Background
Methods
Step 1 – Outcomes of HTA appraisals
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France: The Actual Clinical Benefit (SMR: Service médical rendu; range from substantial, moderate, low, to insufficient), Clinical Added Value (ASMR: Amélioration du service medical rendu; range from I: major, II: substantial, III: moderate, IV: minor, to V: no clinical value added) as well as the timing of HAS decisions were derived from the HAS official website (www.has-sante.fr) and from the website of the Ministry of Health and the Ministry of Budget [12]. Commercialisation in France is effective after HAS opinion and negotiation of the price with the economics committee.
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Italy: The product class (A: essential, fully reimbursed; H: only fully reimbursed in hospitals; C: not reimbursed) as well as specific conditions for reimbursement were obtained from the official journal of AIFA (www.gazzettaufficiale.it). Local marketing authorisation and commercialisation takes place at the same time as AIFA’s decision is officially published. Respective dates were also derived from the ‘Gazzetta Ufficiale’.
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Germany: Appraisals were reviewed on the G-BA’s homepage (www.g-ba.de). Information on the additional benefit (major, important, minor, non-quantifiable, no additional benefit, less additional benefit), the evidence rating (proof, indication, hint), and subgroups were extracted. Commercialisation in Germany occurs after EMA approval and requires a listing of the initial price (prior to negotiation) in the ‘Lauer-Taxe’, the official price list of medicines [13].
Step 2 – Qualitative review and categorization of key appraisal decision drivers
Step 3 – Identification of commonalities and differences across countries
Results
Included medicines
Step 1 –outcome of HTA appraisals
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France: The time gap between EMA approval and HAS appraisal ranged between 112 days (Cobimetinib) and 380 days (Pirfenidon) with a mean of 227 days. SMR ratings were substantial for Vemurafenib, Pertuzumab (metastatic), Vismodegib, Trastuzumab Emtansine, Obinutuzumab in both indications, Cobimetinib, and Alectinib, moderate for Pirfenidon (2nd appraisal), and insufficient for Pertuzumab (neoadjuvant). ASMR ratings were substantial for Trastuzumab Emtansine, moderate for Vemurafenib, Pertuzumab (metastatic), Obinutuzumab (CLL), and Cobimetinib, minor for Pirfenidon, Vismodegib, and Alectinib, and no added benefit for Obinutuzumab (FL).
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Italy: The official publication in the Gazzetta Ufficiale occurred between 164 days (Obinutuzumab CLL) and 837 days (Vismodegib) after EMA approval (mean 465 days). Assigned class was H for all of the products. Obinutuzumab had a class C in the first CLL appraisal which was revised in February 2017. Pertuzumab in its first indication (metastatic) achieved an ‘innovation designation’ while no reimbursement was obtained in the neoadjuvant setting. Trastuzumab Emtansine received a ‘potential innovation’ designation. Payment by result schemes were applied to Vemurafenib, Trastuzumab Emtansine, and Cobimetinib. Cost sharing procedures were implemented for Pertuzumab, Vismodegib and Obinutuzumab (CLL). Alectinib has not yet been fully negotiated.
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Germany: Appraisals generally occurred on average 207 days after EMA approval, with Pirfenidon (appraisal 381 days after EMA approval) being the exception (which was due to the transition period after AMNOG came to effect). Additional subgroups beyond EMA indications were assigned to Pertuzumab (metastatic), Vismodegib, Trastuzumab Emtansine, and Alectinib. An additional benefit was assigned to Vemurafenib, Pirfenidon (Orphan Designation), Pertuzumab (metastatic patients with visceral metastases only), Vismodegib (locally advanced patients only), Trastuzumab Emtansine (patients previously treated with Anthracyclines), Obinutuzumab (Orphan Designation in both indications: CLL and FL), Cobimetinib, and Alectinib (patients eligible for chemotherapy). No additional benefit was assigned to Pertuzumab (neoadjuvant) and the remaining subgroups of Pertuzumab metastatic, Vismodegib, Trastuzumab Emtansine, and Alectinib.
