Oncology drugs and advanced therapy medicinal products (ATMPs as gene therapies) will be subject to JCA from 2025 onward. The main objective of JCA is to promote convergence in the evaluation of new therapies and reduce duplicate submissions across the EU through an early European assessment of the clinical evidence applying common rules and methodologies.
Gene therapies are highly innovative therapies expected to provide opportunities for previously untreatable conditions, targeting patients with high unmet needs and orphan indications, potentially providing a cure. Their potential transformative clinical value for patients, physicians, health systems, and society may have a significant financial impact on health systems.
Challenge
Per definition, JCA requires a comparative analysis of the clinical evidence with one or more other health technologies. Randomized Controlled Trials (RCTs) are considered the gold standard, but the regulation also requests methodology adaptations to include specificities of new technologies where data may be lacking. This will apply to gene therapies where evidence is mostly based on single-arm, non-blinded studies with small sample sizes and short follow-up.
The intended JCA methods and application of foreseen exemptions from standard requirements will be crucial for the acknowledgement of the benefits of ATMPs in future. Evidence of four recently approved gene therapies and respective reimbursement decisions are outlined in Table 1 on the following page.
Table 1: Regulatory / HTA decisions and stated uncertainties of four gene therapies in Europe
Drug | Indication | Primary outcome | Study findings | Reimbursement in Europe | Perceived uncertainties and consequences |
|---|---|---|---|---|---|
| Zynteglo (betibeglogene autotemcel)1,2 | Transfusion-dependent β-thalassaemia | Proportion of patients who met transfusion independence | 89%(n=32/36) of patients across ages and genotypes achieved transfusion independence | In some countries reimbursed | Small number and limited selection of patients. Uncertainty regarding the durability of transfusion independence. Lack of data on long-term efficacy and safety. Approved with evidence development 2019: Conditional approval with evidence development. 2022: Withdrawal in EU+UK |
| Luxturna (voretigene neparvovec)3, 4 | Inherited retinal dystrophy caused by confirmed biallelic RPE65 mutations | Mean change from baseline to one year in binocular multiluminance mobility testing (MLMT) | Monocular MLMT change score significantly improved, similar to the binocular MLMT results | Reimbursed | Small study with 7.5 years’ follow-up and small RCT (phase III) with 3–4 years’ follow-up. Robust evidence of an effect on quality of life is missing. No final assessment of the effects or sustainability of the changes achieved. Conditional approval with evidence development. |
| Zolgensma (onasemnogene abeparvovec)5 | Spinal muscular atrophy (SMA) | Event-free survival | 90.9% (95% CI: 79.7%, 100.0%) event-free survival at 14 months | Reimbursed/ commercial agreement | Uncertainties about the maintenance of the effect of treatment and the evolution of these patients in the longer term, and the absence of a robust comparison (direct or indirect). Uncertainties in population and sub-populations. Methodological uncertainties in ITC of the subgroups of patients with a disease duration of ≤12 weeks. Missing effect on carers’ HRQoL. Conditional approval with evidence development. |
| Libmeldy (Autologous CD34+ cells encoding ARSA gene)6 | Metachromatic leukodystrophy (MLD) | Gross Motor Function Measure score (GMFM) | Improvement of GMFM score improved by >10% of when compared to the untreated historical control at Year 2 after | In some countries reimbursed / commercial agreement | Missing information on long-term safety and efficacy data and the impact on fertility of treatment. Uncertainty around extra health and quality-of-life benefits as well as variation for the different types of the condition. Conditional approval with evidence development. |
Solutions
Due to their nature, most gene therapies will not be able to meet
standard evidence requests and deviate in relevant aspects such as study design and duration, comparator(s), considered outcomes, or population size and some requested analyses might technically not be possible.
- Based on the published JCA guidelines, other levels of evidence may be acceptable in certain circumstances and if specific methodologies are being considered.7,8 Although direct comparative studies are preferred, single-arm study data together with an external control arm are being accepted if a RCT is not possible.
- There is a preference for patient-centered outcomes that directly measure mortality, morbidity, patient related aspects (i.e., preferences, needs) and are based on long-term observations. However, intermediate or surrogate endpoints are acceptable when it is not feasible to measure a final outcome and when there is evidence of a strong association or correlation of effects with the final outcome.
“The Certara team has long standing experience in HTA and advanced methodologies (e.g., external control arms, matching indirect comparisons, network-metanalyses, etc.) that enable the assessment of studies not meeting the standard evidence requirements of JCA.”
Outlook and Benefits
The introduction of clinical assessment methods and JCA for oncology products and ATMPs in 2025 may lead to harmonization in the assessment process and reduction of redundant HTA activities. In the case of gene therapies, it remains to be noted under what conditions these new therapy options are recommended nationwide following a respective assessment.9
If there are no comparative studies to assess the clinical effectiveness and safety of a new therapeutic agent, alternative methods must be considered as suggested in Table 2. Possible weaknesses must be remedied through a complex analytical workup to reduce uncertainties in the outcome.
Certara stays tuned to closely examine the first precedent cases and advises its clients on methodologic and strategic implications.
Table 2: Potential cascade of study types to be considered for assessment of comparative effectiveness
Assessment of therapy preferably to be based on |
If RCTs are not feasible, clinical assessment can be based on |
If an ITC is also not possible (e.g., due to low number of patients or missing data of the comparator) use of |
Potential weaknesses of studies and comparisons |
| RCT | Indirect treatment comparisons (ITC) with treatment alternative(s) and / or single arm studies with external control arm | Observational studies |
|
| Registry studies |
|
||
| Historical comparison |
|
||
| Compare with the own baseline |
|
||
| As requested by regulatory and HTA organizations: Extend study to gain long-term data | |||
References
- Zynteglo – European Medicines Agency. https://www.ema.europa.eu/en/medicines/human/EPAR/zynteglo.
- Die Europäische Kommission. https://ec.europa.eu/health/documents/communityregister/2022/20220324154696/dec_154696_en.pdf
- Luxturna | European Medicines Agency. https://www.ema.europa.eu/en/medicines/human/EPAR/luxturna.
- Luxturna (voretigene neparvovec – European Medicines Agency. https://www.ema.europa.eu/en/documents/overview/luxturnaepar-medicine-overview_en.pdf.
- Zolgensma (onasemnogene abeparvovec – European Medicines Agency. https://www.ema.europa.eu/en/documents/overview/zolgensma-epar-medicine-overview_en.pdf.
- Libmeldy | European Medicines Agency. https://www.ema.europa.eu/en/medicines/human/EPAR/libmeldy.
- Regulation on Health Technology Assessment (europa.eu)
- Services – EUnetHTA, Methodological Deliverables
- Proposed joint clinical assessment methodology would have rejected nearly 90% of the ATMPs currently authorized in the EU BRUSSELS – June 20, 2023.