Bypassing phase 2 in cancer drug development erodes the risk/benefit balance in phase 3 trials

Moyer, Hannah; Bittlinger, Merlin; Nelson, Angela; Fernandez, Luciano; Sheng, Jacky; Wang, Yuetong; Paggio, Joseph C Del; Kimmelman, Jonathan

doi:10.1016/j.jclinepi.2023.03.028

Cited by 1 publication

(4 citation statements)

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“…However, this relationship is confounded by the clinical indications in our sample, and sensitivity analysis did not reproduce it. Notwithstanding these equivocal findings, we think that evidence from other areas, 16 combined with strong ethical, scientific, and policy arguments described above, favors the development of formal policies on phase 2 bypass. Such a policy might establish a presumption against initiating phase 3 trials that are not supported by positive phase 2 results.…”

Section: Discussionmentioning

confidence: 86%

“…Phase 2 bypass and override are about as prevalent in neurology as in cancer drug development. 16 However, the case for phase 2 bypass/override may be more compelling for certain neurologic indications. Unlike in cancer, many neurologic indications lack validated surrogate outcomes, and tissues are often less accessible for pharmacodynamic analysis.…”

Section: Discussionmentioning

confidence: 99%

“…We previously reported that nearly half of the phase 3 trials for solid tumor treatments were not preceded by positive phase 2 trials and that such trials had statistically significantly worse efficacy outcomes. 16 Conducting phase 3 trials without the support of positive phase 2 trials has obvious ethical implications. Patients enrolled in such phase 3 trials may be less likely to receive effective interventions.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Moyer,

Mellett,

Vigneault

et al. 2024

Neurology

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Background and ObjectivesPivotal 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. MethodsWe 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. ResultsOf 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 (

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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