Medicine | EMA Appro-val | Indication | France | Italy | Germany |
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Vemurafenib | Feb 17th 2012 | Melanoma | 1st Appraisal: Oct 3rd, 2012 2nd Appraisal: Mar 22nd, 2017 Publication Price: Feb 1st, 2013 Both Appraisals: SMR: substantial ASMR: moderate (level III) | Publication: Jun 4th, 2013; Class H Payment by Result scheme and sales cap | 1st appraisal: Sep 6th, 2012 2nd appraisal: Mar 6th, 2014 Both appraisals: Indication considerable benefit |
Pirfenidon (Orphan Designation) | Feb 28th, 2011 | Idiopathic Pulmonary Fibrosis | 1st Appraisal: Mar 14th, 2012 2nd Appraisal: Feb 18th, 2015 Publication Price: Oct 16th, 2012 SMR 1st Appraisal: Low SMR 2nd Appraisal: Moderate ASMR: minor (level IV) | 1st Publication: Jun 14th, 2013 Class H ‘success fee’ agreement and stopping rule 2nd Publication: Jul 3st, 2015 Removal of ‘success fee’ and stopping rule due to new evidence submitted | Appraisal: Mar 15th, 2012 Additional benefit non-quantifiable |
Pertuzumab 1st Indication Metastatic | Mar 4th 2013 | Her2+ metastatic Breast Cancer | Appraisal: Jul 24th, 2013 Publication Price: Dec 13th, 2013 SMR: substantial ASMR: moderate (level III) | Publication: June 23rd, 2014 Class H ‘Innovation designation’ | Appraisal: Oct 1st, 2013 • Visceral Metastases: Hint Considerable benefit • Non-visceral Metastases: no additional benefit • Locally recurrent: no additional benefit |
Pertuzumab 2nd Indication Neoadjuvant | Jul 28th 2015 | Neo-adjuvant | Appraisal: Jul 6th, 2016 SMR: insufficient ASMR: not applicable | Publication: Jan 5th, 2017 No reimbursement | Appraisal: Feb 18th, 2016 No additional benefit |
Vismodegib | Jul 12th 2013 | Locally advanced or metastatic Basal Cell Carcinoma | Appraisal: Dec 18th, 2013 Publication Price: Sept 2nd, 2015 SMR: substantial ASMR: minor (level IV) | Publication: April 9th, 2015 Class H Cost sharing agreement | 1st appraisal: Feb 6th, 2014 2nd appraisal: Aug 4th, 2016 Both appraisal: • Metastatic BCC: no additional benefit • Locally Advanced BCC: Hint Minor Benefit |
Trastuzumab Emtansine | Nov 15th, 2013 | Her2+ Breast Cancer | Appraisal: Mar 19th, 2014 Publication Price: Nov 14th, 2014 SMR: substantial ASMR: substantial (level II) | Publication: Sep 26th, 2014 Class H ‘Potential Innovation’ designation Payment by Result scheme | Appraisal: Jun 19th, 2014 • Locally Advanced: no additional benefit • Previous therapy includes Anthracycline: Indication considerable benefit • Previous therapy without Anthracycline: no additional benefit |
Obinutu-zumab 1st indication (Orphan Designation) | Jul 23rd 2014 | Chronic Lymphocytic Leukaemia | Appraisal: Feb 18th, 2015 Publication Price: Dec 24th, 2015 SMR: substantial ASMR: moderate (level III) | 1st Publication: Jan 3rd, 2015 Class C 2nd Publication: Feb 24, 2017 Class H Reimbursed with cost sharing scheme | Appraisal: Feb 5th, 2015 Non-quantifiable additional benefit |
Obinutu-zumab 2nd indication (Orphan Designation) | Jun 13th, 2016 | Follicular Lymphoma | Appraisal: Mar 8th, 2017 SMR: substantial ASMR: no (level V) | Publication: Aug 31st, 2017 Class H Reimbursed with discount (removal of previous cost sharing agreement) | Appraisal: Dec 16th, 2016 Non-quantifiable additional benefit |
Cobimetinib | Nov 20th, 2015 | Melanoma | Appraisal: Mar 16th, 2016 Publication Price: Feb 16th; 2017 SMR: substantial ASMR: moderate (level III) | Publication: Oct 1st, 2016 Class H Reimbursed with Payment by Result Scheme | Appraisal: Jun 2nd, 2016 Indication Considerable benefit |
Alectinib | Feb 16th 2017 | Non-small lung cancer | Appraisal: Dec 13th, 2017 Publication Price: Pending SMR: substantial ASMR: minor (level IV) | Publication: Final Publication pending | Appraisal: Oct 19th, 2017 • Patients eligible for DCP: Hint Minor benefit • Patients not eligible for DCP: no additional benefit |
Step 2 – Qualitative review and categorization of key decision drivers
Medicine | Appraisal France | Appraisal Italy | Appraisal Germany |
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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) |
Country | CUR | TEC | SAF | EFF | ECO | ETH | ORG | SOC | LEG |
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France | 3 | 1 | 6 | 10 | 1 | ||||
Italy | 8 | 5 | 3 | 10 | 4 | ||||
Germany | 6 | 3 | 4 | 10 |
Step 3 – Identification of commonalities and differences across the three countries
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Across all three countries the clinical domains (CUR; TEC; SAF; EFF) were by far more important in driving HTA decisions than the five non – clinical domains (ECO; ETH, ORG, SOC, LEG). Only Italy included the ECO domain in some of their appraisals
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The ‘Clinical Effectiveness’ domain was most important in driving national HTA decisions. While all countries accepted ‘Overall Survival’ as an endpoint, some also recognized surrogate endpoints within their appraisals.
