Cluster Randomized Clinical Trials (CRTs) and Group Randomized Trials (GRTs)

Cluster randomized trials are experiments in which intact social units or clusters of individuals rather than independent individuals are randomly allocated to intervention groups. In cluster randomized trials, the unit of randomization is different from the unit of observation or unit of analysis. In typical clinical trials, the unit of randomization is the individual subject (or patient/participant) while in cluster randomized clinical trials, the unit of randomization is a cluster. The cluster can be a community, a hospital, a school,...

Examples: 

• Medical practices selected as the randomization unit in trials evaluating the efficacy of disease screening programs 
• Communities selected as the randomization unit in trials evaluating the effectiveness of new vaccines in developing countries 
• Hospitals selected as the randomization unit in trials evaluating educational guidelines directed at physicians and/or administrators

Cluster randomized trials may be called Group-Randomized Trials and these two terms can be used interchangeably. Dr. David M. Murray from NIH prefers to use the term 'group-randomized trials' (GRT in short). He had a 7-part online course to help researchers design and analyze group-randomized trials (GRTs). It includes video presentations, slide sets, suggested reading materials, guided activities, and a list of course references (PDF). He provided the definition and the distinguishing characteristics for CRTs or GRTs:

• Groups randomized to study conditions with some connection among participants before and after randomization. 
• Many trials conducted in communities, worksites, schools, etc.
• The unit of assignment is an identifiable group. 
• Different groups are allocated to each condition. 
• The units of observation are members of the groups. 
• The number of groups allocated to each condition is usually limited.

Cluster randomized trial is not a new concept and is probably mainly used in public health field than in drug development field. Cluster randomization is a type of pragmatic trial and focus on evaluating the effectiveness of difference interventions (treatment policy, regimen,...) comparing to the typical clinical trials focusing on evaluating the efficacy. 

Back in 90's, we had used the cluster randomization trial in an iron-deficiency anemia prevention and treatment study in Children in China. We selected several model counties and within each model county, we randomly select townships to implement three different intervention strategies: health education, drug treatment for children with severe anemia; drug treatment for children with moderate and severe anemia. 

While cluster randomized trials are under-used, we started to see more discussions about the cluster randomized trials and also see the results from studies using cluster randomization published. 

In a paper by Mitja et al (NEJM 2021) "A Cluster-Randomized Trial of Hydroxychloroquine for Prevention of Covid-19", the cluster is the ring of the contacts of the index case (Covid-19 patients). "In the ring vaccination trial, a person newly diagnosed with the disease becomes the index case around whom an epidemiologically defined ring is formed. This ring is then randomized to either immediate vaccination (intervention) or delayed vaccination (control) in a 1:1 ratio on an open-label basis." The inclusion criteria specified the eligible subjects are "asymptomatic individuals exposed to a PCR confirmed COVID19 case within 5 days as either a healthcare worker or household contact".

In a paper by Victor et al (NEJM 2018) "A Cluster-Randomized Trial of Blood-Pressure Reduction in Black Barbershops", "the barbershops were assigned to a pharmacist-led intervention (in which barbers encouraged meetings in barbershops with specialty-trained pharmacists who prescribed drug therapy under a collaborative practice agreement with the participants’ doctors) or to an active control approach (in which barbers encouraged lifestyle modification and doctor appointments). The primary outcome was reduction in systolic blood pressure at 6 months."

In a paper by Katzmarzyk et al (NEJM 2020) "Weight Loss in Underserved Patients — A Cluster-Randomized Trial", they "randomly assigned 18 clinics to provide patients with either an intensive lifestyle intervention, which focused on reduced caloric intake and increased physical activity,

or usual care."

Arrossi et al (Lancet Global Health 2015) described a study about "Effect of self-collection of HPV DNA offered by community health workers at home visits on uptake of screening for cervical cancer (the EMA study): a population-based cluster-randomised trial" where 200 community health workers were randomly allocated in a 1:1 ratio to either the intervention group (offered women the chance to self-collect a sample for cervical screening during a home visit) or the control group (advised women to attend a health clinic for cervical screening).

In a recent paper by Mitja et al (NEJM 2020), "A Cluster-Randomized Trial of Hydroxychloroquine for Prevention of Covid-19". The cluster was also defined as the rings from the contact tracing. "We defined trial clusters (called rings) of healthy persons (contacts) who were epidemiologically linked to a PCR-positive case patient with Covid-19 (index case patient). All the contacts in a ring simultaneously underwent cluster randomization (in a 1:1 ratio) to either the hydroxychloroquine group or the usual-care group."

Cluster randomized clinical trials may be good for some vaccine trials. Henao-Restrepo et al (Lancet 2016 published a vaccine study against Ebola virus "Efficacy and effectiveness of an rVSV-vectored vaccine in preventing Ebola virus disease: final results from the Guinea ring vaccination, open-label, cluster-randomised trial (Ebola Ça Suffit!)". Based on the results from this cluster-randomized trial, FDA approval of the vaccine for the prevention of disease caused by Zaire ebolavirus in individuals 18 years of age and older. In this phase 3 open-label, cluster-randomized study comparing immediate versus delayed vaccination against EVD, index cases (persons newly diagnosed with EVD) were identified by the Guinean national surveillance system. A cluster (or ring) definition team defined the cluster population by creating a list of all contacts and contacts of contacts (CCC), relative to the index case, regardless of eligibility for vaccination, including absent CCCs.

The "cluster randomized clinical trials" is the topic for the next UPENN annual conference on statistical issues in clinical trials. I hope that the COVID-19 situation will be under the control and the conference can be held according to the plan. 

References and Further Readings:

• Pragmatic and Group-Randomized Trials in Public Health and Medicine
• Cluster Randomized Trials in "Experimental Design and Randomization Scheme"
• Designing Multi-center Cluster Randomized Trials:An Introductory Toolkit
• Current Issues in the Design of Cluster Randomization Trials
• A brief history of the cluster randomised trial design