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Article

Unequal Access to Newly Registered Cancer Drugs Leads to Potential Loss of Life-Years in Europe

1
Erasmus School of Health Policy & Management, Erasmus University Rotterdam, Burg Oudlaan 50, 3062 PA Rotterdam, The Netherlands
2
IQVIA, Herikerbergweg 314, 1101 CT Amsterdam, The Netherlands
3
Department of Medical Oncology, Erasmus Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(8), 2313; https://doi.org/10.3390/cancers12082313
Received: 30 June 2020 / Revised: 5 August 2020 / Accepted: 7 August 2020 / Published: 17 August 2020
(This article belongs to the Section Cancer Informatics and Big Data)

Abstract

Background. Many new cancer medicines have been developed that can improve patients’ outcomes. However, access to these agents comes later in Europe than in the United States (US). The aim of this study is to assess the access in Europe to newly registered cancer drugs and to get more insight in the implications of these variations for patients. Methods. A retrospective database study was conducted. Analyses involved 12 cancer drugs and 28 European countries in the period 2011–2018. Time to patient access, speed of drug uptake, and the potential loss of life years due to a delay in access have been studied. Results. Marketing approval for the cancer drugs came on average 242 days later in Europe than in the US, and actual patient access varied extensively across Europe. The average time to market in Europe was 403 days (range 17–1187 days). The delay in patient access of ipilimumab and abiraterone may have led to a potential loss of more than 30,000 life years. Conclusion. It takes a long time for patients to get access to newly registered cancer drugs and there is great variation in access. The health outcomes can be substantially improved by faster processes.
Keywords: cancer drugs; access; delay; inequality; life years cancer drugs; access; delay; inequality; life years

1. Introduction

Cancer is a major cause of death and therefore a pressing international public health concern [1,2]. Cancer incidence is increasing in all European countries (EC). Sales of cancer drugs have more than doubled between 2005 and 2014 [3]. Because of the recent scientific advances, many new drugs have been developed that can improve overall survival (OS), prolong time to tumor progression (TTP), or decrease the chance of recurrence of cancer [4]. However, access to those drugs is not equal across Europe, as the time from a marketing approval to the actual availability and clinical use of new drugs varies greatly between European Union Member States [3,5,6]. Gann and colleagues observed delays in access to newly registered cancer drugs in some EC of over 4 years [7]. This is worrying as the access to treatment of a disease may affect patient survival, and lack of access conflicts with an individual’s right to health [8]. This right was first laid down in the 1946 Constitution of the World Health Organization and in the 1948 Universal Declaration of Human Rights and ever since is an important cornerstone of many health policies [8].
Access to health care has been defined as “the timely use of services according to needs” [9,10]. Novel drugs are faced with long procedures before patients will have access, not only in the developmental phase, but also in the regulatory processes, after finalization of the pivotal trials. The United States (US) and the European Union (EU) each have their own agencies that provide market authorization for new medicines, respectively the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Market authorization is based on the evaluation of safety, efficacy, and quality of the product. Both agencies have special fast track procedures and accelerated approval programs. Moreover, for drugs with high potential patient value, FDA can provide a priority review, that has a maximal review time of 6 months [11]. The accelerated access procedure of EMA should maximally take 150 days, i.e., 5 months [12].
After market authorization, most EC have formal procedures that need to be followed before patients will have access to novel drugs. These procedures commonly include regulatory procedures, price regulations, and some form of health technology assessment to determine whether these drugs will be reimbursed by general means, for instance via a national health services system, or via health insurance schemes [6,13,14,15,16]. Given the increasing pressure on health care budgets, these national procedures are becoming increasingly complex. The procedures and the time they take differ substantially across countries.
Although it is in society’s interest that new drugs, which are proven beneficial to patients, are equally accessible for people in need, it seems to be more and more difficult for EC to strike a balance between benefits and costs of novel cancer drugs [17,18]. As countries cope differently, resulting in variations in patient access, a deeper insight into the problem and its anticipated consequences is necessary.
The aim of this study is to assess variations in national patient access to several newly registered cancer drugs across Europe. Therefore, we compared the dates of submissions to FDA and EMA, the time to first uptake, and speed of uptake of these drugs and explored the impact of observed variations in access in terms of health outcomes.

