Practical Issues in conducting multi-country studies by Ken Stanley, Ph.D. Harvard School of Public Health Collaboration Complexities 10 Basic Principles

Collaboration Complexities A clinical trial in a single country is a complex undertaking Medicine Laboratory sciences Quantitative sciences Ethics Politics Regulatory affairs Involvement of multiple countries significantly increases this complexity

1.Alternate study leadership; do not share leadership Common problem in collaborative studies Everyone is trying to be very democratic and accommodating to the views of others A high-quality clinical trial needs a clear structure, hierarchical organization, and clear decision-making mechanism Select one group to be the leader this study; select another group to be the leader next study

Components to be handled by one group Operations office functions (one Study Chair) Statistical center functions Randomization/registration Analysis plan and all analyses Primary & secondary endpoint criteria Data management center functions Forms, data flow, entire database Data management & quality control Data queries & regulatory/routine reports Site performance evaluations

2.Standardize, document and periodically check all key study components Study components include Disease classification/diagnosis/eligibility Primary & secondary endpoints (in detail) Toxicity criteria & reporting Laboratory parameters (especially norms) Intervention (e.g. drug, drug dose, route, timing, modification/cessation) Concomitant medications/management

3.Agreeing to disagree is not an option Many decisions are made by a “committee” While decision is often democratic It must be implemented rigidly by all Each participating site needs to “sign-off” Make sure all staff (esp. the junior clinicians) get the message

4.The discipline of randomization must be established and maintained Randomization is scientific research at its best All staff must support the need to randomize Clinicians must not try to circumvent Randomization staff must not bend the rules Nurses must not try to guess trt. assignment Patients must not try to unblind themselves Set high scientific standards Use randomized, double-blind, placebo- controlled clinical trials whenever possible

5.MDs are notoriously poor at filling out data forms Highest priority for the doctor & nurse must be care of the patient MDs shouldn’t fill out data forms Often fill out only what they feel is important Often try to rely on memory rather than check Often give low priority to “secondary” values Need to identify a “data manager” at each site - priority is collecting high-quality data

6.Data managers are professionals too A good data manager exerts a major positive influence on other study staff Goal is to generate high-quality data Set and maintain high standards Don’t permit bending of the rules Quantitative evaluation of performance Quality data managers are vital to the study Treat them as professionals “Super Dragon” of the int’l. coop. groups

7.Periodic meetings of key staff with wide-open reviews of performance Performance of sites must be monitored Monthly data timeliness & error rates Yearly detailed performance measures Reviewed in open meetings with rep’s from all sites and funding agencies Performance of all components monitored Establish measures, goals, track & report

8.Use an Executive Com. with one participant from each component Common weakness - to form an Executive Committee with only key clinicians A successful clinical trial requires quality work from all components Sites Operations Office Statistical Center Data Management Center Central labs, etc.

9.Use an Independent Data Monitoring Committee (IDMC/DSMB) If a randomized Phase III clinical trial - use an IDMC/DSMB A committee of independent experts Can guide the research Recommend study changes Not vested in the study Best group to make difficult decisions Ensure study meets international standards

10.Only modify an ongoing study if the change is “enthusiastically unanimous” Modifying an ongoing study often takes more core resources than originally starting the study Some participants will not implement the changes - if they silently disagree A study modification not uniformly implemented can severely harm a study

Concluding remarks The major initial “shock” for most new centers is the “discipline” of the clinical trial Clinical trials should be designed to be definitive – whether “+” or “-” Only when a single-country study cannot be definitive – consider a multi-country study The greatest legacy of such studies is often the promotion of good clinical research methodology among the young clinicians