Earlier this month the ethics committee of the Human Genome Organisation (HUGO) issued its statement on gene-therapy research. Its statement was confined to somatic (as opposed to germ-line) gene-therapy research, and the greater part of it dealt with public concerns about the ethical conduct, quality, and safety of such research. These concerns received widespread publicity after a patient died in Pennsylvania in September, 1999, of an adverse effect during a trial of gene therapy for ornithine transcarbamylase deficiency. The case led the then US Secretary of Health and Human Services to ask the Institute of Medicine (IOM) to review policies for the protection of people participating in clinical research. In the first of its two reports, published in April this year, the IOM panel concluded that the most promising system was likely to be one based on accreditation by independent non-governmental organisations, and it recommended that pilot programmes of such systems be instituted. The panel's final report is due next year.
The US Food and Drug Administration has responded to the case by proposing rules that would require researchers doing human trials of gene therapy and xenotransplantation to post on the agency's website known and new safety information about the treatment under investigation. HUGO's statement also refers to the need for public oversight and for continuing review of somatic gene-therapy research. However, apart from recommending that countries have national ethics bodies that cover gene therapy and that all the research be subject to quality and safety controls that conform with international ethical norms, HUGO is less specific than the IOM on how the oversight should be conducted.
The death last month of a healthy volunteer who died soon after a challenge with hexamethonium in a study at Johns Hopkins University of airways response to this agent (see p2114) is bound to intensify public concern about the safety of participants in medical research.
The whole idea of clinical trials is to ensure the safety of patients in general by confirming efficacy and safety of a treatment and by protecting them from exposure to unproven therapy. So efforts have been made to safeguard trial participants, without whose cooperation there would be no proper trials.
The problem is that efforts have been misdirected. Increased regulation is a natural reaction, as exemplified by the IOM's and FDA's responses to the Pennsylvania case, and by the rise (from one to 14 between 1977 and 1999) of federal regulatory actions taken against US institutional review boards (IRBs). The IRB system was set up when large multicentre trials were uncommon. With such trials now rapidly rising in number, IRBs are being inundated with protocol reviews and with reports of adverse reactions that they cannot evaluate sensibly because of lack of accompanying data for risk assessment. What is happening is that regulatory enforcers and IRBs have become preoccupied with adherence to the procedural specifics of outmoded regulations that do not help ensure the safety of participants in modern-day trials.
The UK set up regional multicentre-research ethics committees in 1997. Over the past few years two US federal review panels have called for major modifications to the regulations governing IRBs, and in recent months researchers from the University of Colorado and Duke University have called attention to the need for change, with constructive proposals. With the safety of trial participants being increasingly acknowledged as a factor of paramount importance in clinical research, various means of monitoring trials have evolved, in particular the setting up of data and safety monitoring committees. In addition, there is recognition that responsibility for the safety of participants rests not just with such committees and IRBs, but also with a range of people approving or conducting the trial. The roles of each of these groups, what information they should share, and how they communicate with each other must be clarified.
If the modified system remains bureaucratic, the problems will remain. For a system that is not over-regulated to ensure the safety of trial participants, it has to be underpinned by recognition of the patient's autonomy and the importance of avoiding conflicts of interests among trialists. Fostering a culture of respect for the ethical conduct of trials should thus be part of any safety system.