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Case Study

Joint Clinical Assessment (JCA) And Potential Consequences For The Evaluation Of Gene Therapies

In October 2019, Galderma announced that the U.S. FDA approved AKLIEF® (trifarotene) Cream, 0.005% for the topical treatment of acne. It is the only topical retinoid that selectively targets retinoic acid receptor gamma and is also the first new retinoid molecule to receive FDA approval for the treatment of acne in more than 20 years.

Therapeutic specialty

Oncology

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
 

  

 Observational studies
  • Risk of bias (patient characteristics)
  • Selection bias (treatment access)
  • Confounding
RCT Indirect treatment comparisons (ITC) with treatment alternative(s) and/or single arm studies with external control arm Registry studies
  • Incomplete or inaccurate data collection
  • Patients not representative of the general population
Historical comparison
  • Controls not comparable with patients of those in gene therapy
  • Changes of treatment protocols over time
Compare with the own baseline
  • May not control for confounding factors
  • Missing generalizability

As requested by regulatory and HTA organizations: Extend study to gain long-term data

References
  1. Zynteglo – European Medicines Agency. https://www.ema.europa.eu/en/medicines/human/EPAR/zynteglo.
  2. Die Europäische Kommission. https://ec.europa.eu/health/documents/communityregister/2022/20220324154696/dec_154696_en.pdf
  3. Luxturna | European Medicines Agency. https://www.ema.europa.eu/en/medicines/human/EPAR/luxturna.
  4. Luxturna (voretigene neparvovec – European Medicines Agency. https://www.ema.europa.eu/en/documents/overview/luxturnaepar-medicine-overview_en.pdf.
  5. Zolgensma (onasemnogene abeparvovec – European Medicines Agency. https://www.ema.europa.eu/en/documents/overview/zolgensma-epar-medicine-overview_en.pdf.
  6. Libmeldy | European Medicines Agency. https://www.ema.europa.eu/en/medicines/human/EPAR/libmeldy.
  7. Regulation on Health Technology Assessment (europa.eu)
  8. Services – EUnetHTA, Methodological Deliverables
  9. Proposed joint clinical assessment methodology would have rejected nearly 90% of the ATMPs currently authorized in the EU BRUSSELS – June 20, 2023.

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