A generation ago, we adopted a national system for the protection of human subjects in research. Today, that system is facing new challenges. Many argue that the system has failed to evolve in concert with dramatic changes in the research environment. Accordingly, efforts are underway to reform the existing process to make it both more efficient and more effective. At the same time, many are also reexamining the system in more fundamental ways — going well beyond considerations of policies and compliance and raising questions that go to the very foundations of what constitutes an ethical conduct of human research.

Experimentation involving human subjects is a necessary step in the process of translating scientific discovery and technological advancement into procedures and products that offer the prospect of better lives for all of us. It helps us to better understand why we do the things we do and believe what we believe.

Institutional review boards (IRBs) and investigators are used to talking about risks of harm. Both low risks of great harm and high risks of small harm must be disclosed to prospective subjects and should be explained and categorized in ways that help potential subjects to understand and weigh them appropriately. Everyone on an IRB has probably spent time at meetings arguing over whether a three-page bulleted list of risk description is helpful or overkill for prospective subjects. Yet only a small fraction of all the time and attention lavished on risk disclosure has been devoted to discussing whether and when potential benefit to subjects can reasonably be claimed and, if so, how it should be described in the consent form and process.

Traditionally, IRBs and regulators have worked to ensure that clear lines can be drawn between research that, by definition, carries no potential for direct benefit — because it uses healthy volunteers or because it is not foreseeably focused on the development of treatments — and research that does have the development of effective treatments as its goal.

The institutional review board (IRB) is the social-oversight mechanism charged with protecting research subjects. Performing this task competently requires that the IRB scrutinize informed-consent procedures, the balance of risks and potential benefits, and subject-selection procedures in research protocols. Unfortunately, it may be said that IRBs are spending too much time editing informed-consent forms and too little time analyzing the risks and potential benefits posed by research. This time mismanagement is clearly reflected in the research ethics literature. A review of articles published between 1979 and 1990 in IRB: A Review of Human Subjects Research, for example, reveals a large number of articles on informed consent and confidentiality (142 articles) and considerably fewer on the assessment of risks and potential harms (40), study design (20), and subject-selection procedures (5).

Until a few years ago, the prevailing view was that children should not be participants in clinical research trials because children were incapable of consenting to such nontherapeutic interventions and are particularly vulnerable to abuse. That view has undergone a significant shift in the last few years, particularly in the context of trials to test the safety and effectiveness of drugs. A number of events facilitated this change, including the widespread off-label distribution of drugs to children and developments in the AIDS epidemic. These social forces have shifted the core ethical question from whether children should be research subjects to when children should be research subjects.

The presumption in favor of including children as research subjects for drug trials has manifested itself primarily through two different reforms: a 1997 federal statute and a set of regulations promulgated by the Food and Drug Administration (FDA) that recently became effective. Together they reflect the view that children deserve the same access to safe and effective therapies as adults.

In the summer of 1995, Thomas W. Parham went to his physician, Peter Arcan, for an ordinary check up. During his visit, Dr. Arcan suggested that Mr. Parham join a clinical trial studying a new drug to shrink enlarged prostates. Mr. Parham was confused because he never had prostate problems, but Dr. Arcan stated that the drug might prevent future difficulties. When asked why he joined the study, Mr. Parham stated, “I just followed his advice, just like if he said to take two aspirin instead of one. He’s a doctor and I’m not.”

Mr. Parham should not have been entered into the study because he had been hospitalized a year earlier due to a chronic slow heart rate, a clear study-exclusion criterion that would disqualify him from being a subject in the protocol. However, Dr. Arcan sought an exemption from the drug company stating that Mr. Parham’s heart rate was only “mildly slow,” failing to report the prior hospitalization. After Mr. Parham began taking the study medication, he complained of fatigue, a symptom of a slow heart rate. Within weeks, after requesting to be taken off the study, he was hospitalized and a pacemaker was implanted for his slow heart rate. The drug’s manufacturer, SmithKline Beecham P.L.C., was paying Dr. Arcan $1,610 for each patient enrolled in the study. The fee covered study expenses, but was sufficient to give the recruiting physician a profit for each subject enrolled.