Maximizing the value of the open label extension phase of randomized clinical trials

Over the last 20 years, nephrology has consistently trailed all other medical subspecialities in the performance of randomized clinical trials (RCTs), that are often multicenter and international in scope [1, 2]. In part, this reflects the difficulties in identifying subjects who have rare kidney diseases such as focal segmental glomerulosclerosis, late diagnosis in a substantial proportion of patients, and failure to achieve target enrollment and successful completion of adequately powered studies. At the same time, the costs of drug development from basic science research to completed RCT continue to spiral upward [3]. External events like the global health emergency posed by the COVID-19 pandemic can aggravate the problem by forcing delays in the initiation of RCTs, temporary holds on enrollment into ongoing studies, and logistical interference with patient monitoring in single center and international studies [4]. Taken together, these factors underscore the urgent need for creative strategies that can be applied to the design and implementation of these essential studies.

The introduction of innovative frameworks and analytic approaches such as platform trials and adaptive recruitment and randomization schemes are steps that are being taken to increase the feasibility and productivity of RCTs, particularly for rare diseases. Platform trials and master protocols increase the efficiency of testing multiple interventions by using a shared infrastructure and contemporaneous control groups [5]. Adaptive designs enable reassessment of study arms and cohort size based on planned interim analysis of trial outcome data [6]. Although it was unplanned, the pandemic has led to a decentralization in the performance of clinical research and triggered changes in practice patterns that are potentially beneficial to the conduct of RCTs. Instead of mandating the performance of all visits and laboratory testing at the participating regional academic center, study procedures and safety monitoring are often brought to the patient and conducted where he or she resides. Trained visiting nurses and other ancillary services have been incorporated into study protocols to achieve this goal. These operational approaches are more responsive to patient concerns about convenience and health risks [7].

We recommend another tactic that can be deployed to enhance the value and yield of ongoing RCTs. Many but not all studies that are conducted to inform new drug approval include an open label extension (OLE) phase following the completion of a double-blind (DB) treatment period [8]. There is no standard format for an OLE regarding eligibility criteria, duration, and study procedures. However, they are appended to the DB portion of a trial and are offered to all enrolled subjects who complete the DB phase and who are eligible to continue on the investigational therapy. During the OLE phase of a trial, participating patients who provide consent, including those who were originally randomized to placebo, an active control, or the test therapy, namely drug A, receive the investigational agent in an open label manner, often for a prolonged period. This practice has been adopted for two primary reasons. First, although ethical implementation of a RCT implies therapeutic equipoise, patients who consider enrollment are hopeful that they will derive benefit from the proposed novel therapy. They may be reluctant to consent to the study since they could be assigned to the placebo or standard of care arm. Incorporation of an OLE reassures participants in a RCT that, regardless of which treatment arm they were originally assigned to, they will be provided the study drug without any additional cost if they so desire until the trial is terminated or the drug receives regulatory approval. Second, it offers an opportunity to collect additional data about the long-term safety and efficacy of the test intervention that supplements the findings obtained during the DB phase. Patient management is usually more flexible during the OLE versus the DB portion of the study. The test medication, drug A, and all other concomitant treatments can be adjusted based on safety and efficacy considerations at the discretion of the site investigator. Nonetheless, patients are evaluated at fixed intervals and undergo a standardized clinical and laboratory assessment that reflects prevailing practice. Presently, an OLE is not a formal requirement of either federal- or industry-sponsored RCTs. However, in light of the considerations outlined above, we encourage the designers of RCTs to include an OLE regardless of the funding source.

We suggest that the OLE of the primary study of drug A provide a pragmatic, patient-friendly venue in which to systematically evaluate the impact of additional therapies such as drug B that have recently been approved for clinical use for the same or similar indications but for which there is limited real world experience in community practice. By patient-friendly we mean that the evaluation would be conducted in a manner that maximizes what can be learned from each study participant who has consented to be part of the OLE without imposing undue burden. Because there is therapeutic equipoise surrounding the combined use of drugs A and B, a randomization scheme can justifiably be incorporated into the OLE with the inclusion of a control arm to compare the impact of the addition of drug B vs no drug B on top of continued administration of drug A. Drug B could be an agent with an established safety and efficacy record or a newly approved medication with less extensive clinical exposure in the field. Our proposal would explicitly leverage the ongoing access to drug A which is the defining feature of the OLE. In addition, it would offer patients who participate in the second level study constructed on the OLE framework the opportunity to receive drug B after completion of the defined second tier study period on a continued basis for the remainder of the primary study OLE. Although drug B will be an approved drug, the sponsor of the trial for drug A would commit to providing drug B for the continued duration of the OLE. This feature would alleviate any financial burden that may be incurred by the use of the newly approved drug B for participants who are enrolled in the trial of drug A and who have limited resources.

