With the goal of cancer treatment generally to extend a patient’s life for a meaningful length of time, overall survival (OS) is widely considered the ‘gold standard’ endpoint in oncology clinical trials[1][2]. However, alternative oncology-relevant endpoints beyond OS offer great potential for supporting faster and more efficient access to therapies. So why aren’t these endpoints more widely used, and what might facilitate their broader adoption?
Overall survival: A trusted benchmark, but not always best
The preferred clinical endpoint in oncology clinical trials, OS serves as a trusted benchmark, offering wide ranging advantages over other endpoints[1][2]. Defined as the time from randomization to death, OS is precise, objective, and relatively easy to measure. Given its clinical robustness and patient relevance, OS is universally accepted by regulators and health technology assessment (HTA) bodies alike[2][3].
However, in some disease settings, OS is associated with important limitations[2]. The need for long studies makes OS an unsuitable endpoint in the case of slowly progressing and early-stage cancers, for example. Measurement of OS is also susceptible to confounding, particularly when involving multiple lines of therapies, patient crossover, and the occurrence of non-cancer related deaths. Furthermore, OS does not capture the broader priorities of patients and physicians; for example, when quality of life is a priority over prolonging survival[2]. For pharmaceutical companies, these limitations can translate into time and financial constraints.
Alternative oncology-relevant endpoints provide opportunities to address these concerns, allowing the collection of data at earlier time points than with OS (Figure 1)[1]. Such endpoints allow measurement of outcomes before starting subsequent therapies, giving a more direct measure of treatment efficacy. Some endpoints also offer broader value to patients too – besides being surrogate endpoints for OS, non-OS endpoints can provide standalone information, including on symptoms, function, treatment burden, and quality of life[4].
Figure 1: Alternative oncology-relevant endpoints
Source: Modified from Delgado and Guddati 2021[1]
Abbreviations: EQ-5D, EuroQol 5-dimensions index; NSCLC-SAQ, Non-Small Cell Lung Cancer Symptom Assessment Questionnaire; PROs, patient reported outcomes.
Why aren’t alternative oncology-relevant endpoints used more widely?
Despite their potential value, alternative oncology-relevant endpoints remain underused in clinical trial design. In 2021, non-OS endpoints accounted for just 16% of primary endpoints in Phase II or Phase III oncology trials, with the most common being pathological complete response, relapse rate and disease-free survival[5].
Major barriers to the broader adoption of alternative oncology-relevant endpoints in clinical trials include a lack of agreement on their value and the uncertainty among payers that they accurately capture treatment benefits for patients and healthcare systems[4][6]. While regulators are generally more receptive towards non-OS endpoints, accepting measures that are reasonably likely to predict clinical benefit, HTA bodies typically require validation of surrogacy[4][6]. In general, guidelines published by HTA bodies indicate a preference for OS data or consider surrogate endpoints only where validation studies demonstrate strong correlation with survival[6]. From a payer perspective, this caution is arguably expected; several therapies approved on the basis of improvements in outcomes such as progression-free survival (PFS) have not demonstrated OS benefits[2]. Despite this, few agencies provide detailed methodological guidance for surrogacy validation[7].
This uncertainty is further confounded by differences in the willingness of national HTA bodies to evaluate even well-established alternative oncology-relevant endpoints such as PFS[6]. The resulting complexity feeds a vicious cycle: a lack of standardized methodologies for evidence generation leads to insufficient evidence to quantify the long-term benefits of non-OS endpoints, deterring HTA bodies from giving due consideration to these outcomes in decision making[6].
Moreover, while HTA bodies continue to place particular importance on mortality, patients and clinicians often consider outcomes such as the avoidance of surgery or pain equally or more important than OS in some treatment settings[6]. HTA bodies and payers can perceive patient reported outcomes (PROs) as more subjective, a point of difference that is reflected in the regional variations in the way PRO evidence is reviewed and considered in global HTA decision-making[6]. This lack of alignment contributes to a lack of clarity around PRO requirements, reinforcing uncertainty among stakeholders.
Towards stakeholder alignment on alternative oncology-relevant endpoints
Overcoming the uncertainties and inconsistencies limiting broader adoption of alternative oncology-relevant endpoints requires concerted efforts from all stakeholders and a more harmonized approach towards their use[4][6]. There is growing consensus that, by working together, the oncology community can move closer towards establishing sets of appropriate endpoints for specific cancer types and stages that have wide buy-in from regulatory authorities, reimbursement bodies, pharmaceutical developers, and patients themselves.
