Abstract
Background
We surveyed evidence published by Ireland’s National Centre for Pharmacoeconomics (NCPE) on the cost-effectiveness of cancer drugs approved for funding within the Irish public healthcare system. The purpose is threefold: to assess the completeness and clarity of publicly available cost-effectiveness data of such therapies; to provide summary estimates of that data; to consider the implications of constraints on data availability for accountability regarding healthcare resource allocation.
Methods
The National Cancer Control Programme lists 91 drug-indication pairs approved between June 2012 and July 2020. Records were retrieved from the NCPE website for each drug-indication pair, including, where available, health technology assessment (HTA) summary reports. We assessed what cost-effectiveness data regarding approved interventions is available, aggregated it and considered the consequences of reporting constraints.
Results
Among the 91 drug-indication pairs 61 were reimbursed following full HTA, 22 after a rapid review process and 8 have no corresponding NCPE record. Of the 61 where an HTA report was available, 41 presented costs and quality-adjusted life-year (QALY) estimates of the interventions compared. Cost estimates and corresponding incremental cost-effectiveness ratios (ICERs) are based on prices on application for reimbursement. Reimbursed prices are not published. Aggregating over the drug-indication pairs for which data is available, we find a mean incremental health gain of 0.85 QALY and an aggregate ICER of €100,295/QALY, which exceeds Ireland’s cost-effectiveness threshold of €45,000/QALY.
Conclusion
Reimbursement applications by pharmaceutical manufacturers for cancer drugs typically exceed Ireland’s cost-effectiveness threshold, often by a considerable margin. On aggregate, the additional total net cost of new drugs relative to current treatments needs to be more than halved for the prices sought on application to be justified for reimbursement. Commercial confidentiality regarding prices and cost-effectiveness upon reimbursement compromises accountability regarding the fair and efficient allocation of scarce healthcare resources.
Keywords: Cost-effectiveness, Policy oversight, Resource allocation, Transparency
Introduction
This study considers Ireland’s health technology assessment (HTA) framework for the assessment of cancer drugs and surveys the completeness of the cost-effectiveness evidence made public. It uses this assessment of the constraints on publicly available data to motivate a discussion of the implications for accountability regarding the allocation of scarce healthcare resources.
Cancer drugs are a particular class of intervention that present persistent challenges to achieving value for money for many healthcare systems [1]. Many countries conduct HTAs to determine if drugs provide sufficient value for money to merit reimbursement. HTAs combine systematic reviews, trial data and modelling to estimate the clinical and cost-effectiveness of candidate interventions. Policy makers consider these estimates alongside other considerations when forming their recommendations, such as budget impact and ethical concerns regarding access to care.
Ireland’s HTA framework for pharmaceuticals has been described and examined previously [2–8]. Ireland’s tax-funded public health system is managed by the Health Service Executive (HSE). The provision of pharmaceuticals by the HSE is subject to the 2013 Health Act, Schedule 3, Part 3 of which obliges the HSE to consider the cost-effectiveness and budget impact of candidate interventions alongside seven other points of consideration [9]. This is manifest in the requirement of manufacturers to submit a pharmacoeconomic evaluation (PE) to the HSE’s Corporate Pharmaceutical Unit when seeking approval for the reimbursement of new therapies.
The health economic decision criteria regarding new drugs in Ireland are set as part of an ongoing series of agreements between the pharmaceutical industry, the HSE and government, the most recent of which dates from 2016 [10]. An appendix to the agreement details what level of decision maker within the HSE can authorise approval of a new drug. This differs by levels of budget impact and cost-effectiveness, with the latter expressed at two thresholds of €20,000/quality-adjusted life-year (QALY) and €45,000/QALY. While the agreement does not articulate how these decision thresholds relate to the task of balancing the cost of new interventions with their opportunity cost, the €20,000/QALY and €45,000/QALY limits are widely interpreted as Ireland’s prevailing cost-effectiveness thresholds [7, 11–13]. Clearly only the upper threshold will ultimately be relevant if decisions can be escalated to a higher level within the HSE. The €45,000/QALY threshold is not binding in that drugs exceeding it are not necessarily rejected, but can be put forward for further consideration, which may include additional confidential price negotiations.
The National Centre for Pharmacoeconomics (NCPE) is the independent expert review body commissioned by the HSE to evaluate HTA submissions [14]. The NCPE conducts two tiers of analyses. A rapid review (RR) is a preliminary analysis of an information summary on the candidate technology presented by manufacturers containing clinical evidence and economic considerations including the treatment cost and anticipated budget impact [15–17]. There are several possible recommendations from the NCPE following a RR: that the intervention be forwarded for further consideration without conducting an HTA; a full HTA should be conducted due to questions regarding costs or cost-effectiveness; an HTA should not be conducted and the intervention should not be considered for reimbursement at the submitted price; finally, that a full HTA is not recommended until further data on either or both efficacy and safety is provided [18]. The criteria for a full HTA are described on the NCPE’s website [14]. They broadly correspond to an anticipated large budget impact, questionable clinical efficacy or potentially poor value for money.
On completing a full HTA the NCPE issues the Final Appraisal Report documenting their findings and a reimbursement recommendation to the HSE Drugs Group and publishes a summary of that report (henceforth referred to as an HTA summary) on the NCPE website [4]. The Final Appraisal Report is not made public. The NCPE can make four different post-HTA reimbursement recommendations: that the drug be considered for reimbursement at the assessed price; a conditional recommendation that the drug be considered for reimbursement if the price can be reduced in subsequent negotiations; a conditional recommendation that the drug not be considered for reimbursement unless the price can be reduced in subsequent negotiations; finally, simply to recommend against consideration for reimbursement [18]. Importantly, the second and third conditional recommendations explicitly refer to the possibility for post-submission price negotiations to achieve a better price. In all cases the NCPE also state that their recommendations should be considered within the criteria for reimbursement stated in the 2013 Health Act.
The National Cancer Control Programme (NCCP) is a directorate within the HSE responsible for population cancer control in Ireland [19]. Part of this function is to manage and deliver cancer care in collaboration with care providers. In the case of cancer drugs, the NCPE appraisal report will also be submitted to the NCCP’s Technology Review Committee. This committee considers the NCPE’s PE assessment and can issue one of three recommendations: rejection; adoption; or adoption subject to a price reduction [20]. This recommendation is issued to the NCCP’s Director, who then brings it to the HSE Drugs Group for consideration. If a cancer drug is approved by the HSE Drugs Group, it is then added to the list of approved cancer drugs maintained by the NCCP [21]. Meeting minutes from both the Technology Review Committee and the Drugs Group are published [22, 23].
The NCPE HTA summaries publish costs and ICERs on the basis of the list prices on application. If there are post-HTA price negotiations prior to approval, then these costs, ICERs and list prices will not be representative of the agreed prices on adoption. Although the meeting minutes of both the Technology Review Committee and the Drugs Group are published, the pricing details of approved drugs are redacted. This means there is no publicly available source for the agreed prices, associated costs and ICERs of cancer drugs on reimbursement.
Approved cancer drugs are funded under three schemes, the first of which is the community drug scheme of the Primary Care Reimbursement Services (PCRS), which funds self-administered drugs for community-resident patients. The second is the Oncology Drug Management System (ODMS) for high-cost drugs administered in hospitals. The final source is individual hospital budgets that sponsor drugs administered in hospitals.
Previous studies have assessed aspects of Ireland’s HTA appraisal process, including the choice of appraisal pathways, appraisal times and analyses of particular classes of therapies [3, 5, 7, 24]. The objective of this study is to survey the available evidence on the cost-effectiveness of publicly funded cancer drugs in Ireland and to assess the clarity, consistency and completeness of that data. A secondary objective is to use the available data to derive aggregate cost-effectiveness estimates for approved cancer therapies. The third objective is to use this appraisal of available cost-effectiveness data to inform a discussion on the implications of commercial confidentiality regarding reimbursed prices for accountability regarding the allocation of scarce healthcare funds. No previous study has provided such an analysis to our knowledge.
Methods
We compiled a data set by combining publicly available sources on approved cancer drugs in Ireland. The primary source was the list of all approved treatments maintained by the NCCP [21]. As each drug can have multiple clinical indications we describe each separate drug and indication combination as a drug-indication pair. The NCCP’s list of approved drugs names and dates all drug-indication pairs approved since May 2012, details under which funding scheme reimbursement was made and provides links to NCCP regimen summary documents. The list was assessed in February 2020 and the search updated in July 2020.
We then consulted the NCPE website to find information for the same drug-indication pairs that the NCCP list as approved [25]. The website details what applications have been made for which drugs and for what indications, the dates of each initial application and reports if the drug-indication pair has been subject to RR alone or has undergone full HTA. The website also provides HTA summaries for those pairs subject to full assessment. Recently the NCPE has offered both plain English and technical HTA summary documents. Where both are available we refer to the technical summary.
Nine reviewers recovered data for the drug-indication pairs (RG, CB, AB, DK, NOR, SA, SZ, NA, ZD). Each reviewer was responsible for assessing a portion of the NCCP’s list and cross checking the data extraction of another reviewer.
Each drug-indication pair was categorised according to mechanism of action (MOA) and cancer types according to the International Classification of Diseases (ICD). Cancers were classified using the ICD 10 codes reported in the associated NCCP regimen summaries. Similarly, the drugs’ MOA were classified using the World Health Organisation (WHO) Anatomical Therapeutic Chemical (ATC) codes from the regimen summaries and cross-referenced to the ATC listings maintained by the WHO [26]. Some of the cancer and drug type categories were merged where numbers were small. The NCCP regimen summaries link to European Medicines Agency (EMA) product characteristics descriptions for each therapy, which were used to identify the market authorisation holder for each drug. The orphan status for each drug-indication pair was determined using the European Commission’s register of medicinal products and cross-referenced against the Orphanet database [27, 28].
For those drug-indication pairs in which a full HTA was conducted, the reviewers examined the NCPE HTA summaries. In some cases a single drug approval record on the NCCP website corresponds to multiple indications. We considered each pair separately unless the relevant NCPE HTA summary aggregated the cost-effectiveness of the indications together. In these cases we considered the multiple indications to correspond with a single drug-indication pair. Similarly, in cases in which additional subgroup analyses were presented alongside the primary patient group, we only consider the primary patient group. For those cases that are disaggregated between indications the NCPE HTA summaries typically report incremental cost-effectiveness ratios (ICERs) for the different indications separately but the report budget impact for the indications combined. Accordingly, our results are presented in the same way.
We extracted and reported information from the HTA summaries regarding the comparisons made between treatments, ICERs, budget impact and the NCPE recommendation. Note that the ICERs and budget impact from the HTA summaries relate to list prices, not final reimbursed prices. We retrieved the identity of the applicant firm from the summaries, which is not always synonymous with the market authorisation holder reported by the EMA. We recorded the date the HTA summary was published, the summary length and if the NCPE website reported post-assessment price negotiations were conducted for the drug-indication pairs. We also appraised the time taken to reimbursement as the difference in time in months between the first mention of the drug-indication pair on the NCPE website and the date of listing by the NCCP as an approved drug. Note this total reimbursement time not only includes the time taken for the NCPE to appraise the intervention, but also includes any additional time taken to receive clarifications or amendments from manufacturers to submissions and for any price negotiations subsequent to the NCPE’s appraisal.
Where health effects and ICERs were reported for both QALYs and life years gained, we recorded the outcomes for QALYs. Where summaries reported both the manufacturer-estimated outcomes and outcomes based on what the NCPE stated was the most plausible set of assumptions, we recorded the latter. Where the NCPE summaries reported ICERs based on both deterministic and probabilistic analysis, we recorded the latter. In some summaries, the base-case ICERs were explicitly reported, while in others, several ICERs were given for the intervention relative to various comparators. To identify a single ratio, we recorded the ICER based on a comparison to the current standard of care. Some summaries did not report what the current standard of care is. In these cases, we recorded the highest of the reported ratios as this corresponds with the ICER on the efficient frontier.
We recorded on what basis the budget impact was recorded within the HTA summaries. This included gross and net budget impact over either 1 or 5 years. In cases in which a budget impact is reported as a range, we recorded the midpoint of that range.
We assessed the costs of the interventions reported in the HTA summaries. Standard CEA practice is to base reimbursement decisions on the incremental differences between discounted treatment costs of alternative interventions. Under standard methods such costs are the total treatment costs net of any resulting changes in related care costs such as hospitalisation or treatment reoccurrence. Irish HTA guidelines recommend that analyses are conducted with a lifetime time horizon and are assessed using the health payer perspective [13]. While the NCPE HTA summaries did not typically explicitly state what the cost estimates relate to, we assumed the reported costs accord with standard CEA practice in Ireland.
We recorded the incremental costs and QALYs of the intervention of interest versus the relevant base case comparator where reported. In some instances, costs and QALYs were reported for some comparisons but not others. If the costs and QALYs for what appears the primary comparison of interest could be inferred from the reported figures from other comparisons, we used these. In other cases, the incremental costs and QALYs corresponding with the NCPE’s preferred parameter set were not reported. In these cases, we recorded the incremental costs and QALYs reported for the most relevant scenario for which outcomes were reported. In each drug-indication pair, the recorded ICER, costs and QALYs all correspond to the same incremental comparison.
We conducted a descriptive analysis of the compiled data to demonstrate the completeness of the publicly available evidence and to provide an overview of the relationships between the variables recorded. We compiled the unweighted arithmetic mean of the costs, QALYs, budget impact and ICERs. We also computed a weighted arithmetic mean of the incremental costs and QALYs weighted by the reported 5-year gross budget impact and calculated a weighted aggregate ICER from this.
We use the analysis of the published data and aggregate cost-effectiveness estimates presented in the following results section to inform a discussion regarding the implications of data availability for considerations of accountability regarding healthcare resource allocation.
Results
Appendix Tables 4, 5, 6, 7, 8 provide detailed records of each drug-indication pair assessed. Table 4 records the drug name, approved indication, approval date and the internet addresses of both the NCCP regimen listing and record on the NCPE website. Table 5 details the drugs’ proprietary names, market authorisation holders, ICD10 codes and mechanism of action. It also records if the indication includes metastatic disease and the drugs’ current orphan status. In two instances it is known that the applicant firm is not synonymous with the market authorisation holder. The applicants for dabrafenib and ponatinib are GlaxoSmithKline and ARIAD Pharmaceuticals, respectively. Table 6 details aspects of the appraisal process, including at what stage in the NCPE’s appraisal was the drug recommended for consideration for reimbursement and under what funding pathway it was reimbursed, the total time taken to from application to reimbursement, the length of the HTA summary (if applicable) and whether the NCPE website reports if reimbursement was made following post-assessment price negotiations or not. Table 7 details the information extracted from HTA summaries. This includes the basecase ICER, incremental costs and QALYs, 5-year gross budget impact and records if costs and QALYs were reported for all the treatment strategies mentioned within the summary. Table 8 reports the number of approved drug-indication pairs by market authorisation holder and the associated total 5-year gross budget impact where reported within the NCPE HTA summaries.
Table 4.
