NICE Appraisals of Relugolix-CT and Linzagolix for Endometriosis Symptom Management: Commentary on Clinical and Economic Uncertainties

in the linzagolix TA. Laparoscopic surgery was included as comparator in the economic analysis (though not in ITC) following NICE and the EAG’s request dur - ing the decision problem meeting [2 ]. During clarifica- tion, NICE also requested inclusion of relugolix-CT in the NICE Appraisals of Relugolix-CT and Linzagolix for Endometriosis Symptom Management economic and ITC analysis, with the company finding no difference in relative effectiveness [2 ]. Discontinuation of relugolix-CT and linzagolix was assumed to be due to loss of efficacy, so treatment effect waning was not modelled in either TA. The EAG and AC considered this uncertain and recommended sensitivity analyses, but agreed that in the absence of long-term data, assuming a constant effect similar to GnRH agonists may be reasonable [11]. To reflect the impact on fertility, both models assumed short- and long-term disutilities for all women undergo- ing hysterectomy, but only the linzagolix model adjusted for those wishing to conceive [2 , 3]. Neither model explic- itly captured infertility-related disutility from medical contraceptive treatment(s), which the EAG considered an important omission since GnRH agonists, relugolix CT and linzagolix all have contraceptive effects [2 , 3]. The EAGs considered this approach simplistic, noting that infertility- related disutility attributed to the use of contraceptive medi- cal treatments would last much longer for women on relu - golix-CT or linzagolix (up to menopause, ~16 years) given their long-term use compared with GnRH agonists, which are generally restricted to about 1 year. In the relugolix-CT appraisal, this substantially influenced cost-effectiveness, as most health gains arose from lower post-hysterectomy disu- tility. Finally, the EAGs questioned the companies’ expec- tation that women can conceive immediately after stopping relugolix-CT or linzagolix treatment [2 , 3]. 3.3 Issues with the Model Validation The EAG found the relugolix-CT model insufficiently vali- dated, with limited justification for assumptions and coun- terintuitive results. The first AC required thorough model validation. The EAGs in both appraisals highlighted uncertainty and limited face validity in the utility values. For relugolix-CT, some data sources were also questioned, noting that long- term infertility-related disutility was from the 1990 Global Burden of Disease study [3 ]. The first AC concluded that these disutilities were uncertain and could not fully capture individual variation in fertility-related experience. In the linzagolix appraisal, the EAG identified valid- ity issues with the derivations of transition probabilities between surgery-related health states and questionable meth- ods for utility estimation in post-initial treatment states and presented alternative estimates for both [2]. 3.4 EAG Concerns and Exploratory Scenarios The company’s incremental cost-effectiveness ratios (ICERs) for relugolix-CT versus GnRH agonists fell below the threshold range considered cost-effective by NICE. The EAG did not present a preferred base-case, because key issues with the SR, model validation, and missing comparators would have required major revisions unfea- sible to address with the submitted evidence [3 , 11]. For linzagolix, the EAG’s preferred ICERs compared with leuprorelin and surgery were higher than the com- pany’s, but still below the NICE threshold. Linzagolix was more costly than relugolix-CT at equivalent effectiveness [2]. Multiple exploratory scenarios were tested. For relugo- lix-CT, ICERs varied with assumptions about treatment duration response, and utility values [3 ]. For linzagolix, alternative transition probabilities between surgery-related health states were particularly influential [2 ]. However, ICERs in both appraisals remained well below common thresholds, suggesting that input and structural uncertainty did not cause substantial decision uncertainty. 4 First AC Meeting and Subsequent Revisions 4.1 Relugolix‑CT: 1st and 2nd AC Meetings The first AC concluded that no robust cost-effectiveness estimates could be derived, and did not recommend relugolix-CT. Subsequently, the company updated the SR to include additional comparators and long-term efficacy data from the SPIRIT OLE study [15], revised the ITC showing com- parable effectiveness to multiple GnRH agonists and added surgery as a comparator in the economic model, where relugolix-CT was more effective and more costly. Scenario analyses extending GnRH agonist durations up to 10 years showed relugolix-CT to be less costly and more effective. However, the second AC accepted a 1-year base-case duration given consistent results and practice variation. The company also addressed model validation concerns through additional justification and scenario analyses, including varying hysterectomy-related disutil- ity. The second AC concluded that applying a lower disu- tility across