular events, was also commonly identified in products marketed for weight loss. In the preceding years, from 2014 through 2016, there were 101, 126, and 83 product recalls, consecutively, indicating no promising corrective trends.18
A publication from Newmaster and colleagues reported that when 44 herbal products available on the market underwent DNA testing, 59% did not contain the ingredient(s) listed on the label.19 A similar evaluation conducted by the New York Attorney General’s office on herbal products sold by GNC found that only 22% contained the ingredient(s) listed on the label, 33% tested positive for a botanical material not listed on the label, and 45% contained no plant material at all. In addition, many products contained undeclared allergens, including wheat, rice, and radish.20
Concerns also exist regarding the actual quantity of the active ingredient contained in each product. A report from LeBlanc et al. in 2013 revealed that the vitamin D products utilized in a research study contained anywhere from 52% to 153% of the expected dose. This negatively impacted the researcher’s ability to draw conclusions from study outcomes and also resulted in the inappropriate medical management of many enrolled subjects.21 Individual requests for certificate of analysis (CoA) records from manufacturers for various dietary supplement products have revealed ingredient specification ranges set as high as 250% and as low as 70%.
One of the more sobering cases of misbranding occurred with homeopathic teething tablets that contained high levels of belladonna alkaloids. These teething tablets were labeled as containing only homeopathic, or immeasurable, quantities of the listed ingredients. After receiving reports of serious adverse events, the FDA released multiple requests for a manufacturer recall beginning in 2010. However, the company continued to market the product until 2017.22 Since 2006, 648 adverse events have been reported, including 564 cases of seizures and/or hospitalization and 21 deaths. In spite of multiple FDA warnings, the highest rate of adverse events occurred in 2016, with 110 cases of seizure and five deaths.23 Although belladonna and its alkaloids, atropine and scopolamine, should have been undetectable in these products, a laboratory analysis published by the FDA found that the identified amount of scopolamine per tablet varied up to 4,000-fold from one lot to another, and up to 7-fold between tablets within the same lot.24
Contamination is also a recurring issue in the dietary supplement marketplace. In 2016, one manufacturer was required to recall entire supplement lines that contained 56 times the amount of lead necessary to pose a health risk to an exposed child.25 In early 2018, over 37 distinct products containing kratom were found to be contaminated with salmonella. This contamination was associated with over 200 confirmed infections and 37 hospitalizations.26 Additionally, a report from the Government Accountability Office found that 16 of 40 tested products contained pesticide residues exceeding legal limits.27
Misconceptions: Dietary Supplement Quality
Wholesalers Evaluate Product Quality
A common misconception held by surveyed health care providers is the belief that pharmaceutical wholesalers evaluate the quality of all products on inventory. It is unclear where this belief originated, as this is not a claim made by any of the larger wholesalers. During the authors’ previous attempts to identify high-quality dietary supplement products for institutional use, the vast majority of products stocked by contracted wholesalers did not meet quality standards. Many would not provide documentation by which quality could be assessed; others did not hold registration as a GMP facility with the FDA.
Manufacturers of Generic Pharmaceuticals Distribute High-Quality Dietary Supplements
Another inappropriate assumption made by many health care professionals involves the presumed quality of any product distributed by a manufacturer that also produces generic pharmaceuticals. These companies are regulated by the FDA for GMP of generic pharmaceuticals, which are held to a higher standard than dietary supplements.28 Thus it is a logical conclusion that the manufacture of any other products at the facility would be held to the same standards.
Contact with multiple manufacturers, however, yielded disappointing results. Personal communication with a representative from Mericon Industries revealed that although the FDA audits the portion of the facility that produces hydrocortisone, the rest of the facility is not run in the same fashion. Contact with a representative from Major-Rugby revealed that all dietary supplements marketed under this brand are manufactured by contractors. This creates significant quality concerns. For instance, one contracted manufacturer utilized by Major-Rugby allows a specification of up to 250% of the labeled quantity.29 Other contracted manufacturers with the company had concerning findings on their most recent FDA GMP audits.30
Process for Identifying a High-Quality Dietary Supplement Product
A dietary supplement that is appropriate for patient use should be manufactured under GMP and should not be adulterated, contaminated, or misbranded. While the search for such a high-quality dietary supplement product cannot be guided by traditional approaches, there are four third-party certification programs that can act as a substitute for government oversight (Table 2).
