THE RISE OF GENERIC DRUGS

Meanwhile, new developments in the pharmaceutical marketplace began to undercut the legal foundations previously used to support trade dress in products such as the purple pill and the blue, diamond-shaped tablet. First, in the 1960s and 1970s, a wave of patent expirations for widely used drugs expanded the potential for generic-drug sales among hospitals, pharmacies, and government purchasing agencies. Generic-drug manufacturers evolved from a shadowy group of firms pressing tablets in small, nondescript warehouses into a set of legitimate pharmaceutical firms regulated by the FDA.22
Second, as state and federal government insurance programs took on a larger burden of drug costs, the value of cost containment through substitution of therapeutically equivalent generic-drug products led to a reexamination of the antisubstitution laws. During the 1970s, state laws prohibiting generic substitution were largely reversed and were replaced by laws mandating the interchangeability of brand-name drugs and approved generic drugs. This was aided by the 1978 publication of the Approved Drug Products with Therapeutic Equivalence Evaluations (known as the Orange Book) by the FDA, a compendium of all products approved by the FDA that were found to be bioequivalent and available for generic interchange. Finally, the federal Hatch–Waxman Act of 1984 established an Abbreviated New Drug Application (ANDA) pathway for FDA approval of generic drugs based on bioequivalence to the brand-name version. In the aftermath of this legislation, the number of prescriptions for generic drugs began to rise quickly in the United States.23,24
These alterations had substantial implications for the legal status of pharmaceutical trade dress. Concerns about palming off were mitigated after FDA protocols ensuring bioequivalence of generic drugs undercut the public health risk that courts had used to justify trade dress for pill attributes. The new landscape was formally recognized in 2003 by the Third Circuit Court of Appeals in Shire v. Barr, a case involving the prescription stimulant mixture of dextroamphetamine and amphetamine (Adderall), marketed principally for the treatment of attention deficit–hyperactivity disorder (ADHD). When Shire Pharmaceuticals brought this drug to market in 1996, its promotional materials highlighted how differences in the color, size, and shape of the various doses of Adderall promoted the ability of children with ADHD to adhere to their regimens. Shire sued Barr, the first generic competitor, when it copied Adderall's distinctive dose–color scheme. At trial, Barr argued that Shire's own claims established the functionality of the purported trade dress. The court agreed, finding that because of their functionality, the color, size, and shape of Adderall were nonprotectable.25
TRADE DRESS AND PUBLIC HEALTH
The Shire v. Barr case unraveled the legal protection that previously supported pharmaceutical trade dress.18 Since then, certain Supreme Court cases have further demarcated its boundaries.26 For example, the Court held that trade dress did not apply to functional aspects of temporary road signs even when alternative designs existed that could perform a similar function.6 Thus, the Court clarified that competitors were indeed free to copy features that increased the utility of a product.
However, claims of trade dress remain vital in the pharmaceutical market.19 With increasing generic competition, trade-dress strategies are described in industry publications as ways for innovator firms to retain market share for their products after their patents and market exclusivity expire.18 During at least the past 5 years, brand-name pharmaceutical companies have begun to license their trade dress to manufacturers of so-called authorized generics, which advertise the characteristic of similar appearance as a reason for consumers to use these products.
Proponents of trade-dress protection argue that consumers need to be able to identify the brand by the appearance of the pills because the drugs are dispensed in a standard prescription bottle.19 Yet this argument is undercut by the success of the FDA's bioequivalence protocols, which have been consistent on a pharmacologic level27 and translate into comparable clinical effectiveness for nearly all brand-name and generic drugs.28 Instead, the existence of generic drugs that look different from the brand-name version can have important negative effects on patient outcomes in three key areas — prescription error, medication adherence, and the contribution of the placebo effect — as described below.
It is well known that prescription error can result from confusion regarding the appearance of a drug. Much of the research into this problem emerges from the inpatient setting,29 but confusion borne by outpatients involving pills with different attributes has been reported as well.30,31 Although all pills are imprinted with an identifying code, these codes are indecipherable by most patients, as well as by many physicians.32 Confusion about pills may be exacerbated as a result of regimen complexity or among patients with limited health literacy.33 Patients who take multiple medications are often elderly, with higher rates of visual or cognitive impairment, which increases the risk of errors.34-36 Recently, color and shape differentiation have been shown to be important factors in patients' correct identification of over-the-counter drugs.37
The World Health Organization has estimated that as few as half of all drug regimens for the treatment of chronic diseases are optimally adhered to.38 As the public health problem of nonadherence became increasingly recognized,39 the use of DTC advertisements that included images of pills were defended as increasing adherence to medication regimens for chronic diseases.40 Although no direct research has been carried out on this issue, claims linking pill color and shape to adherence by patients with ADHD were central to the case of Shire v. Barr. Particularly during the transition period after brand-name drugs lose their market exclusivity, consistency in appearance between brand-name drugs and generic drugs could help promote patient adherence.
Finally, a resurgence of research on the placebo effect suggests that drug appearance can have a distinct functionality. For decades, studies have shown that the efficacy of placebo pills varies according to the size, shape, and color of the pills.41-44 The placebo effect is particularly evident in the treatment of patients whose disorder has potential psychosomatic components, such as anxiety, depression, dyspepsia, impotence, obesity, and pain.45,46 Newer research suggests that placebo efficacy varies with external packaging and the perceived dollar value of the treatment being applied.47 Although the classic logic of the randomized, controlled trial casts the placebo effect as a negative foil for measuring therapeutic efficacy, in practice a drug's effectiveness is still due, to some extent, to placebo effects. By not allowing a generic version to fully benefit from the functionality of such effects, differing appearances may reduce the ultimate effectiveness of certain generic drugs.
Literature that measures the magnitude of prescription error, medication adherence, and placebo effects attributable to generic or brand pill appearance is limited; explicit outcomes research in this area is still lacking. No one knows how many medication errors are due to problems related to visual cues. Nonetheless, it is clear that the external attributes of pills can have benefits separate from the therapeutic effect of their active ingredients. It follows that maintaining some consistency of these effects is important to ensure the overall equivalency of brand-name drugs and generic drugs.