Placebo Hypoalgesia and Nocebo Hyperalgesia Induced by Observational Learning May Be Difficult to Disentangle in a Laboratory Setting.

Observational learning (OBL) (seeing pain/pain treatment in others) can evoke placebo hypoalgesia and nocebo hyperalgesia. Data that compare these effects and illuminates the role of expectations and empathy are scarce. Healthy participants (n = 105) were randomized to: 1) placebo OBL, 2) nocebo OBL, or 3) no-observation control group. OBL consisted of a model simulating pain relief or increase after a sham ointment was applied to one arm. Pain was evoked with thermal stimuli on both arms (ointment, contralateral) at baseline and postobservation. Expectations, pain ratings, and physiological data (eg, skin conductance level) were collected. A 3 × 2 × 2 (Group × Arm × Phase) mixed analyses of variance revealed a 3-way interaction that confirmed that OBL modulates pain: F(2, 93) = 6.08, P = .003, ηp2 = .12. Significant baseline-to-post-observation pain increases were shown in the nocebo OBL group, with a bigger increase for the arm with ointment (both P ≤ .007). In the placebo OBL group, pain was higher for the contralateral relative to the ointment arm (P < .001). Baseline-to-post-observation pain increase was significant for the contralateral arm (P < .001). Expectation mediated these effects. Skin conductance level decreased over time during ointment trials in the nocebo OBL group, suggesting reduced physiological arousal. The findings illustrate that OBL modulates pain through expectations. In the placebo OBL group, the pain did not decrease for the ointment but increased for the contralateral stimuli, which may reflect nocebo learning. Experimental OBL paradigms typically examine relative differences between ointment and contralateral cues. This can complicate disentangling placebo hypoalgesia and nocebo hyperalgesia in laboratory settings. Implications for existing theories are discussed. PERSPECTIVE: Data that systematically compare placebo hypoalgesia and nocebo hyperalgesia induced by OBL are scarce. The current work illustrates that these effects may be more difficult to disentangle than previously assumed, which could have implications for existing theories on OBL and placebo effects and their translation to clinical practice.

Learning pain from others: a systematic review and meta-analysis of studies on placebo hypoalgesia and nocebo hyperalgesia induced by observational learning.

ABSTRACT: Observing someone experience pain relief or exacerbation after an intervention may induce placebo hypoalgesia or nocebo hyperalgesia. Understanding the factors that contribute to these effects could help in the development of strategies for optimizing treatment of chronic pain conditions. We systematically reviewed and meta-analyzed the literature on placebo hypoalgesia and nocebo hyperalgesia induced by observational learning (OL). A systematic literature search was conducted in the databases PubMed, PsycINFO, Web of Science, ScienceDirect, PsycARTICLES, Scopus, and Academic Search Ultimate. Twenty-one studies were included in the systematic review, 17 of which were suitable for meta-analysis (18 experiments; n = 764 healthy individuals). The primary end point was the standardized mean difference (SMD) for pain following placebo cues associated during OL with low vs high pain. Observational learning had a small-to-medium effect on pain ratings (SMD 0.44; 95% confidence interval [CI] 0.21-0.68; P < 0.01) and a large effect on pain expectancy (SMD 1.11; 95% CI 0.49-2.04; P < 0.01). The type of observation (in-person vs videotaped) modulated the magnitude of placebo hypoalgesia/nocebo hyperalgesia ( P < 0.01), whereas placebo type did not ( P = 0.23). Finally, OL was more effective when observers' empathic concern (but no other empathy-related factors) was higher ( r = 0.14; 95% CI 0.01-0.27; P = 0.03). Overall, the meta-analysis demonstrates that OL can shape placebo hypoalgesia and nocebo hyperalgesia. More research is needed to identify predictors of these effects and to study them in clinical populations. In the future, OL could be an important tool to help maximize placebo hypoalgesia in clinical settings.

Risk and benefit for umbrella trials in oncology: a systematic review and meta-analysis.

