Clinical Trials

Clinical Trials: A Practical Guide ■❚❙❘numerous negotiations. The consent form and case report forms might then haveto be translated for use in multinational studies and minority ethnic communities.Protocols might also need to be translated for use by international researchers.Selection of centersThe sites that are invited to participate can impact a trial in several ways. The sitesinvited should be both competent at undertaking the research and able to meetrecruitment targets for the trial. The competency of centers can be determined bothby external regulatory bodies – such as the FDA in the USA – or by internal auditcommittees. The purpose of such audits is to protect the rights, safety, and well-beingof trial subjects, particularly as they might be vulnerable due to illness. Most sites nowadhere to international codes of conduct for research, such as the InternationalConference on Harmonisation guidelines for Good Clinical Practice [14].The number of centers needed for a multicenter trial will depend on the estimatednumber of eligible patients at each center. While some coordinating units keeprecords of recruitment rates from each site, other coordinating units performa survey prior to authorizing sites to recruit patients, saving considerable time,frustration, and embarrassment later if recruitment rate projections are overambitious.Such surveys help to keep trials within their budgets.Randomization of patients and interim analysesThe presence of additional sources of variability not present in single-center trials(due to variations in protocol adherence or the level of skill of the investigators atcenters) is a specific drawback of multicenter trials. To minimize this variability,multicenter trials are designed to use a randomization method that equallydistributes patients from each center to each treatment strategy (see Chapter 7).In this way, missing data from a single center are also distributed equally acrossthe treatment groups.Telephone randomization is currently the gold standard (with Internet andinteractive voice-randomization services becoming increasingly popular), andimbalances in randomization can be dealt with by minimization criteria set out inthe protocol. At an early stage in recruitment, the independent data and safetymonitoring board will view the data by center if the sample size is large. Centerswith large deviations in results will be scrutinized in more detail to ensure thatthere are no particular biases or problems. Towards the end of the study, statisticaltests called interaction tests are performed to confirm that treatment outcomes aresimilar across all of the centers and that they are not unique to a few centers.161