Ocriplasmin (1) – Jetrea®

• Clinical trials
  • The pharmaceutical manufacturer’s description in the dossier of the additional benefit for the group ‘patients with vitreomacular traction and mild symptoms’ is based on three randomised controlled clinical trials (TG-MV-004, TG-MV-006, TG-MV-007).
  • In the control groups of studies TG-MV-006 (Ocriplasmin N=219; control N=107) and TG-MV-007 (Ocriplasmin N=245; control N=81), participants received an injection of a placebo solution into the vitreous.
  • In study TG-MV-004, participants in the control group received a sham injection.

a) Patients with vitreomacular traction presenting with mild symptoms

• For the treatment of vitreomacular traction with mild symptoms, there is a hint of considerable additional benefit for ocriplasmin compared with the appropriate comparator therapy.
• Therefore, the probability of additional benefit – despite the existence of three RCTs – is assessed as a hint.
• The G-BA classifies the extent of the additional benefit of ocriplasmin for the group ‘patients with vitreomacular traction with mild symptoms’ as considerable, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the condition and the therapeutic objective in treating the condition.
• Mortality (overall mortality)
  • For the endpoint of mortality, the result of the meta-analysis comparing ocriplasmin with ‘watchful waiting’ was not statistically significant.
• Morbidity – improvement in visual acuity of ≥ 2 lines (10 ETDRS letters)
  • For the endpoint of improvement in visual acuity, a responder analysis was used with a threshold of ≥ 2 lines (corresponding to 10 ETDRS letters).
  • The result of the meta-analysis comparing ocriplasmin with ‘watchful waiting’ was statistically significant in favour of ocriplasmin (RR 1.81; CI [1.26; 2.58]; ARR 12.4%).
  • Within the G-BA, there are differing views regarding the clinical relevance of the endpoint ‘improvement in visual acuity > 2 lines’.
  • A publication that forms a key basis for this endpoint, concerning the validation of its clinical relevance (Koch et al. 2012) was conducted on a patient population differing from that for which ocriplasmin has marketing authorisation, namely patients with ‘age-related macular degeneration (AMD)’ and with a poorer baseline visual acuity of 55 ETDRS letters on average.
  • There are conflicting views within the G-BA regarding the possible influence of baseline visual acuity on the Minimum Important Difference for the clinical relevance of the endpoint ‘improvement in visual acuity > 2 lines’.
• Morbidity – Vitrectomy
  • For the endpoint ‘vitrectomy’, the proportion of patients who, at the investigator’s discretion, underwent a pars plana vitrectomy during the course of the study was recorded.
  • The result of the meta-analysis comparing ocriplasmin with ‘watchful waiting’ was statistically significant in favour of ocriplasmin (RR 0.63; CI [0.46; 0.88]; ARR 9.9%).
  • With regard to the assessment of subgroup characteristics, there is an indication of an effect modification by the characteristic of baseline visual acuity (in ETDRS letters).
  • The results of the subgroup analysis showed a statistically significant effect in the meta-analysis among patients with a baseline visual acuity > 60 ETDRS letters (mild visual impairment; ocriplasmin N=311; control N=133); (RR 0.44; CI [0.27; 0.72]; ARR 11.8%). However, no such effect was observed in those with a value of 35 to 60 (moderate visual impairment; ocriplasmin N=138; control N=56), (RR 0.85; CI [0.52; 1.37]).
  • It is unclear whether the administration of ocriplasmin replaces or postpones vitrectomy.
• Health-related quality of life – NEI VFQ-25 (responders)
  • The result of the meta-analysis for the health-related quality of life endpoint – assessed using the NEI VFQ-25 questionnaire – was not statistically significant when comparing ocriplasmin with ‘watchful waiting’.
• Side effects – deterioration in visual acuity > 2 lines (10 letters ETDRS)
  • For the endpoint ‘deterioration in visual acuity > 2 lines (10 letters ETDRS)’ , the meta-analysisrevealed significant heterogeneity that cannot be explained.
  • Therefore, this endpoint is not used for the assessment of additional benefit.
• Side effects – adverse events (AEs) affecting the eye
  • For the endpoint ‘adverse events affecting the eye’, all AEs coded as occurring in the ‘eye’ were recorded.
  • For this endpoint, the result of the meta-analysis comparing ocriplasmin with a ‘watch-and-wait’ approach was statistically significant to the detriment of ocriplasmin (RR 1.23; CI [1.07; 1.40]; ARR −12.6%).
  • Greater harm from ocriplasmin compared with ‘watchful waiting’ in patients with mild symptoms for the endpoint ‘adverse ocular events’ – which would lead to a downgrading of the extent of the additional benefit with regard to morbidity-related endpoints – is, however, considered to be unsubstantiated.
• Overall assessment
  • Overall, ocriplasmin provides additional benefit for patients with vitreomacular traction and mild symptoms compared with the appropriate comparator therapy ‘watchful waiting’ with regard to the endpoints ‘improvement in visual acuity of ≥ 2 lines (10 letters on the ETDRS chart)’ and the endpoint ‘vitrectomy’.
  • The significant improvement in visual acuity of ≥ 2 lines represents a reduction in non-serious symptoms.
  • A vitrectomy is an invasive procedure associated with corresponding risks. Therefore, the lower number of vitrectomies under treatment with ocriplasmin compared with the appropriate comparator therapy, due to the associated minimisation of complications, is assessed as a significant reduction in serious symptoms.
  • Consequently, when considered as a whole, an additional benefit of ocriplasmin for patients with vitreomacular traction and mild symptoms is identified in the ‘watch-and-wait’ approach, the extent of which is classified as considerable.

b) Patients with vitreomacular traction and severe symptoms

• For patients with vitreomacular traction and severe symptoms, the pharmaceutical manufacturer did not provide the required proof in full ; the additional benefit in relation to the appropriate comparator therapy is deemed not proven (Section 35a(1), fifth sentence, SGB V).

Courtesy translation only, please refer to the German original.