BACKGROUND: Umbrella clinical trials in precision oncology are designed to tailor therapies to the specific genetic changes within a tumor. Little is known about the risk/benefit ratio for umbrella clinical trials. The aim of our systematic review with meta-analysis was to evaluate the efficacy and safety profiles in cancer umbrella trials testing targeted drugs or a combination of targeted therapy with chemotherapy. METHODS: Our study was prospectively registered in PROSPERO (CRD42020171494). We searched Embase and PubMed for cancer umbrella trials testing targeted agents or a combination of targeted therapies with chemotherapy. We included solid tumor studies published between 1 January 2006 and 7 October 2019. We measured the risk using drug-related grade 3 or higher adverse events (AEs), and the benefit by objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). When possible, data were meta-analyzed. RESULTS: Of the 6207 records identified, we included 31 sub-trials or arms of nine umbrella trials (N = 1637). The pooled overall ORR was 17.7% (95% confidence interval [CI] 9.5-25.9). The ORR for targeted therapies in the experimental arms was significantly lower than the ORR for a combination of targeted therapy drugs with chemotherapy: 13.3% vs 39.0%; p = 0.005. The median PFS was 2.4 months (95% CI 1.9-2.9), and the median OS was 7.1 months (95% CI 6.1-8.4). The overall drug-related death rate (drug-related grade 5 AEs rate) was 0.8% (95% CI 0.3-1.4), and the average drug-related grade 3/4 AE rate per person was 0.45 (95% CI 0.40-0.50). CONCLUSIONS: Our findings suggest that, on average, one in five cancer patients in umbrella trials published between 1 January 2006 and 7 October 2019 responded to a given therapy, while one in 125 died due to drug toxicity. Our findings do not support the expectation of increased patient benefit in cancer umbrella trials. Further studies should investigate whether umbrella trial design and the precision oncology approach improve patient outcomes.

Risk and Benefit for Targeted Therapy Agents in Pediatric Phase II Trials in Oncology: A Systematic Review with a Meta-Analysis.

BACKGROUND: For research with human participants to be ethical, risk must be in a favorable balance with potential benefits. Little is known about the risk/benefit ratio for pediatric cancer phase II trials testing targeted therapies. OBJECTIVE: Our aim was to conduct a systematic review of preliminary efficacy and safety profiles of phase II targeted therapy clinical trials in pediatric oncology. METHODS: Our protocol was prospectively registered in PROSPERO (CRD42020146491). We searched EMBASE and PubMed for phase II pediatric cancer trials testing targeted agents. We included solid and hematological malignancy studies published between 1 January, 2015 and 27 February, 2020. We measured risk using drug-related grade 3 or higher adverse events, and benefit by response rates. When possible, data were meta-analyzed. All statistical tests were two-sided. RESULTS: We identified 34 clinical trials (1202 patients) that met our eligibility criteria. The pooled overall response rate was 24.4% (95% confidence interval [CI] 14.5-34.2) and was lower in solid tumors, 6.4% (95% CI 3.2-9.6), compared with hematological malignancies, 55.1% (95% CI 35.9-74.3); p < 0.001. The overall fatal drug-related (grade 5) adverse event rate was 1.6% (95% CI 0.6-2.5), and the average drug-related grade 3/4 adverse event rate per person was 0.66 (95% CI 0.55-0.78). CONCLUSIONS: We provide an estimate for the risks and benefits of participation in pediatric phase II cancer trials. These data may be used as an empirical basis for informed communication about benefits and burdens in pediatric oncology research.

Clinical development success rates and social value of pediatric Phase 1 trials in oncology.

OBJECTIVES: Drug development trials must fulfill social value requirement but no estimates of value provided by pediatric Phase 1 trials in oncology exist. These trials involve a particularly vulnerable population. Our objective was to assess of surrogates of social value of Phase 1 trials performed in pediatric oncology: rates of approval of tested interventions, transition to further phases of testing and citation in subsequent primary research reports. METHODS: We performed an analysis on a subset of eligible trials included in a previous meta-analysis. That study systematically searched EMBASE and PubMed for small sample size, non-randomized, dose escalation pediatric cancer Phase 1 studies of any malignancy, assessing chemotherapy and/or targeted therapy and looked at risk and benefit. The current analysis assessed all studies in that review published between January 1st 2004 and December 31st 2013 for predictors of social value. This time range allowed for at least five years of subsequent development activity. Sources of data included FDA and EMA medicine databases (for approval), ClinicalTrials.gov and EU Clinical Trials Register (for transition) and Google Scholar (for citation). RESULTS: One hundred thirty-nine trials enrolling 3814 patients met the eligibility criteria. Seven trials (5%) led to drugs being registered for pediatric use in therapy of cancer. Fifty-two (37%) transitioned to later phases of pediatric oncology trials according to ClinicalTrials.gov and/or EU Register. Over 90% of trials were cited by at least one subsequent primary research report or systematic review. Most of the citations were preclinical studies. CONCLUSIONS: Our analysis shows that treatments tested in pediatric Phase 1 trials in oncology have low rates of regulatory approval. However, a large proportion of Phase 1 trials inform further testing and development of tested interventions.