2. Methods

This was a retrospective database study. Data were obtained from the following sources: pharmaceutical sales data was obtained from IQVIA’s MIDAS® database [19]. Sales recorded in MIDAS can originate from both retail or hospital setting. The coverage differs by country and setting. Sales were expressed in standard units (SU)—defined as single tablet or vial—making it impossible to differentiate between dosages. We assumed the usage of varying dosages are similar across included countries. IQVIA’s MIDAS® database did not encompass data on selected drugs for the Netherlands. Dutch data on first uptake were available for all drugs. However, sales data were obtained from manufactures (n = 8). We assumed sales data give a good approximation for the usage and access to selected drugs, as it is unlikely that influence of potential stocking of inventories is minimal.
We selected a variety of newly registered cancer drugs. The selection of the drugs was based on diversity in clinical evidence and diversity among indications. We limited our analysis to 12 “end of life medicines” for the indications breast cancer, gastric cancer, prostate cancer, and melanoma. The selected drugs are listed in Table 1. They were first registered between 2011 and 2017 and clinical evidence levels, as determined by the European Society Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS) [20], differed. This scale considers outcomes such as (progression-free) survival and drug toxicity. It was hypothesized that the time to patient access may be shorter for drugs with high clinical benefit score (e.g., ESMO-MCBS score 4 or 5) than for drugs with a lower clinical benefit score (e.g., ESMO-MCBS score 2 or 3). Abiraterone, cabazitaxel, vemurafenib, enzalutamide, Palbociclib, and ribociclib had a priority review by FDA. Abiraterone, vemurafenib, and nivolumab underwent a fast track procedure at EMA.
General and indication-specific cancer data were used for determining the mortality rates per drug indication. Specific cancer mortality data were obtained from Eurostat for the years 2011–2015, mortality for the missing years 2016–2018 was based on extrapolations [21]. Analyses are performed on data from 2010–2018, for 28 European countries (Appendix A).
Subsequently, the time to patient access was determined for each drug. Time to patient access was defined as the sum of: (i) Time from regulatory submission to regulatory approval; (ii) time to first patient access, i.e., time to market (TTM); and (iii) speed of uptake of the drug (Figure 1).
The “time to market” for 28 European countries was calculated from the date of EMA registration of the drug to the dates of first sales in each country (Figure 1). These dates were defined as dates of first uptake and were obtained from IQVIA’s MIDAS® database [19]. The speed of uptake was calculated by aggregating sales data (in standard units (SU) into the first 24 months of availability in a country and dividing by country-and indication-specific mortality, expressed by the number of cancer (specific) deaths as all drugs were registered for end of life settings. In the case of medicines with multiple indications, data were related to the overall cancer mortality in a country. As in general not all patients are in the appropriate medical condition to receive a new drug, we hypothesized that 80% of the eligible patients should have had access to the drugs.
Thereafter, time to first patient access in the 28 European countries was calculated. For the time of first patient access the date of EMA registration and first uptake in a country were calculated for each drug separately. As sales data are being reported on monthly basis, we assumed that the first uptake date would always be on the 1st of every month. Thereafter, these number of days were averaged for all 12 drugs.
Additionally, the speed of uptake in a country has been calculated by using the following formula:
S p e e d   o f   u p t a k e   d r u g   i n   c o u n t r y = n = 1 n = 12 ( s a l e s   v o l u m e   d r u g   a f t e r   1   a n d   2   y e a r s m o r t a l i t y   o f   d r u g   i n d i c a t i o n   i n   t h e s e   y e a r s )
n = type of drug, 12 drugs included in the analysis.
The sales volumes were calculated by summing up the sales volumes after exactly 1 and 2 years after the date of first uptake per drug per country. The outcomes were divided by the mortality that corresponded to the drug indication and the year. Thereof the average rank of all studied drugs per country has been derived.
To illustrate the impact of delay in patient access in European countries, we selected ipilimumab and abiraterone, as these drugs have a high clinical value (ESMO 4) and the trial results have shown an impact on the overall survival, namely an increase by 3.7 months and 3.9 months, respectively [22,23]. We calculated the loss in life years (LYs) due to a delayed access in their first year after market approval as for both drug indications new comparators were introduced later in time. We also estimated the loss in LYs due to a later introduction in Europe as compared to the US. For the number of patients in need for abiraterone and ipilimumab we used the dosing and the median number of cycles from the clinical trials [23,24]. The latter was related to the time to disease progression.
Further, the relation between FDA or EMA and between the ESMO-MCBS on the time to market and the speed of uptake has been studied by means of regression analyses (ANOVA). The ESMO-MCBS score was based on the results of the first publication. All statistical analyses were performed in SPSS Statistics version 25 for Windows (SPSS Inc. Chicago, IL, USA).