Drug-indication pairs and data sources
| Pair number | Drug name | Indication | NCCP URLa | NCPE URLb | Date reimbursed |
|---|---|---|---|---|---|
| 1 | Ipilimumab | Adults with advanced (unresectable or metastatic) malignant melanoma | Melanoma/105.pdf | Drugs/ipilimumab-yervoy/ | May 2012 |
| 2 | Abiraterone | Metastatic castration resistant prostate cancer which has progressed on or after a docetaxel-based chemotherapy regimen | Genitourinary/103-abiraterone-and-prednisolone-therapy.pdf | Drugs/abiratone-acetate-zytiga/ | Jun 2012 |
| 3 | Tegafur/gimeracil/oteracil | Advanced gastric cancer in combination with cisplatin | Gastrointestinal/235-cisplatin-and-teysuno%C2%AE-28-day-cycle.pdf | Drugs/tegafurgimeraciloteracil-teysuno/ | Feb 2013 |
| 4 | Axitinib | Adults with advanced RCC after failure, on a previous line of therapy, i.e., treatment with SUNItinib, or a cytokine | Genitourinary/axitinib104.pdf | Drugs/axitinib-inlyta/ | Mar 2013 |
| 5 | Cabazitaxel | Metastatic castration resistant prostate cancer previously treated with docetaxel containing regimen | Genitourinary/cabazitaxelprotocol.pdf | Drugs/carbazitaxel-jevtana-for-prostate-cancer/ | Mar 2013 |
| 6 | Mifamurtide | High-grade resectable non-metastatic osteosarcoma after macroscopically complete surgical resection, in children, adolescents and young adults | Sarcoma/mifamurtide.pdf | Drugs/mifamurtide-mepact/ | Mar 2013 |
| 7 | Vemurafenib | Adults with BRAF V600 mutation-positive unresectable or metastatic melanoma | Melanoma/102-vemurafenib-monotherapy-regimen.pdf | http://www.ncpe.ie/drugs/vermurafenib-zelboraf/ | Mar 2013 |
| 8 | Afatinib | As monotherapy for EGFR TKI-naïve adults with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating EGFR mutation(s) | Lung/221.pdf | Drugs/afatinib-giotrif/ | Jan 2014 |
| 9 | Bosutinib | Adults with chronic phase, accelerated phase, and blast phase Ph + CML previously treated with one or more TKI(s) and for whom imatinib, nilotinib and dasatinib are not considered appropriate treatment options | Leukemia-bmt/224-bosutinib-monotherapy-regimen.pdf | Drugs/bosutinib-bosulif/ | Jan 2014 |
| 10 | Decitabine | Adults aged 65 years and above with newly diagnosed de novo or secondary AML, according to the WHO classification, who are not candidates for standard induction chemotherapy | Leukemia-bmt/231.pdf | Drugs/decitabine-dacogen/ | Jan 2014 |
| 11 | Eribulin | LABC or MBC which has progressed after at least two chemotherapeutic regimens for advanced disease. Prior therapy should have included an anthracycline and a taxane unless patients were not suitable for these treatments | Breast/228-eribulin-monotherapy.pdf | Drugs/eribulin-halaven/ | Jan 2014 |
| 12 | Pertuzumab | Adults with HER2-positive MBC or locally recurrent unresectable breast cancer, who have not received previous anti-HER2 therapy or chemotherapy for their metastatic disease | Breast/350%20pertuzumab%20and%20trastuzumab%20and%20chemotherapy.pdf | Drugs/pertuzumab-perjeta/ | Feb 2014 |
| 13 | Ruxolitinib | Disease-related splenomegaly or symptoms in adults with post polycythaemia vera myelofibrosis | Leukemia-bmt/229-ruxolitinib-monotherapy-regimen.pdf | Drugs/ruxolitinib-jakavi/ | Feb 2014 |
| Disease-related splenomegaly or symptoms in adults with primary myelofibrosis (chronic idiopathic myelofibrosis) | |||||
| Disease-related splenomegaly or symptoms in adults with post essential thrombocythaemia myelofibrosis | |||||
| 14 | Aflibercept | Combination with irinotecan/5-fluorouracil/folinic acid (FOLFIRI) chemotherapy in adults with metastatic colorectal cancer that is resistant to or has progressed after an oxoliplatin-containing regimen | Gastrointestinal/238-aflibercept-and-folfiri-therapy-14-days.pdf | Drugs/aflibercept-zaltrap/ | Apr 2014 |
| 15 | Crizotinib | Adults with previously treated anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) | Lung/243-crizotinib-monotherapy-regimen.pdf | Drugs/crizotinib-xalkori/ | Jun 2014 |
| 16 | Vandetanib | Aggressive and symptomatic medullary thyroid cancer (MTC) in patients with unresectable locally advanced or metastatic disease | Headandneck/242vandetanibmonotherapy.pdf | Drugs/vandetanib-caprelsa/ | Jun 2014 |
| 17 | Brentuximab vedotin | Adults with relapsed or refractory CD30+ Hodgkin lymphoma (HL): following autologous stem cell transplant (ASCT) | Lymphoma-myeloma/234-brentuximab-vedotin-monotherapy-regimen.pdf | Drugs/brentuximab-vedotin-adcetris/ | Aug 2014 |
| 18 | Brentuximab vedotin | Adults with relapsed or refractory CD30+ Hodgkin lymphoma (HL): following at least two prior therapies when ASCT or multi-agent chemotherapy is not an option | Lymphoma-myeloma/234-brentuximab-vedotin-monotherapy-regimen.pdf | Drugs/brentuximab-vedotin-adcetris/ | Aug 2014 |
| 19 | Brentuximab vedotin | Adults with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL) | Lymphoma-myeloma/234-brentuximab-vedotin-monotherapy-regimen.pdf | Drugs/brentuximab-vedotin-adcetris/ | Aug 2014 |
| 20 | Enzalutamide | Adults with metastatic castration-resistant prostate cancer whose disease has progressed on or after docetaxel | Genitourinary/233-enzalutamide-monotherapy.pdf | Drugs/enzalutamide-xtandi/ | Aug 2014 |
| 21 | Dabrafenib | Adults with unresectable or metastatic melanoma with the BRAF V600 mutation | Melanoma/237dabrafenib.pdf | Drugs/dabrafenib-tafinlar/ | Sep 2014 |
| 22 | Regorafenib | Adults unresectable or metastatic gastrointestinal stromal tumours (GIST) who progressed on or are intolerant to prior treatment with imatinib and sunitinib | Sarcoma/244-regorafenib-monotherapy.pdf | Drugs/regorafenib-stivarga-for-gist/ | Apr 2015 |
| 23 | Regorafenib | Adults with metastatic colorectal cancer (mCRC) who have been previously treated with, or are not considered candidates for, available therapies. These include fluoropyrimidine-based chemotherapy, anti-VEGF and anti-EGFR therapies | Sarcoma/244-regorafenib-monotherapy.pdf | Drugs/rigorafenib-stivarga/ | Apr 2015 |
| 24 | Abiraterone | Metastatic castration resistant prostate cancer in men who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated | Genitourinary/103-abiraterone-and-prednisolone-therapy.pdf | Drugs/abiratone-acetate-zytiga-for-mcrpc-post-adt/ | May 2015 |
| 25 | Radium 223 | Adults with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastases | Genitourinary/257-radium-223-therapy1.pdf | Drugs/radium-223-xofigo/ | May 2015 |
| 26 | Obinutuzumab | Combination with chlorambucil for adults with previously untreated chronic lymphocytic leukaemia (CLL) and with comorbidities making them unsuitable for full-dose fludarabine based therapy | Leukemia-bmt/286 obinutuzumab-and-chlorambucil-therapy.pdf | Drugs/obinutuzumab-gazyvaro/ | Aug 2015 |
| 27 | Pixantrone | Monotherapy for adults with multiply relapsed or refractory aggressive Non-Hodgkin B-cell Lymphomas (NHL) | Lymphoma-myeloma/255-nccp-pixantrone-ver2final-.pdf | Drugs/pixantrone-pixuvri/ | Aug 2015 |
| 28 | Siltuximab | Adults with Multicentric Castleman’s disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpes virus 8 (HHV-8) negative | Lymphoma-myeloma/277-nccp-siltuximab-ver2final-.pdf | NA | Aug 2015 |
| 29 | Trastuzumab Emtansine | Adults with HER2-positive, unresectable locally advanced or metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination. Patients should have either: received prior therapy for locally advanced or metastatic disease, or developed disease recurrence during or within 6 months of completing adjuvant therapy | Breast/206.pdf | Drugs/trastuzumab-emtansine-kadcyla/ | Aug 2015 |
| 30 | Enzalutamide | Metastatic castrate resistant prostate cancer in men who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy (ADT) in whom chemotherapy is not yet clinically indicated | Genitourinary/233-enzalutamide-monotherapy.pdf | News/enzalutamide-xtandi-pre-chemotherapy/ | Jan 2016 |
| 31 | Lenvatinib | Adults with progressive, locally advanced or metastatic, differentiated (papillary/follicular/Hürthle cell) thyroid carcinoma (DTC), refractory to radioactive iodine | Headandneck/295.pdf | Drugs/lenvatinib-lenvima/ | Jan 2016 |
| 32 | Nab-Paclitaxel | Combination with gemcitabine for the first-line treatment of adults with metastatic adenocarcinoma of the pancreas | Gastrointestinal/256.pdf | Drugs/nab-paclitaxel-abraxane/ | Feb 2016 |
| 33 | Pomalidomide | Combination with dexamethasone for adults with relapsed and refractory multiple myeloma who have received at least two prior treatment regimens, including both lenalidomide and bortezomib, and have demonstrated disease progression on the last therapy | Lymphoma-myeloma/245-pomalidomide-and-dexamethasone.pdf | Drugs/pomalidomide-imnovid/ | Feb 2016 |
| 34 | Pembrolizumab (200/400 mg) | First line monotherapy for advanced (unresectable or metastatic) melanoma in adults | Lymphoma-myeloma/455-pembrolizumab-200 mg-monotherapy.pdf | http://www.ncpe.ie/drugs/pembrolizumab-keytruda/ | Jun 2016 |
| Melanoma/pembrolizumab-400 mg-monotherapy-558.pdf | |||||
| 35 | Pembrolizumab (200/400 mg) | Ipilimumab‐refractory patients with unresectable or advanced metastatic melanoma | Lymphoma-myeloma/455-pembrolizumab-200 mg-monotherapy.pdf | Drugs/pembrolizumab-keytruda-for-the-treatment-of-unresectable-or-advanced-metastatic-melanoma-in-adults-refractory-to-ipilimumab/ | Jun 2016 |
| Melanoma/pembrolizumab-400 mg-monotherapy-558.pdf | |||||
| 36 | Ibrutinib | Adults with relapsed or refractory mantle cell lymphoma | Leukemia-bmt/296.pdf | Drugs/ibrutinib-imbruvica-for-mcl/ | Aug 2016 |
| 37 | Ibrutinib | Adults with Waldenström’s macroglobulinaemia who have received at least one prior therapy, or in first line treatment for patients unsuitable for chemo‐immunotherapy | Leukemia-bmt/296.pdf | NA | Aug 2016 |
| 38 | Ibrutinib | Adults with chronic lymphocytic leukaemia who have received at least one prior therapy, or in first line in the presence of 17p deletion or TP53 mutation in patients unsuitable for chemo‐immunotherapy | Leukemia-bmt/296.pdf | News/ibrutinib-imbruvica/ | Aug 2016 |
| 39 | Ceritinib | Adults with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) previously treated with crizotinib | Lung/340-ceritinib-monotherapy.pdf | Drugs/ceritinib-zykadia/ | Dec 2016 |
| 40 | Ponatinib | Adults with Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph + ALL) who are resistant to dasatinib; who are intolerant to dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation | Leukemia-bmt/302.pdf | Drugs/ponatinib-iclusig/ | Dec 2016 |
| 41 | Ponatinib | Adults with chronic phase chronic myeloid leukaemia (CML) who are resistant to dasatinib or nilotinib; who are intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation | Leukemia-bmt/302.pdf | Drugs/ponatinib-iclusig/ | Dec 2016 |
| 42 | Ponatinib | Adults with accelerated phase chronic myeloid leukaemia (CML) who are resistant to dasatinib or nilotinib; who are intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation | Leukemia-bmt/302.pdf | Drugs/ponatinib-iclusig/ | Dec 2016 |
| 43 | Ponatinib | Adults with blast phase chronic myeloid leukaemia (CML) who are resistant to dasatinib or nilotinib; who are intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation | Leukemia-bmt/302.pdf | Drugs/ponatinib-iclusig/ | Dec 2016 |
| 44 | Idelalisib | Monotherapy for adults with follicular lymphoma (FL) that is refractory to two prior lines of treatment | Lymphoma-myeloma/291.pdf | NA | Jan 2017 |
| 45 | Idelalisib | Combination with riTUXimab for adults with chronic lymphocytic leukaemia (CLL) who have received at least one prior therapy | Leukemia-bmt/389.pdf | Drugs/idelalisib-zydelig/ | Jan 2017 |
| 46 | Idelalisib | Combination with riTUXimab for adults with chronic lymphocytic leukaemia (CLL) as first line treatment in the presence of 17p deletion or TP53 mutation in patients who are not eligible for any other therapies | Leukemia-bmt/389.pdf | Drugs/idelalisib-zydelig/ | Jan 2017 |
| 47 | Idelalisib | Combination with Ofatumumab for adults with chronic lymphocytic leukaemia (CLL) who have received at least one prior therapy | Leukemia-bmt/390.pdf | NA | Jan 2017 |
| 48 | Idelalisib | Combination with Ofatumumab for adults with chronic lymphocytic leukaemia (CLL) as first line treatment in the presence of 17p deletion or TP53 mutation in patients who are not eligible for any other therapies | Leukemia-bmt/390.pdf | NA | Jan 2017 |
| 49 | Nintedanib | Combination with docetaxel for adults with locally advanced, metastatic of stage IIIB or IV, or locally recurrent NSCLC of adenocarcinoma tumour histology after first-line chemotherapy | Lung/372.pdf | Drugs/nintedanib-vargatef/ | Feb 2017 |