Results dissemination of registered clinical trials across Polish academic institutions: a cross-sectional analysis.

OBJECTIVES: To establish the rates of publication and reporting of results for interventional clinical trials across Polish academic medical centres (AMCs) completed between 2009 and 2013. We aim also to compare the publication and reporting success between adult and paediatric trials. DESIGN: Cross-sectional study. SETTING: AMCs in Poland. PARTICIPANTS: AMCs with interventional trials registered on ClinicalTrials.gov. MAIN OUTCOME MEASURE: Results reporting on ClinicalTrials.gov and publishing via journal publication. RESULTS: We identified 305 interventional clinical trials registered on ClinicalTrials.gov, completed between 2009 and 2013 and affiliated with at least one AMC. Overall, 243 of the 305 trials (79.7%) had been published as articles or posted their summary results on ClinicalTrials.gov. Results were posted within a year of study completion and/or published within 2 years of study completion for 131 trials (43.0%). Dissemination by both posting and publishing results in a timely manner was achieved by four trials (1.3%). CONCLUSIONS: Our cross-sectional analysis revealed that Polish AMCs fail to meet the expectation for timely disseminating the findings of all interventional clinical trials. Delayed dissemination and non-dissemination of trial results negatively affects decisions in healthcare.

A systematic review of how patients value COPD outcomes.

Our objective was to summarise systematically all research evidence related to how patients value outcomes in chronic obstructive pulmonary disease (COPD).We conducted a systematic review (systematic review registration number CRD42015015206) by searching PubMed, Embase, PsycInfo and CINAHL, and included reports that assessed the relative importance of outcomes from COPD patients' perspective. Two authors independently determined the eligibility of studies, abstracted the eligible studies and assessed risk of bias. We narratively summarised eligible studies, meta-analysed utilities for individual outcomes and assessed the certainty of evidence using the Grading of Recommendations, Assessment, Development and Evaluations approach.We included 217 quantitative studies. Investigators most commonly used utility measurements of outcomes (n=136), discrete choice exercises (n=13), probability trade-off (n=4) and forced choice techniques (n=46). Patients rated adverse events as important but on average, less so than symptom relief. Exacerbation and hospitalisation due to exacerbation are the outcomes that COPD patients rate as most important. This systematic review provides a comprehensive registry of related studies.

Risk and surrogate benefit for pediatric Phase I trials in oncology: A systematic review with meta-analysis.

BACKGROUND: Pediatric Phase I cancer trials are critical for establishing the safety and dosing of anti-cancer treatments in children. Their implementation, however, must contend with the rarity of many pediatric cancers and limits on allowable risk in minors. The aim of this study is to describe the risk and benefit for pediatric cancer Phase I trials. METHODS AND FINDINGS: Our protocol was prospectively registered in PROSPERO (CRD42015015961). We systematically searched Embase and PubMed for solid and hematological malignancy Phase I pediatric trials published between 1 January 2004 and 1 March 2015. We included pediatric cancer Phase I studies, defined as "small sample size, non­randomized, dose escalation studies that defined the recommended dose for subsequent study of a new drug in each schedule tested." We measured risk using grade 3, 4, and 5 (fatal) drug-related adverse events (AEs) and benefit using objective response rates. When possible, data were meta-analyzed. We identified 170 studies meeting our eligibility criteria, accounting for 4,604 patients. The pooled overall objective response rate was 10.29% (95% CI 8.33% to 12.25%), and was lower in solid tumors, 3.17% (95% CI 2.62% to 3.72%), compared with hematological malignancies, 27.90% (95% CI 20.53% to 35.27%); p < 0.001. The overall fatal (grade 5) AE rate was 2.09% (95% CI 1.45% to 2.72%). Across the 4,604 evaluated patients, there were 4,675 grade 3 and 4 drug-related AEs, with an average grade 3/4 AE rate per person equal to 1.32. Our study had the following limitations: trials included in our review were heterogeneous (to minimize heterogeneity, we separated types of therapy and cancer types), and we relied on published data only and encountered challenges with the quality of reporting. CONCLUSIONS: Our meta-analysis suggests that, on the whole, AE and response rates in pediatric Phase I trials are similar to those in adult Phase I trials. Our findings provide an empirical basis for the refinement and review of pediatric Phase I trials, and for communication about their risk and benefit.