FDA Warning Letters to Supplement Manufacturers Often Ignored

The dietary supplement industry has an expansive reach, bringing in 151.9 billion in 2021. More than half of U.S. adults consume dietary supplements, fueling the industry. Dietary supplements include vitamins, minerals, botanicals, amino acids, and enzymes, that according to the US Food and Drug Administration (FDA), are not intended to treat or prevent disease. Controversy over adulterated supplements stretches back decades. Under a 1994 law, the Dietary Supplement Health and Education Act, the products are regulated as food and therefore not subject to pre-market safety and effectiveness testing imposed on medications.

To identify products that are unsafe or contain unapproved ingredients, the FDA relies on post-market surveillance efforts. These include review of adverse event reports and consumer complaints, inspection of dietary supplement firms, and screening of imported products. Additionally, a dietary supplement firm is obligated to report to the FDA events that require medical intervention to prevent death, hospitalization, or birth defect. When a product has the potential to cause serious adverse health consequences, the FDA can issue a Class 1 recall and take it off the market. Unless something catastrophic occurs, it is ultimately a voluntary process left up to the sole discretion of the company. We all know how well that works.

When the FDA finds that a manufacturer has significantly violated FDA regulations, the FDA notifies the manufacturer in the form of a Warning Letter. Warning Letters are meant to alert manufacturers that they have violated FDA guidelines, which aren’t just suggestions. The FDA defines a warning letter as “a correspondence that notifies regulated industry about violations that FDA has documented during its inspections or investigations.” 

The FDA has authority to enforce the Federal Drug and Cosmetic Act, including under other applicable federal laws (such as the Dietary Health Safety and Education Act of 1994, the Nutritional Labeling and Education Act of 1990, and the Fair Packaging and Labeling Act), and other regulations enacted by the Agency. The regulations encompass many aspects of how businesses operate, from manufacturing to claims about the product:

• Approving ingredients
• Mandatory labeling requirements
• False labeling
• Misbranding
• Proper manufacturing processes/GMPs
• What is considered credible scientific research for substantiation

Companies have a period of fifteen working days to respond to the FDA Warning Letter. Their response should address the concerns in the letter, providing their reasoning and supporting information as to why they think the products are not in violation of the law.

The FDA schedules a follow-up inspection for roughly 30 days after it receives the warning letter response. At that point, the FDA reviews whether the company has made effective changes to the products in question. In theory, failure to respond to the letter or adequately address the issues can result in a complete stop of the product’s manufacture and sales. The FDA can fine, seize property, recall, slap on criminal prosecutions, and partner with the Federal Trade Commission and other authorities to add additional charges and pursue enforcement.

Sounds intimidating.

Yet, it has come to light that nearly 30% of dietary supplement manufacturers that have received FDA warning letters still have the products available for sale online over six years later. Pieter A. Cohen, M.D., from Cambridge Health Alliance in Somerville, Massachusetts, and colleagues examined the frequency of drug recalls and presence of FDA-prohibited drugs in supplements after FDA warning letters.

In his review, Dr. Cohen and his team reviewed 31 supplement products that had been issued FDA warning letters.

• Only ONE of the companies recalled their product
• At an average of six years after the warning letters, 9/31 products were still available for sale online.
• Of the nine products still available for sale, four still had at least one prohibited ingredient on the label:
  • One label declared the prohibited ingredient included in the FDA warning letter and three listed other FDA-prohibited ingredients.
  • Five of the nine products were found to contain at least one FDA-prohibited ingredient after chemical analysis
  • Four products contained one prohibited ingredient and one product contained three.
  • Two products contained the ingredient for which the FDA issued the warning letter.

Use at your own risk

A paper written by a team from the California Department of Public Health found that dietary supplement use has been associated with 23,000 emergency department visits and 2,000 hospitalizations in the United States each year. Serious adverse events reported with the use of dietary supplements include stroke, acute liver injury, kidney failure, pulmonary embolisms, and death. Identifying adverse events through post-market surveillance efforts poses some challenges, mainly owing to difficulties in asserting causality and under reporting. A U.S. Government Accountability Office report found that, of adverse event reports received by the FDA, most do not initiate consumer protection actions like inspections or warning letters. Additionally, many consumers and physicians may not attribute symptoms to use of a dietary supplement or know to report to the FDA or the associated dietary supplement firm. In fact, poison control centers received over 1,000 more reports of adverse events associated with dietary supplement use than the FDA did over a 3-year period.

To increase transparency and public knowledge, the FDA’s Center for Drug Evaluation and Research maintains the “Tainted Products Marketed as Dietary Supplements_CDER database” (Tainted Supplements database) as a resource to lower risk to consumers. They study analyzes data from the Tainted Supplements database for adulterated dietary supplements associated with a warning by the FDA over the last decade in order to summarize trends.