3. Results

Table 1 and Appendix A show the dates of the submission to, and approval by the EMA and FDA. The dates of submission to EMA and FDA were almost comparable, with the exception of palbociclib (395 days later in Europe). All drugs were first approved in the US. On average, the time to first registration was 181 days in the US (range 78–303 days) vs. 378 days in Europe (range 262–483 days), implying a difference in duration of the procedures of 197 days. Marketing approval for the cancer drugs came on average 242 days later in Europe than in the US. For the three drugs assessed in the accelerated trajectory of EMA, the average assessment period was 280 days. For drugs in the standard trajectory, this period was 410 days. The 6 drugs undergoing priority review by FDA, took an average time to market approval of 139 days, compared to 223 days for the drugs in the regular trajectory.
In Figure 2, the EMA trajectory is presented per studied drug. The actual EMA assessment time averaged 204 days and the time the applicants needed to answer queries averaged 86 days. The time between submission of the dossier and the start of the regulatory assessment procedure averaged 27 days, while the time between a positive opinion and approval averaged 61 days.
Further, there was no relation found in time between registration by FDA or EMA, and clinical value of the drugs as defined by clinical outcomes (OS, PFS, or TTP), or ESMO-MCBS score. For example, ipilimumab resulted in a gain of 3.7 months in OS and had an ESMO-MCBS score 4 and it took EMA 433 days to approve (FDA: 278 days). In contrast, for cabazitaxel, with 2.4 months increase in time to progression and ESMO-MCBS score 2 market authorization was given 331 days after submission of the EMA dossier (FDA priority review: 78 days).
Figure 3 and Appendix B present the average time from EMA registration to first uptake of the studied drugs across Europe. 2–8 Years after marketing approval, several countries still either had a very low uptake of drugs, or no uptake at all. Palbociclib had the fastest time to market from EMA registration until first uptake in the EC (average: 165 days), followed by nivolumab (average: 210 days), but 2 years after European market approval, these drugs were still not prescribed to patients in four and five countries, respectively. Note that, despite the relatively fast uptake of palbociclib, the time between US and EU market access was almost two years. For nivolumab this period was shorter, namely 179 days.
The average TTM in Europe amounted to 398 days (range 17–1187 days). In general, patients in Germany, the UK, and Austria had the most rapid potential access, with averages of 17, 22, and 31 days, respectively. Greece and many Eastern European countries were below the European average.
Figure 4 shows the speed of uptake of drugs 2 years after approval in a country. Belgium, Switzerland, France, and Austria had the highest uptake after two years. The UK and Sweden had relatively slow uptakes after 2 years.
Concerning the time to first uptake in Eastern EC, Poland was fastest, followed by Slovakia and Slovenia. First patient access to the drugs in these countries was faster than, for instance, Spain, Ireland and Italy. Bulgaria, Romania, Croatia, and Latvia ranked low in time to first access, but both Bulgaria and Czech Republic thereafter had a rapid uptake.
A delay in patient access to new drugs may result in diminished patient benefits. We calculated that in Europe approximately 14,994 patients were eligible for treatment with ipilimumab in the first year after EMA approval (see Table 2 and Appendix C). Taking into account the sales per country in that first year approximately 11,184 melanoma patients were not treated with ipilimumab. Assuming an average gain in OS of 3.7 months (derived from Table 1), this may have resulted in a loss of 3448 life years. Applying the same calculation to prostate cancer patients eligible for abiraterone resulted in 55,853 non-treated patients, which would indicate a loss of 18,152 life years across Europe for abiraterone non-use. The delay in the EMA time to registration compared to the FDA time led to an extra estimated loss of 8639 life years for both drugs.

