Elsevier

The Lancet Oncology

Volume 17, Issue 12, December 2016, Pages e560-e567
The Lancet Oncology

Personal View
Relevance of randomised controlled trials in oncology

https://doi.org/10.1016/S1470-2045(16)30572-1Get rights and content

Summary

Well-designed randomised controlled trials (RCTs) can prevent bias in the comparison of treatments and provide a sound basis for changes in clinical practice. However, the design and reporting of many RCTs can render their results of little relevance to clinical practice. In this Personal View, we discuss the limitations of RCT data and suggest some ways to improve the clinical relevance of RCTs in the everyday management of patients with cancer. RCTs should ask questions of clinical rather than commercial interest, avoid non-validated surrogate endpoints in registration trials, and have entry criteria that allow inclusion of all patients who are fit to receive treatment. Furthermore, RCTs should be reported with complete accounting of frequency and management of toxicities, and with strict guidelines to ensure freedom from bias. Premature reporting of results should be avoided. The bar for clinical benefit should be raised for drug registration, which should require publication and review of mature data from RCTs, post-marketing health outcome studies, and value-based pricing.

Introduction

Randomised clinical trials (RCTs) are the gold standard for the evaluation of new anticancer therapies. The only expected difference between the control and experimental groups in RCTs is the treatment effect of the experimental therapy being studied. However, for reasons listed in panel 1, the design and reporting of many RCTs can render their results of little relevance to clinical practice. Here, we discuss these limitations and suggest ways to improve the clinical relevance of RCTs to everyday management of people with cancer.

Section snippets

Commercial rather than clinical interest

Since 1975, the number and size of RCTs have increased, sponsorship has changed from being largely academic to largely commercial, and authors are now more likely to endorse the experimental arm even if the results show a stable relative effect size.1, 2 Moreover, as outcomes for many cancer types have improved over time, these stable relative effect sizes have translated into smaller absolute benefits.3 Eligibility criteria have also become narrower, so that patients enrolled in a study are

Preclinical and early clinical studies

Many new agents go through phase 3 clinical development despite poor reproducibility of preclinical data,7 an absence of evidence for efficient inhibition of their molecular target, or scarce phase 2 data showing antitumour effects, or as a result of all three reasons.8 As an example, nine large RCTs assessed docetaxel and prednisone in combination with and without nine different targeted drugs for men with metastatic castration-resistant prostate cancer. These negative trials were based on

Surrogate endpoints

Any treatment, for any disease, has two goals: to improve overall survival or to improve quality of life, or to improve both. In many phase 3 RCTs, the primary endpoint is not a direct measure of survival or quality of life, such as relapse-free survival in trials of adjuvant therapy and progression-free survival in trials of patients with metastatic cancer. These endpoints have been accepted for registration of new therapies for some types of cancer, but are poorly correlated with overall

Health-related quality-of-life analysis

Most RCTs that investigate new drugs recruit patients with incurable cancer, but despite their implicit aim to improve palliative care, only a few of these RCTs have included a measure of health-related quality of life (HRQOL) or a dominant patient-reported outcome as a primary or coprimary endpoint.29, 30 Inclusion of HRQOL or patient-reported outcomes is particularly important when progression-free survival is the primary endpoint: improvement in progression-free survival and a validated

Statistical significance versus clinical relevance

Many RCTs recruit large numbers of patients, allowing detection of small differences in survival between the study groups that might be statistically significant. Small differences in long-term survival in trials assessing adjuvant therapy, if reproducible, are important, but small differences in overall survival (leading to the so-called banana-shaped survival curves with transient separation) in trials investigating treatment of incurable cancers are of questionable clinical relevance. Most

Premature analysis and reporting

Most RCTs are initiated with a statistical plan to analyse and report results when a given number of events has occurred, but almost half of all RCTs presented at major oncology conferences present non-final analyses. Moreover, the main conclusion of 10% of these abstracts is reversed when final results are published in a peer-reviewed journal.49 Outside of formal interim analyses that have a mandated early release by the data safety monitoring committee, organisers should not allow

Underestimation of toxicity

Almost all new drugs increase toxicity, and this is underestimated in reports of RCTs.51, 52 By comparing sequential post-marketing reports of toxicity listed on the FDA website with published reports of RCTs investigating targeted drugs, we showed that about 60% of potentially fatal adverse drug reactions were not recognised in the initial FDA label and about 40% were not included in reports of RCTs.51 Reasons for these discrepancies include higher toxicity when new agents are used in everyday

Biased reporting

Substantial bias in the reporting of endpoints for efficacy and toxicity is common in RCT reports, and this bias is prevalent in abstracts, which are read most widely. In a survey57 of 164 reports of RCTs for breast cancer, the results of 92 trials did not show a statistically significant difference in their primary endpoint, yet about 60% of these trials used a secondary endpoint to imply benefit in the concluding statement of the abstract. Moreover, only about a third of the abstracts

Clinical benefit and enthusiasm

In addition to statistical misconceptions, modest gains are often heralded in the media as major breakthroughs, which leads to unrealistic expectations among patients and families. The language used in the reporting of trials, and even in discussions in the clinic, can also be misleading to patients. For example, a patient receiving information about a trial that showed improved progression-free survival is likely to latch on to the word survival, thereby having false hope of extended life

Patient selection

Efficacy describes the treatment benefit observed in an ideal population, such as those with minimal comorbidity and high performance status selected to take part in an RCT. Effectiveness is the difference in outcome in the real world, which is assessed by the application of health outcomes research to a population. A difference in outcome in an RCT (ie, in efficacy) with an agent that increases toxicity is likely to be smaller and might even disappear when applied in routine practice. An

Conclusion

In this Personal View, we have discussed problems related to the design, analysis, and reporting of RCTs that could limit their relevance to everyday clinical practice. Nonetheless, random allocation of participants to receive experimental and standard therapy represents the only strategy that allows unbiased comparison. In panel 3, we provide guidelines to improve the external validity of RCTs, so that they can increase their relevance to everyday clinical practice. Well designed, well

Search strategy and selection criteria

We did not perform a formal literature search for this article. Most articles were selected manually at the discretion of the authors from a review of the contents of high-impact general medical and cancer journals published in the past decade.

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