|Table 2 Third-party reviewers of manufacturing quality, in order of rigor|
|Third-party reviewer||USP verification||NSF certification||NPA certification||FDA registration|
|Approval period||3 years||6 months||2 years||3 years|
|Audit frequency||~1.5 years||6 months||2 years||3 years|
|Quantitative||Yes||Only if specified||No||No|
|Abbreviations: FDA = Food and Drug Administration, NPA = Natural Products Association, USP = United States Pharmacopeia|
The United States Pharmacopeia (USP) is best known for providing reference standards and monographs of active pharmaceutical and natural ingredients that allow for ingredient evaluation. This same organization, however, also provides a paid service for dietary supplement companies wishing to carry a stamp that indicates standards of the highest caliber.31
USP verification provides the most stringent analysis of dietary supplement product quality in the marketplace today. The process involves an audit every three years to verify 21CFR111 GMP compliance. An additional audit is conducted at some point in the interim three-year period. USP verification also means that USP will perform random off-the-shelf tests to verify the contents and integrity of the product. Although only a small fraction of dietary supplement companies choose to undergo this verification process—as of 2018, there were 17 participating manufacturers—those that have chosen to participate show a high level of integrity.32
NSF International, the public health and safety organization, was founded in 1944 as an independent organization to test, audit, and certify products and systems to improve global human health. The activities of this organization extend far beyond dietary supplements and pharmaceutical products.
NSF certification of a dietary supplement manufacturer stands as the second-tier indicator for quality of a dietary supplement product. The process of NSF certification involves audits conducted verifying 21CFR111 GMP compliance every six months, the most frequent of all third-party verifications.33 With 486 actively participating companies as of 2018, the NSF certification program has become an important gauge for dietary supplement quality.34 Unfortunately, not all individual products are evaluated, reducing the reliability of the certification and also preventing manufacturers from placing the NSF stamp on the product label. NSF does offer separate certifications that are not included in the basic GMP certification that meet this higher standard—“Contents Tested and Certified” and “Certified for Sport.” The NSF stamp can be found on the label of any individual product that undergoes this certification.
The Natural Products Association (NPA) was founded in 1936 as a nonprofit organization committed to representing and empowering the natural products industry. This company also developed a third-party certification program for member dietary supplement manufacturers.
NPA certification stands as the third-tier indicator for quality of a dietary supplement product. The process of NPA certification involves audits conducted every two years to verify compliance with 21CFR111. In order for a company to bear the label of NPA certification, it must receive an A rating, indicating that a “member supplier demonstrates excellent compliance with NPA GMPs.” As of 2018, more than 60 companies had met this standard.35 However, NPA does not evaluate the quality of individual products, and as such, certification is often not included in the product labeling.36
Guidance for dietary supplement GMP (21CFR111) was passed in 2007 and was slowly implemented to full expectation in 2010. The FDA began to increase the annual audit rate in 2012, with audits continuing into the present. As many as 48% to 70% of audited facilities have been found to be deficient in GMP across the audits completed thus far.37–39
FDA registration stands as the lowest-tier indicator for quality of a dietary supplement product due to inherent issues with the auditing system. Current legislation mandates FDA audits of each registered facility at a minimum of every three years. However, upon receipt of citations and deficiencies discovered during FDA audits, the FDA relies on the cited manufacturer to respond to and correct these findings. The FDA does not currently have a system in place to re-evaluate these issues, and the company can maintain registration status on the FDA website regardless of audit findings. Due to these obvious limitations, FDA registration alone does not indicate quality. Instead, the citations from the most recent audit must be reviewed for serious concerns, a somewhat impractical expectation for most institutions.
Certificates of Analysis
While audits and certifications act as guidance regarding manufacturer compliance with GMP, they do not necessarily provide insight into the contents of each product in relation to the product label. The exceptions to this are those products that carry USP verification or have been reviewed by the product-specific NSF programs.