| 50 | Trifluridine and tipracil | Adults with metastatic colorectal cancer (CRC) who have been previously treated with, or are not considered candidates for, available therapies including fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-VEGF agents, and anti-EGFR agents | Gastrointestinal/382.pdf | Drugs/trifluridinetipiracil-lonsurf/ | Feb 2017 |
| 51 | Nivolumab 240 mg | Monotherapy for adults with relapsed or refractory classical Hodgkin lymphoma (cHL) after autologous stem cell transplant (ASCT) and treatment with brentuximab vedotin | Genitourinary/483-nivolumab-240 mg-monotherapy-14-day.pdf | Drugs/nivolumab-opdivo-for-classical-hodgkin-lymphoma/ | Oct 2017 |
| 52 | Nivolumab 240/480 mg | As monotherapy for advanced (unresectable or metastatic) melanoma in adults (BRAF positive) | Genitourinary/483-nivolumab-240 mg-monotherapy-14-day.pdf | Drugs/nivolumab-opdivio-for-melanoma/ | Oct 2017 |
| Genitourinary/484-nivolumab-480 mg-monotherapy-28-days.pdf | |||||
| 53 | Nivolumab 240/480 mg | Monotherapy for advanced (unresectable or metastatic) melanoma in adults (BRAF negative) | Genitourinary/483-nivolumab-240 mg-monotherapy-14-day.pdf | Drugs/nivolumab-opdivio-for-melanoma/ | Oct 2017 |
| Genitourinary/484-nivolumab-480 mg-monotherapy-28-days.pdf | |||||
| 54 | Nivolumab 240/480 mg | Monotherapy for advanced renal cell carcinoma (RCC) after prior therapy in adults | Genitourinary/483-nivolumab-240 mg-monotherapy-14-day.pdf | Drugs/nivolumab-opdivo-for-advanced-renal-cell-carcinoma/ | Oct 2017 |
| Genitourinary/484-nivolumab-480 mg-monotherapy-28-days.pdf | |||||
| 55 | Nivolumab Ipilimumab | Combination with ipilimumab for advanced (unresectable or metastatic) melanoma in adults | Melanoma/431-nivolumab-1 mg-ipilimumab-3 mg-therapy.pdf | Drugs/nivolumab-plus-ipilimumab-opdivio-plus-yervoy/ | Oct 2017 |
| 56 | Alectinib | Adults with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) previously treated with crizotinib | Lung/alectinib-monotherapy1.pdf | Drugs/alectinib-alecensa/ | Nov 2017 |
| 57 | Obinutuzumab | Combination with bendamustine for patients with follicular lymphoma (FL) who did not respond or who progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen | Lymphoma-myeloma/424-obinutuzumab-and-bendamustine-therapy.pdf | Drugs/obinutuzumab-gazyvaro-for-follicular-lymphoma/ | Nov 2017 |
| Maintenance therapy in patients with follicular lymphoma (FL) who have responded to induction treatment with obinutuzumab and bendamustine or have stable disease | Lymphoma-myeloma/425%20obinutuzumab-maintenance-therapy-following-o-bendamustine-therapy1.pdf | Nov 2017 | |||
| 58 | Olaparib | Maintenance treatment of adults with platinum-sensitive relapsed BRCA-mutated (germline and/or somatic)—fallopian tube cancer who are in response (complete response or partial response) to platinum-based chemotherapy | Gynaecology/341-olaparib-monotherapy.pdf | Drugs/olaparib-lynparza-2/ | Nov 2017 |
| Maintenance treatment of adults with platinum-sensitive relapsed BRCA-mutated (germline and/or somatic)—high-grade serous epithelial ovarian cancer who are in response (complete response or partial response) to platinum-based chemotherapy | |||||
| Maintenance treatment of adults with platinum-sensitive relapsed BRCA-mutated (germline and/or somatic)—primary peritoneal cancer who are in response (complete response or partial response) to platinum-based chemotherapy | |||||
| 59 | Vismodegib | Adults with local advanced basal cell carcinoma inappropriate for surgery or radiotherapy | Melanoma/vismodegib-monotherapy.pdf | Drugs/vismodegib-erivedge/ | Nov 2017 |
| 60 | Vismodegib | Adults with symptomatic metastatic basal cell carcinoma (MBCC) | Melanoma/vismodegib-monotherapy.pdf | Drugs/vismodegib-erivedge/ | Nov 2017 |
| 61 | Cobimetinib | Combination with vemurafenib for adults with unresectable or metastatic melanoma with a BRAF V600 mutation | Sarcoma/mifamurtide.pdf | Drugs/cobimetinib-cotellic/ | Apr 2018 |
| 62 | Daratumumab | Monotherapy for adults with relapsed and refractory multiple myeloma whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on the last therapy | Lymphoma-myeloma/daratumumab monotherapy.pdf | Drugs/daratumumab-darzalex/ | Apr 2018 |
| 63 | Pembrolizumab (200 mg/400 mg) | First-line for metastatic non-small cell lung carcinoma (NSCLC) in adults whose tumours express PD-L1 with a ≥ 50% tumour proportion score (TPS) with no EGFR or ALK positive tumour mutations | Lymphoma-myeloma/455-pembrolizumab-200 mg-monotherapy.pdf | Drugs/pembrolizumab-keytruda-for-first-line-nsclc/ | Apr 2018 |
| Melanoma/pembrolizumab-400 mg-monotherapy-558.pdf | |||||
| 64 | Trametinib | Combination with dabrafenib for adults with unresectable or metastatic melanoma with a BRAF V600 mutation | Melanoma/dabrafenib and trametinib therapy.pdf | Drugs/trametinib-mekinist/ | Apr 2018 |
| 65 | Nivolumab | Monotherapy for squamous cell cancer of the head and neck in adults progressing on or after platinum-based therapy | Headandneck/483-nivolumab-240 mg-monotherapy.pdf | Drugs/nivolumab-opdivo-for-head-and-neck-cancer/ | May 2018 |
| 66 | Palbociclib | Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer in combination with fulvestrant in women who have received prior endocrine therapy (2nd line) | Breast/414-palbociclib-therapy-28-days.pdf | Drugs/Palbociclib-Ibrance/ | Jun 2018 |
| 67 | Palbociclib | Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer in combination with an aromatase inhibitor (1st line) | Breast/414-palbociclib-therapy-28-days.pdf | Drugs/palbociclib-ibrance/ | Jun 2018 |
| 68 | Carfilzomib | Carlfilzomib, lenalidomide and dexamethasone for adults with multiple myeloma who have received at least one pror therapy | Lymphoma-myeloma/405-carfilzomib-lenalidomide-and-dexamethasone-krd-therapy-28-day.pdf | Drugs/carfilzomib-kyprolis/ | Sep 2018 |
| 69 | Nivolumab | Monotherapy for locally advanced or metastatic non-small cell lung cancer (NSCLC) after prior chemotherapy in adults | Headandneck/483-nivolumab-240 mg-monotherapy.pdf | Drugs/nivolumab-opdivio-for-non-squamous-nsclc/ | Sep 2018 |
| 70 | Pembrolizumab (200 mg/400 mg) | Monotherapy for adults with relapsed or refractory classical Hodgkin lymphoma (cHL) who are transplant-ineligible and have failed brentuximab vedotin | Lymphoma-myeloma/455-pembrolizumab-200 mg-monotherapy.pdf | Drugs/pembrolizumab-keytruda-for-classical-hodgkin-lymphoma/ | Nov 2018 |
| Melanoma/pembrolizumab-400 mg-monotherapy-558.pdf | |||||
| 71 | Ixazomib | Combination with lenalidomide and dexamethasone for adults with multiple myeloma who have received at least one prior therapy | Lymphoma-myeloma/516-ixazomib-lenalidomide-and-dexamethasone-therapy-28-day.pdf | Drugs/ixazomib-ninlaro/ | Dec 2018 |
| 72 | Venetoclax | Chronic lymphocytic leukaemia in the absence of 17p deletion or TP53 mutation in adults who have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor | Leukemia-bmt/400.pdf | Drugs/venetoclax-venclyxto/ | Dec 2018 |
| 73 | Venetoclax | Chronic lymphocytic leukaemia in the presence of 17p deletion or TP53 mutation in adults who are unsuitable for or have failed a B-cell receptor pathway inhibitor | Leukemia-bmt/400.pdf | Drugs/venetoclax-venclyxto/ | Dec 2018 |
| 74 | Cabozantinib | Advanced renal cell carcinoma in adults following prior VEGF targeted therapy | Genitourinary/518 cabozantinib therapy.pdf | Drugs/cabozantinib-cabometyx/ | Jan 2019 |
| 75 | Ribociclib | Postmenopausal women with hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative locally advanced or metastatic breast cancer as initial endocrine-based therapy in combination with an aromatase inhibitor | Breast/525-ribociclib-therapy-28-day.pdf | Drugs/ribociclib-kisqali/ | Feb 2019 |
| 76 | Atezolizumab | Adults with locally advanced or metastatic non-small cell lung cancer after prior chemotherapy | Lung/544-atezolizumab-1200 mg-Monotherapy.pdf | Drugs/atezolizumab-tecentriq/ | Mar 2019 |
| 77 | Avelumab | Adults with metastatic Merkel cell carcinoma who have received 1 or more lines of chemotherapy for metastatic disease (1st line) | Melanoma/535.pdf | Drugs/avelumab-bavencio/ | May 2019 |
| 78 | Avelumab | Adult with metastatic Merkel cell carcinoma who have received 1 or more lines of chemotherapy for metastatic disease (2nd line) | Melanoma/535.pdf | Drugs/avelumab-bavencio/ | May 2019 |
| 79 | Blinatumomab | Adults with relapsed or refractory B cell precursor (BCP) Philadelphia chromosome negative acute lymphoblastic leukaemia (ALL) who have received no prior salvage treatment for relapsed/refractory disease and are considered eligible for transplant | Leukemia-bmt/538-blinatumomab-therapy.pdf | Drugs/blinatumomab-blincyto/ | May 2019 |
| 80 | Blinatumomab | Paediatric patients aged 1 year and older with Philadelphia chromosome negative B-cell precursor ALL which is refractory or in relapse after receiving at least two prior therapies or in relapse after receiving prior allogeneic hematopoietic stem cell transplantation | p567-blinatumomab-paediatric-therapy.pdf | Drugs/blinatumomab-blincyto-paediatric-all/ | May 2019 |
| 81 | Encorafenib and Binimetinib | Adults with advanced (unresectable or metastatic) melanoma with a BRAF V600 mutation | Melanoma/563-envorafenib-and-binimetinib-therapy.pdf | Drugs/encorafenib-braftovi-binimetinib-mektovi/ | May 2019 |
| 82 | Inotuzumab | Monotherapy for adults with relapsed or refractory CD22-positive B cell precursor acute lymphoblastic leukaemia (ALL). Adults with Philadelphia chromosome positive (Ph+) relapsed or refractory B cell precursor ALL should have failed treatment with at least 1 tyrosine kinase inhibitor (TKI) | Leukemia-bmt/537-inotuzumab-ozogamicin-monotherapy.pdf | Drugs/inotuzumab-ozogamicin-besponsa/ | May 2019 |
| 83 | Obinutuzumab | Combination with chemotherapy, followed by maintenance treatment in patients achieving a response, for previously untreated advanced follicular lymphoma (FL) | Lymphoma-myeloma/549-obinutuzumab-and-chop-therapy-%E2%80%93–21-day.pdf | Drugs/obinutuzumab-gazyvaro-for-previously-untreated-advanced-follicular-lymphoma/ | May 2019 |
| 84 | Alectinib | As monotherapy is indicated for the first-line treatment of adults with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) | Lung/alectinib-monotherapy1.pdf | Drugs/alectinib-alecensa/ | Jun 2019 |
| 85 | Brigatinib | Adults with anaplastic lymphoma kinase (ALK) positive advanced non-small cell lung cancer (NSCLC) previously treated with crizotinib | Lung/562-brigatinib-therapy.pdf | Drugs/brigatinib-alunbrig/ | Jun 2019 |
| 86 | Lorlatinib | Monotherapy for adults with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC), following disease progression on (i) alectinib or ceritinib as the first ALK-targeted treatment or (ii) crizotinib and at least one other ALK-targeted treatment | Lung/570 lorlatinib therapy.pdf | Drugs/lorlatinib-lorviqua/ | Oct 2019 |
| 87 | Tivozanib | First line for adults with advanced renal cell carcinoma (RCC) and for adults who are VEGFR and mTOR pathway inhibitor-naïve following disease progression after one prior treatment with cytokine therapy for advanced RCC | Genitourinary/564-tivozanib-therapy.pdf | Drugs/tivozanib-fotivda/ | Oct 2019 |
| 88 | Dacomitinib | Dacomitinib (Vizimpro®) as monotherapy, for the first-line treatment of adults with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR)-activating mutations | Lung/565-dacomitinib-monotherapy.pdf | Drugs/dacomitinib-vizimpro/ | Nov 2019 |
| 89 | Osimertinib | Adults with locally advanced or metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC) | Lung/353-Osimertinib-Monotherapy.Pdf | Drugs/osimertinib-tagrisso-for-the-first-line-treatment-of-metastatic-nsclc/ | Jul 2020 |
| 90 | Pertuzumab | Pertuzumab in combination with trastuzumab and chemotherapy for the neoadjuvant treatment of adults with HER2-positive, locally advanced, inflammatory, or early stage breast cancer at high risk of recurrence | Breast/350%20pertuzumab%20and%20trastuzumab%20and%20chemotherapy.pdf | Drugs/pertuzumab-perjeta-for-her2-positive-breast-cancer/ | Jul 2020 |
| 91 | Venetoclax | Combination with rituximab for adults with chronic lymphocytic leukaemia (CLL) who have received at least one prior therapy | Leukemia-bmt/575-venetoclax-and-rituximab-therapy.pdf | Drugs/venetoclax-venclyxto-in-combination-with-rituximab/ | Jul 2020 |
aNCCP URL stem: https://www.hse.ie/eng/services/list/5/cancer/profinfo/chemoprotocols
bNCPE URL stem: http://www.ncpe.ie/
Table 5.
