Researcher and scientist have been employing two major types of clinical trials in order to generate evidence for an intervention: Pragmatic trial and explanatory trial. Pragmatic approach tests the effectiveness of any therapy in a real life scenario by incorporating an intervention into the routine clinical practice whereas explanatory trials always focus on generating evidences on efficacy of an intervention in an ideal condition. By its design, Pragmatic trial always dominate the reproducibility of study results in real world whereas explanatory trials are always more robust and carry more complexity technically as well as practically. In this article, we will explore the importance and need of both the types of designs in different circumstances.
What Makes Pragmatic Trial Popular ?
- Flexible Inclusion / Exclusion criteria: If a participant has confirmatory diagnosis of an illness that we are interested in, there is high chance of him / her being enrolled into the study assuming ethical aspects of trials are constant. this opportunity of enrollment has been given by the flexible inclusion / exclusion criteria however factors which may affect the integrity of trial are taken into consideration beforehand.
- Simple design with large sample size: Since pragmatic trials are aimed to see whether an intervention actually works or not in real life scenario, these are always being conducted in multiple sites on various countries so that effectiveness can be measured in different hospital settings. Since pragmatic trials designs are simple, easy to understand and any clinical person working in hospital setting can implement them, majority hospital sites will agree to participate which further strengthen the external validity and reproducibility of the study result.
- Heterogeneity: Due to embedded heterogeneity, pragmatic trials always try to involve maximum number of patients, treatments and clinical settings. Since heterogeneity itself can dilute the findings of the trial, very large sample size is designed for such trial which again provides opportunities of participation in trial even from resource limited countries like Nepal.
- Intention to treat analysis: Since participants once randomized into the trial are always qualified for statistical data analysis, those participants who have enrolled into the trial but unable to complete the medication dose as well as loss to follow up before primary outcome was observed will also be contributing in evidence generation.
- Controls the off lable use of potential candidates: After the COVID-19 outbreak, there were many potential candidates recommended from small studies and being used widespread but clear and strong evidence was lacking. Such 'off label' practice was discouraged rather a pragmatic clinical trial was designed which included as many hospital sites as possible. This practice was initially centered to United Kingdom which soon widespread throughout.
- High External Validity: Being an open labeled and study not conducted in the controlled settings, the pragmatic trial results from the study population represent the target population in the future as well. This ability to generalize the findings in extended population is considered as high external validity.
Current Upsurge Of Pragmatic Trial
Though scientific community was well acquainted with the term 'Pragmatic trial' since 1967, it was not the practice of choice for conducting any trial to see the effectiveness of any novel drug over the existing therapy or the placebo. Few terms like 'naturalistic', 'practical' and 'real life' are found to be used since then just to represent need of clinical trial that can be conducted in usual routine clinical settings as well - in short need of a pragmatic trial. Rise of COVID-19 pandemic not only ignited a fire to conduct clinical trials in clinical settings but also changed the pattern of ongoing pragmatic clinical trials. Countries with limited healthcare resource like Nepal also got an opportunity to participate for evidence generation only after globalizing certain pragmatic clinical trials such as RECOVERY (Randomized Evaluation of COVID-19 Therapy), ASCOT Adapt (Australiasian COVID -19 Trial), WHO Solidarity / Solidarity Plus Trial, REMAP - CAP (Randomized Embedded Multifactorial Adaptive Platform for Community Acquired Pneumonia) etc.
Why explanatory trials are still surviving ?
Though pragmatic trials recently gained popularity on resource limited clinical settings due to their flexible designs and easy implementation, explanatory trials are still more scientific and robust to demonstrate the efficacy of a particular therapy on a controlled setting. Here are few points which shows why we should not shift attention completely from such studies:
- Drug discovery research: In order to develop a novel therapy via drug discovery research, blinded randomized controlled trial are needed where efficacy of a therapeutic agent is the only matter of concern for the researcher and all other aspects are kept constant.
- Regulatory approval: For any drug or a vaccine or a therapy to bring into the market, regulatory approval is needed from the regulatory authority of the respective country. Food and drugs administration (FDA) as well as other regulatory agencies gives approval for the candidates studied via conventional explanatory clinical trials design only.
- High Internal Validity: Explanatory trials have higher internal validity as they can better establish cause and effect relationship in inferential research than a pragmatic trial, hence dominates the hierarchy of evidence.
- Reduced Bias: Few integral components of explanatory trials such as randomization, blinding, allocation concealment, stringent inclusion and exclusion criteria etc. plays a major role to control and minimize the systematic errors (biases) while same makes the trial harder in implementation.
- Ambiguous "Real Life Settings": All the pragmatic trials throughout the globe are popular mainly because these are well fit into the real life setting. But real life settings of a country is completely different from other - such as United Kingdom and Nepal. Here, an exactly similar procedure (example: participant follow up) can be extremely easy for a developed nation with well established record keeping system whereas low income country (like Nepal) may wrestle with different mobile networks.
Conclusion:
Finally, both the trial methods have their own unique way of addressing the research question - Pragmatic trial answers in more flexible manner whereas explanatory trials search for evidence in a very controlled environment. Rise of COVID-19 pandemic has triggered scientific community to conduct pragmatic trials throughout the glove so that hospital operating on distinctly variable resource setting got opportunity to participate in a same trial. Such studies are important for development of new therapy whereas if a trial is being conducted in a new chemical entity or the relative risk of participants being negatively affected is higher, such trials should be conducted in explanatory manner. Also if a trial is being conducted for sole purpose of marketing a new drug in the future, such studies are bound to be conducted in a controlled environment and regulatory authority of the respective country should have a close view to them.
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