the population was more appropriate given individual variability. Despite remaining uncertainties around the generalisa - bility of multiple inputs, the EAG found the model robust, and the committee considered the evidence sufficient for decision-making [15]. The second AC agreed that the most plausible ICERs were within acceptable cost-effectiveness range, and recommended relugolix-CT within its market- ing authorisation in April 2025. V. Qendri et al. 4.2 Linzagolix Approval via Streamlined Decision‑Making In June 2025, NICE recommended linzagolix with ABT using the streamlined decision-making approach introduced in 2022 [14]. This approach accelerates guidance for what are supposed to be lower-risk technologies [16, 17]. Evi- dence is reviewed by a subset of committee members, with- out a full meeting, with fewer evidence requirements, shorter timelines, and targeted stakeholder engagement, enabling faster patient access to new treatment [17]. Under this approach, the linzagolix guidance did not critique the evidence, but stated that: “Clinical trial evi- dence shows that linzagolix with hormonal ABT reduces dysmenorrhoea (painful periods) and non-menstrual pelvic pain compared with placebo. ITCs suggest that linzagolix with hormonal ABT gives similar pain relief to leuprorelin acetate and relugolix-CT. The cost-effectiveness estimates for linzagolix with hormonal ABT compared with surgery, leuprorelin acetate and relugolix-CT are within the range that NICE considers an acceptable use of NHS resources” [14]. 5 Key Learnings • Within standard cost-effectiveness analysis, complex, chronic diseases accompanied by individualised treat- ment pathways, such as endometriosis, still require clearly defined care pathways to select appropriate com- parators and evidence networks, as these choices can substantially influence cost-effectiveness outcomes and underpin confident, evidence-based decision-making. • Standard modelling approaches may not fully capture preference-based or individualised treatment pathways, as seen in endometriosis. Nevertheless, scenario analy - ses testing alternative structural and input assumptions produced ICERs well below common thresholds in both TAs considered, suggesting that input and structural uncertainties did not translate into substantial decision uncertainty. • Clinical expert involvement enhances context and plausi- bility, informing uncertain model inputs and aiding inter- pretation of ambiguous clinical and economic evidence. • NICE’s streamlined approach should not bypass qual- ity checks. While clinical evidence, comparators and cost-effectiveness can be reviewed without a full TA process, for the current topic full EAG assessments of both submissions were necessary. However, the linzago- lix guidance was published without a public AC meet- ing. Decisions about which aspects of the process can be streamlined should therefore be made on a case-by-case basis. Transparency could also be improved by publicis- ing the AC’s critique of the evidence. 6 Conclusions The NICE appraisals of relugolix-CT and linzagolix plus ABT illustrate the challenges of evaluating innovative treat- ments for complex, chronic conditions including endome- triosis using short-term trial data. Both agents offer novel mechanisms and convenient oral administration, but were accompanied by considerable uncertainty around treatment positioning, long-term effectiveness and economic impact. These cases offer valuable insights for future assessments, demonstrating how NICE navigates the intersection of inno- vation, evidence gaps and patient needs in complex thera- peutic areas. Funding The EAG reports leading to this work were commissioned by the National Institute for Health and Care Research (NIHR) Evidence Synthesis Programme as project numbers NIHR STA 13/61/26 and STA 16/95/94. See the health technology assessment programme web- site for further project information:https://www.nihr.ac.uk/research- funding/funding-programmes/health-technology-assessment. This summary was compiled after NICE issued the Final Appraisal Deter - mination. The views and opinions expressed herein represent those of the authors and do not necessarily reflect those of NICE or the Department of Health. Declarations Conflict of interest The authors declare no conflicts of interest in rela- tion to this work. ICR is an Editorial Board Member of PharmacoEco- nomics. He was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Ethics approval Not applicable. Informed consent Not applicable. Data availability Not applicable. Consent to participate Not applicable. Consent for publication Not applicable. Code availability Not applicable. Author contributions All authors contributed to the manuscript con- ception and design and were involved with the work of the EAGs. Open Access This article is licensed under a Creative Commons Attri- bution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduc- tion in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. 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