4. Discussion

The results of our study show that, although the dates of submission to EMA and FDA did not differ for most drugs, on average newly registered cancer drugs entered the European market eight months later than the USA market. Moreover, time to patient access to the 12 newly registered cancer drugs included in the analyses differed strongly across Europe. Our analysis is the first showing the potential impact of a delay in access for patients. In the first year after EMA market authorization of ipilimumab and abiraterone almost 67,000 patients were unable to benefit from these drugs, resulting in an estimated loss of 21,600 life years. The longer EMA time to registration, as compared to the FDA time to registration, led to an extra estimated loss of 8693 life years.
Wilking and Jonsson previously studied patients’ access to treatments in the five most common tumor types for the period 1999–2004 [5]. In that period Austria, Spain, and Switzerland were fastest in realizing patient access. As in our study the UK was quite slow in adoption of the cancer treatments. Another study compared the uptake and market share for direct acting antivirals in six European countries [25]. In Germany and France patients had early access and these countries were fast adopters of these drugs. Spain and Italy were late in first uptake, but they were fast adopters after first uptake. In the UK, patients had fast access, but the uptake was slow.
As all European countries cope differently with newly registered drugs, resulting in variation in patient access, a deeper understanding of the facilitators, barriers, and key actors involved in this process is necessary. According to Frost and Reich, access to an innovation depends of several factors, such as availability, affordability, and adoption of the intervention [26]. The availability of a newly registered drug in a country will be influenced by factors like time of market authorization, the duration of the reimbursement procedure and health technology assessment, the used pricing system (e.g., external reference pricing (ERP)) and the value of the drug. Affordability means that the drug is not too expensive. This is mainly influenced by the price, the gross domestic product (GDP) of a country, the health care expenditure of a country, the pharmaceutical spending of country, and the financing (co-payments or limits on number of patients treated). Adoption depends on the acceptance and amount of unmet need of the intervention as perceived by several actors, such as global organizations (FDA or EMA), governments, doctors, and individual patients. Further study of the facilitators, barriers, and key actors involved in the access of new drugs are highly recommended.
Recently, several methods have been developed in Europe and the US to deal with the assessment of the value and pricing of newly registered drugs, and their affordability in the health systems. Examples are the American Society for Clinical Oncology (ASCO) Value in Cancer Care Framework and the ESMO-MCBS [18,27]. These methods focus on the clinical benefit of the drugs and (partly) on value-based pricing, addressing cost or cost-effectiveness of the new drug. In this study we have used the ESMO-MCBS to assess the clinical value of the studied drugs, but other instruments could be used as well. We expected that higher values of the ESMO-MCBS would result in a faster access. However, in our study a higher value, i.e., ESMO-MCBS 4–5, did not lead to a faster access of patients to these drugs.
Our study has a number of limitations. First, this study was based on data from several retrospective data sources. Each data source has several strong and weak points. IQVIA’s MIDAS® database includes worldwide standardized sales data allowing unique cross-country comparisons over time. However, in some countries not all distribution channels (e.g., hospital/retail) are captured and the database does not include direct sales to clinics and private offices in all countries. Moreover, data coverage differs per country, which despite regular quality and validity checks, potentially impacts accuracy of data extrapolations.
Second, there may be differences in the quality of the registrations of cancer mortality in the EC. Some countries may have more reliable data than other countries. However, the methods to calculate the mortality rates are standardized.
