A New Method for Ethical and Efficient Evidence Generation for Off-Label Medication Use in Oncology (A Case Study in Glioblastoma)

Abstract

In oncology, preclinical and early clinical data increasingly support the use of a number of candidate “non-cancer” drugs in an off-label setting against multiple tumor types. In particular, metabolically targeted drugs show promise as adjuvant chemo and radiosensitizers, improving or restoring sensitivity to standard therapies. The time has come for large scale clinical studies of off-label drugs in this context. However, it is well recognized that high-cost randomized controlled trials may not be an economically viable option for studying patent-expired off-label drugs. In some cases, randomized trials could also be considered as ethically controversial. This perspective article presents a novel approach to generating additional clinical data of sufficient quality to support changes in clinical practice and relabeling of such drugs for use in oncology. Here, we suggest that a pluralistic evidence base and triangulation of evidence can support clinical trial data for off-label drug use in oncology. An example of an off-label drug protocol brought to the clinic for glioblastoma patients is presented, along with preliminary retrospective data from the METRICS study (NCT02201381). METRICS is a novel participant-funded, open-label, non-randomized, single-arm real-world study designed to gather high-quality evidence on the safety, tolerability, and effectiveness of four off-label metabolically targeted medicines as an adjunctive cancer treatment for glioblastoma patients.

Recommendations on Off-Label Drug Use in Pediatric Guidelines

“…As a result, it is critical that recommendations on the off-label use of drugs in pediatric guidelines are based on a reliable methodological pathway or framework ( Cheng et al, 2007 ). However, there is currently no standardized framework for creating recommendations for the use of off-label drugs in children ( Casali et al, 2015 ; Agrawal et al, 2019 ; Jiang et al, 2020 ; Stolbach et al, 2020 ; Remi et al, 2021 ). In general, the development of clinical guidelines should follow the GRADE Working Group’s “Five Paradigmatic Situations Warranting Strong Recommendation Despite Low or Very Low-Quality Evidence in Effect Estimates,” which has proven to offer a reliable framework ( Andrews et al, 2013 ).…”

Acceptability of donor funding for clinical trials in the UK: a qualitative empirical ethics study using focus groups to elicit the views of research patient public involvement group members, research ethics committee chairs and clinical researchers

“…This issue therefore warrants further philosophical research to establish the ethical tipping point between PP and pay to play. At least one trial where all the participants had to pay to play has, however, recently received favourable ethics review in the UK 10. RECs may, therefore, be at least open to permitting PP-funded trials with more than one donor.…”

“…At least one trial where all the participants had to pay to play has, however, recently received favourable ethics review in the UK. 10 RECs may, therefore, be at least open to permitting PP-funded trials with more than one donor.…”

“…The idea of patients funding novel treatments is not new, particularly in relation to small-scale, single-arm trials and off-label use. It has been seen, for instance, in regenerative cell treatment6–8 and oncology,9 10 where it has been noted that large scale randomised control trials, especially against placebo, might not be the most ethical or economical way of gathering data on clinical effectiveness 10. More recently, crowdfunding has been considered as a potential source of finance for clinical trials on rare diseases 9…”

Brain Cancer Drug Discovery: Clinical Trials, Drug Classes, Targets, and Combinatorial Therapies

“…Metformin is also a part of an experimental metabolic regimen consisting of metformin, atorvastatin (an antihypercholesterolemic agent), doxycycline (a tetracycline-class antibiotic), and mebendazole (a spindle poison). Currently, this regimen is investigated in various types of cancer, including glioblastoma, in the phase three Safety, Tolerability, and Efficacy of Metabolic Combination Treatments on Cancer (METRICS) trial (NCT02201 381) (Agrawal et al, 2019).…”