This proposed expanded use of the OLE as an accessible drug assessment space can include an evaluation of interactions of drugs A and B on a shared clinical or laboratory efficacy endpoint. If drug B is newly approved, there is likely to be minimal real-world evidence about concomitant use with other drugs. Our proposed incorporation of a focused RCT, namely drug A ± drug B, within the ongoing OLE of drug A would provide valuable information about whether the effects of the two drugs are synergistic, non-additive, or antagonistic to one another. A flexible protocol to guide the dosing of drug B in the second-tier trial can be efficiently implemented and layered on top of the concomitant medications the patient is already receiving including drug A as part of the OLE. A search of the literature did not identify any trials that utilized the OLE as a platform upon which to assess combination therapy.

This approach builds on the growing acceptance of pragmatic trials in nephrology [9]. They promote the evaluation of novel treatments in more realistic settings. A key benefit of our proposal, like the changes in patient monitoring that have emerged in response to the COVID-19 pandemic, is that they bring the trial framework to the patient, in this case the OLE, where he or she already “lives.” It promotes assessment of new drugs in a setting that more closely resembles real world clinical practice in which the specific details of medication use, and treatment plans are left to the discretion of the attending nephrologist. An additional significant benefit is that this approach bypasses the hurdles of new patient identification and recruitment that hamper the conduct of trials in nephrology. Expanded use of the OLE phase enhances the value of the financial investment made in the original RCT design and implementation. Figure 1 illustrates the key features of our proposed trial within a trial during an OLE.

Fig. 1.

This schematic illustrates the key features of our proposed trial within a trial during the Open Label Extension of a Randomized Clinical Trial. The red lines delineate the double blind phase of the study and the blue lines delineate the Open Label Extension

We acknowledge several limitations and disadvantages of this expanded use of OLE to conduct RCTs. There is a potential risk of patient selection bias which could result in an overestimation of drug efficacy [10]. Patient and site investigator fatigue are real concerns at high quality sites that are engaged in multiple studies. Finally, attribution of cause of adverse events may be difficult, especially when testing newly approved drugs.

Our proposal for tiered drug evaluation during an OLE phase cannot completely replace stand-alone RCTs. However, it offers a number of distinct advantages. First, it would provide meaningful information about the net effect on a desired outcome of drug B when it is prescribed together with drug A, potential drug–drug interactions, and adverse effects of combined therapy, both anticipated and unexpected. As a relevant and timely example, this approach could be utilized to provide estimates of the short-term effect of SGLT2 inhibitors or non-steroidal mineralocorticoid receptor antagonists on proteinuria and/or estimated glomerular filtration rate in patients with glomerular disease who are receiving novel test therapies such as endothelin antagonists, complement inhibitors, or new B-cell targeted therapies under trial evaluation in an open label manner. It reflects emerging practice patterns in which these renoprotective agents are likely to be prescribed in combination to patients with chronic kidney disease, including primary glomerular disorders. Second, this methodology would amplify the value of OLE studies, promote greater patient acceptance of RCTs by broadening their scope, and expedite the timely evaluation of emerging novel therapies. Third, by providing timely information about the effect of rational drug combinations, it may accelerate the uptake of new therapeutic agents by clinical nephrologists in practice [11]. Finally, it leverages the collective expertise and resources of clinical researchers, community nephrologists, and industry sponsors to facilitate the timely performance of clinical studies that are urgently needed to improve long-term kidney health outcomes.

Data availability

The Points of View article does not contain any new patient data.

Declarations

Conflict of interest

Howard Trachtman, Rosanna Coppo, Moin Saleem, and Alex Mercer have consultancy arrangements with Travere Therapeutics, Inc. Radko Komers is an employee of Travere Therapeutics, Inc. Howard Trachtman wrote the initial draft of the manuscript, and the final version was reviewed and approved by all of the authors.

Ethical statement

Institutional review board review and approval were not required because the article contains no individual patient data or new findings.