Third, some drugs had registrations for the same indication or for a specific sub-indication (e.g., melanoma for patients with PDL-1 expression) and could be used as substitutes. Further, some drugs are used for multiple indications (e.g., nivolumab: lung cancer, melanoma). In case of multiple indications, we used overall cancer mortality rates of the countries to compare the uptake. As a result, we could not calculate the exact loss in life years as a result of the delay in access of patients to these treatments. Loss in palliative effect of the drugs (i.e., lost potential effects on quality of life rather than survival) is something we could also not assess.
Fourth, data about uptake of drugs should ideally be collected by using registry data, capturing data on patient and disease characteristics, and real-world use of the drugs (dosing and number of days/cycles). In the absence of such data in Europe, we used data from IQVIA MIDAS, Eurostat, and clinical trials [19,21,22,23]. Data on speed of uptake were based on sales data and on country specific cancer mortality rates as the drugs were end of life products. We estimated that 80% of the patients in real life were eligible for the drugs, as some patients would be too unfit and/or would have too many co-morbidities to enable treatment. For the number of patients in need for abiraterone and ipilimumab we used data from the clinical trials. It is possible that in clinical practice patients may receive fewer cycles, implying that more patients may have received these drugs. If so, this has resulted in a slight overestimation of loss of life years.
Fifth, the inclusion of drugs was based on a pragmatic approach. A different selection of drugs may have resulted in different time to access estimated. Moreover, this study was focused on patient access to oncology drugs. Time to access and uptake may be different in other disease areas.
Finally, we selected two drugs to give an illustration of life years lost in Europe due to delays in patient access. The estimation of life years lost is based on a high-level calculation. It would be worthwhile to conduct a study including more drugs and more elaborate calculations.
Time to patient access in Europe is influenced by the complexity of national reimbursement processes. Most pharmaceutical companies first launch their product in Germany as it is the largest European market and reimbursement is automatic once EMA has approved drugs. A year of free pricing is allowed while price and reimbursement negotiations are ongoing [28]. Countries in which the reimbursement is dependent on the outcome of cost-effectiveness assessments (e.g., UK and The Netherlands) or in which lengthy negotiations with national and regional decision-makers have to take place (e.g., Spain and Italy) take a longer time to first access and have more limited uptake after two years. We assumed market access to be similar in all countries because of the centralized EMA procedure, however Norway and Switzerland have their own agencies, resulting in a 75-and 66-day delay, respectively [29,30]. Therefore, time to patient access in Norway and Switzerland has been slightly overestimated.
Several aspects can help shortening the time to patient access and increase uptake.
Specific early access programs can help facilitate early launches as exemplified in France, Sweden, and Italy [27]. Since the current processes of early access programs are generally complex, governments may be able to better facilitate these programs, for instance by allowing pharmaceutical companies to provide the medicines for free during the process of price negotiations and to reimburse the drugs according to the negotiated price once the negotiations have ended. The FDA assessment was on average substantially faster than the EMA assessment. This was during the whole study period (2010–2018). Therefore, improvements in the EMA procedure seem possible [31]. For instance, shortening the time from EMA submission to procedure start and the time from positive opinion to approval may accelerate the process by almost 3 months.
The coming decade, the number of patients with cancer is estimated to increase by 68% [32]. As stated before, patients have a right to health, i.e., the highest attainable standard of health as a fundamental right of every human being [8]. This makes it a legal obligation of countries to ensure timely access to acceptable and affordable health care of appropriate quality [32]. Fortunately, this issue will be addressed in the Pharmaceutical Strategy for Europe commissioned by the European Commission [33]. As many novel cancer drugs have entered the market and many others are upcoming, it is of utmost importance that all patients in need get access to the drugs with high clinical value as soon as possible.

