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Going head-to-head: Comparative evidence in immunology on the rise
When innovators must consider H2H trials and comparative RWE
Nov 25, 2025
Introduction: The growing importance of comparative evidence
The immunology market is rapidly maturing as prolific innovators keep launching novel therapies while low(er) cost biosimilars have been gaining traction. This trend continues as immunology is heading for a major patent cliff in the early to mid-2030s, with more off-patent versions of advanced therapies to follow. Consequently, many immunology indications are becoming increasingly crowded, and fierce inter- and intra-class competition is playing out.
Such an abundance of choice, across innovative and mature therapies, gives payers more leverage in negotiations with manufacturers for market access, position on formularies or in treatment algorithms, while expanding options for HCPs. At the same time, both payers and HCPs find it much harder to compare different therapies, understand their relative benefits and value, and to navigate an increasingly complex treatment landscape.
Therefore, the importance of robust comparative evidence is elevated to enable a ‘like-for-like’ comparison of therapeutic options, as the ultimate proof of a given therapy’s differentiation. For immunology innovators entering a crowded market, comparative evidence is critical to support three strategic objectives:
i. Winning against other brands in head-on competition for patients in the same line of therapy.
ii. Moving upstream into an earlier line of therapy by displacing an inferior legacy standard of care (SoC) and redefining clinical practice.
iii. Accelerating switches, for example, from a first-line, payer-mandated low(er) cost biosimilar, or an entrenched, legacy SoC therapy benefitting from HCP familiarity.
In this blog, we will explore trends in immunology head-to-head (H2H) clinical trials spanning two and a half decades, from 2000 until 2024.
Head-to-head trials in immunology
Using the Citeline Trialtrove database, we identified industry-sponsored immunology H2H trials which evaluate an advanced therapy against an active comparator. Subsequently, we categorised those H2H trials by the type of comparator used:
- H2H trials comparing an advanced therapy, e.g., a biologic or targeted small molecule drug, against a non-advanced therapy, such as methotrexate, azathioprine or corticosteroids
- H2H trials comparing two advanced therapies
- H2H trials comparing a biosimilar against its reference biologic
Observed trends in the volume and type of immunology H2H trials broadly track the evolution of the immunology treatment landscape over the past 25 years (see Figure 1):
- The ten-year average of annual H2H trial starts jumps from 4 for the period of 2000-2009 to 14 for 2010-2019 and more recently to a five-year average of 15 for 2020-2024, driven by an increasingly crowded and competitive immunology market.
- Between 2000 and 2010, when TNF inhibitors were establishing themselves as the first generation of advanced therapies, the vast majority of H2H trials compared these agents to non-advanced therapies, reflecting the standard of care (SoC) at that time.
- From 2011 onwards, when an increasing number of next generation advanced therapies entered the market and TNF inhibitors were approaching loss of exclusivity, we saw a sharp rise in the number of both H2H trials assessing biosimilars against their reference biologics and H2H trials comparing two advanced therapies.
- Furthermore, from 2018 onwards, numbers of H2H trials with non-advanced therapy comparators declined, because they no longer represent the competitive frontier in immunology.
As discussed earlier, intense competition as a result of the proliferation of treatment options in many immunology indications, within and across different therapy classes, has been driving the need for comparative evidence. Consequently, H2H trials are most prevalent among highly crowded immunology indications.
Specifically, between 2000 and 2024 psoriasis and rheumatoid arthritis together accounted for 56% of all H2H trials comparing two advanced therapies, excluding biosimilars. Other immunology indications that are becoming increasingly crowded, e.g., psoriatic arthritis, Crohn’s disease, ulcerative colitis or axial spondyloarthritis, have seen growing H2H trial activity over the past decade (see Figure 2).
Unsurprisingly, leading immunology players also dominate H2H trials. Between 2000 and 2024, the top 5 industry sponsors held a combined share of 57% of immunology H2H trials comparing two advanced therapies, including 15% for AbbVie, 14% for J&J, 10% for Novartis, and 9% each for Lilly and Pfizer.
