Concerns about adverse events, including deaths, in recent large clinical trials, both publicly and privately sponsored, prompted Elias A. Zerhouni, Director, National Institutes of Health (NIH) to convene a meeting at the NIH on January 11–12, 2005, to discuss “Moving from Observational Studies to Clinical Trials: Why Do We Sometimes Get It Wrong?” (a detailed summary and video archive of the meeting are available at http://www.meetinglink.org/omar/ct/index.htm). “It is time for an ‘M and M’ [Morbidity and Mortality] conference [on medical evidence],” Zerhouni said at the meeting. He challenged attendees to develop innovative ideas to aid decision and policy making, commenting that the credibility of the scientific enterprise was at stake. “Forty percent of science news relates to health or medicine,” he noted, “and we are seeing a gradual erosion of public trust.”
Experts in trial design and analysis reviewed sources of error that can affect clinical investigations from early observational studies to Phase 3 clinical trials. Speakers provided telling examples of biased observational data leading to unnecessary clinical trials, poor trial design and analysis, and misleading communication of results. Participants also proposed ways to maximize the quality of evidence available and considered the impact of the “-omics” revolution on the design of future clinical trials. Ample time was allowed for discussion, allowing the authors, who constituted the Planning Committee, to generate the recommendations (listed in Box 1) that serve as the organizational framework for this article.
Box 1. Recommendations Arising from the Meeting
- Be aware of and eliminate bias and confounders to the extent possible.
- Establish formal means of setting priorities for conducting large clinical trials.
- Employ meta-analyses and systematic reviews to enhance means of weighing evidence, but beware of potential systematic biases.
- Give equal weight to determining safety and efficacy in clinical trials.
- Validate biomarkers and surrogate end points before basing policy guidelines for public health on them.
- Employ the technologies of the “-omics” revolution and systems biology approaches, but with caution.
- Communicate results of clinical trials in an accurate and timely manner.
- Establish two-way communications with communities, consumers, and patient advocacy groups during development, implementation, and reporting of clinical trials.
- Establish criteria to inform public policy and decision making.