5. Conclusions

This study shows that it takes a long time for European patients to get access to newly registered cancer drugs. Further, there is great inter-country variation of access to new cancer drugs. The delay in access may result in a potential loss of many life years. The health outcomes of European patients can substantially be improved by enabling faster and more general use of available new medicines.

Author Contributions

C.A.U.-d.G. and R.H.: substantial contributions to the design and analysis of the work; C.A.U.-d.G., R.H., M.K., J.V.: substantial contribution to interpretation of data for the work; C.A.U.-d.G.: drafting the work; all authors: revising the work critical; all authors: final approval of the version to be published; all authors: agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the “Vereniging Innovatieve Geneesmiddelen” (VIG), The Netherlands with an unrestricted grant.

Conflicts of Interest

C.A. Uyl-de Groot: Unrestricted grants from Boehringer Ingelheim, Astellas, Celgene, Sanofi, Janssen-Cilag, Bayer, Amgen, Genzyme, Merck, Gilead, Novartis, Astra Zeneca and Roche outside the submitted work. R. Heine: none. M. Krol: none. J. Verweij: Non-executive medical director: Octimet. Stock options: Octimet. Honoraria for consulting in last 24 months: Basilea, Genmab, InteRNA, Octimet, CoBioRes.

Appendix A

Table A1. Time from drug submission to drug approval by EMA (A) and FDA (B).
(A)
(A)
DrugDate of EMA SubmissionStart ProcedureRapporteur’s First Assessment Report List of Question to the ApplicantAnswers from the ApplicantOutstanding IssuesResponse to Outstanding IssuesCHMP Positive OpinionApprovalAccelerated Assessment (EMA)Total EMA (in Days)
Abiraterone 17 December 201019 January 201111 April 201120 May 201117 June 2011n.a.n.a.21 July 20115 September 201116 December 2010262
Cabazitaxel20 April 201026 May 201012 August 201024 September 201015 October 2010n.a.n.a.20 January 201117 March 2011n.a.331
Dabrafenib24 July 201215 August 20125 November 201214 December 201221 February 201325 April 201323 May 201327 June 201326 August 2013n.a.398
Ipilimumab5 May 201026 May 201015 August 201024 September 201012 January 201117 Mar 201118 April 201119 May 201112 July 2011n.a.433
Nivolumab2 September 201424 September 201415 December 201422 January 201520 February 201526 March 201530 March 201523 April 201519 June 201524 July 2014290
Vemurafenib4 May 201125 May 201112 August 201122 September 201114 October 201117 November 201124 November 201115 December 201117 February 201214 April 2011289
Pertuzumab1 December 201121 December 201114 March 201220 April 201217 August 201218 October 201212 November 201213 December 20124 March 2013n.a.459
Enzalutamide26 June 201215 August 20122 November 201214 December 201216 January201321 March 201325 March 201325 April 201321 June 2013n.a.360
Pembrolizumab4 June 201425 June 201412 September 201424 October 201420 February 201523 April 201527 April 201521 May 201517 July 2015n.a.408
Ramucirumab23 August 201325 September 201312 December 201323 January201424 April 201426 June 201414 August 201425 September 201419 December 2014n.a.483
Palbociclib30 July 201520 August 20159 November 201517 December 201522 April 201623 June 201615 August 201615 September 20169 November 2016n.a.468
Ribociclib5 September 201629 September 201620 December 201626 January201717 February 201721 April 201722 May 201722 June 201722 August 2017n.a.351
Average time from submission to approval EMA 378
Average time accelerated assessment EMA 280
Average time no accelerated assessment EMA 410
EMA: European Medicines Agency; CHMP: Committee for Medicinal Products for Human Use.
(B)
(B)
Date of FDA SubmissionDate of FDA ApprovalPriority Review (FDA)Total Time FDA (in Days)
Abiraterone 20 December 201028 April 2011Yes129
Cabazitaxel31 March 201017 June 2010Yes78
Dabrafenib30 July 201229 May 2013No303
Ipilimumab10 June 201015 March 2011No278
Nivolumab30 July 201422 December 2014No145
Vemurafenib28 April 201117 August 2011Yes 111
Pertuzumab6 December 20118 June 2012No185
Enzalutamide22 May 201231 August 2012Yes101
Pembrolizumab27 February 20143 September 2014No188
Ramucirumab23 August 201321 April 2014No241
Palbociclib30 June 20143 February 2015Yes218
Ribociclib29 August 201613 March 2017Yes196
Average time from submission to approval FDA 181
Average time priority review FDA 139
Average time no priority review FDA 223
FDA: USA Food and Drug Association.