Deep dive: Head-to-head trials in psoriasis
Psoriasis (PsO) is one of the most crowded immunology indications. Currently, 15 approved molecules representing targeted therapies compete across 8 advanced mechanisms of action, with more advanced therapies expected to enter in the next 3-5 years.
Such fierce competition has led to an equally intense evidence battle and made PsO ground zero for immunology H2H trials (see Figure 3).
Observed patterns in PsO H2H trials and their focus clearly reflect the competitive dynamics in this market:
- H2H data have become table stakes for both new therapy classes and later entrants within an established class, e.g., Tremfya, Skyrizi, Bimzelx or Sotyktu.
- The choice of H2H comparators reflects the evolving SoC and competitive frontier in PsO. For example, for new biologics showing superiority vs. anti-TNFs is not enough, they need to beat an IL-17 therapy.
- The same applies to novel orals, e.g., Sotyktu and zasocitinib ran H2H trials against first generation oral therapy Otezla. Sotyktu, relatively more efficacious and now approved, became the comparator in recent H2H trials of zasocitinib and icotrokinra. Icotrokinra, with best-in-class potential among novel oral therapies, is going one step further with its ICONIC-ASCEND H2H trial, seeking to show superiority vs. injectable biologic Stelara.
- Future-proofing through H2H trials: Several leading PsO biologics generated H2H data vs. Humira, and/or Stelara. Such data may serve as a defence against these comparators’ respective off-patent versions, by accelerating switches from first-line, often payer-mandated biosimilars; or Skyrizi’s H2H data vs. Otezla, to help accelerate switches from first-line oral Otezla, especially once low cost Otezla/apremilast generics become available. Furthermore, Skyrizi H2H data vs. oral therapies Otezla and Sotyktu may open the door for its potential expansion into patients with milder PsO.
Psoriasis serves as a bellwether for the growing role of H2H trials in the wider immunology market, a trend that has already reached other indications, such as Crohn’s disease or ulcerative colitis, and can be expected to continue as further market segments become more crowded.
Key considerations for immunology innovators
Embarking on a H2H trial is a high-stakes endeavour and therefore requires a robust business case, including a rigorous assessment of potential risks, costs and rewards, alongside careful planning and flawless trial execution.
An innovator’s high confidence in their novel therapy to outperform the standard of care (SoC), or a different comparator, is an obvious prerequisite. This should be anchored in a deep understanding of the disease biology, an asset’s MoA and underlying science, its performance in prior trials, and the strengths and weaknesses of competing therapies.
Furthermore, there are a number of critical considerations for ensuring a H2H trial is given the best possible chance to succeed and be impactful.
1. A clear strategic objective aligned with the brand strategy:
a. Where do we want our therapy to be positioned in the treatment algorithm, and therefore who is the competitor/comparator to beat? The answer needs to consider an evolving SoC to ensure H2H trial results will be clinically relevant.
b. What is the basis of differentiation for our therapy, e.g., superior efficacy, or demonstrating ‘equivalent’ efficacy but offering better safety, tolerability or more convenient administration?
2. Translating strategic objectives into H2H trial design:
a. Superiority vs. noninferiority: Which design aligns best with the study objectives, informed by the brand strategy? What is a clinically meaningful superiority delta, or non-inferiority margin? How difficult will it be to demonstrate these? Finally, how does this translate into sample size requirements for adequate power?
b. Endpoints: Which benefits are most relevant to patients, HCPs and payers, and therefore which new, compelling H2H data would facilitate a change in clinical practice and/or expansion of market access?
c. Concomitant treatment: Should background therapy be allowed, e.g., MTX in RA or corticosteroids in IBD, alongside the investigated advanced therapies? This could distort the effect size but on the other hand may better reflect clinical practice.
