Every payer ultimately asks the same question: “Compared with what?” This single question shapes the narrative of a new therapy’s value. Comparators determine how efficacy, safety, and value are judged, and the choice remains one of the most scrutinised and strategically decisive factors influencing market access outcomes.
Comparators anchor cost-effectiveness analyses, price negotiations, and a product’s position within clinical pathways. A poorly chosen comparator can lock a therapy into an unfavourable reference point, erode price potential, and restrict reimbursement options. Conversely, selecting a clinically relevant, forward-looking comparator aligned with the evolving standard of care can reinforce differentiation and preserve value as new entrants reshape the therapeutic landscape.
This article explores where comparator requirements converge and diverge across major regulatory and health technology assessment (HTA) bodies, and why getting the comparator question right, early on in the development process, remains one of the most powerful levers for market access success.
Direct comparators in randomised controlled trials – The gold standard, but not without traps
Direct comparators tested through randomised controlled trials (RCTs) remain the most robust means of generating comparative evidence. Head-to-head trials provide the clearest demonstration of relative efficacy and value by directly comparing a new intervention with an accepted standard of care or active alternative under controlled conditions. When designed and executed rigorously, such trials not only meet regulatory standards but also strengthen the HTA narrative, allowing payers to assess clinical and economic added value with confidence.
A comparator arm with an intervention that is misaligned with clinical practice or irrelevant to the target population can trigger a domino effect, undermining the entire evidence generation and patient access plan. The emphasis on methodological rigour, such as randomisation, blinding, and intention-to-treat (ITT) analysis – underpins trust in the results and their relevance to actual clinical practice.
Direct trials can demonstrate superiority, non-inferiority, or equivalence relative to the chosen comparator, using explicit statistical frameworks to interpret findings.2,3 Understanding hazard ratios is central to this process. They remain a cornerstone metric for assessing relative treatment effect, directly shaping perceptions of clinical value, cost-effectiveness, and reimbursement potential. A robust, statistically significant hazard ratio — supported by clear confidence intervals and consistent subgroup effects — strengthens the credibility of comparative efficacy claims and reinforces payer confidence in the magnitude and durability of clinical benefit.1
Comparator selection – A strategic decision disguised as a clinical one
Choosing the right comparator is a multidimensional challenge. Clinically, it must reflect the current standard of care, ensuring the trial addresses meaningful, decision-relevant questions. Ethically, patients must not be deprived of effective therapy—particularly in high-burden or life-threatening conditions where placebo arms are no longer acceptable. Strategically, the comparator should anticipate the therapy’s future role: aligning with today’s practice yet remaining relevant at launch.
Geographic variation adds another layer of complexity. Standards of care differ across jurisdictions, shaped by formularies, access policies, and clinical culture. For global trials, designing a comparator strategy that holds across major markets (for example, the EU4, United Kingdom, United States, and Japan) is critical. Misalignment between a global trial comparator and local treatment practices can lead to costly post-hoc bridging analyses and delayed reimbursement.
Regulatory and HTA alignment – Where consensus meets contradiction
Across regulatory agencies, there is broad agreement that comparators should reflect real-world, evidence-based practice. The European Medicines Agency (EMA), United States Food and Drug Administration (FDA), and the new European Union Joint Clinical Assessment (JCA) emphasise clinically meaningful comparators. Meanwhile, the National Institute for Health and Care Excellence (NICE) and Haute Autorité de Santé (HAS) extend this requirement to include the therapies routinely used within their healthcare systems.
However, divergence persists. Regulators may accept placebo-controlled designs to establish efficacy, while HTA bodies expect evidence against the local standard of care to assess cost-effectiveness. This misalignment often creates gaps between regulatory approval and reimbursement readiness, potentially impacting product launch.
Early consultation with HTA agencies—through initiatives such as the EU Joint Scientific Consultation (JSC) and NICE Scientific Advice4 can help pre-empt these evidence gaps.
Mid-trial turbulence – When the standard of care changes halfway
A common challenge is the evolution of the therapeutic landscape during trial conduct. The emergence of new comparators mid-study can render results partially outdated. Proactive mitigation strategies include adaptive trial designs, pre-specified bridging analyses, and planned indirect comparisons using network meta-analysis. These approaches help preserve the relevance and interpretability of data without restarting development from scratch.
Strategic implications – More than just a methodological choice
Comparator choice is not merely a scientific consideration but a strategic investment. It shapes the product’s future price anchor, influences its competitive benchmark in HTA deliberations, and frames payer perceptions of value. Early, cross-functional comparator planning can therefore protect both evidentiary robustness and pricing integrity, thus accelerating access and sustaining value.
