# Require head-to-head trials against the best in class for later entrants

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

## TL;DR

Once two drugs of a kind exist, a third should have to prove itself against the best of them, not against an outdated comparison, so patients and payers learn which is actually better.

## Summary

Regulators (or payers, through reimbursement rules) require that registration trials for the third and later entrants in an established mechanistic class use the best available in-class agent as the active comparator, or at minimum include a randomised head-to-head arm. Exceptions apply where the new agent addresses a population the incumbents do not. This makes me-too development more expensive and more informative at once: it either yields comparative evidence patients need or diverts capital to novel mechanisms.

## Fields

- Kind: Idea
- Last checked: 2026-09-08
- Hypothesis: A head-to-head requirement reduces late-in-class registration filings by at least a quarter within five years and produces comparative effectiveness evidence for the majority of remaining in-class approvals, where today almost none exists.
- Rationale: The EU and payers such as Germany's G-BA already prefer active comparators; the WHO and IQWiG have argued that placebo- or obsolete-comparator trials waste patients. Comparative trials among PD-1 antibodies and among TROP2 ADCs are essentially absent despite dozens of products.
- Proposed test: Implement through a payer coalition's reimbursement criteria (faster than legislation) and count filings and comparator choices in oncology over three years against a pre-period.
- Maturity: speculative
- Actor: regulator

## Sources

- Bottleneck evidence (Incentives reward me-too drugs and marginal gains): Upadhaya et al., PD1/PDL1 inhibitor clinical trial landscape (Nat Rev Drug Discov 2022): https://doi.org/10.1038/d41573-022-00030-4

## Connected records

- ideas: [A legal right to obtain marketed cancer drugs at cost for combination trials](https://onco.cc/ideas/idea-fund-compulsory-combination-access/), [An abbreviated approval path for follow-on antibodies within a validated class](https://onco.cc/ideas/idea-fund-abbreviated-pathway-me-too-biologics/), [Shorter exclusivity for later-in-class drugs without added benefit](https://onco.cc/ideas/idea-fund-benefit-indexed-exclusivity/)
- drugs: [Datopotamab deruxtecan](https://onco.cc/drugs/datopotamab-deruxtecan/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Sacituzumab govitecan](https://onco.cc/drugs/sacituzumab-govitecan/)
- terms: [Standard of care](https://onco.cc/terms/standard-of-care/)
- bottlenecks: [Incentives reward me-too drugs and marginal gains](https://onco.cc/bottlenecks/b-incentive-misalignment/), [Trial design, endpoints and cost](https://onco.cc/bottlenecks/b-trial-design/)
- key papers: [Challenges and opportunities in the PD1/PDL1 inhibitor clinical trial landscape](https://onco.cc/key-papers/paper-upadhaya-nat-rev-drug-discov/)

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