3. Optimal trial execution:
a. Timing: Should the H2H trial run alongside pivotal phase 3 studies or start after regulatory approval? What are the risks to securing regulatory approval in the former scenario? What is the opportunity cost of late H2H data in the latter scenario?
b. Blinding: Double blinding in H2H trials comparing two active interventions is challenging, e.g., two drugs may have different packaging, physical appearance, different injector devices, or even different routes of administration. Sponsors will need to understand the practical implications for trial execution, timelines and cost.
c. Sourcing of the active comparator: Sponsors must have a clear plan for securing supply of the active comparator, e.g., direct purchase from the manufacturer, access via barter, or purchase via a wholesaler. The associated, potentially significant cost must be included in the business case for the H2H trial and reflected in clinical development budgets.
Conducting a H2H trial is not for the faint-hearted. Once a compelling business case has been made, immunology innovators must ensure their brand strategy is translated into an optimal H2H trial design, subsequently delivered with clinical operational excellence.
Beyond H2H clinical trials: comparative RWE
While this blog has focused on industry-sponsored, H2H randomised controlled trials (RCTs), it is important to note that comparative RWE is becoming increasingly critical to understand different therapies’ real-world effectiveness and safety, and to bridge the gap between clinical trials and routine clinical practice. Unlike clinical trial populations, patients seen by HCPs are more diverse, e.g., across a wider range of ages, disease severity, comorbidities, and likely treated with multiple medications concurrently.
Examples of comparative real-word studies evaluating different advanced immunology therapies include:
- A multicentre, retrospective, observational cohort study of ulcerative colitis patients treated with vedolizumab or TNF-antagonist therapy to compare safety and effectiveness; using the North American multicentre VICTORY consortium registry (>2,500 patients from 12 different centres in the US and Canada) [1].
- A study evaluating real-world comparative effectiveness of biologic therapy for IBD and the impact of drug sequencing in 13,222 UK patients, using the UK IBD BioResource, a national research platform [2].
- A multicentre, retrospective real-world study comparing the effectiveness and safety of four JAK inhibitors (tofacitinib, baricitinib, peficitinib, upadacitinib) in patients with rheumatoid arthritis; using the ANSWER cohort, an observational, multicentre registry of 11,673 RA patients in Japan [3].
As a source of unique insight that complements RCT data, comparative RWE has a crucial role to play in shaping clinical practice, and in informing guidelines, market access and reimbursement decisions, especially in an increasingly crowded and complex immunology landscape.
Final thoughts
The proliferation of treatment options across many immunology indications has elevated comparative evidence as a strategic priority, including H2H clinical trials and comparative RWE. It provides the ultimate proof of differentiation to demonstrate a therapy’s superiority to payers and HCPs within a hyper-competitive environment.
The rise of AI-powered searches as a key channel for HCPs to access medical information, including clinical data and RWE, further amplifies the importance of comparative data as algorithms apply evidence hierarchies.
Immunology innovators must carefully consider a comparative evidence strategy as part of their integrated evidence plans, informed by a clear understanding of risks, rewards and practical challenges, to succeed in an unforgiving immunology market.
References
1. Faleck, D. et al, Comparative Safety and Effectiveness of Vedolizumab to Tumor Necrosis Factor Antagonist Therapy for Ulcerative Colitis. Clin Gastroenterol Hepatol. 2022 Jan;20(1):126-135. https://doi.org/10.1016/j.cgh.2020.10.003
2. C. Kapizioni, R. Desoki, Biologic Therapy for Inflammatory Bowel Disease: Real-World Comparative Effectiveness and Impact of Drug Sequencing in 13 222 Patients within the UK IBD BioResource, Journal of Crohn's and Colitis, Volume 18, Issue 6, June 2024, Pages 790–800, https://doi.org/10.1093/ecco-jcc/jjad203
3. Shinya Hayashi et al, Real-world comparative study of the efficacy of Janus kinase inhibitors in patients with rheumatoid arthritis: the ANSWER cohort study, Rheumatology, Volume 63, Issue 11, November 2024, Pages 3033–3041, https://doi.org/10.1093/rheumatology/kead543