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Speech before

American Society for Pharmacology

and Experimental Therapeutics

and American Society for Nutritional Sciences

Remarks

by

Lester M. Crawford, D.V.M., Ph.D.

Acting Commissioner of the FDA

for

Public Affairs Workshop

April 19, 2004

Good afternoon, and thank you, Rudy (Giuliano, professor of pharmacology, UNC) for the introduction. I greatly appreciate this opportunity to participate in a discussion of significant public health issues that are currently -- and have been for some time -- high on the agenda of the Food and Drug Administration.

Dietary supplements and botanical products are a relatively small part of the FDA-regulated 80 percent of the American food supply -- which includes practically everything we eat expect for meat, poultry, and some egg products -- but they are important. They are important because an estimated 50 percent of Americans use them in the expectation of meaningful health benefits. They are important because they are prolific -- there are some 29,000 dietary supplements on the market, and another 1,000 are added each year. And they are important because the $19 billion dietary supplement industry is a significant part of our economy.

Most of these products are safe to use and contribute to good health: for example, folic acid helps reduce the risk of neural tube defects, and calcium helps build strong bones. But some dietary supplements pose a potential health risk because of the way they are manufactured or handled, or because they contain ingredients that have the same complex pharmacologic properties as drugs. In fact, they bear little resemblance to genuine food ingredients.

The principal law governing these products, the Dietary Supplements Health and Education Act of 1994 -- we call it DSHEA -- regards them as food, which means that they are generally considered safe. Unlike the FDA-approved prescription and nonprescription medications, which must be proven to be safe and effective, dietary supplements that were in use before DSHEA was passed -- which is the vast majority of these products -- can be marketed without any review by the FDA. Their manufacturers are not required to report adverse events associated with these products; and the burden of proof about their lack of safety is generally on the FDA.

But the law prohibits these products to be adulterated, misbranded, or carry false or misleading claims. Moreover, DSHEA does not apply the presumption of safety to dietary ingredients introduced after October 1994, when the law went into effect. For these new dietary supplements, DSHEA requires that the FDA be notified 75 days before they're put on the market, and that they be supported by evidence of their safety. If these conditions are not met, the product is considered adulterated, and unfit for human use. DSHEA thus attempts to strike a balance between consumers what they want, which is access to dietary supplements, and FDA's need for authority to act against those products that could be harmful.

FDA is committed to vigorously implement the DSHEA provisions to ensure that all marketed dietary supplements are safe and of high quality, thereby protecting the health of consumers and providing a level playing field for the products' manufacturers. One of the agency's strategies is to regulate the manufacturing processes, which is specifically authorized by DSHEA. We used this authority last spring to propose that the dietary supplement industry comply with good manufacturing processes similar to those that apply to the production of food and other regulated products.

The proposed rule, when finalized, will have no bearing on the dietary supplements' safety and effectiveness, but it will set high standards for their manufacture, storage and handling to ensure that they don't contain impurities or contaminants, and that they are truthfully labeled. The proposal, which is guided by FDA's strategic plan's emphasis on effective risk management, has prompted more than 400 substantive comments from FDA's stakeholders. These responses now being analyzed in preparation for the final ruling.

FDA is also using DSHEA to ban pre-1994 dietary supplements that are shown to harm human health. The requisite proof that such products pose a "significant or unreasonable risk of illness or injury" must be quite exacting, but as shown by the recent FDA ban on ephedrine alkaloids -- best known as ephedra -- it can be effectively used. When we have solid scientific proof that a dietary supplement does more harm than good, we can get it off the market. We certainly had such evidence in the case of ephedra, which was found to be associated with numerous "sentinel events," such as heart attack, seizure, stroke and death, but offere only highly limited, short term benefits for athletes and dieters.

The banning of ephedra is part of our agency's aggressive enforcement of DSHEA against products that are contaminated or labeled with fraudulent health claims. We embarked on this policy in December 2002 by greatly increasing our enforcement activities in partnership with the Federal Trade Commission -- which regulates advertising -- the Department of Justice, and state and foreign law enforcement agencies.

