Randomized controlled trials (RCTs) are the mainstay of clinical research; it is estimated that about 18,000 RCTs are published each year. However, traditional RCTs usually take a long time to complete, are expensive, and the results are challenging to generalize to the real-world since they are derived under ideal conditions with strict inclusion and exclusion criteria. This brings in an additional layer of complexity for decision-making by the healthcare stakeholders and reimbursement authorities. With an intention to resolve this challenge, fuelled by the increasing global shift towards personalized medicine and value-based payment models, new methods for generating efficacy and safety evidence of interventions in real-world settings are continuously sought after.[1,2]
This has been a major driver for a rapid increase in interest in comparative effectiveness research (CER), which aims to compare the benefits, risks, and sometimes costs of alternative healthcare interventions (medicines, medical devices, procedures and health services) in real-world settings. CER aims to assist consumers, clinicians, purchasers, and policymakers in making informed decisions, thereby improving healthcare at both the individual and population levels.
CER was brought into spotlight with the introduction of the American Recovery and Reinvestment Act in 2009 which provided support of $1.1 US billion over 2 years for conducting CER. This stimulated an increase in the observational studies in the short run and conducting RCTs in the long run. In 2020, the Patient-Centered Outcomes Research Institute (PCORI) had invested nearly $2.6 billion in more than 700 patient-centered CER studies in the USA. In 2011, it was estimated that CER may contribute to a $31.6 billion reduction in research and development costs over a 10 year period by improving market access and reimbursement from private insurers.
CER involves non-inferiority trials between two interventions having similar therapeutic effects differing in other aspects relevant to stakeholders like costs, adverse effect profile, and route of administration. Among several trial designs, key trial design proposed in CER is Pragmatic Clinical Trials (PCT). PCTs are in fact RCTs, conducted in a real-world setting: the evidence generated through PCTs can be translated into patient care more efficiently and with a better generalizability. While traditional RCTs use a placebo or well-controlled alternative intervention in a tightly controlled study setting, PCTs are intended to maintain the internal validity of RCTs and maximize the external validity (generalizability and applicability). PCTs are designed and implemented in ways that would better address the demand for evidence about real-world risks, and benefits for informing clinical and health policy decisions.[4,7]
PCTs are gaining traction in CER due to their potential to efficiently generate evidence to inform real-world health care decisions by embedding research into routine care with the goals of implementation research. A notable example of CER through PCTs is the ALLHAT trial reported in 2004, which concluded that thiazides are as effective as ACE inhibitors in the management of Hypertension. Similarly, the 2006 CATIE trial reported that atypical antipsychotics are ineffective compared to placebo in elderly patients with dementia.
Despite its advantages, the “embedded” nature of PCTs (i.e RCTs embedded in real-world setting) faces ethical and regulatory challenges. Existing GCP guidelines intended for traditional RCTs are insufficient in the areas of PCTs, and appropriate reforms are needed that are relevant to conduct PCTs. The design and quality of a CER depend on the proper choice of the non-inferiority margin. However, defining the non-inferiority margin can be complex and quite challenging. Attrition bias adds to these complexities. These concerns are being sorted out with the evidence from previous studies, preliminary data, and/or clinical judgment that are very helpful in allowing the trialists to make reasonable assumptions about an anticipated effect of the reference treatment.[10,11]
Challenges also exist in sustaining the behavioural change following decisions from CER. For example, based on CER, a clinical decision was made not to use stents for stable angina: this reduced stent implants by 13% in the US for 4 years; however, by 2009, the number of implants returned back to previous levels.
Development of proper regulatory standards can enable the realization of the full potential of CER conducted through pragmatic trials to fill the research-practice gap in healthcare decision-making, reduce variability in clinical practice, and determine the high-quality care for all patients. Indeed, CER has the potential to provide the best possible treatment choices to the patients and the healthcare providers.
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