About 80 percent of the supplements were contaminated by pharmaceuticals that should not have been in the product. Despite these contaminants, fewer than half the products were recalled. The presence of unknown drugs in supplements “poses a serious public health risk,” the researchers wrote. Unfortunately the vast majority of consumers know nothing about this and mistakenly believe the products are carefully regulated and accurately labeled.

Factors to consider before using supplements

Even when dietary supplements contain only ingredients that are listed on their labels and are manufactured under stringent conditions, there are still concerns. In some situations supplements can help manage your health and provide benefits. In these instances, supplements are intended to do just that- supplement the levels of vitamins and minerals that you may not be getting from your diet or because of a deficiency due to other reasons. It is still crucial to partner with your provider, as a variety of details need to be considered, including side effects, interactions, lifestyle, whether you are pregnant or nursing, and your overall individual health. Some examples of frequently used supplements include:

• Calcium and vitamin D to help keep bones strong and reduce bone loss. 
• Folic acid decreases the risk of certain birth defects.
• Ginkgo biloba to help support brain health
• Omega-3 fatty acids from fish oils might help some people with heart disease. 
• A combination of vitamins C and E, zinc, copper, lutein, and zeaxanthin (known as AREDS) may slow down further vision loss in people with age-related macular degeneration (AMD). 

The National Institutes of Health share some examples of negative effects of supplements:

• Vitamin K can reduce the ability of the blood thinner warfarin to prevent blood from clotting.
• St. John’s wort can speed the breakdown of many medicines and reduce their effectiveness (including some antidepressants, birth control pills, heart medications, anti-HIV medications, and transplant drugs).
• Antioxidant supplements, such as vitamins C and E, might reduce the effectiveness of some types of cancer chemotherapy.

Side effects occur most often occur due to taking too much of a supplement, or not considering other sources of the element. Many food manufacturers enrich foods with vitamins and minerals, increasing the overall amount that people ingest- often without realizing. the NIH shares that for example, too much vitamin A can cause headaches and liver damage, reduce bone strength, and cause birth defects. Excess iron causes nausea and vomiting and may damage the liver and other organs.

Lastly, consider this

Unless your provider specifically tells you that you need to introduce a supplement to your routine, don’t. Even those that are most commonly used and have passed third party inspections and are considered “safe”, may have their share of risk. Some recent studies are also casting doubt on the effectiveness of many supplements long thought to be cornerstones to our health routine. Consumer reports shares these examples (and you can read more from CR about the dangers of vitamins and supplements, here):

• Omega-3 fish oil. The widely held view that fish-oil pills help prevent cardiovascular disease hit a snag when a study of 12,500 people with diabetes or prediabetes and a high risk of heart attack or stroke found no difference in the death rate from cardiovascular disease or other outcomes between those given a 1-gram fish-oil pill every day and those given a placebo, according to a June 11, 2012, New England Journal of Medicine online report. But the results may be clouded by the fact that participants were already taking other heart medication. Most people can get enough omega-3s by eating fatty fish at least twice a week. The American Heart Association says that people who have coronary artery disease may want to talk to their doctor about omega-3 supplementation.
• Calcium. The latest blow against calcium supplements was a report by German and Swiss researchers who followed almost 24,000 adults for an average of 11 years. They found that regular users of calcium supplements had an 86 percent increased heart-attack risk compared with those who didn’t use supplements, as reported in the June 2012 issue of the journal Heart. On the other hand, there was a statistically significant 30 percent reduction of heart-attack risk among adults with a moderately high intake of calcium from food itself.
• Antioxidants. Far from reducing cancer risk, as a lot of people believe, high doses of some antioxidant supplements may actually increase it, evidence suggests. The discouraging news appeared in the May 16, 2012, issue of the Journal of the National Cancer Institute. Based on current evidence, vitamins C and E haven’t been found to shield people from cancer; vitamin E, beta-carotene, and vitamin C don’t seem to protect against getting or dying from cancer; selenium doesn’t prevent prostate cancer; and there’s no convincing evidence that beta-carotene or vitamin A, C, or E supplements prevent gastrointestinal cancers. Still worse, the researchers wrote, “Some clinical trials show that some of these antioxidant nutrients may increase cancer risk.”
• Ginkgo biloba. This is an herb often hyped as able to improve memory, vascular and brain health, but it shouldn’t be paired with blood thinners, blood pressure medications, or certain antidepressants. More recent studies (read here), have also found that ginkgo biloba may actually increase the risk of stroke on top of not having any significant impact on memory.

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This new information further adds to previous data that revealed the potential risks involved in using dietary supplements. Apart from potentially consuming harmful ingredients, it is especially important for those who have medical conditions, including high blood pressure, diabetes, liver or heart disease, or are pregnant or nursing or are on any medication to discuss any and all supplements that are being taken so providers can best evaluate the risks, interactions, and benefits to your health.

To report products that may have caused you harm, or to inquire about action taken with specific products, you can contact the FDA:

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