We then announced that we'd be particularly vigilant in monitoring firms that falsely claim that their dietary supplements treat life-threatening diseases; obesity; autism; behavioral disorders; Down's Syndrome and other types of mental retardation; smoking; and alcoholism. We're also taking special care to protect consumers from products with colloidal silver.

In the last 6 months alone, our agency has carried out 180 inspections of domestic dietary supplement manufacturers; issued 119 warning letters to distributors; refused entry to 1,171 foreign shipments; and seized or supervised the voluntary destruction of almost $18 million worth of products. As of April 1, for example, we sent letters to 16 firms warning them to stop making false claims that their dietary supplements were an effective treatment for obesity.

In addition to these programs, we're using the DSHEA authority to supervise dietary supplements put on the market after the law was passed. For example, our agency last month sent letters to 23 companies directing them to cease distributing dietary supplements containing androstenedione, or andro. These products are marketed to stimulate testerostone and muscle growth, but they can pose health risks similar to those inherent in steroid, because they act like steroids once metabolized by the body.

But even as we make good use of all of these tools available to us under the law, there is no question that our agency is challenged when it comes to evaluating the performance of dietary supplements that appear to cause adverse events. Getting accurate information about their safety and effectiveness requires extensive scientific research including literature reviews, pharmacology, animal and in vitro studies, epidemiological investigations, and can even call for clinical studies. Such evidence-based review is endorsed by the recent recommendations of the Institute of Medicine on the evaluation of dietary supplement safety.

As our agency learned from outlawing ephedra, research of this magnitude can place great demands on FDA's resources, and it is in this area where we have a critical need for extramural assistance. I am happy to note that, thanks to institutions that share our concern for protecting the public health, this highly expert assistance has been forthcoming. We benefit in particular from fruitful scientific cooperation with the Office of Dietary Supplements, or ODS, and the National Center for Complementary and Alternative Medicine of the National Institutes of Health.

FDA's main role in this cooperative effort is to help prioritize the ODS' safety and efficacy research on the basis of public health criteria, and use the developed science to guide our risk assessment and risk management activities. Last month, for example, we suggested to ODS four priority topics for evidence-based review.

One of them is ephedra substitutes, primarily Citrus aurantium or bitter orange, which is reported to contain potentially bioactive substances such as synephrine, octopamine and tyramine. Synephrine is a sympathomimetic compound that has been shown to increase systemic arterial pressure in humans and animals.

The second compound we recommended for ODS's review is usnic acid, a complex polycyclic chemical that's produced naturally by certain lichens. Usnic acid has been marketed as an ingredient in dietary supplements that were claimed to enhance weight control, and were implicated in hepatotoxicity.

The third product to which we gave high priority for evidence-based review is pyrrolizidine alkaloids, or PAs, that are present in a wide variety of plants, prominently including the water plant comfrey. Scientific literature clearly associates oral exposure to PAs with veno-occlusive disease in animals, and we need further research on the prevalence of PAs in the marketplace, and an assessment of their chemistry and toxicity in dietary supplements.

We also recommended a review of kava, a botanical ingredient containing a mixture of components called kava pyrones. Dietary supplements with kava have been associated with liver failures, and we would like the ODS to identify the kava pyrones that cause this effect.

In addition to ODS, we also receive critical scientific assistance from the National Center for Natural Products Research at the University of Mississippi. This is a consortium where scientists from FDA, academia and industry cooperate in exploring issues bearing on food safety. For example, this partnership has enabled us to develop analytical methods for "fingerprinting" authentic versions of ephedra, and distinguish them from products that are adulterated.

These two examples of productive collaboration bring me to my last point, which is that the FDA needs more of such support. There is much to be said for the utility of high quality, safe dietary supplements. However, because our agency carries the burden of proof before it can act against such products as are unsafe, we need your help.

We need your help to identify supplements that are dangerous to human health, and to develop the necessary data to prove their lack of safety. We also need your help to ensure that the health claims made for dietary supplements are truthful and not misleading. Keeping our consumers reliably informed about the dietary supplements they buy is a team effort that very much calls for an involvement of the academic community.

Our agency, and our nation, greatly appreciate your collaboration in the past, and I am looking forward to more of it in the future.

Thank you.

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