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This is the first in a series of updates concerning compliance initiatives underway by the U.S. Food and Drug Administration (FDA) that affect various segments of the regulated industry. This issue focuses on court actions, Warning Letters, recalls, and other matters pertaining to dietary supplements. We will periodically outline actions and issues affecting prescription and over-the-counter (OTC) drugs, medical device and diagnostic products, food, cosmetics, animal drugs, and biologics.
Background
FDA regulates dietary supplements pursuant to authority granted it by the Dietary Supplement Health and Education Act of 1994 (DSHEA). A dietary supplement is defined in DSHEA as a product taken by mouth that contains a dietary ingredient intended to supplement the diet. Generally, such ingredients may include: vitamins, minerals, herbs or other botanicals, amino acids, and substances such as enzymes, organ tissues, glandulars, and metabolites that will usually be found in forms such as tablets, capsules, soft gels, gel caps, liquids, or powders. DSHEA places dietary supplements in a special category under the general umbrella of “foods,” not drugs, and requires that every supplement be labeled a dietary supplement. The dietary supplement or dietary ingredient manufacturer is responsible for ensuring that a dietary supplement or ingredient is safe before it is marketed. FDA is responsible for taking action against any unsafe dietary supplement product after it reaches the market. Generally, manufacturers do not need to register their products with FDA nor get FDA approval before producing or selling dietary supplements. Manufacturers must make sure that product label information is truthful and not misleading.
All domestic and foreign companies that manufacture, package, label, or hold dietary supplements, including those involved with testing, quality control, and dietary supplement distribution in the U.S., must comply with the Dietary Supplement Current Good Manufacturing Practices (GMP) for quality control. In addition, the manufacturer, packer, or distributor whose name appears on the label of a dietary supplement marketed in the United States is required to submit to FDA all serious adverse event reports associated with use of the dietary supplement in the United States. Since for the most part there are few pre-market requirements for supplements, the FDA compliance activities center on reviewing adverse event reports, the suitability of ingredients, compliance with the GMP requirements, and a review of claims made to assure that supplements are not promoted for drug claims. A sampling of compliance matters for supplements follows.
Court Proceedings
Three recent proceedings involve actions to enforce the provisions discussed above. A court in Port Washington, New York, directed a seizure by U.S. marshals of supplements where the company involved had claimed the ingredients of the supplements could prevent or treat a variety of diseases such as senile dementia, brain atrophy, atherosclerosis, kidney dysfunction, gangrene, depression, osteoarthritis, dysuria, and prostrate, liver, and lung cancers. FDA alleged the products did not comply with any monograph, had not been cleared by the agency, and the ingredients in use were not recognized as generally safe and effective for any of the claimed uses. It was also alleged that the products failed to comply with GMPs for dietary supplements.
A second court action in New York illustrates the effect of failing to follow GMPs. A U.S. district court judge signed a Consent Decree whereby the manufacturer had to stop production and distribution of all dietary supplements, and recall and destroy all affected product due to repeated failure to comply with the GMPs. This drastic action was required even though there had been no illnesses reported from the use of the products. It was enough for the government to show that, after inspections, there was not sufficient evidence that the company had controlled the quality of its products by compliance with the GMPS. To get back in business, the firm had to agree to make fundamental changes to its operations and hire an auditor to oversee and review progress made toward compliance. The auditor had to make reports to the court over the next two years.
Another Consent Decree just approved by a federal judge in Minnesota shows the breadth of actions that can be required when FDA can demonstrate to the court’s satisfaction that a dietary supplement manufacturer had distributed product with drug claims, which product also was produced without compliance with GMPs. The company agreed to stop distributing its products until all disease claims were removed from its websites and product labels and the company complied with GMPs. (Enforcement of the GMPs is a powerful tool for the agency. It is often more straightforward to demonstrate non-compliance than it is to prove allegations about claims relating to illness and the like, and, as shown above, the consequences to a company can be dire.)
The court actions discussed above resulted from a failure of the company involved and the agency to resolve issues often raised in a Warning Letter that was issued after an unsatisfactory inspection and informal discussion of the issues involved. The Warning Letters might be issued to a single company or they might go to all companies distributing a product when an inspection or other investigations uncover ingredients that are in question.
An example of the latter is a series of Warning Letters sent several months ago to ten manufacturers and distributors of dietary supplements containing dimethylamylamine, more popularly known as DMAA, for marketing products for which evidence of the safety of the product had not been submitted to FDA. Also referred to as 1,3-dimethylamylamine, methylhexanamine, or geranium extract, the ingredient is in dietary supplements and is often touted as a “natural” stimulant. Specifically, the Warning Letters cite the companies for marketing products for which a notification had not been submitted for the use of DMAA as a New Dietary Ingredient (NDI). Under current law, dietary supplement manufacturers or distributors who use certain dietary ingredients not marketed in a dietary supplement prior to October 15, 1994, are responsible for notifying FDA of evidence to support their conclusion that their dietary supplements containing NDIs are safe. Manufacturers or distributors must submit notification at least 75 days before marketing their products. The companies warned were marketing products for which this requirement had not been met.
The Warning Letters also advised the companies that FDA is not aware of evidence or history of use to indicate that DMAA is safe. Under the DSHEA, manufacturers, marketers, and distributors of dietary supplements are responsible for ensuring that they are marketing a safe product. The letters noted further that DMAA is known to narrow the blood vessels and arteries, which can elevate blood pressure and may lead to cardiovascular events ranging from shortness of breath and tightening in the chest to heart attack. FDA had received 42 adverse event reports on products containing DMAA. While FDA acknowledged that the complaints do not establish that DMAA was the cause of the incidents, some of the reports included cardiac disorders, nervous system disorders, psychiatric disorders, and death.
Among the Warning Letters sent to individual companies is one sent to a Georgia company by the Atlanta FDA district office, alleging multiple violations of the GMPs, including the absence of a master manufacturing record for each formulation and batch size, a lack of product specifications for the purity, identity, strength, and composition of finished batches of each supplement, written production and process control system records, and dozens of other claimed GMP violations. Similar letters pertaining to GMP violations recently went to companies in Minnesota, Maine, Michigan, California, Pennsylvania, and Oregon.
The matters reported above, for the most part, are serious allegations still in the process of being resolved, and with the exception of the court cases, not adjudicated findings of wrongdoing.
If you have questions regarding these matters, please call or e-mail Jayne P. Bultena (703-532-7956) or Michael F. Cole (202-465-5629).