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Published on: February 6, 2015
Bypassing phase 2 in cancer drug development erodes the risk/benefit balance in phase 3 trials
Hannah Moyer1, Merlin Bittlinger1, Angela Nelson1
1Department of Equity, Ethics and Policy, McGill University, Montreal, Quebec, Canada.
Objectives:
Drug developers sometimes launch phase 3 (P3) trials without supporting evidence from phase 2 (P2) trials. We call this practice "P2 bypass." The aims of this study were to estimate the prevalence of P2 bypass and to compare the safety and efficacy results for P3 trials that bypassed with those that did not.
Study Design And Setting:
We created a sample of P3 solid tumor trials registered on ClinicalTrials.gov with primary completion dates between 2013 and 2019. We then attempted to match each with a supporting P2 trial using strict and broad criteria. P3 outcomes were meta-analyzed using a random effects model with subgroup contrast between trials that bypassed and those that did not.
Results:
129 P3 trial arms met eligibility and nearly half involved P2 bypass. P3 trials involving P2 bypass produced significantly and nonsignificantly worse pooled efficacy estimates using broad and strict matching criteria, respectively. We did not observe significant differences in safety outcomes between P3 trials that bypassed P2 and those that did not.
Conclusion:
The risk/benefit balance of P3 trials that bypassed P2 is less favourable than for trials supported by P2.
Insights
Nearly half of phase 3 (P3) cancer trials bypass phase 2 (P2) studies. These P3 trials showed worse efficacy, suggesting a less favorable risk/benefit balance for drug development without prior P2 data.
Area of Science:
- Clinical trial design
- Oncology drug development
- Evidence-based medicine
Background:
- Drug developers may initiate phase 3 (P3) trials without supporting phase 2 (P2) trial data, a practice termed
- P2 bypass.
- This approach can impact the perceived risk/benefit balance of new therapeutics.
Purpose of the Study:
- To determine the prevalence of P2 bypass in solid tumor P3 trials.
- To compare the safety and efficacy outcomes of P3 trials with and without P2 support.
Main Methods:
- A sample of P3 solid tumor trials from ClinicalTrials.gov (2013-2019) was analyzed.
- Trials were matched with supporting P2 trials using strict and broad criteria.
- P3 trial outcomes were meta-analyzed, comparing bypassed versus non-bypassed trials.
Main Results:
- Approximately 47% of eligible P3 trial arms utilized P2 bypass.
- P3 trials with P2 bypass demonstrated significantly worse pooled efficacy estimates.
- No significant differences in safety outcomes were observed between bypassed and non-bypassed P3 trials.
Conclusions:
- The risk/benefit profile of P3 trials that bypass P2 is less favorable.
- P2 bypass may lead to suboptimal efficacy outcomes in late-stage clinical trials.
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