Under the FD&C Act, the FDA has the responsibility of assuring that product labels and promotional statements are not false or misleading in any particular. Thus, the FDA has the responsibility of assuring that statements made on product labels or in advertising are truthful and that the ads themselves do not mislead readers or listeners. It should be noted that there is a distinction between product labels (i.e., package inserts) and promotional labeling (i.e., written, printed or graphic material that accompanies the product, excluding the product label). Product labels establish the conditions under which a pharmaceutical product may be used safely and effectively. They must be approved by the FDA prior to initial marketing. Promotional labeling and product advertisements are regulated by the FDA as promotional materials and must be submitted to the FDA at the time of their initial dissemination.
While the FDA's responsibility to assure that product labels, promotional labeling and advertisements are truthful, how the FDA should discharge this responsibility or what standards it should use are open to the interpretation. For the most part, the FDA has relied on the product label as the arbiter of truth. The FDA expends enormous efforts ensuring that the product label accurately represents the body of knowledge about a drug when it is approved for marketing. In doing so, the FDA thoroughly reviews manufacturers’ draft labeling which it may rewrite extensively to ensure that it is not false or misleading.
Once the product label is approved, the FDA maintains that advertising claims that are consistent with the product label are be truthful. Marketers do not need to use the precise words in the label and the FDA does not object to advertising claims as long as the advertisement and the label convey the same meaning. Thus, it has been long maintained that companies wishing to make certain advertising claims should attempt to include those claims in their product label. However, product labels are intended to provide necessary prescribing information and have precise content and format specifications. Thus, marketing claims may not be included in product labels for two reasons. First, the claim may not be sufficiently substantiated and therefore not held to be truthful. Second, the claim may be sufficiently substantiated but not included in the product label because it does not provide the type of the information specified in the content and format regulations.
FDA regulations specify the nature and amount of evidence needed to support certain types claims included in product labels. Specifically, claims that describe new uses of a product or claims that contain a drug comparison require substantial evidence. Substantial evidence is further defined as consisting of one or more adequate and well controlled studies on the basis of which qualified experts could conclude that the drug has the purported effects. Usually, substantial evidence is provided by two adequate and well controlled studies. However, recent changes in the efficacy requirement now specify that one adequate and well-controlled study plus corroborating evidence can constitute substantial evidence .
For other statements that do not describe the drug's uses or make comparative claims, the nature and extent of substantiation is unclear. Such claims must not be false or misleading and some level of evidence is needed to support them. However, there are no specific regulations guiding the requirements for substantiation. Rather, the FDA has generally relied on the approved product label, whenever possible, to determine the acceptability of promotional claims. The nature and extent of substantiation required depends on whether the product label is relevant, and on the degree to which the FDA deems the supporting evidence to be convincing.
Label Content and Format
Product labels must contain certain information in a specified format (see 21CFR 201.57). There are 11 required sections and 2 optional sections of the label. Most of the specified sections describe a product's risks (e.g., warnings, precautions, and contraindications). It should be noted that the FDA has proposed new content and format requirements for product labels, although these address primarily format issues and do not contain any different substantiation requirements .
Information about a product's benefits is likely to be confined to a small number of sections. Product uses are described in the Indications and Uses section. As discussed above, this information must be supported by substantial evidence. Additional parameters pertaining to the clinical effects of a drug may be described in one of the optional sections entitled Clinical Studies. The Clinical Studies section of medication labels is reserved for additional information that conveys a fuller and more understandable presentation of the product's uses and effects. Information in this section must be based upon the outcome of at least one adequate and well-controlled study.
Thus, information presented in the Indications and Uses section of the product label must be supported by substantial evidence (usually more than a single study) while information presented in the Clinical Studies section can be derived from a single study, albeit an adequate and well-controlled study. It should be noted that theoretically there can be considerable variance in the characteristics of an adequate and well-controlled study. The FDA regulations as per 21CFR 314.126 (b)  describe the methodologies acceptable for adequate and well-controlled studies which include not only placebo-controlled trials, but also include active treatment, no treatment, and historical controls. As a matter of practice, nonconcurrent controlled studies are rarely viewed as adequate and well-controlled studies.