Drug and disease information
| Pair number | Drug name | Proprietary name | Market authorisation holder | Indication | ICD 10 code | Disease category | Metastatic disease | Mechanism of action | Orphan status |
|---|---|---|---|---|---|---|---|---|---|
| 1 | Ipilimumab | Yervoy | Bristol-Myers Squibb | Adults with advanced (unresectable or metastatic) malignant melanoma | C43 | Skin | Yes | Monoclonal antibodies | Negative |
| 2 | Abiraterone | Zytiga | Janssen-Cilag | Metastatic castration resistant prostate cancer which has progressed on or after a docetaxel-based chemotherapy regimen | C61 | Prostate | Yes | Immunomodulating agents and other non-antineoplastic therapies | Negative |
| 3 |
Tegafur/ Gimeracil/ Oteracil |
Teysuno | Nordic Group | Advanced gastric cancer in combination with cisplatin | C16 | Digestive Organs | Yes | Antimetabolites, plant alkaloids, cytotoxic antibiotic and related substances | Negative |
| 4 | Axitinib | Inlyta | Pfizer | Adults with advanced RCC after failure, on a previous line of therapy, i.e., treatment with SUNItinib, or a cytokine | C64 | Kidney | No | Protein kinase inhibitors | Negative, Withdrawn |
| 5 | Cabazitaxel | Jevtana | Sanofi-Aventis | Metastatic castration resistant prostate cancer previously treated with docetaxel containing regimen | C61 | Prostate | Yes | Antimetabolites, plant alkaloids, cytotoxic antibiotic and related substances | Negative |
| 6 | Mifamurtide | Mepact | Takeda | High-grade resectable non-metastatic osteosarcoma after macroscopically complete surgical resection, in children, adolescents and young adults | C41 | Other | No | Immunomodulating agents and other non-antineoplastic therapies | Negative |
| 7 | Vemurafenib | Zelboraf | Roche | Adults with BRAF V600 mutation-positive unresectable or metastatic melanoma | C43 | Skin | Yes | Protein kinase inhibitors | Negative |
| 8 | Afatinib | Gilotrif | Boehringer Ingelheim | As monotherapy for EGFR TKI-naïve adults with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating EGFR mutation(s) | C34 | Lung | Yes | Protein kinase inhibitors | Negative |
| 9 | Bosutinib | Bosulif | Pfizer | Adults with chronic phase, accelerated phase, and blast phase Ph + CML previously treated with one or more TKI(s) and for whom imatinib, nilotinib and dasatinib are not considered appropriate treatment options | C92 | Leukaemias | No | Protein kinase inhibitors | Positive, 1/13/818 |
| 10 | Decitabine | Dacogen | Janssen-Cilag | Adults aged 65 years and above with newly diagnosed de novo or secondary AML, according to the WHO classification, who are not candidates for standard induction chemotherapy | C92 | Leukaemias | No | Antimetabolites, plant alkaloids, cytotoxic antibiotic and related substances | Positive, 3/06/370 |
| 11 | Eribulin | Halaven | Eisai | LABC or MBC which has progressed after at least two chemotherapeutic regimens for advanced disease. Prior therapy should have included an anthracycline and a taxane unless patients were not suitable for these treatments | C50 | Breast | Yes | Other antineoplastic agents | Negative |
| 12 | Pertuzumab | Perjeta | Roche | Adults with HER2-positive MBC or locally recurrent unresectable breast cancer, who have not received previous anti-HER2 therapy or chemotherapy for their metastatic disease | C50 | Breast | Yes | Monoclonal antibodies | Negative |
| 13 | Ruxolitinib | Jakavi | Novartis | Disease-related splenomegaly or symptoms in adults with post polycythaemia vera myelofibrosis | D45 | Other | No | Protein kinase inhibitors | Negative |
| Disease-related splenomegaly or symptoms in adults with primary myelofibrosis (chronic idiopathic myelofibrosis) | D47 | ||||||||
| Disease-related splenomegaly or symptoms in adults with post essential thrombocythaemia myelofibrosis | D47 | ||||||||
| 14 | Aflibercept | Eylea | Bayer | Combination with irinotecan/5-fluorouracil/folinic acid (FOLFIRI) chemotherapy in adults with metastatic colorectal cancer that is resistant to or has progressed after an oxoliplatin-containing regimen | C18 | Digestive Organs | Yes | Immunomodulating agents and other non-antineoplastic therapies | Negative |
| 15 | Crizotinib | Xalkori | Pfizer | Adults with previously treated anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) | C34 | Lung | No | Protein kinase inhibitors | Negative |
| 16 | Vandetanib | Caprelsa | Genzyme | Aggressive and symptomatic medullary thyroid cancer (MTC) in patients with unresectable locally advanced or metastatic disease | C73 | Other | Yes | Protein kinase inhibitors | Negative |
| 17 | Brentuximab vedotin | Adcetris | Takeda | Adults with relapsed or refractory CD30 + Hodgkin lymphoma (HL): following autologous stem cell transplant (ASCT) | C81 | Lymphomas | No | Monoclonal antibodies | Negative |
| 18 | Brentuximab vedotin | Adcetris | Takeda | Adults with relapsed or refractory CD30 + Hodgkin lymphoma (HL): following at least two prior therapies when ASCT or multi-agent chemotherapy is not an option | C81 | Lymphomas | No | Monoclonal antibodies | Negative |
| 19 | Brentuximab vedotin | Adcetris | Takeda | Adults with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL) | C84 | Lymphomas | No | Monoclonal antibodies | Negative |
| 20 | Enzalutamide | Xtandi | Astellas | Adults with metastatic castration-resistant prostate cancer whose disease has progressed on or after docetaxel | C61 | Prostate | Yes | Immunomodulating agents and other non-antineoplastic therapies | Negative |
| 21 | Dabrafenib | Tafinlar | Novartis | Adults with unresectable or metastatic melanoma with the BRAF V600 mutation | C43 | Skin | Yes | Protein kinase inhibitors | Negative |
| 22 | Regorafenib | Stivarga | Bayer | Adults unresectable or metastatic gastrointestinal stromal tumours (GIST) who progressed on or are intolerant to prior treatment with imatinib and sunitinib | C26 | Digestive Organs | Yes | Protein kinase inhibitors | Negative |
| 23 | Regorafenib | Stivarga | Bayer | Adults with metastatic colorectal cancer (mCRC) who have been previously treated with, or are not considered candidates for, available therapies. These include fluoropyrimidine-based chemotherapy, anti-VEGF and anti-EGFR therapies | C18 | Digestive Organs | Yes | Protein kinase inhibitors | Negative |
| 24 | Abiraterone | Zytiga | Janssen-Cilag | Metastatic castration resistant prostate cancer in men who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated | C61 | Prostate | Yes | Immunomodulating agents and other non-antineoplastic therapies | Negative |
| 25 | Radium 223 | Xofigo | Bayer | Adults with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastases | C61 | Prostate | Yes | Immunomodulating agents and other non-antineoplastic therapies | Negative |
| 26 | Obinutuzumab | Gazyvaro | Roche | Combination with chlorambucil for adults with previously untreated chronic lymphocytic leukaemia (CLL) and with comorbidities making them unsuitable for full-dose fludarabine based therapy | C91 | Leukaemias | No | Monoclonal antibodies | Negative |
| 27 | Pixantrone | Pixuvri | Les Laboratoires Servier | Monotherapy for adults with multiply relapsed or refractory aggressive Non-Hodgkin B-cell Lymphomas (NHL) | C85 | Other blood cancers | No | Antimetabolites, plant alkaloids, cytotoxic antibiotic and related substances | Negative, Withdrawn |
| 28 | Siltuximab | Pixuvri | Les Laboratoires Servier | Adults with Multicentric Castleman’s disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpes virus 8 (HHV-8) negative | D36 | Other | Yes | Immunomodulating agents and other non-antineoplastic therapies | Negative |
| 29 | Trastuzumab Emtansine | Kadcyla | Roche | Adults with HER2-positive, unresectable locally advanced or metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination. Patients should have either: received prior therapy for locally advanced or metastatic disease, or developed disease recurrence during or within 6 months of completing adjuvant therapy | C50 | Breast | Yes | Monoclonal antibodies | Negative |
| 30 | Enzalutamide | Xtandi | Astellas | Metastatic castrate resistant prostate cancer in men who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy (ADT) in whom chemotherapy is not yet clinically indicated | C61 | Prostate | Yes | Immunomodulating agents and other non-antineoplastic therapies | Negative |
| 31 | Lenvatinib | Lenvima | Eisai | Adults with progressive, locally advanced or metastatic, differentiated (papillary/follicular/Hürthle cell) thyroid carcinoma (DTC), refractory to radioactive iodine | C73 | Other | Yes | Protein kinase inhibitors | Negative, Withdrawn |
| 32 | Nab-Paclitaxel | Abraxane | Celgene | Combination with gemcitabine for the first-line treatment of adults with metastatic adenocarcinoma of the pancreas | C25 | Digestive Organs | Yes | Antimetabolites, plant alkaloids, cytotoxic antibiotic and related substances | Positive, 3/06/419 |
| 33 | Pomalidomide | Imnovid | Celgene | Combination with dexamethasone for adults with relapsed and refractory multiple myeloma who have received at least two prior treatment regimens, including both lenalidomide and bortezomib, and have demonstrated disease progression on the last therapy | C90 | Other blood cancers | No | Immunomodulating agents and other non-antineoplastic therapies | Negative |
| 34 | Pembrolizumab (200/400 mg) | Keytruda | Merck Sharp & Dohme | First line monotherapy for advanced (unresectable or metastatic) melanoma in adults | C43 | Skin | Yes | Monoclonal antibodies | Negative |
| 35 | Pembrolizumab (200/400 mg) | Keytruda | Merck Sharp & Dohme | Ipilimumab‐refractory patients with unresectable or advanced metastatic melanoma | C43 | Skin | Yes | Monoclonal antibodies | Negative |
| 36 | Ibrutinib | Imbruvica | Janssen-Cilag | Adults with relapsed or refractory mantle cell lymphoma | C83 | Lymphomas | No | Protein kinase inhibitors | Positive, 3/13/1115 |
| 37 | Ibrutinib | Imbruvica | Janssen-Cilag | Adults with Waldenström’s macroglobulinaemia who have received at least one prior therapy, or in first line treatment for patients unsuitable for chemo‐immunotherapy | C88 | Other blood cancers | No | Protein kinase inhibitors | Positive, 3/14/1264 |
| 38 | Ibrutinib | Imbruvica | Janssen-Cilag | Adults with chronic lymphocytic leukaemia who have received at least one prior therapy, or in first line in the presence of 17p deletion or TP53 mutation in patients unsuitable for chemo‐immunotherapy | C91 | Leukaemias | No | Protein kinase inhibitors | Positive, 3/14/1264 |
| 39 | Ceritinib | Zykadia | Novartis | Adults with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) previously treated with crizotinib | C34 | Lung | No | Protein kinase inhibitors | Negative |
| 40 | Ponatinib | Iclusig | Incyte | Adults with Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph + ALL) who are resistant to dasatinib; who are intolerant to dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation | C91 | Leukaemias | Yes | Protein kinase inhibitors | Negative |
| 41 | Ponatinib | Iclusig | Incyte | Adults with chronic phase chronic myeloid leukaemia (CML) who are resistant to dasatinib or nilotinib; who are intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation | C92 | Leukaemias | Yes | Protein kinase inhibitors | Negative |
| 42 | Ponatinib | Iclusig | Incyte | Adults with accelerated phase chronic myeloid leukaemia (CML) who are resistant to dasatinib or nilotinib; who are intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation | C92 | Leukaemias | Yes | Protein kinase inhibitors | Negative |
| 43 | Ponatinib | Iclusig | Incyte | Adults with blast phase chronic myeloid leukaemia (CML) who are resistant to dasatinib or nilotinib; who are intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation | C92 | Leukaemias | Yes | Protein kinase inhibitors | Negative |
| 44 | Idelalisib | Zydelig | Gilead | Monotherapy for adults with follicular lymphoma (FL) that is refractory to two prior lines of treatment | C82 | Lymphomas | No | Other antineoplastic agents | Negative, Withdrawn |
| 45 | Idelalisib | Zydelig | Gilead | Combination with riTUXimab for adults with chronic lymphocytic leukaemia (CLL) who have received at least one prior therapy | C91 | Leukaemias | No | Other antineoplastic agents | Negative, Withdrawn |
| 46 | Idelalisib | Zydelig | Gilead | Combination with riTUXimab for adults with chronic lymphocytic leukaemia (CLL) as first line treatment in the presence of 17p deletion or TP53 mutation in patients who are not eligible for any other therapies | C91 | Leukaemias | No | Other antineoplastic agents | Negative, Withdrawn |
| 47 | Idelalisib | Zydelig | Gilead | Combination with Ofatumumab for adults with chronic lymphocytic leukaemia (CLL) who have received at least one prior therapy | C91 | Leukaemias | No | Other antineoplastic agents | Negative, Withdrawn |
| 48 | Idelalisib | Zydelig | Gilead | Combination with Ofatumumab for adults with chronic lymphocytic leukaemia (CLL) as first line treatment in the presence of 17p deletion or TP53 mutation in patients who are not eligible for any other therapies | C91 | Leukaemias | No | Other antineoplastic agents | Negative, Withdrawn |
| 49 | Nintedanib | Ofev | Boehringer Ingelheim | Combination with docetaxel for adults with locally advanced, metastatic of stage IIIB or IV, or locally recurrent NSCLC of adenocarcinoma tumour histology after first-line chemotherapy | C34 | Lung | Yes | Protein kinase inhibitors | Negative |
| 50 | Trifluridine and Tipracil | Lonsurf | Les Laboratoires Servier | Adults with metastatic colorectal cancer (CRC) who have been previously treated with, or are not considered candidates for, available therapies including fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-VEGF agents, and anti-EGFR agents | C18 | Digestive Organs | Yes | Antimetabolites, plant alkaloids, cytotoxic antibiotic and related substances | Negative |
| 51 | Nivolumab 240 mg | Opdivo | Bristol-Myers Squibb | Monotherapy for adults with relapsed or refractory classical Hodgkin lymphoma (cHL) after autologous stem cell transplant (ASCT) and treatment with brentuximab vedotin | C81 | Lymphomas | No | Monoclonal antibodies | Negative |
| 52 | Nivolumab 240/480 mg | Opdivo | Bristol-Myers Squibb | As monotherapy for advanced (unresectable or metastatic) melanoma in adults (BRAF positive) | C43 | Skin | Yes | Monoclonal antibodies | Negative |
| 53 | Nivolumab 240/480 mg | Opdivo | Bristol-Myers Squibb | Monotherapy for advanced (unresectable or metastatic) melanoma in adults (BRAF negative) | C43 | Skin | Yes | Monoclonal antibodies | Negative |
| 54 | Nivolumab 240/480 mg | Opdivo | Bristol-Myers Squibb | Monotherapy for advanced renal cell carcinoma (RCC) after prior therapy in adults | C64 | Kidney | Yes | Monoclonal antibodies | Negative |
| 55 | Nivolumab Ipilimumab | Opdivo | Bristol-Myers Squibb | Combination with ipilimumab for advanced (unresectable or metastatic) melanoma in adults | C43 | Skin | Yes | Monoclonal antibodies | Negative |
| 56 | Alectinib | Alecensa | Roche | Adults with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) previously treated with crizotinib | C34 | Lung | No | Protein kinase inhibitors | Negative |
| 57 | Obinutuzumab | Gazyvaro | Roche | Combination with bendamustine for patients with follicular lymphoma (FL) who did not respond or who progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen | C82 | Lymphomas | No | Monoclonal antibodies | Positive, 3/15/1504 |
| Roche | Maintenance therapy in patients with follicular lymphoma (FL) who have responded to induction treatment with obinutuzumab and bendamustine or have stable disease | C82 | Lymphomas | No | Monoclonal antibodies | Positive, 3/15/1504 | |||
| 58 | Olaparib | Lynparza | AstraZeneca | Maintenance treatment of adults with platinum-sensitive relapsed BRCA-mutated (germline and/or somatic)—fallopian tube cancer who are in response (complete response or partial response) to platinum-based chemotherapy | C48 | Other | No | Other antineoplastic agents | Negative |
| AstraZeneca | Maintenance treatment of adults with platinum-sensitive relapsed BRCA-mutated (germline and/or somatic)—high-grade serous epithelial ovarian cancer who are in response (complete response or partial response) to platinum-based chemotherapy | C56 | Other | No | Other antineoplastic agents | Negative | |||
