Better Clinical Trial Designs

Clinical trial designs

In order to reduce the diversity gap between men and women and among various subpopulations represented in clinical trials, and to moderate the costs of these studies, we need to innovate in trial design. In other words, we need to think outside the box.

The design, execution, and analysis of clinical trials has become so complex that even for huge multinational drug companies with vast R&D experience, bringing a new medicine to market on average takes 12-15 years and costs well over a billion dollars. The increasing promise of personalized medicine–“the right drug for the right patient at the right time”–notwithstanding, the development of a new medicine is generally focused on the ultimate marketing to a broad range of people. (Examples include drugs like statins, anti-hypertensives, antibiotics, pain relievers and sleep-inducers, for example.)

However, there is wide variation in the responses of different subpopulations to certain drugs; for example, BiDil, a combination drug for congestive heart failure, is approved specifically for black patients (although it can be prescribed “off-label” for anyone).

There are wide differences in the ability of various ethnic groups and individuals to clear medications from the bloodstream because of heterogeneity in the activity of the enzymes that metabolize drugs. For that reason, drug safety and efficacy are affected by the variability in the genes that code for these enzymes.

This phenomenon is important because (with the exception of drugs that must be converted in the body from an inactive to an active form) individuals with low-metabolizing enzymes clear certain drugs slowly and have more medication in their blood for longer periods than those with high-metabolizing ones.

Aging causes important differences in responses to drugs; for several reasons, older patients are far more likely to experience adverse drug reactions. For one thing, clearance by the kidneys and liver, the two most important routes for the elimination of drugs, is reduced; as people age, these organs get less blood flow and there is diminished activity of the hepatic enzymes that metabolize drugs.

Another interesting age-related anomaly concerns the decrease in total body water and the relative increase in body fat seen in older people. Also, women have a higher percentage of body fat than men. Because of these differences, in the elderly of both sexes and in women, water-soluble drugs become more concentrated in the blood and fat-soluble drugs have longer half-lives.

These phenomena have critical implications for the clinical testing of new drugs for safety and efficacy. For example, if investigators perform a successful clinical trial that includes only men aged 20-50, how do we know whether it will be safe and effective for children, women and the elderly at the dose(s) tested? The short answer is, we don’t. We rely on post-marketing trials and surveillance to ascertain how widely applicable the data from the clinical trials are.

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