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Implementation of the CUR domain differed across countries, with Germany mostly focussing on the topic ‘Target Population’ (i.e. Subgroups) and Italy recognizing unmet medical need and lack of treatment alternatives.
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Also, the implementation of the TEC differed across countries, with Italy recognizing innovation designation and novelty of treatment while the three respective decisions in Germany (both indications of Obinutuzumab and Pirfenidon) were driven by the specific regulation for medicines with Orphan designation.
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The impact of Safety (SAF) was heterogeneous across the countries and no specific patterns were identified.
Discussion
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Different from e.g. Germany full commercial availability of innovative medicines in France requires HAS appraisal and subsequent price agreement with the Healthcare Products Pricing Committee (CEPS). Time between EMA approval and HAS appraisal averaged at 227 days in our review and full commercialisation in France occured 557 days post EMA approval, indicating a major delay in market access for innovative products [16].
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◦ In France, the two components of HTA appraisal include clinical benefit (SMR) as well as added benefit (ASMR), with the latter focussing on relative effectiveness analysis. While the SMR is based on criteria such as the efficacy, safety, place in therapeutic strategy, existence of therapeutic alternatives, severity of condition, and public health impact, the ASMR determines the relative value of the medicine compared to the current standard of care. Both SMR and ASMR appreciation experienced a shift towards clinical evidence i.e. the EUnetHTA EFF domain over the past decade [17]. By far the most frequently assigned SMR category is ‘important’, while most commonly ASMR appraisals reveal a category of ‘V’ i.e. no improvement versus current standard. Within their annual activity overview 2016, HAS reported more than 750 (re-) appraisals with only 25 thereof considered a therapeutic progress (i.e. ASMR ≤ 4) versus current standard of care. Nevertheless, in only 7 of the innovative products and 20 of the re-evaluated products SMR was considered insufficient [18]. Thus, despite recent discussions about a reform of the SMR-ASMR system [17] the HTA practice including the two ratings prevailed, providing HAS with an opportunity to assign different SMR levels also to products without additional benefit. For all but two of the appraisals in our review a clinically added value was proven, with Obinutuzumab in follicular lymphoma still receiving a substantial SMR despite an ASMR ‘V’ rating.
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The clinical decision drivers within the Italian appraisals are less transparent than in France or Germany. While AIFA’s appraisal decisions are publicly available within the Gazzetta Ufficiale, the level of detail regarding HTA decision criteria within those reports is limited. Nevertheless, an advantage in Overall Survival and a high level of unmet need with a lack of treatment alternatives were identified as strong drivers of a positive AIFA decision. Importantly, the introduction of innovative pharmaceuticals in Italy is usually conducted via some kind of a ‘managed access’ scheme. Almost all of the medicines within our review had some kind of a ‘payment by result’ or ‘cost sharing scheme’. Thus, potential budget impact is proactively managed by AIFA. However, while those considerations are more explicitly discussed in Italy, and therefore more transparent, budget impact considerations are also impacting HTA appraisals in France and Germany. Half of the votes within each G-BA appraisal are derived from the ‘National Association of Statutory Health Insurance Funds’ who later on in the process is in charge of the price negotiations. This principle of G-BA’s governance indicates a strong link between HTA appraisals and price and budget impact considerations.
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Characteristic features of the German HTA appraisals and the respective decision drivers are the reflection of added benefit in relation to a specific comparator as well as the underlying level of evidence (proof/ indication/ hint/no evidence), the separation of subgroups, a stringent definition of ‘patient relevance’ which often precludes the consideration of key clinical trial endpoints, and the special regulation for Orphan Medicines where an additional benefit is granted by the law even if G-BA sometimes seems sceptical about it (e.g. Obinutuzumab FL). Furthermore, Germany applies a very strict time schedule to its HTA appraisals which is embedded in the respective law.