| AstraZeneca | Maintenance treatment of adults with platinum-sensitive relapsed BRCA-mutated (germline and/or somatic)—primary peritoneal cancer who are in response (complete response or partial response) to platinum-based chemotherapy | C57 | Other | No | Other antineoplastic agents | Negative | |||
| 59 | Vismodegib | Erivedge | Roche | Adults with local advanced basal cell carcinoma inappropriate for surgery or radiotherapy | C44 | Skin | No | Other antineoplastic agents | Negative |
| 60 | Vismodegib | Erivedge | Roche | Adults with symptomatic metastatic basal cell carcinoma (MBCC) | C44 | Skin | Yes | Other antineoplastic agents | Negative |
| 61 | Cobimetinib | Cotellic | Roche | Combination with vemurafenib for adults with unresectable or metastatic melanoma with a BRAF V600 mutation | C43 | Skin | Yes | Protein kinase inhibitors | Negative |
| 62 | Daratumumab | Darzalex | Janssen-Cilag | Monotherapy for adults with relapsed and refractory multiple myeloma whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on the last therapy | C90 | Other blood cancers | No | Monoclonal antibodies | Negative |
| 63 | Pembrolizumab 200 mg/400 mg | Keytruda | Merck Sharp & Dohme | First-line for metastatic non-small cell lung carcinoma (NSCLC) in adults whose tumours express PD-L1 with a ≥ 50% tumour proportion score (TPS) with no EGFR or ALK positive tumour mutations | C34 | Lung | Yes | Monoclonal antibodies | Negative |
| 64 | Trametinib | Mekinist | Novartis | Combination with dabrafenib for adults with unresectable or metastatic melanoma with a BRAF V600 mutation | C43 | Skin | Yes | Protein kinase inhibitors | Negative |
| 65 | Nivolumab | Opdivo | Bristol-Myers Squibb | Monotherapy for squamous cell cancer of the head and neck in adults progressing on or after platinum-based therapy | C76 | Other | No | Monoclonal antibodies | Negative |
| 66 | Palbociclib | Ibrance | Pfizer | Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer in combination with fulvestrant in women who have received prior endocrine therapy (2nd line) | C50 | Breast | Yes | Protein kinase inhibitors | Negative |
| 67 | Palbociclib | Ibrance | Pfizer | Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer in combination with an aromatase inhibitor (1st line) | C50 | Breast | Yes | Protein kinase inhibitors | Negative |
| 68 | Carfilzomib | Kyprolis | Amgen | Carlfilzomib, lenalidomide and dexamethasone for adults with multiple myeloma who have received at least one pror therapy | C90 | Other blood cancers | No | Other antineoplastic agents | Positive, 3/08/548 |
| 69 | Nivolumab | Opdivo | Bristol-Myers Squibb | Monotherapy for locally advanced or metastatic non-small cell lung cancer (NSCLC) after prior chemotherapy in adults | C34 | Lung | Yes | Monoclonal antibodies | Negative |
| 70 | Pembrolizumab 200 mg/400 mg | Keytruda | Merck Sharp & Dohme | Monotherapy for adults with relapsed or refractory classical Hodgkin lymphoma (cHL) who are transplant-ineligible and have failed brentuximab vedotin | C81 | Lymphomas | No | Monoclonal antibodies | Negative |
| 71 | Ixazomib | Ninlaro | Takeda | Combination with lenalidomide and dexamethasone for adults with multiple myeloma who have received at least one prior therapy | C90 | Other blood cancers | No | Other antineoplastic agents | Negative |
| 72 | Venetoclax | Venclyxto | AbbVie | Chronic lymphocytic leukaemia in the absence of 17p deletion or TP53 mutation in adults who have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor | C91 | Leukaemias | No | Other antineoplastic agents | Negative |
| 73 | Venetoclax | Venclyxto | AbbVie | Chronic lymphocytic leukaemia in the presence of 17p deletion or TP53 mutation in adults who are unsuitable for or have failed a B-cell receptor pathway inhibitor | C91 | Leukaemias | No | Other antineoplastic agents | Negative |
| 74 | Cabozantinib | Cometriq | Ipsen | Advanced renal cell carcinoma in adults following prior VEGF targeted therapy | C64 | Kidney | Yes | Protein kinase inhibitors | Negative |
| 75 | Ribociclib | Kisqali | Novartis | Postmenopausal women with hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative locally advanced or metastatic breast cancer as initial endocrine-based therapy in combination with an aromatase inhibitor | C50 | Breast | Yes | Protein kinase inhibitors | Negative |
| 76 | Atezolizumab | Tecentriq | Roche | Adults with locally advanced or metastatic non-small cell lung cancer after prior chemotherapy | C34 | Lung | Yes | Monoclonal antibodies | Negative |
| 77 | Avelumab | Bavencio | Merck | Adults with metastatic Merkel cell carcinoma who have received 1 or more lines of chemotherapy for metastatic disease (1st line) | C4A | Skin | Yes | Monoclonal antibodies | Negative |
| 78 | Avelumab | Bavencio | Merck | Adult with metastatic Merkel cell carcinoma who have received 1 or more lines of chemotherapy for metastatic disease (2nd line) | C4A | Skin | Yes | Monoclonal antibodies | Negative |
| 79 | Blinatumomab | Blincyto | Amgen | Adults with relapsed or refractory B cell precursor (BCP) Philadelphia chromosome negative acute lymphoblastic leukaemia (ALL) who have received no prior salvage treatment for relapsed/refractory disease and are considered eligible for transplant | C91 | Leukaemias | No | Monoclonal antibodies | Positive, 1/15/1047 |
| 80 | Blinatumomab | Blincyto | Amgen | Paediatric patients aged 1 year and older with Philadelphia chromosome negative B-cell precursor ALL which is refractory or in relapse after receiving at least two prior therapies or in relapse after receiving prior allogeneic hematopoietic stem cell transplantation | C91 | Leukaemias | No | Monoclonal antibodies | Positive, 1/15/1048 |
| 81 | Encorafenib and Binimetinib | Braftovi | Pierre Fabre Médicament | Adults with advanced (unresectable or metastatic) melanoma with a BRAF V600 mutation | C43 | Skin | Yes | Protein kinase inhibitors | Negative |
| 82 | Inotuzumab | Besponsa | Pfizer | Monotherapy for adults with relapsed or refractory CD22-positive B cell precursor acute lymphoblastic leukaemia (ALL). Adults with Philadelphia chromosome positive (Ph+) relapsed or refractory B cell precursor ALL should have failed treatment with at least 1 tyrosine kinase inhibitor (TKI) | C91 | Leukaemias | No | Monoclonal antibodies | Negative |
| 83 | Obinutuzumab | Gazyvaro | Roche | Combination with chemotherapy, followed by maintenance treatment in patients achieving a response, for previously untreated advanced follicular lymphoma (FL) | C82 | Lymphomas | No | Monoclonal antibodies | Positive, 3/15/1504 |
| 84 | Alectinib | Alecensa | Roche | As monotherapy is indicated for the first-line treatment of adults with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) | C34 | Lung | No | Protein kinase inhibitors | Negative |
| 85 | Brigatinib | Alunbrig | Takeda | Adults with anaplastic lymphoma kinase (ALK) positive advanced non-small cell lung cancer (NSCLC) previously treated with crizotinib | C34 | Lung | No | Protein kinase inhibitors | Negative |
| 86 | Lorlatinib | Lorviqua | Pfizer | Monotherapy for adults with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC), following disease progression on (i) alectinib or ceritinib as the first ALK-targeted treatment or (ii) crizotinib and at least one other ALK-targeted treatment | C34 | Lung | No | Protein kinase inhibitors | Negative |
| 87 | Tivozanib | Fotivda | EUSA Pharma | First line for adults with advanced renal cell carcinoma (RCC) and for adults who are VEGFR and mTOR pathway inhibitor-naïve following disease progression after one prior treatment with cytokine therapy for advanced RCC | C64 | Kidney | No | Protein kinase inhibitors | Negative |
| 88 | Dacomitinib | Darzalex | Janssen-Cilag | Dacomitinib (Vizimpro®) as monotherapy, for the first-line treatment of adults with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR)-activating mutations | C34 | Lung | Yes | Protein kinase inhibitors | Negative |
| 89 | Osimertinib | Tagrisso | AstraZeneca | Adults with locally advanced or metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC) | C34 | Lung | Yes | Protein kinase inhibitors | Negative |
| 90 | Pertuzumab | Perjeta | Roche | Pertuzumab in combination with trastuzumab and chemotherapy for the neoadjuvant treatment of adults with HER2-positive, locally advanced, inflammatory, or early stage breast cancer at high risk of recurrence | C50 | Breast | No | Monoclonal antibodies | Negative |
| 91 | Venetoclax | Venclyxto | AbbVie | Combination with rituximab for adults with chronic lymphocytic leukaemia (CLL) who have received at least one prior therapy | C91 | Leukaemias | No | Other antineoplastic agents | Negative |
Table 6.
Reimbursement process
| Pair number | Drug name | Indication | Appraisal pathway | Funding stream | Time taken to reimburse, months | HTA summary length, pages | Subsequent price negotiations |
|---|---|---|---|---|---|---|---|
| 1 | Ipilimumab | Adults with advanced (unresectable or metastatic) malignant melanoma | After HTA | ODMS | 11 | 3 | Yes |
| 2 | Abiraterone | Metastatic castration resistant prostate cancer which has progressed on or after a docetaxel-based chemotherapy regimen | After HTA | PCRS | 7 | 5 | Yes |
| 3 | Tegafur/Gimeracil /Oteracil | Advanced gastric cancer in combination with cisplatin | At RR | PCRS | 10 | N/A | No |
| 4 | Axitinib | Adults with advanced RCC after failure, on a previous line of therapy, i.e., treatment with SUNItinib, or a cytokine | Undocumented | PCRS | 3 | N/A | No |
| 5 | Cabazitaxel | Metastatic castration resistant prostate cancer previously treated with docetaxel containing regimen | After HTA | ODMS | 21 | 5 | Yes |
| 6 | Mifamurtide | High-grade resectable non-metastatic osteosarcoma after macroscopically complete surgical resection, in children, adolescents and young adults | Undocumented | ODMS | 32 | N/A | No |
| 7 | Vemurafenib | Adults with BRAF V600 mutation-positive unresectable or metastatic melanoma | After HTA | PCRS | 14 | 3 | Yes |
| 8 | Afatinib | As monotherapy for EGFR TKI-naïve adults with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating EGFR mutation(s) | At RR | PCRS | 3 | N/A | No |
| 9 | Bosutinib | Adults with chronic phase, accelerated phase, and blast phase Ph + CML previously treated with one or more TKI(s) and for whom imatinib, nilotinib and dasatinib are not considered appropriate treatment options | Undocumented | PCRS | 3 | N/A | No |
| 10 | Decitabine | Adults aged 65 years and above with newly diagnosed de novo or secondary AML, according to the WHO classification, who are not candidates for standard induction chemotherapy | After RR | ODMS | 1 | N/A | No |
| 11 | Eribulin | LABC or MBC which has progressed after at least two chemotherapeutic regimens for advanced disease. Prior therapy should have included an anthracycline and a taxane unless patients were not suitable for these treatments | After HTA | ODMS | 34 | 5 | Yes |
| 12 | Pertuzumab | Adults with HER2-positive MBC or locally recurrent unresectable breast cancer, who have not received previous anti-HER2 therapy or chemotherapy for their metastatic disease | After HTA | ODMS | 12 | 5 | No |
| 13 | Ruxolitinib | Disease-related splenomegaly or symptoms in adults with post polycythaemia vera myelofibrosis | After HTA | PCRS | 18 | 5 | Yes |
| Disease-related splenomegaly or symptoms in adults with primary myelofibrosis (chronic idiopathic myelofibrosis) | |||||||
| Disease-related splenomegaly or symptoms in adults with post essential thrombocythaemia myelofibrosis | |||||||
| 14 | Aflibercept | Combination with irinotecan/5-fluorouracil/folinic acid (FOLFIRI) chemotherapy in adults with metastatic colorectal cancer that is resistant to or has progressed after an oxoliplatin-containing regimen | At HTA | Individual hospital budgets | 12 | 5 | No |
| 15 | Crizotinib | Adults with previously treated anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) | After HTA | PCRS | 16 | 4 | Yes |
| 16 | Vandetanib | Aggressive and symptomatic medullary thyroid cancer (MTC) in patients with unresectable locally advanced or metastatic disease | Undocumented | PCRS | 11 | N/A | No |
| 17 | Brentuximab vedotin | Adults with relapsed or refractory CD30+ Hodgkin lymphoma (HL): following autologous stem cell transplant (ASCT) | After HTA | ODMS | 19 | 6 | Yes |
| 18 | Brentuximab vedotin | Adults with relapsed or refractory CD30+ Hodgkin lymphoma (HL): following at least two prior therapies when ASCT or multi-agent chemotherapy is not an option | Undocumented | ODMS | 19 | NA | Yes |
| 19 | Brentuximab vedotin | Adults with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL) | Undocumented | ODMS | 19 | NA | Yes |
| 20 | Enzalutamide | Adults with metastatic castration-resistant prostate cancer whose disease has progressed on or after docetaxel | After HTA | PCRS | 13 | 7 | Yes |
| 21 | Dabrafenib | Adults with unresectable or metastatic melanoma with the BRAF V600 mutation | At HTA | PCRS | 11 | 7 | No |
| 22 | Regorafenib | Adults unresectable or metastatic gastrointestinal stromal tumours (GIST) who progressed on or are intolerant to prior treatment with imatinib and sunitinib | Undocumented | PCRS | 6 | N/A | No |
| 23 | Regorafenib | Adults with metastatic colorectal cancer (mCRC) who have been previously treated with, or are not considered candidates for, available therapies. These include fluoropyrimidine-based chemotherapy, anti-VEGF and anti-EGFR therapies | After HTA | PCRS | 18 | 4 | No |
| 24 | Abiraterone | Metastatic castration resistant prostate cancer in men who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated | After HTA | PCRS | 27 | 5 | Yes |
| 25 | Radium 223 | Adults with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastases | After HTA | ODMS | 16 | 7 | Yes |
| 26 | Obinutuzumab | Combination with chlorambucil for adults with previously untreated chronic lymphocytic leukaemia (CLL) and with comorbidities making them unsuitable for full-dose fludarabine based therapy | After HTA | ODMS | 11 | 7 | Yes |
| 27 | Pixantrone | Monotherapy for adults with multiply relapsed or refractory aggressive Non-Hodgkin B-cell Lymphomas (NHL) | At RR | ODMS | 4 | N/A | No |
| 28 | Siltuximab | Adults with Multicentric Castleman’s disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpes virus 8 (HHV-8) negative | Undocumented | ODMS | N/A | NA | |
| 29 | Trastuzumab Emtansine | Adults with HER2-positive, unresectable locally advanced or metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination. Patients should have either: received prior therapy for locally advanced or metastatic disease, or developed disease recurrence during or within 6 months of completing adjuvant therapy | After HTA | ODMS | 21 | 5 | Yes |
| 30 | Enzalutamide | Metastatic castrate resistant prostate cancer in men who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy (ADT) in whom chemotherapy is not yet clinically indicated | After HTA | PCRS | 12 | 7 | Yes |
| 31 | Lenvatinib | Adults with progressive, locally advanced or metastatic, differentiated (papillary/follicular/Hürthle cell) thyroid carcinoma (DTC), refractory to radioactive iodine | Undocumented | PCRS | 6 | N/A | No |
| 32 | Nab-Paclitaxel | Combination with gemcitabine for the first-line treatment of adults with metastatic adenocarcinoma of the pancreas | After HTA | ODMS | 23 | 5 | Yes |
| 33 | Pomalidomide | Combination with dexamethasone for adults with relapsed and refractory multiple myeloma who have received at least two prior treatment regimens, including both lenalidomide and bortezomib, and have demonstrated disease progression on the last therapy | After HTA | PCRS | 28 | 6 | Yes |
| 34 | Pembrolizumab 200/400 mg | First line monotherapy for advanced (unresectable or metastatic) melanoma in adults | At HTA | ODMS | 10 | 6 | No |
| 35 | Pembrolizumab 200/400 mg | Ipilimumab‐refractory patients with unresectable or advanced metastatic melanoma | After HTA | ODMS | 10 | 5 | Yes |
| 36 | Ibrutinib | Adults with relapsed or refractory mantle cell lymphoma | After HTA | PCRS | 19 | 6 | Yes |
| 37 | Ibrutinib | Adults with Waldenström’s macroglobulinaemia who have received at least one prior therapy, or in first line treatment for patients unsuitable for chemo‐immunotherapy | Undocumented | PCRS | N/A | N/A | NA |
| 38 | Ibrutinib | Adults with chronic lymphocytic leukaemia who have received at least one prior therapy, or in first line in the presence of 17p deletion or TP53 mutation in patients unsuitable for chemo‐immunotherapy | After HTA | PCRS | 19 | 6 | Yes |