Appendix B

Table A2. Time from EMA registration until first uptake per drug per country (in days).
Table A2. Time from EMA registration until first uptake per drug per country (in days).
CountryAbirate-RoneCabazi-TaxelDabra-FenibIpili-MumabNivolu-MabVemura-FenibPertuzu-MabEnzalu-TamidePembroli-MumabRamuci-MumabPalboci-ClibRiboci-ClibAverageNo Access *
1Germany26036012132807211010170
2UK0159719121300410071220
3Austria006750121358072112271310
4Sweden0036191213026411920101370
5France016867002582720103390 821
6Finland33106717212130877270173 911
7Switzerland261515980165008710331484101950
8Norway570128385741352112613310001631180
9Netherlands **176247531972013514012116402341631280
10Portugal00918232434703035703768402070
11Poland14976674203741661191494074051432222320
12Slovakia1497667538470030363472253112 2431
13Slovenia270381371172652258423299043601912880
14Spain118762794461966234544522253143571013030
15Ireland1496853711727437889391377131538 3051
16Italy5432294325971044701501771942531434053080
17Hungary36216903404464313119299256131843753470
18Belgium3003502482932563784544223778923873433920
19Czech392 1283 621409454118225131143 4203
20Bulgaria788838949 562288393483256376265 5202
21Romania75712036741113781052421214742 296 5722
22Croatia14261568736 3481974546953468623873436691
23Latvia1334 1200 285 173 7488
24Lithuania106113847971633 500819 591405326 8353
25Servia96921151283 684576969499 10145
26Greece 1018 1548 4059909
27Bosnia 1558 7435461610925 10767
28Estonia11222056889 682 11878
Average4045494842882103152643902512611651924031.9
* Number of countries with no access; ** Data missing for cabazitaxel, enzalutamide, palbociclib, dabrafenib; EMA: European Medicines Agency.

Appendix C

Table A3. Calculation of number of lost life years ipilimumab (A) and abiraterone (B).
(A)
(A)
ANumber of Melanoma Deaths in 2012 *Number of Patients Need Ipilimumab (80%)Perc. Patients not Treated 1 Year after EMA approvalNumber of Patients Not TreatedNumber of Lost Life Years after EMA ApprovalNumber of Lost Life Years between FDA-EMA Approval **Total Number of Lost Life Years due to Delay
Austria38530853%163503181
Belgium31525289%225692695
Bulgaria161129100%129401353
Croatia188150100%150461562
Czech Republic463370100%37011438152
Estonia5544100%4414418
Finland22217892%164501868
France1853148241%601185150336
Germany 2705216459%1278394219613
Hungary407325100%32510033133
Ireland21617383%143441761
Italy17571406100%1406433143576
Latvia7761100%6119625
Lithuania10483100%8326834
Netherlands88771089%62919472266
Norway383306100%3069431125
Poland15641251100%1248385127512
Portugal25920798%204632184
Romania44335441%146453681
Serbia276221100%221682290
Slovakia236189100%189581977
Slovenia13010499%103321142
Spain971777100%77724079318
Sweden56945594%42913246178
Switzerland39931958%184573289
United Kingdom2466197381%1606495200695
Total/Average17,49213,99388%11,184344814184867
Source: reference 19; * Time between FDA and EMA approval of abiraterone: 130 days; Perc: percentage; EMA: European Medicines Agency; FDA: USA Food and Drug Association.
(B)
(B)
BNumber of Prostate Cancer Deaths in 2012 *Number of Patients Need Abiraterone (80%)Perc. Patients not Treated 1 Year after EMA ApprovalNumber of Patients Not TreatedNumber of Lost Life Years after EMA ApprovalNumber of Lost Life Years between FDA-EMA Approval **Total Number of Lost Life Years due to Delay
Austria123899063%626204115318
Belgium1513121096%1157376140516
Bulgaria959767100%76724989338
Croatia780624100%62420372275
Czech Republic16931354100%1354440157597
Estonia268215100%215702595
Finland91473199%72123485319
France9217737475%554918038542657
Germany 12,158972678%7588246611263592
Hungary12851028100%1028334119453
Ireland903723100%72123484318
Italy65025202100%520216916022293
Latvia400320100%32010437141
Lithuania598478100%47815555211
Netherlands3154252389%22547332921025
Norway1263101083%839273117390
Poland5475438099%435814165071923
Portugal1776142199%1404456164621
Romania24321945100%1945632225857
Serbia1104883100%883287102389
Slovakia99779899%78925692349
Slovenia44535698%34911341155
Spain6266501295%475515455802126
Sweden2532202689%1795583235818
Switzerland1465117280%938305136440
United Kingdom12,63910,11191%9195298811704159
Total/Average77,97562,38094%55,85318,152722125,373
Source: reference 19; * Time between FDA and EMA approval of abiraterone: 130 days; Perc: percentage; EMA: European Medicines Agency; FDA: USA Food and Drug Association.

