Introduction
Advanced therapy medicinal products (ATMPs) are medicines based on genes, cells, or engineered tissues, including gene therapies, somatic cell therapies, and tissue-engineered products. Their clinical effects can be substantial, but the evidence base at launch is often limited and the pricing is frequently concentrated in an upfront payment. These characteristics place pressure on health technology assessment (HTA) processes that rely on comparative clinical benefit, economic evaluation, and explicit or implicit affordability checks.
ATMP value assessment commonly turns on four intersecting questions. The first is whether the clinical evidence demonstrates an added benefit compared with relevant alternatives in the population likely to be treated in practice. The second is whether short-term data can support claims about long-term durability, disease modification, or cure. The third is whether cost-effectiveness analysis, usually expressed using quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs), remains informative when benefits may occur over decades but key parameters are uncertain. The fourth is whether the budget impact of adoption is manageable over the time horizon used for health system planning, given high per-patient costs, uncertain uptake, and service delivery constraints.
Comparative evidence and endpoint selection
Most HTA systems start from a comparative framework, asking whether outcomes are better than those achieved with current care. For ATMPs, the comparator is not always straightforward because existing care may vary between countries, specialist centres, and patient subgroups, and because referral pathways can change once a new therapy becomes available. Trials may be single-arm for rare conditions or ethically difficult settings, making the credibility of external controls central to HTA scrutiny.
Endpoint selection can become contentious. Surrogate endpoints may be necessary in early trials, but HTA bodies often prioritise patient-relevant outcomes, including survival, functional status, and validated measures of health-related quality of life. When evidence relies on intermediate markers, assessment tends to focus on the strength of the causal link between the marker and outcomes that matter to patients and payers, and on whether the marker behaves similarly across age groups, disease stages, and treatment settings.
Durability, extrapolation, and the “one-time” claim
A recurrent methodological issue is how to translate short follow-up into long-term claims. ATMP assessments frequently depend on extrapolation beyond observed data, and small changes in assumptions can dominate cost-effectiveness results. HTA critique often concentrates on whether the duration of effect is biologically plausible, whether waning should be modelled and how, and whether retreatment or downstream interventions should be assumed if response is lost.
Where cure is claimed, modelling choices typically include whether to represent a cured fraction, how to define cure operationally, and whether long-term morbidity and mortality risks converge fully to general population levels. These decisions are sensitive to the natural history of the condition, the comparability of treated cohorts to historical data, and the availability of long-term registries.
Economic evaluation and handling uncertainty
Economic evaluation for ATMPs often uses cost-utility analysis with QALYs to compare incremental costs and health gains. The challenge is less the method itself than the degree of uncertainty in inputs that drive lifetime value: long-term survival, late adverse effects, discontinuation trajectories, and quality-of-life changes. Structural uncertainty can be particularly influential, for example when alternative model forms (such as different survival curves or alternative assumptions about disease progression) yield materially different results when fitted to the same data.
Assessment therefore places substantial weight on sensitivity analyses and scenario analyses that test plausible ranges of key assumptions, including the therapy price, duration of effect, and the use of subsequent treatments. Transparency about model structure, parameter sources, and validation against external datasets is often treated as part of evidential credibility rather than a purely technical preference.
Affordability and budget impact
Alongside cost-effectiveness, many jurisdictions apply an affordability lens through explicit budget impact analysis or through deliberative consideration of expected expenditure. Budget impact focuses on cash-flow and short-term fiscal pressure, typically over a multi-year horizon aligned with payer planning cycles, rather than on lifetime value. For ATMPs, budget impact estimates can be difficult because eligible population size may be uncertain, diagnosis rates can increase after launch, and uptake may be constrained by service capacity even when clinical demand is high.
Budget impact is also shaped by how costs fall across budgets. ATMPs may be reimbursed through hospital budgets, special funds, or national programmes, and costs related to testing, inpatient care, complications, and follow-up monitoring may sit outside the drug budget. HTA bodies and payers often expect clear assumptions on uptake, displacement of existing treatments, and the timing of costs and offsets. Where budget impact is high relative to available budgets, decisions may incorporate phased adoption, prioritisation rules, or financial agreements that change the timing of payments without necessarily changing the underlying cost-effectiveness.