| 39 | Ceritinib | Adults with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) previously treated with crizotinib | After RR | PCRS | 16 | N/A | Yes |
| 40 | Ponatinib | Adults with Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph + ALL) who are resistant to dasatinib; who are intolerant to dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation | After HTA | PCRS | 36 | 7 | No |
| 41 | Ponatinib | Adults with chronic phase chronic myeloid leukaemia (CML) who are resistant to dasatinib or nilotinib; who are intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation | After HTA | PCRS | 36 | 7 | No |
| 42 | Ponatinib | Adults with accelerated phase chronic myeloid leukaemia (CML) who are resistant to dasatinib or nilotinib; who are intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation | After HTA | PCRS | 36 | 7 | No |
| 43 | Ponatinib | Adults with blast phase chronic myeloid leukaemia (CML) who are resistant to dasatinib or nilotinib; who are intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation | After HTA | PCRS | 36 | 7 | No |
| 44 | Idelalisib | Monotherapy for adults with follicular lymphoma (FL) that is refractory to two prior lines of treatment | Undocumented | PCRS | N/A | N/A | NA |
| 45 | Idelalisib | Combination with riTUXimab for adults with chronic lymphocytic leukaemia (CLL) who have received at least one prior therapy | After HTA | PCRS | 24 | 8 | Yes |
| 46 | Idelalisib | Combination with riTUXimab for adults with chronic lymphocytic leukaemia (CLL) as first line treatment in the presence of 17p deletion or TP53 mutation in patients who are not eligible for any other therapies | After HTA | PCRS | 24 | 8 | Yes |
| 47 | Idelalisib | Combination with Ofatumumab for adults with chronic lymphocytic leukaemia (CLL) who have received at least one prior therapy | Undocumented | PCRS | N/A | N/A | NA |
| 48 | Idelalisib | Combination with Ofatumumab for adults with chronic lymphocytic leukaemia (CLL) as first line treatment in the presence of 17p deletion or TP53 mutation in patients who are not eligible for any other therapies | Undocumented | PCRS | N/A | N/A | NA |
| 49 | Nintedanib | Combination with docetaxel for adults with locally advanced, metastatic of stage IIIB or IV, or locally recurrent NSCLC of adenocarcinoma tumour histology after first-line chemotherapy | After HTA | PCRS | 24 | 5 | Yes |
| 50 | Trifluridine and Tipracil | Adults with metastatic colorectal cancer (CRC) who have been previously treated with, or are not considered candidates for, available therapies including fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-VEGF agents, and anti-EGFR agents | After RR | PCRS | 7 | N/A | No |
| 51 | Nivolumab 240 mg | Monotherapy for adults with relapsed or refractory classical Hodgkin lymphoma (cHL) after autologous stem cell transplant (ASCT) and treatment with brentuximab vedotin | After RR | ODMS | 8 | N/A | Yes |
| 52 | Nivolumab 240/480 mg | As monotherapy for advanced (unresectable or metastatic) melanoma in adults (BRAF positive) | After HTA | ODMS | 27 | 6 | Yes |
| 53 | Nivolumab 240/480 mg | Monotherapy for advanced (unresectable or metastatic) melanoma in adults (BRAF negative) | After HTA | ODMS | 27 | 6 | Yes |
| 54 | Nivolumab 240/480 mg | Monotherapy for advanced renal cell carcinoma (RCC) after prior therapy in adults | After HTA | ODMS | 17 | 7 | Yes |
| 55 | Nivolumab Ipilimumab | Combination with ipilimumab for advanced (unresectable or metastatic) melanoma in adults | After HTA | ODMS | 11 | 8 | Yes |
| 56 | Alectinib | Adults with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) previously treated with crizotinib | After HTA | PCRS | 8 | 7 | Yes |
| 57 | Obinutuzumab | Combination with bendamustine for patients with follicular lymphoma (FL) who did not respond or who progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen | After HTA | ODMS | 17 | 5 | Yes |
| Maintenance therapy in patients with follicular lymphoma (FL) who have responded to induction treatment with obinutuzumab and bendamustine or have stable disease | |||||||
| 58 | Olaparib | Maintenance treatment of adults with platinum-sensitive relapsed BRCA-mutated (germline and/or somatic)—fallopian tube cancer who are in response (complete response or partial response) to platinum-based chemotherapy | After HTA | PCRS | 32 | 5 | Yes |
| Maintenance treatment of adults with platinum-sensitive relapsed BRCA-mutated (germline and/or somatic)—high-grade serous epithelial ovarian cancer who are in response (complete response or partial response) to platinum-based chemotherapy | |||||||
| Maintenance treatment of adults with platinum-sensitive relapsed BRCA-mutated (germline and/or somatic)—primary peritoneal cancer who are in response (complete response or partial response) to platinum-based chemotherapy | |||||||
| 59 | Vismodegib | Adults with local advanced basal cell carcinoma inappropriate for surgery or radiotherapy | After HTA | PCRS | 53 | 5 | Yes |
| 60 | Vismodegib | Adults with symptomatic metastatic basal cell carcinoma (MBCC) | After HTA | PCRS | 53 | 5 | Yes |
| 61 | Cobimetinib | Combination with vemurafenib for adults with unresectable or metastatic melanoma with a BRAF V600 mutation | After HTA | PCRS | 23 | 6 | Yes |
| 62 | Daratumumab | Monotherapy for adults with relapsed and refractory multiple myeloma whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on the last therapy | After HTA | ODMS | 22 | 6 | Yes |
| 63 | Pembrolizumab 200 mg/400 mg | First-line for metastatic non-small cell lung carcinoma (NSCLC) in adults whose tumours express PD-L1 with a ≥ 50% tumour proportion score (TPS) with no EGFR or ALK positive tumour mutations | After HTA | ODMS | 15 | 6 | Yes |
| 64 | Trametinib | Combination with dabrafenib for adults with unresectable or metastatic melanoma with a BRAF V600 mutation | After HTA | PCRS | 27 | 6 | Yes |
| 65 | Nivolumab | Monotherapy for squamous cell cancer of the head and neck in adults progressing on or after platinum-based therapy | After RR | ODMS | 11 | N/A | Yes |
| 66 | Palbociclib | Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer in combination with fulvestrant in women who have received prior endocrine therapy (2nd line) | After HTA | PCRS | 20 | 6 | Yes |
| 67 | Palbociclib | Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer in combination with an aromatase inhibitor (1st line) | After HTA | PCRS | 20 | 6 | Yes |
| 68 | Carfilzomib | Carlfilzomib, lenalidomide and dexamethasone for adults with multiple myeloma who have received at least one pror therapy | After HTA | ODMS | 32 | 6 | Yes |
| 69 | Nivolumab | Monotherapy for locally advanced or metastatic non-small cell lung cancer (NSCLC) after prior chemotherapy in adults | After HTA | ODMS | 38 | 6 | Yes |
| 70 | Pembrolizumab 200 mg/400 mg | Monotherapy for adults with relapsed or refractory classical Hodgkin lymphoma (cHL) who are transplant-ineligible and have failed brentuximab vedotin | After RR | ODMS | 10 | N/A | Yes |
| 71 | Ixazomib | Combination with lenalidomide and dexamethasone for adults with multiple myeloma who have received at least one prior therapy | After HTA | PCRS | 23 | 8 | Yes |
| 72 | Venetoclax | Chronic lymphocytic leukaemia in the absence of 17p deletion or TP53 mutation in adults who have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor | After RR | PCRS | 22 | N/A | Yes |
| 73 | Venetoclax | Chronic lymphocytic leukaemia in the presence of 17p deletion or TP53 mutation in adults who are unsuitable for or have failed a B-cell receptor pathway inhibitor | After RR | PCRS | 22 | N/A | Yes |
| 74 | Cabozantinib | Advanced renal cell carcinoma in adults following prior VEGF targeted therapy | After HTA | PCRS | 20 | 8 | Yes |
| 75 | Ribociclib | Postmenopausal women with hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative locally advanced or metastatic breast cancer as initial endocrine-based therapy in combination with an aromatase inhibitor | after HTA | PCRS | 16 | 6 | Yes |
| 76 | Atezolizumab | Adults with locally advanced or metastatic non-small cell lung cancer after prior chemotherapy | After HTA | ODMS | 17 | 5 | Yes |
| 77 | Avelumab | Adults with metastatic Merkel cell carcinoma who have received 1 or more lines of chemotherapy for metastatic disease (1st line) | After HTA | ODMS | 17 | 7 | Yes |
| 78 | Avelumab | Adult with metastatic Merkel cell carcinoma who have received 1 or more lines of chemotherapy for metastatic disease (2nd line) | After HTA | ODMS | 17 | 7 | Yes |
| 79 | Blinatumomab | Adults with relapsed or refractory B cell precursor (BCP) Philadelphia chromosome negative acute lymphoblastic leukaemia (ALL) who have received no prior salvage treatment for relapsed/refractory disease and are considered eligible for transplant | After HTA | ODMS | 40 | 5 | Yes |
| 80 | Blinatumomab | Paediatric patients aged 1 year and older with Philadelphia chromosome negative B-cell precursor ALL which is refractory or in relapse after receiving at least two prior therapies or in relapse after receiving prior allogeneic hematopoietic stem cell transplantation | After RR | ODMS | 3 | N/A | Yes |
| 81 | Encorafenib and Binimetinib | Adults with advanced (unresectable or metastatic) melanoma with a BRAF V600 mutation | After RR | PCRS | 3 | N/A | Yes |
| 82 | Inotuzumab | Monotherapy for adults with relapsed or refractory CD22-positive B cell precursor acute lymphoblastic leukaemia (ALL). Adults with Philadelphia chromosome positive (Ph+) relapsed or refractory B cell precursor ALL should have failed treatment with at least 1 tyrosine kinase inhibitor (TKI) | After HTA | ODMS | 20 | 6 | Yes |
| 83 | Obinutuzumab | Combination with chemotherapy, followed by maintenance treatment in patients achieving a response, for previously untreated advanced follicular lymphoma (FL) | After HTA | ODMS | 20 | 6 | Yes |
| 84 | Alectinib | As monotherapy is indicated for the first-line treatment of adults with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) | After HTA | PCRS | 18 | 7 | Yes |
| 85 | Brigatinib | Adults with anaplastic lymphoma kinase (ALK) positive advanced non-small cell lung cancer (NSCLC) previously treated with crizotinib | After RR | PCRS | 6 | N/A | Yes |
| 86 | Lorlatinib | Monotherapy for adults with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC), following disease progression on (i) alectinib or ceritinib as the first ALK-targeted treatment or (ii) crizotinib and at least one other ALK-targeted treatment | After RR | PCRS | 3 | N/A | Yes |
| 87 | Tivozanib | First line for adults with advanced renal cell carcinoma (RCC) and for adults who are VEGFR and mTOR pathway inhibitor-naïve following disease progression after one prior treatment with cytokine therapy for advanced RCC | After RR | PCRS | 8 | N/A | Yes |
| 88 | Dacomitinib | Dacomitinib (Vizimpro®) as monotherapy, for the first-line treatment of adults with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR)-activating mutations | After RR | PCRS | 6 | N/A | Yes |
| 89 | Osimertinib | Adults with locally advanced or metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC) | After HTA | PCRS | 23 | 5 | Yes |
| 90 | Pertuzumab | Pertuzumab in combination with trastuzumab and chemotherapy for the neoadjuvant treatment of adults with HER2-positive, locally advanced, inflammatory, or early stage breast cancer at high risk of recurrence | After HTA | ODMS | 25 | 8 | No |
| 91 | Venetoclax | Combination with rituximab for adults with chronic lymphocytic leukaemia (CLL) who have received at least one prior therapy | After HTA | PCRS | 21 | 8 | Yes |
Table 7.
Available cost-effectiveness evidence
| Pair number | Drug name | Indication | Basecase ICER | Costs and effects reported for all strategies | Incremental costs, € | Incremental effects, QALYs | Gross 5-year budget impact, €M |
|---|---|---|---|---|---|---|---|
| 1 | Ipilimumab | Adults with advanced (unresectable or metastatic) malignant melanoma | 147,899 | None | NA | NA | 6.75 |
| 2 | Abiraterone | Metastatic castration resistant prostate cancer which has progressed on or after a docetaxel-based chemotherapy regimen | 160,388 | None | NA | NA | 9.84 |
| 5 | Cabazitaxel | Metastatic castration resistant prostate cancer previously treated with docetaxel containing regimen | 120,084 | None | NA | NA | 5.60 |
| 7 | Vemurafenib | Adults with BRAF V600 mutation-positive unresectable or metastatic melanoma | 131,883 | None | NA | NA | 12.10 |
| 11 | Eribulin | LABC or MBC which has progressed after at least two chemotherapeutic regimens for advanced disease. Prior therapy should have included an anthracycline and a taxane unless patients were not suitable for these treatments | 76,610 | None | NA | NA | 5.40 |
| 12 | Pertuzumab | Adults with HER2-positive MBC or locally recurrent unresectable breast cancer, who have not received previous anti-HER2 therapy or chemotherapy for their metastatic disease | 206,720 | None | NA | NA | 39.37 |
| 13 | Ruxolitinib | Disease-related splenomegaly or symptoms in adults with post polycythaemia vera myelofibrosis | 70,252 | All | 84,292 | 1.20 | NA |
| Disease-related splenomegaly or symptoms in adults with primary myelofibrosis (chronic idiopathic myelofibrosis) | |||||||
| Disease-related splenomegaly or symptoms in adults with post essential thrombocythaemia myelofibrosis | |||||||
| 14 | Aflibercept | Combination with irinotecan/5-fluorouracil/folinic acid (FOLFIRI) chemotherapy in adults with metastatic colorectal cancer that is resistant to or has progressed after an oxoliplatin-containing regimen | 64,132 | All | 15,410 | 0.24 | 5.94 |
| 15 | Crizotinib | Adults with previously treated anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) | 165,616 | Some | 41,690 | 0.25 | 6.28 |
| 17 | Brentuximab vedotin | Adults with relapsed or refractory CD30+ Hodgkin lymphoma (HL): following autologous stem cell transplant (ASCT) | 78,106 | Some | 85,786 | 1.10 | 5.53 |
| 20 | Enzalutamide | Adults with metastatic castration-resistant prostate cancer whose disease has progressed on or after docetaxel | 98,949 | None | NA | NA | NA |
| 21 | Dabrafenib | Adults with unresectable or metastatic melanoma with the BRAF V600 mutation | 84,473 | Some | 113,613 | 1.35 | 7.10 |
| 23 | Regorafenib | Adults with metastatic colorectal cancer (mCRC) who have been previously treated with, or are not considered candidates for, available therapies. These include fluoropyrimidine-based chemotherapy, anti-VEGF and anti-EGFR therapies | 126,246 | All | 12,653 | 0.10 | 4.00 |
| 24 | Abiraterone | Metastatic castration resistant prostate cancer in men who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated | 171,384 | Some | 85,466 | 0.50 | NA |
| 25 | Radium 223 | Adults with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastases | 80,361 | None | NA | NA | 5.90 |
| 26 | Obinutuzumab | Combination with chlorambucil for adults with previously untreated chronic lymphocytic leukaemia (CLL) and with comorbidities making them unsuitable for full-dose fludarabine based therapy | 67,409 | Some | 15,504 | 0.23 | 7.60 |
| 29 | Trastuzumab Emtansine | Adults with HER2-positive, unresectable locally advanced or metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination. Patients should have either: received prior therapy for locally advanced or metastatic disease, or developed disease recurrence during or within 6 months of completing adjuvant therapy | 98,809 | None | NA | NA | 19.74 |
| 30 | Enzalutamide | Metastatic castrate resistant prostate cancer in men who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy (ADT) in whom chemotherapy is not yet clinically indicated | 126,709 | All | 84,634 | 0.67 | 71.38 |
| 32 | Nab-Paclitaxel | Combination with gemcitabine for the first-line treatment of adults with metastatic adenocarcinoma of the pancreas | 73,867 | Some | 10,553 | 0.15 | 4.50 |
| 33 | Pomalidomide | Combination with dexamethasone for adults with relapsed and refractory multiple myeloma who have received at least two prior treatment regimens, including both lenalidomide and bortezomib, and have demonstrated disease progression on the last therapy | 102,485 | Some | 59,527 | 0.58 | 15.20 |
| 34 | Pembrolizumab 200/400 mg | First line monotherapy for advanced (unresectable or metastatic) melanoma in adults | Dominant | None | -3,092 | 0.42 | 63.00 |
