Link Between Placebo Use and Severe Adverse Events in Clinical Trials Warrants Deliberation

Results from a recent meta-analysis show that placebo use in double-blind, randomized clinical trials is associated with a significant number of grade 3 to 4 adverse events, prompting the study investigators to implore consideration of these findings by investigators, sponsors, regulatory authorities, and patient support groups (JAMA Network Open. 2018;1[8]:e185617).

The review and meta-analysis by Matías Rodrigo Chacón, MD, Research Department, Argentine Association of Clinical Oncology, Buenos Aires, Argentina, and colleagues was conducted to determine the frequency of placebo adverse events in randomized clinical trials of modern cancer drugs in the adjuvant setting.

“Several reports have associated the placebo effect with objective response and improvement of a clinical condition in oncology, but only a few studies have analyzed the adverse events…in the placebo groups of the clinical trials,” they explained.

Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guideline, Dr Chacón and colleagues carried out a systematic literature search of the studies published on PubMed.

They searched for publications between January 1, 2000, and April 15, 2018, and used the terms “adjuvant,” “maintenance,” “consolidation,” and “placebo” (as well as specific cancer type–related keywords) to narrow down their results. Clinical trials were considered for inclusion only if they were double-blind, randomized, placebo-controlled, in phase 3, and enrolling patients who had undergone macroscopically complete resections.

Control groups in said trials could not have received any other anticancer treatments aside from placebo, and only studies of targeted therapies or immunotherapies were included—chemotherapy, interferon, and endocrine therapy were factors for exclusion.

Ultimately, a random-effects meta-analysis was performed on data from 10 adjuvant, double-blind, randomized, placebo-controlled, phase 3 clinical trials; collectively, these studies involved a total of 11,143 patients (6270 [56.3%] in the intervention group with a mean age of 55.6 years and 4873 [43.7%] in the placebo group with mean age of 55.9 years).

There were 4 cancer types covered in these trials, including melanoma, non–small cell lung cancer, gastrointestinal stromal tumor, and renal cell carcinoma. Patients had a mean age of 55.6 years

According to Dr Chacón and colleagues, the mean incidence of placebo adverse events of any grade was 85.1% (95% confidence interval [CI], 79.2%-91.0%). Hypertension, fatigue, and diarrhea were the most common grade 3 to 4 adverse events reported in patients in the placebo arms of the trials.

The pooled incidence of grade 3 to 4 adverse events with placebo was 18% (95% CI, 15%-21%), with a high level of heterogeneity (86%). An association was determined between the frequency of grade 3 to 4 placebo adverse events and the treatment and placebo groups, and the mean incidence of study drug discontinuation caused by placebo adverse events was 3.9% (95% CI, 2.7%-5.2%).

Of note, grade 3 to 4 adverse events with placebo reached values >20% in 3 trials. When Dr Chacón and colleagues conducted the same analysis on trials involving oral and parenteral placebos, the incidence of grade 3 to 4 placebo adverse was 19% (95% CI, 16%-23%) for oral placebos and 17% (95% CI, 12%-23%) for parenteral placebos.

When incidence of grade 3 to 4 placebo adverse events was subdivided by cancer-type subgroup, 18% (95% CI, 14%-23%) were in randomized clinical trials of melanoma and 19% (95%CI, 14%-25%) were in randomized clinical trials of renal cell carcinoma, with high heterogeneity (85% and 91%, respectively).

“According to the findings of this meta-analysis, placebo administration may be associated with severe AEs [adverse events]. This finding, frequently not included in the informed consents, should be known before making an autonomous decision of participating in an RCT,” Dr Chacón and colleagues said.

“Although many patients may experience high-grade AEs after a local cancer treatment, the high rate of severe placebo AEs in RCTs suggests that the use of placebo in any situation in the adjuvant setting should be carefully considered,” they concluded.—Hina Khaliq