Harper Sam, Afonso Daniela, Watts Karina, Doble Brett, Eklund Oskar, Vadgama Sachin, Snider Julia Thornton, Palmer Stephen, Taylor Matthew
York Health Economics Consortium, University of York, Heslington, York, UK.
Kite, a Gilead Company, 2400 Broadway, Santa Monica, CA, 90404, USA.
Pharmacoeconomics. 2025 Aug 7. doi: 10.1007/s40273-025-01529-5.
Health technology assessment (HTA) of haemato-oncology therapies typically requires extrapolation of long-term survival beyond a trial's follow-up. Health technology assessment agencies must balance caution around uncertainty in early follow-up trial data whilst aiming to provide timely access. This study qualitatively and quantitatively assessed how eight HTA agencies considered maturing data and external evidence.
The eight HTA appraisals were based on ZUMA-7, a phase III trial for axicabtagene ciloleucel (axi-cel) for second-line diffuse large B-cell lymphoma. ZUMA-7 survival data were submitted with either a 25-month ('Interim') or 47-month ('Primary') follow-up. To inform axi-cel Interim survival extrapolations, external evidence was available from a prior mature single-arm trial for third-line or later diffuse large B-cell lymphoma (ZUMA-1). A qualitative assessment of eight different submissions to HTA agencies was undertaken to determine key discussion points. The value and cost of waiting for evidence to mature between Interim and Primary analyses were quantified using value of information methods to evaluate the impact of waiting for further evidence collection on population health.
Agencies used varied approaches to account for uncertainty in survival extrapolations in both Interim and Primary analyses. No agency considered external evidence fully during Interim submissions; one used it partially to inform clinical plausibility; four did not consider it. Health technology assessment agencies that did not consider the relevance of ZUMA-1 were more inclined to wait for more mature evidence to mitigate uncertainty. When ZUMA-1 aided in determining a plausible range for Interim extrapolations, the less valuable more mature evidence became, with the cost of waiting for Primary analysis results exceeding the value conferred.
There was limited consideration of external evidence during the included HTA submissions. In the future, it is recommended that external evidence should be considered to a greater degree by both manufacturers and HTA agencies when extrapolating survival to ensure appropriate and timely HTA decisions that minimise the undue burden on healthcare systems.
血液肿瘤治疗的卫生技术评估（HTA）通常需要在试验随访期之外推断长期生存率。卫生技术评估机构必须在早期随访试验数据的不确定性方面保持谨慎，同时致力于提供及时的准入。本研究对八个HTA机构如何考虑数据成熟度和外部证据进行了定性和定量评估。
八项HTA评估基于ZUMA-7，这是一项关于axi-cel用于二线弥漫性大B细胞淋巴瘤的III期试验。ZUMA-7生存数据提交时的随访时间为25个月（“中期”）或47个月（“主要”）。为了为axi-cel中期生存推断提供信息，可从先前一项针对三线或更晚期弥漫性大B细胞淋巴瘤的成熟单臂试验（ZUMA-1）中获取外部证据。对提交给HTA机构的八项不同材料进行了定性评估，以确定关键讨论点。使用信息价值方法量化了在中期分析和主要分析之间等待证据成熟的价值和成本，以评估等待进一步证据收集对人群健康的影响。
各机构在中期分析和主要分析中采用了不同方法来处理生存推断中的不确定性。在中期提交材料时，没有一个机构充分考虑外部证据；一个机构部分使用外部证据来确定临床合理性；四个机构未考虑外部证据。未考虑ZUMA-1相关性的卫生技术评估机构更倾向于等待更成熟的证据以减轻不确定性。当ZUMA-1有助于确定中期推断的合理范围时，更成熟证据的价值就越低，等待主要分析结果的成本超过了所带来的价值。
在所纳入的HTA提交材料中，对外部证据的考虑有限。未来，建议制造商和HTA机构在推断生存率时应更大程度地考虑外部证据，以确保做出适当及时的HTA决策，将对医疗系统的不当负担降至最低。