| 35 | Pembrolizumab 200/400 mg | Ipilimumab‐refractory patients with unresectable or advanced metastatic melanoma | 85,766 | Some | 72,280 | 0.84 | 1.80 |
| 36 | Ibrutinib | Adults with relapsed or refractory mantle cell lymphoma | 89,931 | Some | 33,010 | 0.37 | 7.00 |
| 38 | Ibrutinib | Adults with chronic lymphocytic leukaemia who have received at least one prior therapy, or in first line in the presence of 17p deletion or TP53 mutation in patients unsuitable for chemo‐immunotherapy | 82,786 | Some | 243,725 | 2.94 | 32.00 |
| 40 | Ponatinib | Adults with Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph + ALL) who are resistant to dasatinib; who are intolerant to dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation | 42,000 | None | NA | NA | NA |
| 41 | Ponatinib | Adults with chronic phase chronic myeloid leukaemia (CML) who are resistant to dasatinib or nilotinib; who are intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation | 20,000 | None | NA | NA | NA |
| 42 | Ponatinib | Adults with accelerated phase chronic myeloid leukaemia (CML) who are resistant to dasatinib or nilotinib; who are intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation | Dominant | None | NA | NA | NA |
| 43 | Ponatinib | Adults with blast phase chronic myeloid leukaemia (CML) who are resistant to dasatinib or nilotinib; who are intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation | 20,000 | None | NA | NA | NA |
| 45 | Idelalisib | Combination with riTUXimab for adults with chronic lymphocytic leukaemia (CLL) who have received at least one prior therapy | 57,440 | All | 102,325 | 1.78 | 27.51 |
| 46 | Idelalisib | Combination with riTUXimab for adults with chronic lymphocytic leukaemia (CLL) as first line treatment in the presence of 17p deletion or TP53 mutation in patients who are not eligible for any other therapies | 71,388 | All | NA | NA | NA |
| 49 | Nintedanib | Combination with docetaxel for adults with locally advanced, metastatic of stage IIIB or IV, or locally recurrent NSCLC of adenocarcinoma tumour histology after first-line chemotherapy | 72,751 | None | NA | NA | 0.22 |
| 52 | Nivolumab 240/480 mg | As monotherapy for advanced (unresectable or metastatic) melanoma in adults (BRAF positive) | 101,282 | None | NA | NA | 98.80 |
| 53 | Nivolumab 240/480 mg | Monotherapy for advanced (unresectable or metastatic) melanoma in adults (BRAF negative) | 76,540 | None | NA | NA | |
| 54 | Nivolumab 240/480 mg | Monotherapy for advanced renal cell carcinoma (RCC) after prior therapy in adults | 55,864 | All | 63,110 | 1.44 | 26.73 |
| 55 | Nivolumab Ipilimumab | Combination with ipilimumab for advanced (unresectable or metastatic) melanoma in adults | 47,748 | Some | 101,354 | 2.12 | 61.00 |
| 56 | Alectinib | Adults with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) previously treated with crizotinib | 178,358 | Some | 99,169 | 0.56 | 13.60 |
| 57 | Obinutuzumab | Combination with bendamustine for patients with follicular lymphoma (FL) who did not respond or who progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen | 52,248 | Some | 60,142 | 1.15 | 6.15 |
| Maintenance therapy in patients with follicular lymphoma (FL) who have responded to induction treatment with obinutuzumab and bendamustine or have stable disease | |||||||
| 58 | Olaparib | Maintenance treatment of adults with platinum-sensitive relapsed BRCA-mutated (germline and/or somatic)—fallopian tube cancer who are in response (complete response or partial response) to platinum-based chemotherapy | 111,248 | All | 93,447 | 0.84 | 4.86 |
| Maintenance treatment of adults with platinum-sensitive relapsed BRCA-mutated (germline and/or somatic)—high-grade serous epithelial ovarian cancer who are in response (complete response or partial response) to platinum-based chemotherapy | |||||||
| Maintenance treatment of adults with platinum-sensitive relapsed BRCA-mutated (germline and/or somatic)—primary peritoneal cancer who are in response (complete response or partial response) to platinum-based chemotherapy | |||||||
| 59 | Vismodegib | Adults with local advanced basal cell carcinoma inappropriate for surgery or radiotherapy | 556,657 | None | NA | NA | NA |
| 60 | Vismodegib | Adults with symptomatic metastatic basal cell carcinoma (MBCC) | 240,902 | None | NA | NA | NA |
| 61 | Cobimetinib | Combination with vemurafenib for adults with unresectable or metastatic melanoma with a BRAF V600 mutation | 326,868 | Some | 168,266 | 0.51 | 22.10 |
| 62 | Daratumumab | Monotherapy for adults with relapsed and refractory multiple myeloma whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on the last therapy | 127,785 | None | 39,334 | 0.31 | 17.60 |
| 63 | Pembrolizumab 200 mg/400 mg | First-line for metastatic non-small cell lung carcinoma (NSCLC) in adults whose tumours express PD-L1 with a ≥ 50% tumour proportion score (TPS) with no EGFR or ALK positive tumour mutations | 96,376 | Some | 105,811 | 1.10 | 65.30 |
| 64 | Trametinib | Combination with dabrafenib for adults with unresectable or metastatic melanoma with a BRAF V600 mutation | 244,822 | Some | 182,417 | 0.75 | 24.80 |
| 66 | Palbociclib | Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer in combination with fulvestrant in women who have received prior endocrine therapy (2nd line) | 256,993 | Some | 63,306 | 0.25 | 78.64 |
| 67 | Palbociclib | Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer in combination with an aromatase inhibitor (1st line) | 217,312 | Some | 116,925 | 0.54 | |
| 68 | Carfilzomib | Carlfilzomib, lenalidomide and dexamethasone for adults with multiple myeloma who have received at least one pror therapy | 125,759 | Some | 107,801 | 0.86 | 26.40 |
| 69 | Nivolumab | Monotherapy for locally advanced or metastatic non-small cell lung cancer (NSCLC) after prior chemotherapy in adults | 202,393 | Some | 88,117 | 0.44 | 57.10 |
| 71 | Ixazomib | Combination with lenalidomide and dexamethasone for adults with multiple myeloma who have received at least one prior therapy | 703,426 | Some | NA | NA | 39.30 |
| 74 | Cabozantinib | Advanced renal cell carcinoma in adults following prior VEGF targeted therapy | 208,156 | Some | 68,960 | 0.33 | 16.30 |
| 75 | Ribociclib | Postmenopausal women with hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative locally advanced or metastatic breast cancer as initial endocrine-based therapy in combination with an aromatase inhibitor | 220,591 | All | 41,816 | 0.14 | 16.02 |
| 76 | Atezolizumab | Adults with locally advanced or metastatic non-small cell lung cancer after prior chemotherapy | 152,458 | Some | 60,710 | 0.40 | 38.73 |
| 77 | Avelumab | Adults with metastatic Merkel cell carcinoma who have received 1 or more lines of chemotherapy for metastatic disease (1st line) | 130,984 | Some | 82,319 | 1.40 | 2.10 |
| 78 | Avelumab | Adult with metastatic Merkel cell carcinoma who have received 1 or more lines of chemotherapy for metastatic disease (2nd line) | 54,540 | Some | 77,213 | 1.84 | |
| 79 | Blinatumomab | Adults with relapsed or refractory B cell precursor (BCP) Philadelphia chromosome negative acute lymphoblastic leukaemia (ALL) who have received no prior salvage treatment for relapsed/refractory disease and are considered eligible for transplant | 472,215 | Some | 104,693 | 0.22 | 9.20 |
| 82 | Inotuzumab | Monotherapy for adults with relapsed or refractory CD22-positive B cell precursor acute lymphoblastic leukaemia (ALL). Adults with Philadelphia chromosome positive (Ph +) relapsed or refractory B cell precursor ALL should have failed treatment with at least 1 tyrosine kinase inhibitor (TKI) | 68,568 | Some | 84,064 | 1.23 | 5.82 |
| 83 | Obinutuzumab | Combination with chemotherapy, followed by maintenance treatment in patients achieving a response, for previously untreated advanced follicular lymphoma (FL) | 95,606 | Some | 43,809 | 0.46 | 29.10 |
| 84 | Alectinib | As monotherapy is indicated for the first-line treatment of adults with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) | 146,721 | Some | 98,979 | 0.67 | 13.60 |
| 89 | Osimertinib | Adults with locally advanced or metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC) | 115,912 | All | 78,556 | 0.68 | 50.23 |
| 90 | Pertuzumab | Pertuzumab in combination with trastuzumab and chemotherapy for the neoadjuvant treatment of adults with HER2-positive, locally advanced, inflammatory, or early stage breast cancer at high risk of recurrence | 75,400 | All | 40,734 | 0.54 | 52.36 |
| 91 | Venetoclax | Combination with rituximab for adults with chronic lymphocytic leukaemia (CLL) who have received at least one prior therapy | 96,130 | Some | 120,024 | 1.25 | 42.00 |
Table 8.
Number of approvals and reported 5-year gross budget impact by market authorisation holder
| Market authorisation holder | Approvals, n | 5-year gross budget impact, €M |
|---|---|---|
| Roche | 13 | 254.5 |
| Bristol-Myers Squibb | 8 | 250.4 |
| Janssen-Cilag | 8 | 66.4 |
| Pfizer | 7 | 90.7 |
| Takeda | 6 | 44.8 |
| Gilead | 5 | 27.5 |
| Novartis | 5 | 47.9 |
| Bayer | 4 | 15.8 |
| Incyte | 4 | NA |
| Merck Sharp & Dohme | 4 | 130.1 |
| AbbVie | 3 | 42.0 |
| Amgen | 3 | 35.6 |
| Les Laboratoires Servier | 3 | NA |
| Astellas | 2 | 71.4 |
| AstraZeneca | 2 | 55.1 |
| Boehringer Ingelheim | 2 | 0.2 |
| Celgene | 2 | 19.7 |
| Eisai | 2 | 5.4 |
| Merck | 2 | 2.1 |
| EUSA Pharma | 1 | NA |
| Genzyme | 1 | NA |
| Ipsen | 1 | 16.3 |
| Nordic Group | 1 | NA |
| Pierre Fabre Médicament | 1 | NA |
| Sanofi-Aventis | 1 | 5.6 |
| Total | 91 | 1181.6 |
The NCCP list of approved cancer therapies contained 77 drugs, drug combinations or distinct drug dosages as approved between May 2012 and July 2020. Following the separation and merging of indications described in the methods, there are 91 drug-indication pairs in total. While most drugs only have one approved indication, the four most commonly approved drugs (including combination therapies) are nivolumab, idelalisib, ponatinib and pembrolizumab with 7, 5, 4 and 4 approved indications, respectively. The NCPE website reports reimbursement was made following post-appraisal price negotiations in 65 of the 91 drug-indication pairs.
NCPE HTA summaries are only published for drug-indication pairs subject to full HTA review. There were 61 pairs with published HTA summaries available. The summaries range from 3 to 8 pages long, have a mean length of approximately 6 pages and have increased in length modestly over the period assessed.
We found 8 pairs for which there is no clear record of a cost-effectiveness appraisal on the NCPE website, either RR or full HTA. There was no mention of siltuximab (pair 28) on the NCPE website at all at the time of analysis. In the remaining 7 cases (pairs 18, 19, 22, 37, 44, 47 and 48), there were records of the drugs, but not for the indications in question.
While there were 61 pairs with HTA summaries, not all reported health economic outcomes. ICERs or an outcome of dominance were reported in all 61, but relevant incremental costs and QALYs were only reported in 41 summaries. There were 48 summaries that reported the 5-year gross budget impact, yielding a total of €1.2Bn. As gross budget impact does not account for possible substitutions of older therapies by new drugs in the same indication, the €1.2Bn total will exceed the net budget impact at the list prices on application. There were a further 8 studies that reported a 1-year budget impact.
We assessed the sample of pairs for which HTA summaries are available to assess how the completeness of data changed over time. In particular, we assessed what proportion of the sample included any two or more of an estimate of incremental costs, incremental QALYs or a 5-year budget impact (either gross or net). Dividing the sample in two chronologically according to the date of completion of the NCPE HTA review, 52% of the sample included any two or more data items for the first half of the sample, rising to 77% for the second half of the sample. While only a crude measure, this indicates that the completeness of reporting of cost-effectiveness data within the NCPE HTA summaries has increased over time.
Figure 1 shows a correlation matrix of a selection of data from this analysis compiled with a series of histograms on the diagonal. The bars in the histogram and the points in the scatter plots shaded light grey correspond to approvals following a full HTA, those in dark grey correspond to approvals without full HTA. The sample size in each plot varies as the number of available data points varies (given as n in each plot). The first histogram shows the distribution of approvals over time. The first approval listed by the NCCP is in May 2012 and the most recent in July 2020. While there is no distinct trend in approvals, clearly more have been approved annually from between 2016 and 2019 than earlier in the sample. Although the number of approvals without requiring full HTA has been few, the number increased in 2018 and 2019.
Fig. 1.
Correlation matrix of selected metrics of appraisal. *Total time between initial listing on the NCPE website and listing by the NCCP as approved
Table 1 summarises at what stage of the HTA appraisal process had a drug reached prior to approval and under what funding pathway was the drug reimbursed. The table also details the time taken to reimburse in months. Of the 91 pairs, 3 were recommended for consideration at RR and subsequently approved. A further 19 were subsequently approved following a RR, but without progressing to full HTA. In these cases, a recommendation for consideration for reimbursement was not made at RR, but it appears subsequent negotiation avoided the need for a full HTA, even if recommended by the NCPE. Similarly, there were 3 and 58 recommendations at or after the full HTA stage, respectively. The three pairs recommended for consideration at HTA were aflibercept, dabrafenib and pembrolizumab as first line monotherapy for melanoma (pairs 14, 21, 34, respectively). This indicates that only a small minority of applications are considered sufficiently cost-effective to recommend consideration for reimbursement at the full HTA stage and most required further negotiation before they could progress to subsequent approval.
Table 1.
Reimbursement time according to appraisal pathways and funding stream
| Drug-indication pairs, n | Mean time taken to reimbursea, months | |
|---|---|---|
| Appraisal pathway | ||
| At RR | 3 | 6 |
| After RR | 19 | 10 |
| At HTA | 3 | 11 |
| After HTA | 58 | 22 |
| Undocumented | 8 | NA |
| Total | 91 | 18 |
| Funding stream | ||
| PCRS | 53 | 19 |
| ODMS | 37 | 18 |
| Individual hospital budgets | 1 | 12 |
| Total | 91 | 18 |
aTotal time between initial listing on the NCPE website and listing by the NCCP as approved
The overall mean time taken from application to reimbursement is 18 months. The mean reimbursement time appears shorter under RR than full HTA. Similarly, the reimbursement time for those pairs approved following post-HTA negotiations is longer than those at the other appraisal stages. The second histogram in Fig. 1 shows that most approvals are made in less than 24 months, but there are some outliers at over 4 years. The distribution of RR approvals is shown in dark grey, most of which are within 12 months. As mentioned in the methods, the total time to reimbursement assessed here is not synonymous with the time taken to appraise a given intervention, a detailed description and examination of which in an Irish context is given by Connolly et al. [3].
Somewhat over half of the approved drug-indication pairs are reimbursed under the PCRS. Only one pair (14—aflibercept) was listed for funding by individual hospital budgets. The remaining approvals were under the ODMS. There is no apparent difference in the reimbursement time between PCRS and ODMS funded drugs.
Table 2 summarises the approved pairs according to their therapeutic class and mechanism of action and contains aggregate estimates of budget impact, incremental costs and QALYs and ICERs from the HTA summaries. Lymphomas, leukaemias and lung cancer are the top three disease categories by number of approvals. They count for half of all approvals between them. Of the total approved indications, 48 included metastatic disease. Regarding the therapeutic categories, protein kinase inhibitors and monoclonal antibodies are the two notably large groups, accounting for two thirds of all approvals. At the time of investigation, 11 pairs held positive orphan status.
Table 2.