FDA recently disseminated a new guidance for the content and format for the Clinical Studies section of the label . This guidance states that the end points discussed in the clinical trials section should be essential to establishing effectiveness or should provide additional useful and valid information about the effects of the drug. The guidance goes on to state that, “end points presented should be end points the Agency has accepted as evidence of effectiveness, or closely related end points that may be more easily understood by clinicians. When it would be informative, the Clinical Studies section can also discuss other end points that were shown to be affected by the drug and end points expected to be influenced by the drug, but were not.” Thus, the FDA seems to remain open to the inclusion of PRO measures that are meaningful to prescribers. The number of studies needed to support information in the Clinical Trials section is not explicitly discussed in the guidance. However, it does state that the information should support effectiveness statements and that the Clinical Studies section should be carefully scrutinized to ensure that its content does not imply claims for indications that are not adequately supported. Thus, it appears that the FDA has become more concerned about the use of statements in the Clinical Studies section that may be used in advertising or promotion, although the new guidance does not bar the use of results from a single study in this section to support advertising claims.
Regulation of PRO Claims in Advertising
In recent months, the nature of the FDA regulation of PRO claims used in advertising has become more apparent. Examination of letters noting advertising violations that the Division of Drug Marketing, Advertising and Communications (DDMAC) sent to pharmaceutical companies reveals that several clear trends have emerged in FDA's regulation of quality of life and other PRO claims . For example:
In a letter dated March 7, 2000, DDMAC objected to promotional claims for Neoral™ (cyclosporine for microemulsion). Neoral is used to treat transplant rejection. Under the title of Unsubstantiated Claims, DDMAC objected to claims that the drug affected quality-of-life issues in that it reduced the ability to work or to manage a home, restricted recreational activities, limited personal and/or social relationships, and had a variety of physical and emotional effects. DDMAC claimed that these statements were misleading because “they imply that Neoral has an effect on physical, mental and social functioning that has not been demonstrated by substantial evidence.” In the same letter, DDMAC objected to patient satisfaction claims. In the Neoral promotional material, under the heading of Neoral Promotes Patient Satisfaction, the manufacturer provided quotes such as, “I’ve got my life back—the Neoral difference” and “Neoral makes me feel like a normal human being.” DDMAC objected, stating that these were false and misleading because they made “implied and explicit claims that Neoral promotes patient satisfaction that are not supported by substantial evidence.
In a letter dated March 30, 2000, DDMAC objected to a variety of claims for Relenza™, (zanamivir for inhalation), used to treat the flu. In the advertisement, the manufacturer presented several pictures and statements that emphasized the importance of a single day. The ad contained statements such as:
“Even a day can make a difference;”
“She could miss the busiest day of the year;”
“He could miss the playoff game;”
“She could miss the school bake sale;”
“He could miss the annual stockholders meeting;”
“She could miss her granddaughter's recital;” and
“So when the flu virus gets you, you can get it back, and get back to your life sooner.”
The FDA interpreted these statements as unsubstantial claims for improved functional status and productivity.
In a letter dated March 30, 2000, DDMAC objected to claims for a Duragesic™ (fentanyl transdermal delivery system), a potent pain reliever. Among the objections listed, DDMAC cited the claim that the patch affected patients’ quality of life, which required “substantial supporting evidence in the form of adequate and well-controlled studies designed to specifically address these outcomes.”
In a letter dated April 28, 2000, DDMAC objected to claims for Lotronex™ (alosetron hydrochloride), a drug used to treat certain forms of irritable bowel syndrome (IBS). The manufacturer had described the disabling effects of IBS in terms of health-related quality of life, economic costs, and worker productivity. DDMAC cited these as unsubstantiated because the use of such burden of illness claims in conjunction with promotional material about the drug implied that the drug would improve these outcomes, which was unsubstantiated.
In a letter dated June 20, 2001, DDMAC objected to a web site link for Fosamax™ (alendronate sodium), a drug used for osteoporosis. The link, entitled “Preserving your Independent Lifestyle,” was considered misleading because it implied an outcome that had not been demonstrated by substantial evidence.
In a letter dated June 29, 2001, DDMAC objected to claims that Neurontin™ (gabapentin), an antiepileptic drug. DDMAC cited misleading claims for quality-of-life parameters, such as social limitations, memory difficulties, energy level and work limitations. According to the letter, these claims were based on a study that was not considered to provide substantial evidence, as it was an uncontrolled study.
It is apparent from these DDMAC letters that FDA has concluded that substantial evidence must be used to support PRO claims used in advertising. We suggest that this conclusion is in conflict with the FDA's existing policy for product labels. Further, we believe that an alternative conceptualization for PRO claims, with a more flexible substantiation policy, would provide a more reasonable basis for FDA regulation than the current substantial evidence standard.