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.

• The Patient-Centered Outcomes Research Institute (PCORI), an independent nonprofit, nongovernmental organization located in Washington, DC was authorized by Congress in 2010. PCORI seeks to fund pragmatic clinical trials, large simple trials, or large-scale observational studies that compare two or more alternatives for addressing prevention, diagnosis, treatment, or management of a disease or symptom; improving healthcare system-level approaches to managing care; communicating or disseminating research results to patients, caregivers, or clinicians; or eliminating health or healthcare disparities.
•  Duke University has a website for Rethinking Clinical Trials – A Living Textbook of Pragmatic Clinical Trials 
• In a paper by Dr Patsopoulos “A pragmatic view on pragmatic trials”, the following was stated:

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.

• NIH organized a workshop on “Ethical and Regulatory Issues of Pragmatic Clinical Trials Workshop” in June 2016. The videocast of the workshop is available to the public.
• Special Issue of Clinical Trials in 2015 included a total 12 articles discussing the ethical and regulatory issues in pragmatic clinical trials. These articles can be found from Duke website.
• Dr Sandra Kweder from FDA (2013) Opportunities for Large Simple Trials – An FDA Perspective 

•  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

• FDA encourage the use of of Streamlined Trial Approaches  1) August 24, 2011: Draft Guidance: Oversight of ClinicalInvestigations: A Risk-Based Approach to Monitoring 2) February 2012: Draft Guidance: Determining the Extent ofSafety Data Collection Needed in Late Stage Premarketand Post approval Clinical Investigations (AE Lite)
• Large simple trials designs are consistent with FDA’s 1) Evolving overall approach to safety assessment which emphasizes a focus on information that is useful and informative rather than information that reflects what is already known 2) Risk-based monitoring approaches 3) Quality-by-Design and quality risk management initiative for clinical trials 

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.