A key step towards this goal will be agreeing upon the endpoints that matter most to patients, which will almost certainly differ by cancer type and stage[4][6]. For example, while extending survival may remain a priority in treatment settings with poor prognoses, for cancers where prognosis is improving, disease progression and quality of life may prove more valuable. Once alignment is reached on which outcomes are most valuable to patients, appropriate endpoints and PROs should then be defined through consultation with clinicians and healthcare professionals[6].
There also exists an opportunity for greater harmonization in the methodologies used to validate endpoints and generate data[4][6]. This is particularly important for PROs where there is lack of standardization in data collection methods, analysis and interpretation. Alignment on the levels of uncertainty that are acceptable to regulatory and HTA decision-makers and other stakeholders is also important, requiring greater transparency on the evidence needed to support regulatory approval and reimbursement in specific treatment settings[4][6]. Much work has already been undertaken to establish the surrogate and standalone value of alternative oncology-relevant endpoints. However, the use of real-world evidence and other health economics and outcomes research (HEOR) studies to evaluate the long-term clinical and economic impact of treatments may help accelerate efforts to bridge these gaps[6].
Global HTA bodies and professional organizations are already taking steps towards a more harmonized approach to assessing the surrogate and standalone value of non-OS endpoints. For example, an ongoing collaboration between HTA bodies including the National Institute for Health and Care Excellence (NICE), Scottish Medicines Consortium (SMC) and Canadian Agency for Drugs and Technologies in Health (CADTH) is developing methodological guidance and a new joint scientific advice procedure on the use of surrogate outcomes for cost-effectiveness analysis[8]. The International Society for Pharmacoeconomics and Outcomes Research (ISPOR) has also established a taskforce to set good practices for surrogacy evaluation and validation of the relationships between outcomes informing HTA decisions[9]. These initiatives run alongside broader efforts to harmonize HTA decision-making processes within the European Union under Joint Clinical Assessment, providing an opportunity to promote greater standardization around non-OS endpoints[10][11].
By supporting more transparent and consistent approaches for the evaluation of alternative oncology-relevant endpoints, these programs have the potential to promote more predictable outcomes in HTA decision-making – a necessary step towards building confidence in the value and suitability of alternative endpoints in clinical trial design.
Looking beyond overall survival
Overall survival remains an important measure of the value of cancer therapies, yet there exists a growing role for oncology-relevant endpoints beyond this ‘gold standard’. By considering patients’ needs, addressing uncertainties, and building consensus around the best outcomes to use in specific treatment settings, oncology-relevant endpoints beyond OS have the potential to facilitate faster and more cost-efficient access to novel cancer treatments.
Clarivate has supported our clients bring the next generation of innovative oncology treatments to market, empowering early-stage R&D and robust clinical trial design, through to navigating regulatory and market access pathways. Within Clarivate’s Evidence, Value and Access consultancy, our reimbursement dossiers, value stories, and objection handlers have supported clients achieve their market access goals in breast cancer, bladder cancer, leukemia and beyond, and our team have expertise with novel technologies such as CAR-T therapies. To learn more about our capabilities and how we can support you, please get in touch here.
This post was written by Richard Massey, Director, Value Communication and Clara Ricci, Senior Medical Writer.
References
[1]Delgado, A. and A.K. Guddati, Clinical endpoints in oncology – a primer. Am J Cancer Res, 2021. 11(4): p. 1121-1131.
[2]Cimen, A., et al., Shifting perspectives on the value of non-OS endpoints and PROs: Considerations across stakeholder groups to support oncology HTA decision-making. Journal of Clinical Oncology, 2023. 41(16_suppl): p. e13646-e13646.
[3]McKee, A.E., et al., The role of the U.S. Food and Drug Administration review process: clinical trial endpoints in oncology. Oncologist, 2010. 15 Suppl 1: p. 13-8.
[4]Fameli, A., et al., Looking Beyond Survival Data: How Should We Assess Innovation in Oncology Reimbursement Decision Making. Values & Outcomes Spotlight, 2023. 9(5): p. S5.
[5]IQVIA report, Evolving oncology endpoints – a new horizon for health outcomes 2021.
[6]European Federation of Pharmaceutical Industries and Federations report, Improving the understanding, acceptance and use of oncology–relevant endpoints in HTA body / payer decision-making 2023
[7]Grigore, B., et al., Surrogate Endpoints in Health Technology Assessment: An International Review of Methodological Guidelines. PharmacoEconomics, 2020. 38(10): p. 1055-1070.
[8]NICE, International health technology assessment collaboration expands
[9]ISPOR, Surrogate Endpoint Statistical Evaluation for HTA Decision Making
[10]European Commission, Questions and Answers: Adoption of Regulation on Health Technology Assessment
