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Risk Management
The Regulation of Patient-Reported Outcome Claims
  by Louis A. Morris, Pharmaceutical Executive, May 2004

t is now well recognized that the effects of prescription drugs can be characterized by more than traditional safety and efficacy parameters. Although clinically meaningful end points are needed to understand a drug's usefulness and benefit as a safe and effective therapy, the
impact of a drug on a variety of parameters--such as lifestyle, work style, and personal and quality-of-life outcomes--has become an important component for characterizing the effects of a drug. Recently, Burke 1 has characterized and described these types of claims as patient-reported outcome (PRO) claims.

To make PRO claims in advertising and labeling, pharmaceutical companies and the Food and Drug Administration (FDA) must decide if the claims are truthful, i.e., not false or misleading. This is the standard specified in the Food, Drug and Cosmetic (FD&C) Act that ensures that pharmaceutical products are not misbranded and that the company does not violate the law. As a matter of regulation, the FDA has long maintained that advertising claims must be consistent with the approved product label or sufficiently substantiated by additional data. The nature and extent of these additional data, however, have been a matter of debate.

In papers and presentations, experts in the field of outcomes assessment have suggested a variety of methodological stipulations to assure that rigorous standards are applied to support quality of life and similar claims 2. In addition, statements by FDA officials in regulatory letters (see below) and in presentations 3 make it clear that the FDA uses rigorous standards for promotional review. Unfortunately, meeting such standards incurs considerable time and expense on behalf of companies attempting to support such promotional efforts.

Further, as with economic claims, one may question "how much" support is actually necessary. If a drug has been demonstrated to be safe and effective on primary efficacy measures that are described in the product's indications, what is the nature and amount of additional evidence needed to demonstrate support for claims that are logically consistent with the clinically meaningful outcomes noted as the product's indications? As discussed below, the FDA's initial response to this question seems to be that considerable evidence is required.

We argue that a more variable standard should be applied to the regulation of PRO claims. This standard should be based on the degree to which PRO claims make representations about new uses for a product or merely generalize established clinical effects into additional areas of functioning. We believe that such a variable standard is consistent with the recent congressional mandate regarding flexible substantiation for health-economic (HE) claims as well as with the FDA's own internal standards for product labels.

This paper is divided into four sections. First, we briefly review various types of advertising claims as a means of characterizing products; second, we discuss the FDA's legal and regulatory approach to reviewing claims, and PRO claims in particular; third, we discuss a conflict between the FDA's approach to regulating claims in product labels and in product promotional vehicles; and fourth, we argue that most PRO claims more aptly represent extrapolations of the drug's benefits rather than new uses for the drug and that these extrapolations should require a lesser standard for substantiation. We discuss two alternative rationales for changing to a more flexible substantiation policy. Finally, we conclude that consistency between product labels and promotional materials is necessary for effective regulation and that future debate regarding the substantiation of PRO claims should include issues such as the benefits of a truthful claim and the costs of developing substantiation.

Advertising Claims
We can characterize descriptions of any product, including pharmaceutical products, in three different ways 4. First, we can describe products as physical entities. For drugs, the physical dimensions include not only the chemical entity, but also, the intended uses that legally defines the chemical as a pharmaceutical product. Other clinical outcomes such as side effects, precautions, and warnings can also be included in this description. This means that the physical characteristics of a product (e.g., a purple pill) as well as the clinical indications of the product (e.g., treats gastroesophageal reflux disease [GERD]) can be characterized as physical claims.

Second, we can describe products in terms of their benefits. For drugs, benefits often correspond to patients' perceptions of how the drug impacts on their life and functioning. Thus, a drug used to treat GERD may also reduce fear and concern about going to sleep or allow a person to participate more freely in social activities with friends. Many of these benefits may be captured in health-related quality-of-life (HRQL) scales that measure the impact of a disease on a variety of dimensions 5.

PRO claims can be direct extrapolations of a drug's uses and effects without reference to quality-of-life measures per se. In our GERD example, reduction of anxiety associated with sleep and any number of benefit claims could be supported by individual questionnaire items or scale measures, without reference to broader quality-of-life concepts. Other parameters of impact, such as productivity or satisfaction, which measure perceived outcomes with reference to expectations or norms, can be considered PRO claims.

Third, we can describe products in terms of their symbolic characteristics. Even a cursory examination of pharmaceutical advertisements reveals a wide array of symbolism. For example, AggrenoxĂ (aspirin and dipyridamole), a stroke reducing drug, uses an egg carton to symbolize how it protects against broken parts. PrevacidĂ (lansoprazole), a proton pump inhibitor used for multiple gastrointestinal conditions, uses a full-service gas pump to symbolize its wide range of uses and therapy options.

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