als (Califf and DeMets, 2002a,b). The case of anticoagulant drugs illustrates this need. These drugs are characterized by a complex balance of benefit (prevention of blood clots) and risk (bleeding) (Schünemann et al., 2004). Aspirin has been available for over 100 years and heparin for over 50 years. Yet the best dose of each for preventing arterial thrombosis remains controversial. Multiple new drugs, including direct antithrombins, low-molecular-weight heparins, P2Y12 inhibitors, and glycoprotein IIb/IIIa inhibitors, have been developed in the past two decades and have been demonstrated to provide a net balance of benefit on average in patients entered into clinical trials. Yet little is known about the appropriate dose of these agents in children, the very elderly, and patients with renal impairment. The adjusted dosing regimens for heparin and coumadin, each of which has been marketed for more than four decades, were delineated relatively recently after thousands of patients had been entered into clinical trials that included outcome measurement to determine the degree of anticoagulation with each agent that led to prevention of thrombosis without unacceptable bleeding.
Once a drug is on the market, the expansion to new indications continues throughout its life cycle. Most postmarket studies funded by industry are intended specifically to expand the market for a drug, and such studies are usually not undertaken unless the calculated probabilities indicate that the study will yield a positive financial return (Tunis et al., 2003). Direct comparisons of a drug with an alternative drug or other treatment rarely meet this financial test because there is too great a risk of finding that there is no difference or that the competing treatment is better.
An increasing number of reports over the past several decades have called for a marked increase in pragmatic clinical trials that answer questions relevant to clinical practice (Crowley et al., 2004). A new approach is needed that includes industry participation, but also independent oversight to stimulate more such trials. Lacking the results of such trials, neither prescriber nor patient can know what treatment plan is best.
A critical issue is where to draw the line between the premarketing development phase and the point at which the drug is allowed on the market. Scientifically, the gaining of knowledge about a drug should be a continuous process in which new information is used to refine understanding of the drug’s uses, benefits, and risks at particular doses in particular patients. In actuality, however, the development of scientific knowledge about drugs is quite discontinuous, and the process is dependent on clearing a series of hurdles with defined criteria. In particular, tremendous effort and expense go into the New Drug Application (NDA) required to obtain initial approval for marketing (see Chapter 2). Ideally, at the time of initial marketing, the balance of a drug’s benefit and risk would be known so that the label for its use could be clear. In reality, however, the costs of drug