Known and unknown diseases and risk factors (including lifestyles of subjects) may influence the results of a clinical study. For example, some diseases alter the pharmacokinetics of drugs (see Chapters 3 through 5). Other drugs and some foods alter the pharmacokinetics of many drugs. Concentrations of blood or tissue components being monitored as a measure of the effect of the new agent may be influenced by other diseases or other drugs. Attempts to avoid this hazard usually involve the crossover technique (when feasible) and proper selection and assignment of patients to each of the study groups. This requires obtaining accurate diagnostic tests and medical and pharmacologic histories (including use of recreational drugs, over-the-counter drugs, and “supplements”) and the use of statistically valid methods of randomization in assigning subjects to particular study groups. There is growing interest in analyzing genetic variations as part of the trial that may influence whether a person responds to a particular drug. It has been shown that age, gender, and pregnancy influence the pharmacokinetics of some drugs, but these factors have not been adequately studied because of legal restrictions and reluctance to expose these populations to unknown risks.
C. Subject and Observer Bias and Other Factors
Most patients tend to respond in a positive way to any therapeutic intervention by interested, caring, and enthusiastic medical personnel. The manifestation of this phenomenon in the subject is the placebo response (Latin, “I shall please”) and may involve objective physiologic and biochemical changes as well as changes in subjective complaints associated with the disease. The placebo response is usually quantitated by administration of an inert material with exactly the same physical appearance, odor, consistency, etc, as the active dosage form. The magnitude of the response varies considerably from patient to patient and may also be influenced by the duration of the study. In some conditions, a positive response may be noted in as many as 30–40% of subjects given placebo. Placebo adverse effects and “toxicity” also occur but usually involve subjective effects: stomach upset, insomnia, sedation, and so on.
Subject bias effects can be quantitated—and minimized relative to the response measured during active therapy—by the single-blind design. This involves use of a placebo as described above, administered to the same subjects in a crossover design, if possible, or to a separate control group of well-matched subjects. Observer bias can be taken into account by disguising the identity of the medication being used—placebo or active form—from both the subjects and the personnel evaluating the subjects’ responses (double-blind design). In this design, a third party holds the code identifying each medication packet, and the code is not broken until all the clinical data have been collected.
Drug effects seen in clinical trials are obviously affected by the patient taking the drugs at the dose and frequency prescribed. In a recent phase 2 study, one third of the patients who said they were taking the drug were found by blood analysis to have not taken the drug. Confirmation of compliance with protocols (also known as adherence) is a necessary element to consider.
The various types of studies and the conclusions that may be drawn from them are described in the accompanying text box. (See Box: Drug Studies—The Types of Evidence.)
As described in this chapter, drugs are studied in a variety of ways, from 30-minute test tube experiments with isolated enzymes and receptors to decades-long observations of popula-tions of patients. The conclusions that can be drawn from such different types of studies can be summarized as follows. Basic research is designed to answer specific, usually single, questions under tightly controlled laboratory conditions, eg, does drug x inhibit enzyme y? The basic question may then be extended, eg, if drug x inhibits enzyme y, what is the concentra-tion-response relationship? Such experiments are usually repro-ducible and often lead to reliable insights into the mechanism of the drug’s action. First-in-human studies include phase 1–3 trials. Once a drug receives FDA approval for use in humans, case reports and case series consist of observations by clinicians of the effects of drug (or other) treatments in one or more patients. These results often