Clinical trials with external control, historical control, concurrent control, contemporaneous control, and synthetic control

Three critical features for modern clinical trials are control, randomization, blinding. For the golden standard of RCTs (randomized controlled clinical trials), a concurrent control group is critical. With recent advances in clinical trial designs, non RCTs such as real-world data (RWD)/real-world evidence (RWE), single arm trial, registry studies have been much discussed. The control group is now expanded to include concurrent control, external control, historical control, contemporaneous control. 

Concurrent Control: ICH E10 "Choice of Control Group in Clinical Trials" defined the concurrent control as the following: 

A concurrent control group is one chosen from the same population as the test group and treated in a defined way as part of the same trial that studies the test treatment, and over the same period of time. The test and control groups should be similar with regard to all baseline and on-treatment variables that could influence outcome, except for the study treatment. Failure to achieve this similarity can introduce a bias into the study. Bias here (and as used in ICH E9) means the systematic tendency of any aspects of the design, conduct, analysis, and interpretation of the results of clinical trials to make the estimate of a treatment effect deviate from its true value. Randomization and blinding are the two techniques usually used to minimize the chance of such bias and to ensure that the test treatment and control groups are similar at the start of the study and are treated similarly in the course of the study (see ICH E9). Whether a trial design includes these features is a critical determinant of its quality and persuasiveness.

Concurrent control is the feature of the RCTs and involves the randomization. The subjects are randomized into the test group or control group over the same period of time. 

External Control and Historical Control: ICH E10 "Choice of Control Group in Clinical Trials" defined the external control (including historical control) as the following:

External Control (Including Historical Control)

An externally controlled trial compares a group of subjects receiving the test treatment with a group of patients external to the study, rather than to an internal control group consisting of patients from the same population assigned to a different treatment. The external control can be a group of patients treated at an earlier time (historical control) or a group treated during the same time period but in another setting. The external control may be defined (a specific group of patients) or non defined (a comparator group based on general medical knowledge of outcome). Use of this latter comparator is particularly treacherous (such trials are usually considered uncontrolled) because general impressions are so often inaccurate. So-called baseline controlled studies, in which subjects' status on therapy is compared with status before therapy (e.g., blood pressure, tumor size), have no internal control and are thus uncontrolled or externally controlled (see section 2.5).

 Historical control is also external control. External control may or may not be historical control 

Contemporaneous Control may also be called contemporaneous cohort. In clinical trials with contemporaneous control group, subjects are recruited (not randomized) into the test group and the control group over the same period of time. The key idea is to compare subjects in the same time frame. For example, in a comparison of surgery versus chemotherapy for breast cancer, you wouldn't want to use surgery patients from 20 years ago as a control group to compare against a current chemo group. 

An great example of a clinical trial with a contemporaneous control group is a study assess the EVLP (ex-vivo lung perfusion) lung versus traditional (normal) lung in lung transplantations. In a non-randomized study "Extending Preservation and Assessment Time of Donor Lungs Using the Toronto EVLP System™ at a Dedicated EVLP Facility", according to the the study protocol, a contemporaneous control group was included to provide context for EVLP results and to inform control measures for future research. For every EVLP lung transplantation, a contemporaneous control lung transplantation with matched study center, single and double lung transplantation, lung allocation score. It is possible that for some EVLP lung transplants, the contemporaneous controls may not be identified which results in the large sample size in EVLP group than the contemporaneous control group. 

Once the donor lung is accepted following EVLP, the eligible recipient, who has provided written informed consent, and receives the lung transplant, is enrolled into the study. Patients who consent for the current EVLP , but receive a conventional (i.e., non-EVLP) lung transplant will be considered for a contemporaneous control group matched to the EVLP treatment group (66 subjects each). This matching will take place on a patient-by-patient basis and only after an EVLP subject has been enrolled at that Study Center. Investigators and their team will be notified by the Sponsor on a real-time basis of the specific matching criteria required for a control subject as EVLP subjects are enrolled. In order to be considered for eligibility, the control patient must “match” a priori to at least one EVLP subject who has already been enrolled at that Study Center based on the following criteria: SLT versus DLT and Lung Allocation Score Disease Diagnosis Group (LASDDG).

Contemporaneous control group is external, but concurrent control. Contemporaneous control group is similar to the matched control group in epidemiological case-control and cohort studies - similar statistical analysis approaches (such as conditional logistic regression) may be used for analyses.

Synthetic Control: synthetic control was discussed in a previous post "Synthetic Control Arm (SCA), External Control, Historical Control". Synthetic control includes subjects who are selected from historical clinical trials and who are on standard of case, and whose baseline characteristics match the current-day experiment group. Synthetic control is historical control, not concurrent control, but with matched baseline characteristics with the concurrent experiment treatment group. 

One Extra Point: 

One interesting discussion is about the control group in platform trial where multiple treatment arms are compared to the common control group. Since the different treatment arms may be added to or removed from the platform at different times, for a specific treatment - control group comparison, the control group may be not recruited over the same period of time. This issue was discussed in a NEJM paper "
Platform Trials — Beware the Noncomparable Control Group" and a JAMA paper "How to Use and Interpret the Results of a Platform Trial".

In platform trial, control group from a randomized trial may not be concurrent control.