Table 2 Key appraisal decision drivers, categorized according to the EUnetHTA core model terminology

Pirfenidon

1) EFF (moderate effect on FVC; Mortality impact unclear)

2) CUR (limited to patients with FVC ≥ 50% and DLCO ≥ 30%)

3) SAF (Tolerability Monitoring)

4) ORG (smoking cessation required)

1) EFF (initial appraisal: limited and inconsistent data; second appraisal: new clinical data)

2) CUR (lack of treatment alternatives)

3) ECO (treatment costs/ budget impact)

4) SAF (initial safety concerns)

1) TEC (Orphan Designation)

2) EFF (Patient relevance of FVC was challenged; trial outcomes considered not consistent)

3) CUR (Stage of Disease difficult to determine)

Vemurafenib

1) EFF (OS & PFS benefit)

2) SAF (concerns regarding 2nd skin cancer)

3) CUR (Targeted therapy)

1) EFF (Clinical Data; OS and PFS benefit)

2) CUR (high unmet need)

3) ECO (concerns budget impact)

4) TEC (Novelty of Treatment)

1) EFF (OS benefit considered relevant

No additional benefit in morbidity or Quality of Life. PFS not accepted)

2) CUR (Severity of Condition)

3) SAF (Side effects considered manageable)

Pertuzumab

1st indication Metastatic

1) EFF (Treatment expected to have substantial impact on morbidity and mortality; median OS not reached and no QoL benefit has been shown)

1) EFF (OS benefit)

2) TEC (High clinical value recognized through Innovation designation)

3) CUR (severity of condition)

4) ECO (budget impact concerns)

1) EFF (Additional benefit only in patients with visceral metastasis driven by OS benefit.

No Morbidity of QoL benefit accepted. PFS considered not relevant to patients)

2) CUR (G-BA separated 3 patient groups; no additional benefit in patients with non-visceral and locally advance disease)

3) SAF (Safety results difficult to interpret as based on different observation periods)

Pertuzumab 2nd indication Neoadjuvant

1) EFF (Clinical Data insufficient; based on proof-of-concept study only)

1) EFF (Proof of concept study only; Surrogate endpoint was challenged)

1) EFF (Validity of surrogate endpoint pCR considered unclear; Trial did not show differences in OS and relapse rates)

Vismodegib

1) CUR (absence of valid treatment alternative)

2) EFF (efficacy demonstration limited to one none comparative trial)

3) SAF (high efficacy/ adverse effects ratio)

1) CUR (High Unmet medical need)

2) TEC (Innovative Technology recognized)

3) EFF (proof-of-concept trial with single arm design is considered premature)

4) SAF (safety concerns)

1) EFF (Single Arm trial controversially discussed; Externally visible lesions implicitly accepted as relevant to patients)

2) CUR (Discussion about spontaneous remissions)

Trastuzumab Emtansine

1) EFF (PFS & OS advantage)

2) SAF (acceptable safety profile)

1) EFF (OS benefit)

2) TEC (Clinical value recognized through Innovation designation)

3) CUR (Severity of condition acknowledged)

4) ECO (Economic concerns regarding budget impact)

5) SAF (No additional safety signals)

1) EFF (Additional benefit in patients with prior Anthracycline treatment based on OS benefit; QoL benefit acknowledged)

2) CUR (G-BA separated 3 patient groups and requests Anthracycline as comparative treatment in subset of Her2+ patients)

3) SAF (reduction in side effects e.g. diarrhoea)

Obinutuzumab CLL

1) EFF (Improvement in PFS and Minimal Residual Disease but no OS demonstrated)

2) SAF (Toxicity of dual therapy containing Obinutuzumab greater than with Rituximab)

1) CUR (Therapeutic alternative available)

2) EFF (Lack of OS benefit was critically reviewed)

1) TEC (Additional benefit guaranteed due to Orphan Designation)

2) EFF (OS data considered immature; PFS not considered relevant to patients; No QoL benefit)

3) SAF (Adverse events rate with Obinutuzumab higher than with Rituximab)

Obinutuzumab FL

1) EFF (Improvement in PFS but no OS demonstrated; many issues regarding clinical trial design were raised)

1) EFF (No OS benefit)

2) CUR (unmet need recognized)

1) TEC (Additional benefit guaranteed due to Orphan Designation)

2) EFF (OS effect based on low number of events; VAS of EQ-5D with positive trend)

Cobimetinib

1) EFF (Improvement in PFS and OS)

2) CUR (Recommended as first line treatment option equal to trametinib/dabrafenib)

1) EFF (Clinical value recognized; OS/PFS)

2) TEC (Innovative Technology recognized)

1) EFF (Moderate OS benefit; positive QoL effects; mostly positive impact on disease symptoms (pain, sleep, fatigue).

Alectinib

1) EFF (Improvement in PFS; partial responses on cerebral metastases)

2) SAF (Hepatic and gastrointestinal side effect)

1) EFF (Clinical value recognized; PFS)

2) CUR (Unmet need recognized)

1) CUR (Separation of subgroups: Patients eligible for DCP yes/ no)

2) SAF (Less side effects vs DCP)

3) EFF (no OS benefit; cross over rate acknowledged; PFS and CNS Response rates not considered relevant for patients)