Treatment effectiveness and extrapolation

Treatment effectiveness was modelled as an improvement in PASI and HAQ scores from baseline. The assumptions and methods applied for each are discussed below. The estimates used to population the model were derived from the manufacturers NMA (section 4.3), directly from the PSUMMIT trials or the NMA undertaken by the ERG for the golimumab STA.24 The relative treatment effects were used in conjunction with the assumption that treatment halts disease progression, while patients receiving conventional management strategies were subject to the natural history of the disease. This enables the changes in HAQ and PASI score over time to be modelled appropriately.

5.3.5.1 PASI Score

PASI score changes were applied dependent on PASI 75 response. Individuals on treatment who experienced PASI 75 response were assumed to experience a reduction (i.e. improvement) in their PASI score in week 12 (at the first cycle), whilst PASI 75 non-responders experienced a smaller reduction (i.e. improvement) in PASI score. While a patient continues on treatment the PASI score remains constant, however upon treatment discontinuation and withdrawal to conventional

management, PASI scores were assumed to rebound back to the baseline PASI value. Due the nature of the skin element of the condition no natural history deterioration of PASI score was applied, so PASI scores in the conventional management arm remained constant at the baseline value.

These assumptions are in line with previous submission and the ERG felt that they were appropriate. However, the ERG identified that there were errors in the calculation of the baseline PASI scores.

The baseline PASI scores applied in the model are shown in Table 21. For the anti-TNFα naïve population, the majority of PASI scores for the included trials used to derive the estimate were >8, which was inconsistent with the manufacturer’s baseline value (7.97). The ERG therefore recalculated the baseline PASI estimate, using a weighted mean calculation. For details of the ERG’s calculations see appendix 10.2. One study reported a median PASI instead of a mean value.28 Since the median value is not an accurate assessment of an entire population’s expected value, this value was excluded

The baseline PASI value used for the anti-TNFα experience population was similarly checked by the ERG. Although the point estimate was found to be correct, the standard error around the point estimate was not.

The errors identified in the manufacturer’s baseline PASI values were corrected for in the ERG’s additional analysis (section 6).

Table 21. Manufacturer and ERG baseline PASI scores

Manufacturer’s estimate ERG’s estimate

Anti-TNFα naïve population Baseline PASI 7.97 (SE: 4.44) 10.46 (SE: 1.06)

Source/method of estimation

Pooled estimate of 9 trials.7, 8, 26-32, 43

Weighted average of 8 trials (excluding Mease 2000 median value) Anti-TNFα experienced

population

Baseline PASI 12.08 (SE:0.96) 12.08 (SE:0.48)

Source/method of estimation PSUMMIT 2 anti-TNFα experienced subgroup Weighted average of PSUMMIT 2 anti-TNFα experienced subgroup

In line with previous submissions, the change in PASI score for PASI 75 responders and non-

responders was derived using data on baseline PASI and the proportion of PASI 50/75/90 responders. Four mutually exclusive outcomes were defined:

1. P(<PASI 50|<PASI 75) i.e. the probability of a change in PASI between 0 and 49% given that the improvement was less than 75%;

2. P(> PASI 50|< PASI 75); 3. P(<PASI 90| > PASI 75); and 4. P(>PASI 90| PASI 75).

If PASI change was between 0 and 49% the manufacturer’s made the conservative assumption that the improvement in PASI for those patients would be 0; if the change was between 50 and 74% a change of 50% was assumed; if the change was between 75% and 89% a change of 75% was assumed; and if the change was between 90 and 100% a change of 90% was assumed.

The ERG believes that this approach was reasonable and is consistent with previous submissions.

The sources used by the manufacturer to derive PASI response rates are shown in Table 22. For the anti-TNFα naïve population, the proportions of PASI 50/75/90 responders at week 12 and week 24 were derived from the manufacturer’s NMA where possible, and using Yang et. al or Rodgers et. al. otherwise.12, 24 The manufacturer’s NMA is discussed fully and critiqued in section 4.3.

Table 22. Sources used to derive PASI response rates in the MS

Parameter

Sources used to derive parameter

Anti-TNFα naïve population Anti-TNFα experienced population

PASI 50 Manufacturer’s NMA PSUMMIT 2

PASI 75 Ustekinumab: PSUMMIT 1 and 2

Etanercept, infliximab, adalimumab: Rodgers et. al.12

Golimumab: Yang et. al.24

PSUMMIT 2

PASI 90 Etanercept: Rodgers et. al. 12

All others: Manufacturer’s NMA

PSUMMIT 2

For the anti-TNFα experienced subgroup, effectiveness estimates were derived from a weight-based analysis of the PSUMMIT 2 trial. The effect of this has been partially explored in section 6, however due to the limited data provided in the MS, a full ITT analysis has not been possible.

A further issue concerns the effectiveness of the conventional management arm. The manufacturer assumed that PASI scores would remain constant for patients receiving conventional management. For PASI 75 response, in the manufacturer’s NMA results, the placebo arm was associated with a ****PASI 75 response rate at week 12 and ****in week 24 for anti-TNFα naïve patients; and a ****PASI 90 response rate at week 12 and ****PASI 90 response rate at week 24. The ERGs clinical advisor stated that patients in the conventional management arm receiving treatments such as MTX might be expected to have fairly good PASI response scores, as skin conditions often respond well to DMARDs. It is not clear therefore that the manufacturer’s assumption of constant PASI in the conventional management arm was appropriate. Nevertheless, since the rates of response in the conventional management arm appear to be relatively low, the ERG does not expect this assumption to be a key driver in the model.

5.3.5.2 PASI Score changes

The PASI score changes for PASI 75 responders and non-responders for the anti-TNFα naïve and experienced populations are shown in Table 23 and Table 24.

Ustekinumab 90mg _{**** ****} Golimumab 50mg _{**** ****} Golimumab 100mg _{**** ****} Adalimumab _{**** ****} Etanercept 25mg and 50mg _{**** ****} Infliximab _{**** ****}

Table 24. PASI score change for PASI 75 responders and non-responders for the anti-TNFα experienced subgroup analysis (taken from manufacturer’s model, ‘Inp_Efficacy! F247:D248’)

Treatment

PASI score change from baseline