The Food and Drug Administration (FDA) promotes and protects the public health by regulating a wide variety of consumer and medical-care products. FDA is responsible for ensuring that human food, animal feed, and cosmetics are safe and truthfully labeled; that human and animal drugs, medical devices, and biologics are safe, effective, and truthfully labeled; and that radiation from x-ray equipment and electronic products (such as television receivers and microwave ovens) does not exceed acceptable limits. FDA is now exercising its responsibility to protect minors from chemicals in cigarettes. Thus, a wide array of safety issues are considered in conjunction with a broad spectrum of benefits. FDA also conducts research on risk-assessment methods and mechanisms of adverse health effects. In this section, the Commission offers recommendations about food safety, drug approval, and dietary supplements.

FINDING 6.3.1: The Delaney clause of the Federal Food, Drug, and Cosmetic Act prohibits FDA approval of food additives (section 409) and color additives (section 721) that have been shown in appropriate studies to cause cancer in laboratory animals (or humans). Exactly what is covered by the Delaney clause is very complicated. Prohibition was an appropriate response to unknowns about cancer-causing chemicals when FFDCA was enacted in 1958, but it is inconsistent with modern analytic detection methods and current scientific knowledge.

RECOMMENDATION: The language of the Delaney clause should be modified to permit consideration of the quantitative risk that a covered food additive or color additive might pose, specifying that direct or indirect addition of carcinogens to foods should be prohibited to the extent needed to provide reasonable certainty of no harm, as is in keeping with well-established FDA statutory language.

RATIONALE

The Delaney clause, inserted in 1958 into section 409 of the FFDCA specifies that "no [food] additive shall be deemed to be safe if it is found to induce cancer when ingested by man or animal"; equivalent language in section 721 specifies that "a color additive shall be deemed unsafe . . ." In fact, definitions of food additives are extremely complicated. Excluded from the category of food additives under the Delaney clause are uses of substances generally recognized as safe (GRAS), ingredients sanctioned before 1958 (such as sodium nitrite and BHA in some uses), and pesticide residues on raw agricultural commodities. All intentionally added substances and uses not excluded are covered, such as artificial sweeteners and pesticides that concentrate in processed food. Color additives, covered separately from food additives, may be added to foods, drugs, cosmetics, and even devices. Indirect additions to the food supply are covered by the Delaney clause, including chemicals that migrate into foods from packaging or other food-contact surfaces. Although FDA has been a leader in developing methods for quantitative risk assessment of carcinogens, under the prohibition of the Delaney clause the methods cannot be used. (See also the discussion in section 6.1.3 of this report about the inconsistencies between FIFRA and sections 408 and 409 of FFDCA in the case of pesticides.)

In 1962, Congress enacted an amendment to the Delaney clause known as the diethylstilbestrol (DES) proviso. This amendment permitted the use of carcinogenic compounds as animal-feed additives and veterinary drugs as long as "no residue of the additive shall be found by methods approved by the Secretary by regulation in any edible portion of the animals after slaughter or in any food such as milk or eggs yielded by or derived from living animals." To define no residue, FDA developed a quantitative, negligible-risk standard known as the sensitivity-of-method standard. The FDA commissioner is authorized to specify which analytic detection method should be used to characterize concentrations of additives. The methods chosen typically have a sensitivity corresponding to detection of a concentration associated with an upper-bound lifetime incremental cancer risk of one in a million (10^-6).

The Delaney clause does not define found to induce cancer and therefore does not invite exceptions for substances that induce tumors in rodents by mechanisms that are not relevant to human cancer risk (see section 3.1). However, even in 1958, Delaney required the FDA to determine whether evidence of carcinogenicity in animals had been obtained in "appropriate studies", with emphasis on feeding studies for obvious reasons of relevance. Because the clause focuses on the potentially carcinogenic properties of additives, it does not consider risks of other adverse health effects that can far outweigh risks of cancer, such as risks of developmental or neurologic toxicity, although those risks do get full attention from FDA under other authorities. Nevertheless, the requirement under the Delaney clause to reach a decision on animal carcinogenicity and appropriateness of studies makes a disproportionate claim on agency and petitioner resources, which might better be spread over investigations and reviews of all serious health effects and over decisions of whether any proposed uses of an additive would be deemed safe. Quantitative risk-assessment methods are applied routinely to determine acceptable concentrations of natural, unavoidable food contaminants (such as aflatoxin in peanuts and corn, or mercury in swordfish) or of trace contaminants of food and color additives, and to determine the urgency of regulatory actions.

