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Use of Placebo in Urologic Oncology Randomized Controlled Trials - Beyond the Abstract

Placebo usage is a mainstay of modern medical research in randomized controlled trials (RCTs). In oncology RCTs, however, placebo usage can be controversial for a number of reasons. Namely, placebo can lead to inadvertent harm for patients by sidestepping standard-of-care treatment regimens, and the FDA mandates that placebo should only be considered when a known effective therapy is unacceptable.1

Current ethical stances in the clinical trials space conclude that placebo use is not acceptable when deferral of therapy will cause harm, which is often the case in malignant disease settings.2,3 Thus, modern oncology clinical trials tend to be limited to using placebo as part of a combination therapy regimen (added on to a known effective regimen) or when the standard of care is simply surveillance.

One of the major advantages of placebo-controlled trials is to enable blinding and mitigate bias. Yet in oncology trials, the experimental therapies being investigated can often have harsh side effect profiles whose adverse events (AEs) can drastically differ from those encountered with the use of an inert placebo.4,5 In such a setting, even when blinded by design, inadvertent unblinding of both subjects and investigators may occur. Compounding the issue, events such as disease progression may lead to unblinding when subjects are crossed over into an active therapy.6 Faced with these growing challenges to implementation, placebo use in oncology RCTs warrants a closer investigation.

In our recent study published in Urology Practice, we addressed this question using a sample of 60 urologic oncology RCTs utilizing placebo listed on ClinicalTrials.gov over a 10-year period.7 Between placebo and experimental study arms, we did not identify any statistically significant differences in mortality or study incompletion rates. However, we did find significant differences in serious adverse event (SAE) rates between the arm types in 75% of the categories/organ systems tabulated. As we hypothesized, every time there was a difference in SAE rates, the SAE occurred more often in the experimental arms. This was also true for the analysis of standard AEs, and the relationship persisted in sensitivity analyses that omitted the 5 open-label design RCTs identified. Thus, the results of this contemporary investigation into placebo use in modern urologic oncology RCTs support our hypothesis that most of these trials are conducted in a potentially unblinded fashion, either due to intentional open-label design or significantly different toxicity profiles between the study drug and the placebo.

Our results are likely to be of interest to those who grapple with clinical trial design and implementation challenges related to placebo-control and introduce important considerations for study design and interpretation. The most direct way to address the findings of our study regarding the potential for unblinding in oncology RCTs would be to implement an active placebo (i.e., one with toxicities) as opposed to an inert one.8 To be clear, we do not endorse this step, and present the notion here simply for purposes of discussion.

Active placebo, like standard placebo, has no therapeutic benefit. However, in contrast to standard placebo, it can produce AEs that can serve to maintain study blinding. For example, atropine was historically used as an active placebo in psychiatry trials to mimic the anticholinergic toxicities of tricyclic antidepressant study drugs.9,10 A review of antidepressant trials published in 1982 found evidence of a placebo amplification effect, whereby studies using inert placebos were more likely to produce positive results than those using active placebos.9 The explanation these authors suggested was that study subjects experiencing AEs were likely to suspect they were enrolled in the experimental arm and taking the “real” medication, thus reducing the effect size of the experimental agent over placebo. Although this approach produced a more accurate measurement of effect size, the risk/benefit of enrollment into the active placebo arm poses an ethical dilemma for clinical trialists.

Active placebo use starkly contrasts with the "do no harm" principle of medical ethics. Since there is no therapeutic benefit to placebo, the toxicities associated with an active placebo create a risk/benefit ratio in favor of risk. Thus, IRBs would likely be reluctant to accept their implementation, especially in oncology trials where the toxicity profiles being emulated may be serious and life-threatening. Less than 1% of modern-day trials utilize active placebo,10,11 and whether its use truly maintains blinding is debatable.12 Taken together, our position is ultimately to accept the limitations of standard placebo in oncology trials and interpret study results cautiously knowing biases may persist. Not all biases invalidate study results, and the impact of unblinding due to AEs should be interpreted in this context.

Written by: Trevor C. Hunt, MD,1 Zijing Cheng, MS,1,2 Karen Doersch, MD, PhD,1,3 and Jathin Bandari, MD1

  1. Department of Urology, University of Rochester Medical Center, Rochester, NY, USA
  2. Department of Health Services Research and Policy, University of Rochester Medical Center, Rochester, NY, USA
  3. Division of Urology, Department of Surgery, Anschutz Medical Campus, University of Colorado, Aurora, CO, USA
References:

  1. Services USDoHaH, Administration FaD, (CDER) CfDEaR, (CBER) CfBEaR. Placebos and Blinding in Randomized Controlled Cancer Clinical Trials for Drug and Biological Products: Guidance for Industry. Silver Spring, MD: Food and Drug Administration;2019. FDA-2018-D-3092.
  2. Ellenberg SS, Temple R. Placebo-controlled trials and active-control trials in the evaluation of new treatments - Part 2: Practical issues and specific cases. Annals of Internal Medicine. 2000;133(6):464-470.
  3. Temple R, Ellenberg SS. Placebo-controlled trials and active-control trials in the evaluation of new treatments. Part 1: ethical and scientific issues. Ann Intern Med. 2000;133(6):455-463.
  4. Kushnir I, Clemons M, Fergusson D, Bossé D, Reaume MN. Attitudes towards open‐label versus placebo‐control designs in oncology randomized trials: A survey of medical oncologists. Journal of Evaluation in Clinical Practice. 2022;28(3):495-499.
  5. Roydhouse JK, Fiero MH, Kluetz PG. Investigating Potential Bias in Patient-Reported Outcomes in Open-label Cancer Trials. JAMA Oncology. 2019;5(4):457.
  6. Doussau A, Agarwal I, Fojo T, Tannock IF, Grady C. Design of placebo-controlled randomized trials of anticancer agents: Ethical considerations based on a review of published trials. Clin Trials. 2021;18(6):690-698.
  7. Cheng Z, Campbell T, Hunt TC, Li A, Doersch K, Bandari J. Use of Placebo in Urologic Oncology Randomized Controlled Trials. Urol Pract. 2024;11(6):940-948.
  8. Cheng Z, Campbell T, Hunt TC, Li A, Doersch K, Bandari J. Reply by Authors. Urol Pract. 2024;11(6):948.
  9. Thomson R. Side effects and placebo amplification. Br J Psychiatry. 1982;140:64-68.
  10. Jensen JS, Bielefeldt AØ, Hróbjartsson A. Active placebo control groups of pharmacological interventions were rarely used but merited serious consideration: a methodological overview. Journal of Clinical Epidemiology. 2017;87:35-46.
  11. Boutron I, Estellat C, Guittet L, et al. Methods of Blinding in Reports of Randomized Controlled Trials Assessing Pharmacologic Treatments: A Systematic Review. PLoS Medicine. 2006;3(10):e425.
  12. Laursen DRT, Nejstgaard CH, Bjørkedal E, et al. Impact of active placebo controls on estimated drug effects in randomised trials: a systematic review of trials with both active placebo and standard placebo. Cochrane Database of Systematic Reviews. 2023;2023(3).
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