A certificate of analysis (CoA) often acts as the only method available for evaluating the contents of a specific lot or batch of a dietary supplement product. As these documents are not regulated, the line items vary but will always contain specifications regarding the quantity of the active ingredient(s). Pharmaceutical standards generally require ingredient specifications to fall within 90% to 110% of the labeled quantity of the product. However, these requirements do not apply to the dietary supplement industry, which may result in the receipt of CoAs with large and constantly evolving ranges.
Depending on the manufacturer, a CoA may also provide other valuable information, such as details regarding inactive ingredients. Some CoAs also provide the results for heavy metal content testing and/or bacterial and fungal contamination. Unfortunately, this information is not available on all CoAs, making it difficult to assess anything more than ingredient quantity.
It is apparent that the passage of a DSHEA amendment requiring adherence to GMP has been ineffective in assuring product integrity for the consumer. In fact, in April 2013, an FDA official stated that at least 70% of dietary supplement manufacturers surveyed in the past five years have “run afoul of the US FDA’s manufacturing regulations.”37 As of 2017, FDA auditing outcomes have improved only slightly, with an estimated noncompliance rate as high as 48%.38,39
The prevailing mentality that “dietary supplements, at the worst, will simply not help” appears to be misleading in light of the recurring events of the past decade, some of which were mentioned above. The increasingly common practice of foregoing proven prescription therapies for the use of a natural alternative that typically has no evidence for efficacy introduces a risk for harm.40,41 Contamination, adulteration, and varying ingredient quantities in these same natural alternatives further increase the risk for serious harm and adverse events. Although prescription medications can also cause harm, these potential harms are commonly identified, evaluated, and communicated prior to their release on the market, and the potential harms are weighed against the potential benefits of that specific medication.
Development of a Dietary Supplement Policy
In response to these concerns, we recommend the development of an institutional dietary supplement policy (DSP). This DSP should mandate compliance with the following three criteria for all dietary supplements on an institutional formulary: 1) available safety data, 2) available efficacy data, and 3) the availability of a high-quality product. For dietary supplements that do not meet these requirements, the DSP should disallow the stocking of these products by the institution. We also recommend the implementation of a waiver to be signed by all patients interested in using any nonformulary dietary supplements during admission.
These recommendations are supported by the American Society of Health-System Pharmacists (ASHP), whose guideline states that formulary inclusion of a dietary supplement should follow the same rigorous evaluation process as prescription and nonprescription drugs. In addition, ASHP recommends the implementation of a signed waiver that releases the hospital of liability for use during admission.42 If implemented correctly, such a waiver could serve multiple purposes. First, it provides an opportunity to inform patients of the concerns associated with dietary supplements, including, but not limited to, the scarcity of information on safety, efficacy, and quality. Additionally, it can be written to discourage the use of nonformulary dietary supplements during a hospital admission, eliminating the unknowns associated with such use. Finally, a mandatory waiver would dramatically increase doctors’ awareness of dietary supplement use by their patients. A recent survey indicated that this occurs only 20% of the time, although as many as 52% of hospitalized patients report use of dietary supplements.9
Compliance with a DSP that requires evaluation of safety and efficacy data is relatively straightforward and falls in line with other formulary evaluations. However, adhering to the standard of carrying only high-quality products can quickly become a tedious and complex task, for which little guidance is readily available. The misconceptions and GMP verification options described above should act as a guideline for the development of an institutional policy on the evaluation of dietary supplement quality. USP verification should be considered the gold standard, followed by NSF certification and then NPA certification. If no third-party certification is available, FDA registration can be considered if the most recent audit had no significant findings. For all products without USP verification or product-specific NSF certification, a CoA should be obtained for each new lot received.
Poor quality, contamination, and adulteration are prevalent in the dietary supplement marketplace. The passage of mandatory good manufacturing practices by the FDA has done little to address these issues and protect the public from legitimate risks and safety concerns. Therefore, we recommend the institutional implementation of a policy that guarantees the quality of those dietary supplements that are included on the institutional formulary and utilizes a patient waiver for nonformulary inpatient use of dietary supplements. In order to effectively execute this policy, it is imperative to understand the current limitations surrounding regulation of dietary supplements and to develop an algorithm to identify high-quality dietary supplement products for institutional use. Adherence to this process is complex and time-consuming, but it is the only way to ensure optimal care and minimize risk to hospitalized patients.
Disclosure: The authors report no financial or commercial interest in regard to this article.