{"entity":{"id":"idea-tr2-contribution-of-components-mandate","kind":"idea","name":"No accelerated approval for a combination without proof each part contributes","aka":[],"tldr":"Regulators should refuse to approve a two-drug combination unless there is evidence that both drugs are doing something, so patients are not exposed to useless extra toxicity and cost.","summary":"Several combinations (for example anti-TIGIT plus PD-L1, IDO inhibitor plus PD-1) reached phase 3 without randomised evidence of the added agent's contribution and failed. FDA guidance on co-development already asks for contribution-of-components data but allows exceptions. Making a randomised contribution assessment (or a factorial design) a firm condition of accelerated approval for combinations would redirect development effort towards combinations with evidence of synergy.","asOf":"2026-09-08","links":[{"label":"Bottleneck evidence (Too many combinations to test): Palmer & Sorger, Combination cancer therapy can confer benefit via patient-to-patient variability without drug additivity or synergy (Cell 2017)","url":"https://doi.org/10.1016/j.cell.2017.11.009"}],"tags":[],"related":["tigit-plus-pd1-caution"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":["tiragolumab","epacadostat"],"companies":[],"institutions":[],"pathways":[],"terms":["accelerated-approval"],"trials":["impassion131"],"people":[],"bottlenecks":["b-combination-space","b-incentive-misalignment"],"keyPapers":["paper-palmer-cell"],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"Combination phase 3 failure rates fall by at least a third within five years of a firm contribution-of-components requirement, as measured against the preceding five years.","rationale":"The TIGIT and IDO programmes together consumed thousands of patients and billions of dollars with single-arm or non-randomised phase 2 evidence. Randomised phase 2 with a contribution arm would have flagged the lack of effect.","test":"Audit the last decade of combination phase 3 failures for whether a contribution-of-components study existed; model the effect of a requirement; implement via guidance and track.","maturity":"early-clinical","actor":"regulator","cost":"small","horizonYears":2},"route":"/ideas/idea-tr2-contribution-of-components-mandate/","neighbours":{"pairing":[{"id":"tigit-plus-pd1-caution","kind":"pairing","name":"Caution: TIGIT + PD-(L)1 blockade","route":"/pairings/tigit-plus-pd1-caution/"}],"drug":[{"id":"epacadostat","kind":"drug","name":"Epacadostat","route":"/drugs/epacadostat/"},{"id":"tiragolumab","kind":"drug","name":"Tiragolumab","route":"/drugs/tiragolumab/"}],"term":[{"id":"accelerated-approval","kind":"term","name":"Accelerated approval","route":"/terms/accelerated-approval/"}],"trial":[{"id":"impassion131","kind":"trial","name":"IMpassion131","route":"/trials/impassion131/"}],"bottleneck":[{"id":"b-incentive-misalignment","kind":"bottleneck","name":"Incentives reward me-too drugs and marginal gains","route":"/bottlenecks/b-incentive-misalignment/"},{"id":"b-combination-space","kind":"bottleneck","name":"Too many combinations to test","route":"/bottlenecks/b-combination-space/"}],"paper":[{"id":"paper-palmer-cell","kind":"paper","name":"Combination Cancer Therapy Can Confer Benefit via Patient-to-Patient Variability without Drug Additivity or Synergy","route":"/key-papers/paper-palmer-cell/"}]}}