Sunday, October 16, 2016

Pragmatic Clinical Trials (PCT) or Large Simple Trials (LST)

Pragmatic trials or large simple trials are becoming a hot topic discussed in recent scientific meetings. These are not really new clinical trial designs, but the trials conducted more close to the real world. The concept of pragmatic trials is not new. I saw an article in British Medical Journal dated back to 1998 Understanding controlled trials: What are pragmatic trials?” where it said “Trials of healthcare interventions are often described as either explanatory or pragmatic. Explanatory trials generally measure efficacy-the benefit a treatment produces under ideal conditions, often using carefully defined subjects in a research clinic. Pragmatic trials measure effectiveness-the benefit the treatment produces in routine clinical practice.

FDA commissioner, Dr Califf, has long been a proponent of the pragmatic trials. In his speech at 8th Annual Conference on Statistical Issues in Clinical Trials, he called the traditional clinical trials as Mechanistic trials with intention to evaluate a biological or mechanistic hypothesis and Pragmatic trials are those with Intention to inform decision makers about health and healthcare.

The practical adaptation of pragmatic clinical trials is:
(1) an intent to inform decision-makers (patients,         clinicians, administrators, and policymakers), as opposed to elucidating a biological or social mechanism;
(2) an intent to enroll a population relevant to the decision in practice and representative of the patients/populations and clinical settings for whom the decision is relevant; and
(3) either an intent to
        (a) streamline procedures and data collection so that the trial can focus on adequate power for informing the clinical and policy decisions targeted by the trial
        (b) measure a broad range of outcomesPragmatic clinical trials fit for the purpose of informing decision-makers regarding the comparative balance of benefit and risk of a biomedical or behavioral health intervention at the individual or population level
New England Journal of Medicine recently published a paper “Pragmatic Trials” by Dr Ford and Norrie. They proposed nine dimensions for pragmatic trials.

Here are some useful information for pragmatic clinical trials.

Clinical trials have been the main tool used by the health sciences community to test and evaluate interventions. Trials can fall into two broad categories: pragmatic and explanatory. Pragmatic trials are designed to evaluate the effectiveness of interventions in real-life routine practice conditions, whereas explanatory trials aim to test whether an intervention works under optimal situations. Pragmatic trials produce results that can be generalized and applied in routine practice settings. Since most results from exploratory trials fail to be broadly generalizable, the “pragmatic design” has gained momentum.
  •  FDA has increasing interest in clinical trial simplification 1) To decrease difficulty and cost of conducting trials  2) To encourage larger trials that are simple, pragmatic, and robust  3) To reduce unnecessary data collection (e.g., laboratory and/or safety data unlikely to result in a greater understanding of product), which is often cited as major reason physicians are unwilling to participate in clinical trials
  • FDA emphasizes data quality, not quantity, and not proscriptive trial design

Here is a table I would compare the explanatory trials and the pragmatic trials:
Explanatory trials (or Mechanistic trials) 
Pragmatic trials (or Large simple trials)
Trials for demonstrating the efficacy
Trials for demonstrating the effectiveness
Limited sample size
Large sample size
Extensive data collection on safety for example adverse events
Limited or selected data collection on safety for example adverse events
Extensive data collection on laboratory tests and vital signs
No or limited data collection on laboratory tests and vital signs
Many inclusion/exclusion criteria
Less inclusion/exclusion criteria
More strict in terms of the protocol deviations, and study drug compliance
More lenient in terms of the protocol deviations and study drug adherence
Homogeneous patient population
More heterogeneous patient population
Conducted in ideal setting or optimal situation
Conducted in real world setting
Results may not be generalizable
Results are more generalizable
Usually not for comparative effectiveness
Usually for comparative effectiveness
The trial results are usually used for drug approval
The trial results are usually used for decision making
Usually with Placebo as control
Usually with comparison of different active drugs
Usually for pre-market studies
Usually for post-market studies
Usually single sponsor
May be involved in multiple sponsors
Less likely to use electronic medical records (EMRs)
More likely to use electronic medical records (EMRs)

The pragmatic trials and the precision medicine seem to be two trends in the clinical trial fields. While the pragmatic trials encourage the large simple trial to mimic the real world situation, the precision medicine encourage the clinical trials with smaller and targeted population, enrichment design, and homogeneous population. 


Anonymous said...

More than two decades ago, Dr. Temple of FDA was espousing "large, simply studies." There truly is nothing new under the sun :-)

Scitech Central said...

Journal of Clinical Trials & Research is an international peer reviewed scholarly journal whose primary aim is to dissemination and development of knowledge on all aspects of clinical trial design, management.Clinical Trials & Research