Prevalence and Impact of Bypassing or Overriding Phase 2 Trials in Neurologic Drug Development.

BACKGROUND AND OBJECTIVES: Pivotal trials for neurologic drugs in clinical development are often initiated without a phase 2 trial ("bypass") or despite a negative phase 2 efficacy result ("override"). Such practices may degrade the risk/benefit ratio of phase 3 trials. The aim of this study is to estimate the proportion of phase 3 trials for 10 neurologic diseases started without a positive phase 2 trial, to identify factors associated with this practice, and to investigate any association with unfavorable phase 3 trial outcomes. METHODS: We searched ClinicalTrials.gov for phase 3 trials completed during 2011-2021, with at least 1 research site in the United States, Canada, the European Union, the United Kingdom, or Australia, and investigating drugs or biologics for treatment of 10 neurologic conditions. Our primary objective was to assess the prevalence of phase 2 bypass/override by searching for preceding phase 2 trials. We used Fisher exact tests to determine whether phase 3 trial characteristics and trial results were associated with phase 2 bypass/override. RESULTS: Of the 1,188 phase 3 trials captured in our search, 113 met eligibility for inclusion. Of these, 46% were not preceded by a phase 2 trial that was positive on an efficacy endpoint (31% bypassed and 15% overrode phase 2 trial). Phase 2 bypass/override was not associated with industry funding (77% vs 89%, 95% CI 0.75-7.55, p = 0.13) or testing already approved interventions (23% vs 15%, 95% CI 0.60-5.14, p = 0.33). Overall, phase 3 trials based on phase 2 bypassed/override were statistically significantly less likely to be positive on their primary outcome (31% vs 57%, respectively, 95% CI 1.21-6.92, p = 0.01). This effect disappeared when indications characterized by nearly universal positive or negative results were excluded. Trials that bypassed/overrode phase 2 trials were not statistically significantly more likely to be terminated early because of safety or futility (29% vs 15%, respectively, 95% CI 0.15-1.18, p = 0.11) and did not show increased risk of adverse events in experimental arms (RR = 1.46, 95% CI 1.19-1.79, vs RR = 1.36, 95% CI 1.10-1.69, respectively, p = 0.65). DISCUSSION: Almost half of the neurologic disease phase 3 trials were initiated without the support of a positive phase 2 trial. Although our analysis does not establish harm with bypass/override, its prevalence and the scientific rationale for phase 2 trial testing favor development of criteria defining when phase 2 bypass/override is justified.

Survival Benefit Associated With Participation in Clinical Trials of Anticancer Drugs: A Systematic Review and Meta-Analysis.

Importance: Many cancer clinical investigators view clinical trials as offering better care for patients than routine clinical care. However, definitive evidence of clinical benefit from trial participation (hereafter referred to as the participation effect) has yet to emerge. Objective: To conduct a systematic review and meta-analysis of the evidence examining whether patient participation in cancer trials was associated with greater survival benefit compared with routine care. Data Sources: Studies were found through PubMed and Embase (January 1, 2000, until August 31, 2022), as well as backward and forward citation searching. Study Selection: Studies were included that compared overall survival of trial participants and routine care patients. Data Extraction and Synthesis: Data extraction and methodological quality assessment were completed by 2 independent coders using Covidence software. Data were pooled using a random-effects model and analyzed based on the quality of the comparison between trial participants and routine care patients (ie, extent to which studies controlled for bias and confounders). Main Outcomes and Measures: The hazard ratio (HR) for overall survival of trial participants vs routine care patients. Results: Thirty-nine publications were included, comprising 85 comparisons of trial participants and routine care patients. The meta-analysis revealed a statistically significant overall survival benefit for trial participants (HR, 0.76 [95% CI, 0.69-0.82]) when all studies were pooled, regardless of design or quality. However, survival benefits diminished in study subsets that matched trial participants and routine care patients for eligibility criteria (HR, 0.85 [95% CI, 0.75-0.97]) and disappeared when only high-quality studies were pooled (HR, 0.91 [95% CI, 0.80-1.05]). They also disappeared when estimates were adjusted for potential publication bias (HR, 0.94 [95% CI, 0.86-1.03]). Conclusions and Relevance: Many studies suggest a survival benefit for cancer trial participants. However, these benefits were not detected in studies using designs addressing important sources of bias and confounding. Pooled results of high-quality studies are not consistent with a beneficial effect of trial participation on its own.

Patient advisors for victims of traumatic amputation: a critical intervention / Le patient-ressource chez les victimes d'amputation traumatique

Patient advisors for victims of traumatic amputation: a critical intervention. Since 2014, the Centre of Expertise in Reimplantation and Microsurgical Revascularization at the University of Montreal (CEVARMU) has been recruiting on an ad hoc basis former patients, who have completed the rehabilitation process, to accompany and support new patients at the Centre during their care process. Considered full-fledged partners of the care team, these patient advisors are invited to meet with patients who are hospitalized or in the rehabilitation process to not only share their experience but also ensure that the treatment plans proposed to the patients are well understood and meet their needs. Around forty interventions have been conducted by five patient advisors, helping to strengthen the credibility of professional interventions, break down patients' isolation, and give new meaning to the work of health professionals.

Le patient-ressource chez les victimes d'amputation traumatique. Depuis 2014, le Centre d'expertise en réimplantation ou revascularisation microchirurgicale d'urgence (CEVARMU) fait appel, sur une base ponctuelle, à d'anciens patients ayant terminé leur processus de réadaptation afin d'accompagner et de soutenir les patients nouvellement arrivés au centre dans leur propre processus de soins. Considérés comme des partenaires à part entière de l'équipe, ces patients-ressources sont invités à venir rencontrer, sur une base bénévole, les patients hospitalisés ou qui sont en processus de réadaptation afin de témoigner de leur expérience mais aussi de s'assurer que les plans de traitement proposés aux patients soient bien compris par ces derniers et qu'ils répondent à leurs besoins. Une quarantaine d'interventions ont été réalisées par cinq patientsressources et ont permis de renforcer la crédibilité des interventions des professionnels, de briser l'isolement des patients et de redonner du sens au travail des professionnels.