The Regulation (EU) 2021/2282 on health technology assessment (HTAR) for medicines will come into effect in January 2025; initially, new oncology medicines and advanced therapy medicinal products will be assessed at EU level. How will this work in practice? What does this mean for national HTA bodies, such as the National Centre for Pharmacoeconomics (NCPE) Ireland that uses a cost-effectiveness framework to inform decision-making for medicines?

Joint work to be conducted under the Regulation includes joint clinical assessments (JCA), joint scientific consultations (JSC), and production of procedures and methodological guidance. A review was undertaken of key areas that will be impacted by the HTAR in the Irish HTA process for medicines, including timing, evidence synthesis structure, capacity building, and resource implications.

The HTAR will alter the current process for medicines assessment in Ireland, from early scientific advice to cost-effectiveness assessment post-authorization. JSCs will represent an additional step. Significant training and capacity implications are associated with the JCA, which will require earlier engagement with stakeholders. The NCPE’s pragmatic HTA early triaging process, the “Rapid Review,” may be delayed due to the non-duplication clause in the HTAR. The availability of high-quality comparative effectiveness evidence may help avoid full HTAs in some cases. The benefit of the JCA will be realized if the results can directly inform treatment-effectiveness estimates in cost-effectiveness modeling.

The HTAR will significantly impact on medicines reimbursement procedures in Ireland. For the HTAR to be effective in achieving its aims, sufficient resources will need to be built into the EU HTA system. The balance between the extra resources needed and the resources spared will depend on the quality of the comparative effectiveness evidence available for the JCA.

Surrogate endpoints are increasingly being used in the pivotal trials of cancer drugs to underpin (conditional) regulatory approval. We examined the relationship between the use of surrogate measures in pivotal trials underpinning cancer drug approvals by the European Medicines Agency (EMA) between 2017 and 2022 and health technology assessment (HTA) recommendations made by the National Centre for Pharmacoeconomics in Ireland (NCPE).

A previously published methodology was used to identify cancer drug indications that received (conditional) marketing authorization between 2017 and 2022, inclusive. EMA-approved cancer drugs were categorized using the following benefit categories, based on pivotal trial endpoints: overall survival (OS), progression-free survival (PFS), disease response (DR), and single-arm trials (SATs). The NCPE website was searched to identify indications that had undergone, at least, a rapid review (RR) assessment. The NCPE recommendation for each assessment was recorded. Additional data including the incremental quality-adjusted life years (QALY) gain reported in cost-effectiveness analyses were extracted for indications that had undergone a full HTA.

One hundred and eight cancer drug indications were identified, comprising 68 cancer drugs. In 2017, OS, PFS, and SAT benefit underpinned equal proportions of approvals (28.6% each). In 2022, SAT underpinned the largest proportion of approvals (53.6%). As of June 2023, 77 indications (71.3%) had undergone at least a RR assessment; 31 indications had completed a full HTA appraisal. All of the indications underpinned by SAT evidence (n=7) received a conditional negative recommendation. Indications with SAT evidence had a mean incremental QALY gain of 1.88 (standard deviation [SD] 1.20), whereas indications with an OS benefit had a mean incremental QALY gain of 0.81 (SD 0.36).

The proportion of cancer drug indications receiving regulatory approval on the basis of SAT evidence, where no direct comparative evidence is available, is increasing. This results in additional uncertainty in the comparative benefit of cancer drugs supported by SAT evidence. The study is limited by the sample size of HTA appraisals included. Further in-depth analysis of factors influencing NCPE recommendations is needed.

Time to reimbursement has been described as a hurdle to availability of new medicines to European patients, with assessment and decision-making processes frequently quoted as taking the majority of time. In light of the upcoming Regulation (EU) 2021/2282 on health technology assessment (HTAR), the aim was to examine timelines and health technology assessment (HTA) recommendations for orphan drugs in Ireland.

The study reviewed all orphan drug submissions to the National Centre for Pharmacoeconomics (NCPE) from January 2020 to December 2023 inclusive. The number of days from marketing authorization to rapid review (RR) commissioning was calculated. The RR and HTA recommendations were identified for all medicines. The timelines for the RR and HTA process were evaluated.

Of the 66 submissions identified, 38 percent were made prior to marketing authorization (MA), eight percent were made within 30 days of MA, and 79 percent were made 30 days post MA. RRs were completed within 32 days (mean). Full HTA was recommended in 62 percent (n=41). Price negotiations were recommended in 38 percent (50% of which have been reimbursed to date). Where a full HTA was recommended (n=41), 20 have been completed to date (price negotiations were recommended in 90%). For those 20 HTAs completed, 11 have been reimbursed to date; a decision is pending for the remainder. HTAs were completed within 200 days (mean).

Data shows that the majority of submissions were made 30 days post MA. A pragmatic approach may have to be taken nationally to accommodate the HTAR post 2024 and those submissions that are made prior to publication of a joint clinical assessment. The majority of orphan drug HTA recommendations lead to reimbursement recommendations.

There is ongoing debate as to whether conventional pharmacoeconomic evaluation (PE) methods are appropriate for orphan medicinal products (OMPs). The National Centre for Pharmacoeconomics (NCPE) in Ireland has a well-defined process for conducting pharmacoeconomic evaluations of pharmaceuticals, which is the same for OMPs and non-OMPs. The objective of this study was to identify whether supplementary criteria considered in the pharmacoeconomic evaluation of OMPs would affect final reimbursement recommendations.

A literature search was conducted to identify criteria. Orphan drug pharmacoeconomic evaluations completed by the NCPE between January 2015 and December 2017 were identified and supplementary criteria, where feasible, were applied.

Fourteen pharmacoeconomic evaluations were included in the study. Three criteria that could feasibly be applied to the NCPE evaluation process were identified, all three of which essentially broadened the economic perspective of the pharmacoeconomic evaluation. Higher cost-effectiveness threshold: Despite being arbitrarily raised from EUR 45,000/QALY to EUR 100,000/QALY, only one orphan drug demonstrated cost-effectiveness at this higher threshold. Weighted QALY gain: here, a weighted gain of between one and three is applied to drugs demonstrating QALY gains between 10 and 30, respectively. No OMPs included in the study showed a QALY gain of more than 10. Thirteen demonstrated QALY gains less than 10 and one could not be evaluated. Societal perspective: six submissions incorporated societal perspective as a scenario analysis. Despite incremental cost-effectiveness ratios (ICERs) being reduced between 4 percent and 58 percent, only two OMPs demonstrated cost-effectiveness at the higher threshold (EUR 100,000/QALY).

Application of supplementary criteria to the pharmacoeconomic evaluation of OMPs had a minor effect on three products assessed. However, for the majority, the final cost-effectiveness outcomes remained the same. The study highlights that other criteria are being considered in the decision to reimburse.