Introduction to special issue

Lemons, Oranges, and Complexity

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Science  10 Oct 2008:
Vol. 322, Issue 5899, pp. 209
DOI: 10.1126/science.322.5899.209

Faced with an epidemic of scurvy, British surgeon James Lind decided to test some cures in 1747. In a legendary trial, he put 12 sickly sailors on a fixed diet and divided the group into twos. Each pair received a different supplement—cider, seawater, dilute acid, and so on. The result: After 6 days, the two who ate lemons and oranges improved so much that they were sent back on duty. The navy was slow to recognize the significance of Lind's work but eventually decreed that citrus (a source of vitamin C that prevents scurvy) must be in all sailors' rations.

By modern standards, Lind's test was weak. It had no control group. No placebo. No blinding of data. But it worked. By controlling the environment and varying treatments, it made possible an accurate reading of the human body's response. This idea, with many refinements, drives the modern clinical trial. But now the clinical trial itself is facing an epidemic—of rising costs and blurred objectives.

On page 210, David Malakoff reports on the view, as one U.S. researcher puts it, that the “system isn't working.” Malakoff describes factors that are driving inflation. Among them are complex rules for reporting, the proliferation of required tests, the difficulty of recruiting and keeping volunteers, and waste in the design and management of trials. But there is an encouraging note, too: Public and private organizations are aware of these problems and are pushing for reform.

One counterpoint to problems in the West is a boom in the East. Dennis Normile describes the expansion of clinical studies in Asia on page 214. A desire to cut costs is only part of this trend; China and India see clinical trials as a means of growing their economies and developing skills.

Jocelyn Kaiser reports on page 217 about ongoing efforts to make Western trial data more accessible. A mandate requiring disclosure of results from all trials of drugs approved by the U.S. Food and Drug Administration takes effect this fall, for example. On page 219, Constance Holden gives an update on efforts to ensure that U.S. government-sponsored trials are balanced by gender. And Jennifer Couzin dissects an important series of interventions designed to prevent heart disease by controlling cholesterol (p. 220). The results raise fundamental questions about how cholesterol functions in the body—and about the usefulness of certain biomarkers as surrogates for health outcomes.

A video report by Robert Frederick on progress in testing drugs for children, “Pediatric Medicines: Prescribing Off-Label,” appears online at

The subtlety and cost of these modern clinical trials would amaze James Lind.

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