To its credit, adoption of the Delaney clause called attention to substances that might cause cancer and to the importance of caution when knowledge is limited. The Commission has concluded from various testimony, however, that the direct impact of the Delaney clause on reducing cancer risks for the public has not been large, partly because most food-protection decisions are governed by other strong provisions of the food-safety laws and partly because the clause has been invoked decisively only a few times. Furthermore, FDA's efforts to regulate sodium nitrite in 1979 (under multiple provisions of FFDCA) highlighted the need to balance risks and benefits at different concentrations when a chemical has major health benefits (in this case, prevention of botulism in stored meats).

Debate about the role of food additives and pesticide residues in relation to the role of other dietary factors that increase or decrease cancer risk led to the National Research Council report Carcinogens and Anticarcinogens in the Human Diet (NRC 1996b). That report concluded that calories, fat, and fiber are more important for overall cancer risk than individual food constituents, whether synthetic or naturally occurring.

FINDING 6.3.2: Despite acceleration of the drug-approval process, especially for HIV-AIDS and cancer treatment agents, and despite providing guidance to pharmaceutical and biotechnology firms during various stages of drug development, FDA is often criticized by patient groups eager for access to new agents or agents approved in other countries. At the same time, FDA bears a heavy responsibility to assure the public that the risks of serious adverse effects have been fully investigated and properly evaluated by disinterested experts.

RECOMMENDATION: FDA should sustain its efforts to provide early guidance on appropriate studies and to complete reviews and necessary inspections expeditiously. Accelerated reviews and approvals should be linked to rigorous post-marketing surveillance. In keeping with its counterpart agencies in other countries, FDA should update criteria for toxicity-testing and clinical-trial protocols so that properly documented studies meeting those criteria in other countries can be used as evidence for FDA review. And FDA should continue to work with other countries to harmonize procedural and paperwork requirements, as well as the protocols. Such efforts should be broadened beyond HIV-AIDS and cancer treatment agents to other classes of therapies.

RATIONALE

There is an inevitable tension between careful premarketing assessment before regulatory approval of drugs, vaccines, and other medical products and the desire to make important advances in patient care available to patients. The Commission supports FDA efforts to accelerate the review process, use fee-based enhancement of FDA staff resources, and give guidance to firms and their clinical and biostatistical investigators. Moving towards accelerated reviews must be accompanied by requirements for strict postmarketing surveillance, perhaps including restriction of early prescribing rights to qualified and certified specialists who must closely study their patients' side effects and report them promptly.

In this global economy, FDA is building on many years of public and private international partnerships seeking harmonization of testing protocols and risk-assessment methods to make appropriate use of studies and documentation from other nations that meet mutually agreed-on regulatory standards. Nevertheless, approvals in other countries with different benefit and risk criteria and with different degrees of reliance on postmarketing surveillance cannot automatically lead to approval by FDA. More attention in this country to off-label use and postmarketing surveillance of both benefits and risks would be desirable.

FINDING 6.3.3: The Nutrition Labeling and Education Act of 1990 sets up a framework for justifying health claims on food labels, including those for dietary supplements. This framework requires substantial scientific evidence and review and approval by FDA. FDA published the mandated regulations in January 1993 and approved several health claims. Soon thereafter, however, the Dietary Supplement Health and Education Act of 1994 (DSHEA) changed FDA's authority to regulate the safety and labeling of dietary supplements. The agency now has the burden of proving that a dietary supplement is adulterated before it can act to protect public health. DSHEA also created a presidential commission that was directed to reconsider what evidence would be necessary to make health claims for vitamins and other dietary supplements. Today, dietary supplements can carry FDA-approved health claims. DSHEA also permits manufacturers to make statements of nutritional support without prior approval from FDA. A Keystone Center Dialog report (1996) on health claims for foods and dietary supplements supported the 1990 act and the 1993 FDA regulations and made additional suggestions.

Recent evidence of hazards from herbal supplements promoted among young people for a "natural high" illustrates the consequences of allowing biologically active substances on the market without adequate evidence of safety. Also, evidence from clinical trials of lack of benefit of and probable harm from beta-carotene supplements in smokers at high risk of lung cancer and heart disease illustrate the importance of assuring that health claims are supported by sound science before they are used to promote the sale of products.

RECOMMENDATION: FDA's authority to require scientific evidence to justify manufacturers' claims of safety of and health benefits from nutritional supplements should be reaffirmed and strengthened.

RATIONALE

Vitamin supplements, herbs, and "natural" foods are increasingly marketed with claims of health benefits, reflecting preliminary data from epidemiologic analyses or medical testimonials. Evidence from clinical trails is rarely available. Since 1994, overwhelming evidence has been published that one of the most popular and most promising supplements, beta-carotene, previously considered anticarcinogenic, does not reduce risks of lung cancer and heart disease; instead, beta-carotene is associated with increases in those risks in people at high risk (ATBC 1994, Omenn et al. 1996). In light of the public's and scientists' desire to prevent cancer, heart disease, and other major diseases, we should strengthen the scientific basis of public-health advice, regulatory approval, and product marketing.