# No accelerated approval for a combination without proof each part contributes

Source: https://onco.cc/ideas/idea-tr2-contribution-of-components-mandate/  
OnCo record `idea-tr2-contribution-of-components-mandate` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Fields

- Kind: Idea
- Last checked: 2026-09-08
- 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.
- Proposed 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

## Sources

- 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): https://doi.org/10.1016/j.cell.2017.11.009

## Connected records

- pairings: [Caution: TIGIT + PD-(L)1 blockade](https://onco.cc/pairings/tigit-plus-pd1-caution/)
- drugs: [Epacadostat](https://onco.cc/drugs/epacadostat/), [Tiragolumab](https://onco.cc/drugs/tiragolumab/)
- terms: [Accelerated approval](https://onco.cc/terms/accelerated-approval/)
- trials: [IMpassion131](https://onco.cc/trials/impassion131/)
- bottlenecks: [Incentives reward me-too drugs and marginal gains](https://onco.cc/bottlenecks/b-incentive-misalignment/), [Too many combinations to test](https://onco.cc/bottlenecks/b-combination-space/)
- key papers: [Combination Cancer Therapy Can Confer Benefit via Patient-to-Patient Variability without Drug Additivity or Synergy](https://onco.cc/key-papers/paper-palmer-cell/)

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