Cross-over designs – When ethics meet evidence
Cross-over or treatment-switching designs occupy a unique niche in evidence generation, particularly in oncology, rare diseases, and high-unmet-need conditions, particularly where withholding effective therapy is unethical. These designs allow patients in the control arm to switch to the investigational therapy once pre-defined criteria are met, improving ethical conduct and recruitment feasibility. However, they can also complicate estimation of overall survival (OS), a key endpoint for regulators and HTA agencies, by diluting the observed treatment effect and introducing immortal-time bias.
To address these challenges, several statistical adjustment methods exist, including the Rank Preserving Structural Failure Time Model (RPSFTM), Inverse Probability of Censoring Weights (IPCW), and two-stage models.5 Newer parametric variants enhance transparency. NICE’s Decision Support Unit (DSU) highlights the importance of transparent reporting and rigorous testing of assumptions.
While HTA bodies recognise the ethical rationale for cross-over, payers scrutinise adjustment validity, constant-effect assumptions, and consistency with real-world outcomes. Poorly justified adjustments can lead to reliance on unadjusted data, diminishing incremental cost-effectiveness and weaker price potential. Therefore, manufacturers should treat cross-over as a design feature with downstream implications. Early consultation with HTA experts can prevent post-hoc disputes and strengthen the value narrative.
External comparators and synthetic control arms – Making the most of limited evidence
In ultra-rare diseases or oncology, where RCTs are often unfeasible or unethical, external comparators or synthetic control arms offer pragmatic alternatives. These methods enable comparative assessment when only single-arm or open-label trials are possible. Although regulators may accept such evidence, HTA bodies often continue to demand comparative data, even in ultra-rare contexts.
External comparators can draw on disease registries, electronic medical records, insurance claims, or historical trial arms. Statistical techniques such as propensity-score matching, Matching-Adjusted Indirect Comparison (MAIC), Simulated Treatment Comparison (STC).6 Yet, external comparators carry bias risks from differing patient characteristics and data quality. Transparent justification and sensitivity analyses are essential.
HTA agencies accept external comparators when justified but often regard such evidence as supportive rather than definitive. NICE and HAS, for example, may grant conditional reimbursement but highlight residual uncertainty. For sponsors, this means external evidence can enable faster access but often requires follow-up data collection or risk-sharing agreements.
Strategically, early integration of real-world data (RWD) into clinical development—through registry partnerships and harmonised data capture—can transform external comparators from a defensive necessity into a competitive advantage. Done well, externally controlled evidence not only fills data gaps but also signals innovation in how comparative effectiveness is demonstrated.
Conclusion
Comparator choice sits at the intersection of science and strategy. It determines how evidence is interpreted, how innovation is valued, and how fast access is achieved. Direct comparators offer the gold standard, cross-over designs test ethical and analytical boundaries, and external comparators expand the toolkit when RCTs fall short.
Across all approaches, one truth holds: early, cross-functional comparator planning is essential. Integrating clinical, regulatory, and market access perspectives from the start prevents against irrelevant or obsolete evidence, accelerates HTA readiness, and sustains pricing integrity in a value-driven environment.
At Remap Consulting, we help biopharma companies anticipate these challenges and design evidence strategies that align with HTA and payer expectations. Whether you need support in study design, HTA planning, or strategy validation, Remap Consulting partners with you to strengthen evidence generation, engage with payers and accelerate reimbursement success.
References
- Remap Consulting (2021) Hazard ratio and HTA agencies. [online]. Available at: https://remapconsulting.com/hta/hazard-ratio-and-hta-agencies/
- Cuzick J, Sasieni P. Interpreting the results of noninferiority trials—a review. British journal of cancer. 2022 Nov 9;127(10):1755-9.
- Wang B et al., Shanghai Arch Psychiatry. 2017;29(6):385-388
- National Institute for Health and Care Excellence (NICE). Strategic and scientific advice. [Internet]. London. Available from: https://www.nice.org.uk/what-nice-does/life-sciences-how-to-get-your-product-to-market/nice-advice-service/strategic-and-scientific-advice*)
- Latimer NR, Abrams KR. NICE DSU Technical Support Document 16: Adjusting survival time estimates in the presence of treatment switching. (2014) Available from http://www.nicedsu.org.uk
- Phillippo, D.M., Ades, A.E., Dias, S., Palmer, S., Abrams, K.R., Welton, N.J. NICE DSU Technical Support Document 18: Methods for population-adjusted indirect comparisons in submission to NICE. 2016. Available from http://www.nicedsu.org.uk