Broader value elements and decision modifiers
Because ATMPs may target severe, rare, or otherwise high-burden conditions, HTA deliberation often takes a wide perspective. Commonly discussed considerations include severity of disease, unmet need, value of hope in the presence of high clinical uncertainty, spillover effects on carers and families, and system-level benefits such as reducing the need for repeated hospitalisations. The role of such elements varies across jurisdictions: some systems treat them as modifiers within formal methods, while others incorporate them in committee deliberation without changing the core economic model.
For paediatric and ultra-rare conditions, additional pressure points include the appropriateness of generic quality-of-life instruments, the feasibility of collecting robust patient-reported outcomes, and whether conventional thresholds remain meaningful when evidence generation is constrained by very small patient numbers.
Managed access, conditional reimbursement, and evidence development
Given uncertainty and affordability concerns, payers may combine HTA conclusions with managed access mechanisms. These can include coverage with evidence development, outcomes-based agreements, and arrangements that link continued reimbursement to follow-up data. The limiting factors are often practical: agreeing measurable outcomes that reflect meaningful benefit, ensuring data capture is complete and comparable, and allocating administrative responsibility across clinical centres, manufacturers, and payers.
A persistent tension is that the data most valued for long-term uncertainty reduction may only become available over many years, whereas pricing and budget decisions are required at or soon after launch. This creates reliance on intermediate re-appraisals and on governance processes that specify what evidence will trigger review, what constitutes failure to deliver the expected value, and how any financial consequences will be implemented.
Cross-jurisdiction convergence and divergence
Internationally, HTA frameworks share many methodological foundations, but ATMPs expose differences in comparator standards, accepted endpoints, and the balance between formal modelling and deliberative judgement. Regional initiatives, including joint clinical assessments in the European Union, are likely to increase alignment on clinical evidence expectations, while economic evaluation, budget impact practice, and pricing decisions remain strongly country-specific because they reflect local opportunity costs, budgets, and service organisation.
Summary
ATMPs are gene, cell, and tissue-based medicines that often combine high upfront cost with evidence that is limited at launch. HTA appraisal therefore concentrates on comparators, endpoint relevance, and the credibility of external controls where randomised evidence is unavailable. Long-term value claims depend heavily on extrapolation and on assumptions about durability, waning, and cure, which can dominate cost-effectiveness results. Economic evaluation remains central, but uncertainty management through scenario and sensitivity analysis is often as influential as the base-case ICER. Affordability considerations, commonly operationalised through budget impact, can constrain adoption even when cost-effectiveness appears favourable. Managed access arrangements may address uncertainty and budget pressure, but they depend on feasible outcomes, reliable data capture, and governance that supports re-assessment.
Links
Canada - Patented Medicine Prices Review Board: Budget impact analysis guidelines (June 2020).
European Commission: Health technology assessment.
European Union: Regulation (EU) 2021/2282 on health technology assessment (15 December 2021).
Scientific publications
de Labry-Lima AO, Ponce-Polo A, García-Mochón L, Ortega-Ortega M, Pérez-Troncoso D, Epstein D. Challenges for economic evaluations of advanced therapy medicinal products: a systematic review. Value Health. 2023 Jan;26(1):138-150. doi: 10.1016/j.jval.2022.07.004.
Gonçalves E. Value-based pricing for advanced therapy medicinal products: emerging affordability solutions. Eur J Health Econ. 2022 Mar;23(2):155-163. doi: 10.1007/s10198-021-01276-2.
Greco A, Frederix GWJ, Hooft L, Ten Ham RMT. A systematic review of challenges and opportunities in the implementation of managed entry agreements for advanced therapy medicinal products. Clin Ther. 2025 Feb;47(2):e16-e26. doi: 10.1016/j.clinthera.2024.11.019.
Pinho-Gomes AC, Cairns J. Evaluation of advanced therapy medicinal products by the National Institute for Health and Care Excellence (NICE): an updated review. PharmacoEconomics Open. 2022;6(2):147-167. doi: 10.1007/s41669-021-00295-2.
Ten Ham RMT, Frederix GWJ, Wu O, Goettsch W, Leufkens HGM, Klungel OH, Hoekman J. Key considerations in the health technology assessment of advanced therapy medicinal products in Scotland, the Netherlands, and England. Value Health. 2022 Mar;25(3):390-399. doi: 10.1016/j.jval.2021.09.012.