Cost-effectiveness evidence on approved cancer drugs in Ireland: the limits of data availability and implications for public accountability.

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.

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 reimburse a , 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 a Total 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.

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 ). 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

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

See Tables 4 , 5 , 6 , 7 , 8 . Table 4 Drug-indication pairs and data sources Pair number Drug name Indication NCCP URL a NCPE URL b 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 a NCCP URL stem: https://www.hse.ie/eng/services/list/5/cancer/profinfo/chemoprotocols b NCPE 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

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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.

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