Health economic outcomes by disease and treatment characteristics
| Drug-indication pairs, n | Total 5-year gross budget impact, €M | Mean 5-year gross budget impact, €M | Mean incremental costs, € | Mean incremental effects, QALYs | Mean ICERs, €/QALY | |
|---|---|---|---|---|---|---|
| Disease category | ||||||
| Breast | 7 | 212 | 35 | 65,695 | 0.37 | 164,634 |
| Digestive organs | 6 | 14 | 5 | 12,872 | 0.16 | 88,082 |
| Kidney | 4 | 43 | 22 | 66,035 | 0.89 | 132,010 |
| Lung | 13 | 245 | 35 | 81,862 | 0.59 | 141,323 |
| Prostate | 6 | 93 | 23 | 85,050 | 0.58 | 126,313 |
| Skin | 15 | 300 | 30 | 99,296 | 1.15 | 171,566 |
| Leukaemias | 18 | 124 | 21 | 111,723 | 1.27 | 99,794 |
| Lymphomas | 9 | 48 | 12 | 55,687 | 0.77 | 78,973 |
| Other blood cancers | 6 | 99 | 25 | 68,887 | 0.58 | 264,864 |
| Other | 7 | 5 | 5 | 88,870 | 1.02 | 90,750 |
| Total | 91 | 1182 | 25 | 79,231 | 0.80 | 141,393 |
| Metastatic disease | 48 | 820 | 29 | 76,836 | 0.74 | 128,288 |
| Therapeutic category | ||||||
| Antimetabolites, plant alkaloids, cytotoxic antibiotic and related substances | 6 | 10 | 5 | 10,553 | 0.15 | 96,976 |
| Immunomodulating agents and other non-antineoplastic therapies | 9 | 108 | 22 | 61,259 | 0.50 | 114,915 |
| Monoclonal antibodies | 28 | 614 | 31 | 65,993 | 0.90 | 118,796 |
| Protein kinase inhibitors | 34 | 304 | 22 | 96,492 | 0.71 | 141,084 |
| Other antineoplastic agents | 14 | 145 | 24 | 105,899 | 1.18 | 226,618 |
| Total | 91 | 1182 | 25 | 79,231 | 0.80 | 141,598 |
| Orphan status | 11 | 114 | 16 | 86,248 | 0.88 | 141,773 |
The number of approvals in the reported disease and therapeutic categories is small in many cases. Accordingly, it is important not to over-interpret the estimates disaggregated by category. The three largest disease categories in terms of gross budget impact were skin, lung and breast cancer, which together account for almost two thirds of the total. Naturally, the total budget impact depends in part on the number of approvals, so we also present the mean budget impact per approval within each category. While the disparities in mean budget impact are smaller, the same three categories still carry the three largest budget impacts. These mean figures still reflect, in part, the anticipated patient population size within each category. The mean incremental cost provides a per-patient estimate of the discounted net incremental cost of care and, therefore, does not reflect the size of the indications. On this basis, skin, lung and breast cancer do not appear notably different from the others. Similar conclusions apply to the therapeutic categories, in that the very large total budget impact of monoclonal antibodies and protein kinase inhibitors appear largely to reflect the number of approvals as the mean budget impact and incremental costs much more aligned with the overall means. While the mean budget impact of metastatic disease is effectively the same as the overall mean, orphan treatments appear to have a lower mean budget impact.
The third histogram shown in Fig. 1 shows the heavily right skewed distribution of 5-year gross budget impact, with clear mode between €5–10 M. Almost 60% of approvals have an estimated 5-year gross budget impact less than €20 M, while approximately 20% have a budget impact greater than €40 M.
Table 3 reports selected findings from the analysis including aggregated outcomes. The range of incremental health gains reported is 0.10 to 2.94 QALYs, with an unweighted mean of 0.80. An unweighted mean of the reported ICERs is €141,598/QALY. The estimated weighted mean intervention cost, QALY gains and resulting aggregate ICER when weighting according to the gross 5-year budget impact are €85,164, 0.85 and €100,295/QALY, respectively. Note that the unweighted and weighted ICERs differ in part because not all HTA summaries report budget impact or costs and QALYs, so the weighted values are based on fewer studies (the unweighted mean ICER from pairs used to determine the weighted aggregate ICER is 133,843/QALY, which is less than the overall unweighted mean). The distribution of incremental health effects in Fig. 1 shows most are below 0.75 QALYs, but only very few exceed 1.5 QALYs. The distribution of ICERs shown in Fig. 1 shows few below the €45,000/QALY threshold, a cluster between 2 and 3 times the threshold and several very high outliers. Overall, of the 61 drug-indication pairs for which full HTA summaries are available 5 (8%) either have ICERs within Ireland’s threshold or are more effective and less costly than their comparators, while the remaining 56 (92%) have ICERs above the threshold.
Table 3.
Aggregate cost and effects estimates
| 5-year gross budget impact, €M | Incremental costs, € | Incremental health effects, QALYs | Basecase ICER, €/QALY | |
|---|---|---|---|---|
| Minimum | 0.22 | − 3092 | 0.10 | 20,000 |
| Maximum | 98.80 | 243,725 | 2.94 | 703,426 |
| Unweighted mean | 24.62 | 79,231 | 0.80 | 141,598 |
| Weighted mean | – | 85,164 | 0.85 | 100,295 |
Overall, the correlation plots indicate few notable relationships. There is a negative association between the QALYs gained and ICERs, but it is not pronounced. There may be some indication that the variance in appraisal duration, budget impact and ICERs are increasing over time (Table 3).
Discussion
We need to explicitly acknowledge this study's main limitation at the outset of the discussion, namely, that we only have access to the drug costs, budget impact and ICERs corresponding to the list prices on application for reimbursement, not the actual agreed prices paid following negotiation. The agreed prices will be lower than those on application in most cases, although by what margin we cannot know. Furthermore, the effective prices will also be lower due to rebates and risk sharing schemes.
The following discussion describes what is useful about the currently reported cost-effectiveness estimates. We then outline some of the inconsistencies and other reporting gaps we observed in the NCPE summaries. Finally, we consider the implications of constraints on complete reporting for accountability regarding resource allocation.
Usefulness of NCPE summaries
Although the list prices and ICERs published in the HTA summaries are not informative of actual resource allocation decisions, NCPE summary publications do still provide useful information. First, publishing evidence of ICERs breaching the threshold reveals the list prices sought by manufacturers will lead to aggregate net harm to the health system. We found that 92% of the drug indication pairs for which information was available were not cost-effective at the prices on application. This provides justification for the sometimes long negotiating periods required to agree prices. Moreover, the published ICERs give an indication of how much costs need to be moderated relative to those at list prices. The weighted aggregate ICER from our analysis of just over €100,000/QALY is more than twice the current threshold. We see that the additional total net costs of new cancer drugs at list prices need to be reduced, on aggregate, by more than half if reimbursement is not to represent an unfair and ethically questionable use of resources (assuming that the QALYs gained treating cancer are of equal value as those foregone by other patients). Indeed, that interpretation rests on the assumption the current €45,000/QALY threshold is a fair representation of the opportunity cost of other care in Ireland. Since it is arguably a substantial underestimate [29, 30], the additional total net costs would need to be very substantially less than half than those at list prices for new cancer drugs to avoid being net damaging to the Irish health system.
Another important benefit offered by the HTA summaries is that they provide evidence on other aspects of the HTA appraisal, such as the treatment comparisons considered, the size of anticipated health gains and some indication of the strength of evidence presented. Public discourse on novel drugs often features descriptions of "game changers", "breakthrough" treatments or other such terms [16, 17]. While of course some drugs may achieve complete remission in some patients, we believe it important the public appreciate that new cancer drugs approved in Ireland over nearly a decade will provide a mean of 0.85 QALYs; less than 1 year equivalent of good health. A sober assessment of the health gains offered by new treatments may inform a more balanced consideration of the choices between new drugs and the great many other interventions that the Irish health service struggles to provide timely access to [30].
Inconsistencies and reporting gaps
We noticed some inconsistent reporting within the NCPE HTA summaries. Budget impact was not reported on a consistent basis, as it was variously reported in gross or net terms and the timeframe varied between summaries. Similarly, the anticipated patient population size was not always reported. The incremental costs and QALYs were not reported in all summaries and were also not always reported for all strategies mentioned in the summaries, thus precluding comparisons between strategies other than those reported by the NCPE. Overall, however, while not formally assessed against any objective criteria, we consider the consistency of reporting to be high across the NCPE HTA summaries. Moreover, as noted in the results, we find the completeness of reporting of costs, QALYs and budget impact within the HTA summaries to have increased over time.
One specific issue we noticed within the HTA summaries was the reporting of multiple ICERs for a given strategy based on comparisons to multiple interventions. A narrow textbook interpretation of CEA would suggest that this is incorrect and that any given intervention should only have one ICER on the efficient frontier. Moreover, the reporting of multiple ICERs including those based on comparisons to dominated strategies could cause confusion to decision makers regarding an intervention's cost-effectiveness. In practice, there may often not be a single relevant comparator. The current standard of care may vary between patients and depend on clinical judgement. Accordingly, the reporting of multiple ICERs is not necessarily reason for concern.
While the choice of comparator may be context-dependent it still deserves scrutiny. We found only five drug-indication pairs that were either dominant or had ICERs within the threshold (pairs 34 and 40–43). In the example of pair 34 pembrolizumab was dominant relative to the comparator of ipilimumab which itself was previously found to be cost-ineffective. Accordingly, pembrolizumab would not have been found to be cost-effective had the previous approval not exceeded the cost-effectiveness threshold. Accepting comparisons against cost-ineffective comparators prompts concerns of a spiral of increasing cost-ineffectiveness. If decision makers permit cost-ineffective choices to accumulate on top of each other, this will result in ever less efficient treatment within each indication. Accordingly, there may need to be more critical examination of the treatment status quo.
The RR process is a pragmatic way to triage the analytical workload of assessing new interventions and avoiding a full HTA process. A drawback of the current RR process is that no summary information is published on interventions appraised under this pathway. It seems reasonable that at least some of the information considered at RR could be published.
A small proportion of drug-indication pairs have no corresponding NCPE record. While they are few and the indications may be narrow, it is nevertheless disconcerting that at least some approvals appear to have effectively bypassed the controls applied to other interventions.
Our conclusion regarding the availability of data is that the NCPE HTA summaries provide a largely consistent, if not fully complete record of the costs and QALYs of the interventions on application. While there are evidence gaps arising from the lack of any reporting for interventions approved following RR and some concerns about ICER estimates based on comparisons to cost-ineffective technologies, the largest concern remains the unavailability of agreed prices and ICERs on approval.
Implications for accountability
Withholding agreed prices because of commercial confidentiality is an understandable consequence of price negotiation between the State and manufacturers. This confidentiality is valuable to manufacturers for their negotiations in other markets [31]. Offering confidentiality to manufacturers may help decision makers secure savings for the State and is common practice in many countries [32, 33]. It is also suggested that price confidentiality might offer broader benefits in facilitating what is known as price discrimination, thereby permitting access to more countries on a pricing basis that reflects variation in ability to pay than would be achieved if common prices were paid by all nations [34]. A cost of such price confidentiality is compromised accountability regarding public health expenditure. Without actual agreed prices, there is no meaningful assessment that external parties can make of healthcare resources allocation, effectively protecting decision makers from scrutiny. This is concerning, as many interests including clinicians, patient advocacy groups, politicians and manufacturers will seek to call attention to the benefit of new treatments, while insufficient attention may be given to the countervailing costs to other patients.
The lack of meaningful accountability is particularly concerning given the mixed performance of Ireland’s healthcare system when compared internationally. Aspects of the Irish health system perform well, evidenced by rapid improvements in life expectancy and better than average performance in amenable mortality estimates relative to other EU nations [35]. Ireland also performs well on composite measures of health outcomes in general and on cancer mortality in particular [36]. Despite this, the Irish health system performs poorly in terms of access as it both lacks universal coverage and exhibits long waiting lists for elective care and has been ranked lowest out of 35 European nations with respect to waiting times [35, 36]. Indeed, the fact that the Irish health system provides demonstrably poor access to basic and cost-effective services is indicative that resources are not being used most efficiently [29].
A potential solution to this accountability problem would be the publication of some form of aggregated cost-effectiveness metrics based on reimbursed prices. The aggregated costs and QALYs presented in this analysis are an example of such reporting. The estimated incremental costs and QALYs aggregated over all interventions newly adopted each year could be published annually. Alternatively, it would be possible to publish the number of interventions reimbursed within intervals of multiples of the threshold as previously suggested by O’Mahony and Coughlan [29] and exemplified by the final histogram in Fig. 1 of this analysis. Either proposal would offer a degree of accountability regarding the allocation of health spending without revealing the agreed price paid for any given drug.
The above proposals would provide evidence of the effectiveness of current appraisal and price negotiation systems. It may be the case that current processes are highly effective at achieving value for money. The reporting proposal would give due credit without publishing confidential prices. Some may contend the onus should be on pharmaceutical manufacturers to be more transparent regarding the prices they charge. Indeed, the World Health Organisation has issued a resolution urging greater price transparency [37]. Despite this, we perceive the responsibility for compiling and publishing such analyses most naturally falls on public regulators rather than private commercial entities: in this case, that part of the decision-making process that is privy to the prices on reimbursement, namely, the HSE Drugs Group. While this manuscript has considered confidentiality regarding prices of cancer therapies, the same concerns and potential solutions apply to all drug spending.
We have already noted the primary limitation of this study, but there are others to acknowledge. We only assessed approved cancer drugs. Necessarily the analysis excludes drug-indication pairs that were assessed by the NCPE but ultimately rejected. Similarly, our analysis can only assess officially approved drugs and cannot appraise off-label use. Furthermore, the health economic outcomes extracted from the 61 pairs subject to HTA are not likely to be representative of the other interventions approved after RR, which will likely have both lower budget impact and ICERs on aggregate. In cases in which two budget impact estimates were published, we formed a point estimate by taking the mid-point between the published values. Such an estimate does not account for any possible skewness in costs. We have not conducted a statistical analysis of the outcomes recorded within our review, partly because the sample sizes within the disease and therapeutic categories are too small in most cases, but also because we consider the value of such an analysis questionable without access to the actual agreed prices. Our analysis reports the number of drug-indication combinations for which the NCPE record reimbursement was made following post-appraisal price negotiations. Given that the NCPE is not a party to such negotiations we do not know if the NCPE’s reporting of such negotiations is exhaustive or not.
Finally, a concluding note regarding data availability on agreed prices in Ireland. Like other research [24, 38], this analysis could only use list prices on application. Notably, a recent study investigating the potential of value of information analysis regarding cancer drugs in Ireland did have the benefit of access to confidential agreed prices [11]. Accordingly, there is precedent for the use of confidential pricing information in Ireland for research purposes.
Conclusion
To date there has been no single analysis of the cost-effectiveness of cancer drugs in Ireland. Our analysis shows that each new approval for which data is published yields approximately 0.85 QALYs on average. Appreciating the size of this health gain may provide the public with a more realistic expectation of new cancer therapies. The aggregate ICER on application of approximately €100,000/QALY indicates that the additional costs of new drugs relative to existing therapies would need to be more than halved for reimbursement at list prices to be a fair and ethically justifiable use of scarce health resources. While the current publication of HTA summaries by the NCPE provide much useful data, additional reporting is required to accommodate commercial confidentiality while delivering meaningful accountability regarding decision maker choices regarding drug spending in Ireland. The most suitable body to provide such reporting is the HSE Drugs Group.
Appendix
Author contributions
JOM conceived the research question. RG, CB, AB, and DK were responsible for the initial study design and data collection and manuscript drafting. NA, SA, SZ, SD, and NOR refined the data collection and revised the manuscript. Final oversight of the manuscript production was conducted by JOM.
Funding
Open Access funding provided by the IReL Consortium. This research received no specific funding. The corresponding author is supported by the Health Research Board (of Ireland) under grant number EIA-2017-054. No other authors were in receipt of grant funding.
Availability of data and materials
All of the data used in this study are already in the public domain.
Code availability
Not applicable.
Declarations
Conflict of interest
There are no conflict of interest to report.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
All of the data used in this study are already in the public domain.
Not applicable.