In health technology assessment, demonstrating the clinical value of a treatment traditionally relies on direct comparative clinical trials. However, in practice, such data are not always available. Indirect treatment comparisons are therefore becoming an increasingly important methodological tool in health economic evaluations and reimbursement decisions.
Yet a key question remains: when can two treatments truly be considered similar?
This issue has been highlighted in an original analysis published by IQVIA on LinkedIn, which discusses the growing use of indirect treatment comparisons in healthcare decision-making.
Indirect Treatment Comparisons: A Method Used Increasingly in Health Technology Assessment
Indirect treatment comparisons (ITC) consist of comparing two interventions that have not been evaluated directly within the same clinical trial. These analyses generally rely on a common comparator.
For example, if two medicines have each been compared with placebo in separate trials, it becomes possible to estimate their relative efficacy indirectly.
Today, indirect treatment comparisons are widely used in evaluations conducted by health technology assessment agencies such as NICE in the United Kingdom or HAS in France.
HAS – methodological guidelines for economic evaluation:
https://www.has-sante.fr/jcms/p_3197550/en/guide-2020-choix-methodologiques-pour-l-evaluation-economique-a-la-has
However, indirect treatment comparisons raise a major methodological challenge: how can similarity or non-inferiority be demonstrated when direct comparative data are lacking?
A Methodological Issue That Remains Widely Debated
A recent analysis published in Value in Health examined precisely this methodological challenge and the role of indirect treatment comparisons in supporting economic evaluation and reimbursement decisions.
https://www.valueinhealthjournal.com/article/S1098-3015(25)02362-9
The authors show that, in many cases, submissions to regulatory and HTA agencies rely on relatively simple arguments such as:
- absence of statistically significant differences between treatments
- overlapping confidence intervals
- converging results from several meta-analyses
However, the absence of statistical difference does not necessarily mean that treatments are equivalent.
In other words:
absence of evidence is not evidence of absence.
This principle highlights one of the key methodological risks associated with indirect treatment comparisons.
Why Non-Inferiority Is Difficult to Demonstrate With Indirect Treatment Comparisons
In conventional clinical trials, non-inferiority is demonstrated using a predefined non-inferiority margin.
This margin represents the maximum acceptable loss of efficacy compared with a reference treatment.
However, when using indirect treatment comparisons, several methodological challenges arise:
- heterogeneity of patient populations across studies
- differences in trial design
- changes in treatment standards over time
- bias linked to historical comparators
One phenomenon often discussed in this context is “placebo creep.”
This concept describes the gradual improvement of outcomes observed in control groups over time as standards of care evolve.
These methodological complexities make the interpretation of indirect treatment comparisons particularly challenging.
The Contribution of Bayesian Approaches
The authors highlight the potential value of Bayesian statistical approaches to improve the interpretation of indirect treatment comparisons.
Unlike classical statistical approaches, Bayesian methods make it possible to express results in terms of probability of clinical similarity.
These approaches rely in particular on two key concepts:
- MCID (Minimum Clinically Important Difference): the smallest clinically meaningful difference between treatments
- ROPE (Region of Practical Equivalence): an interval representing differences considered clinically negligible
Using these concepts, Bayesian approaches allow researchers to integrate both:
- statistical uncertainty
- the clinical relevance of observed differences
Similar methodological recommendations have also been discussed within the International Society for Pharmacoeconomics and Outcomes Research (ISPOR).
Indirect Treatment Comparisons: A Growing Role in Reimbursement Decisions
An analysis of submissions evaluated by NICE between 2017 and 2024 shows that indirect treatment comparisons are playing an increasingly important role in market access decisions.
For pharmaceutical companies, these methods can:
- avoid costly head-to-head clinical trials
- accelerate access to reimbursement
- compare multiple existing therapeutic strategies
However, the authors also highlight a persistent gap between the sophistication of available methodological tools and their actual use in submissions to HTA agencies.
In France, indirect treatment comparisons remain only partially accepted by the Transparency Committee (CT). Many submitted analyses are still viewed with caution due to methodological concerns.
https://www.valueinhealthjournal.com/article/S1098-3015(25)02362-9/fulltext
Toward Greater Transparency in Indirect Treatment Comparisons
To strengthen the robustness of health technology assessments based on indirect treatment comparisons, several methodological recommendations are emerging:
- clearly define non-inferiority margins
- justify their clinical relevance
- conduct sensitivity analyses
- transparently document methodological assumptions
As healthcare systems increasingly rely on comparative evidence to guide decision-making, the quality and transparency of indirect treatment comparisons are becoming a strategic issue for health technology assessment.