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Figure 1. Patient newly registered drug access pathway. EMA: European Medicines Agency; FDA: USA Food and Drug Association; HTA: health technology assessment; TTM: time to market.
Figure 1. Patient newly registered drug access pathway. EMA: European Medicines Agency; FDA: USA Food and Drug Association; HTA: health technology assessment; TTM: time to market.
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Figure 2. EMA trajectory of 12 newly registered oncological drugs (in days). EMA: European Medicines Agency.
Figure 2. EMA trajectory of 12 newly registered oncological drugs (in days). EMA: European Medicines Agency.
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Figure 3. Time to first uptake for 12 newly registered oncological drugs across Europe (in days).
Figure 3. Time to first uptake for 12 newly registered oncological drugs across Europe (in days).
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Figure 4. Speed of drug uptake for 12 newly registered oncological drugs in first two years across Europe (average rank, range) (Note: Too little access data for ranking: Lithuania, Greece, Bosnia, Estonia).
Figure 4. Speed of drug uptake for 12 newly registered oncological drugs in first two years across Europe (average rank, range) (Note: Too little access data for ranking: Lithuania, Greece, Bosnia, Estonia).
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Table 1. Newly registered oncological drugs, first indications, clinical values, and duration of EMA and FDA procedures.
Table 1. Newly registered oncological drugs, first indications, clinical values, and duration of EMA and FDA procedures.
DrugFirst Indication Gain PFS, OS, TTP (Median, Months)ESMO-MCBS *Date of EMA SubmissionDate of EMA ApprovalAccelerated Assessment (EMA)Total Time EMA (in Days)Date of FDA SubmissionDate of FDA ApprovalPriority Review (FDA)Total Time FDA (in Days)Time between EMA and FDA Approval (in Days)
Abiraterone Prostate cancer3.9 months OS417 December 20105 September 201116 December 201026220 December 201028 April 2011Yes129130
CabazitaxelProstate cancer2.4 months TTP220 April 201017 March 2011n.a.33131 March 201017 June 2010Yes78273
DabrafenibMelanoma2.4 months PFS424 July 201226 August 2013n.a.39830 July 201229 May 2013No30389
IpilimumabMelanoma3.7 months OS405 May 201012 July 2011n.a.43310 June 201015 March 2011No278119
NivolumabMelanoma4.0 months PFS402 September 201419 June 201524 July 201429030 July 201422 December 2014No145179
VemurafenibMelanoma3.7 months PFS404 May 201117 February 201214 April 201128928 April 201117 August 2011Yes111184
PertuzumabBreast cancer6.1 months PFS401 December 20114 March 2013n.a.45906 December 201108 June 2012No185269
EnzalutamideProstate cancer4.8 months OS426 June 201221 June 2013n.a.36022 May 201231 August 2012Yes101294
PembrolizumabMelanoma1.3 months PFS304 June 201417 July 2015n.a.40827 February 201403 September 2014No188317
RamucirumabGastric cancer2.2 months OS223 August 201319 December 2014n.a.48323 August 201321 April 2014No241242
PalbociclibBreast cancer10.3 months PFS330 July 20159 November 2016n.a.46830 June 201403 February 2015Yes218645
RibociclibBreast cancerPFS not reached305 September 201622 August 2017n.a.35129 August 201613 March 2017Yes196162
Average time (in days) 378 181242
Average time accelerated assessment/priority review (in days) 280 139n.a.
Average time in case no accelerated assessment/no priority review (in days) 410 223n.a.
* Ref. [22] PFS: progression-free survival; OS: overall survival; TTP: time to progression, ESMO-MCBS: European Society Medical Oncology-Magnitude of Clinical Benefit Scale; EMA: European Medicines Agency; FDA: USA Food and Drug Association; n.a.: not applicable.
Table 2. Potential life years lost due to delay in access in abiraterone and ipilimumab across Europe.
Table 2. Potential life years lost due to delay in access in abiraterone and ipilimumab across Europe.
CountryAbirateroneIpilimumab
DifferenceDelay in AccessTotalDelay in AccessDifferenceTotal
in Track after EMALifeafter EMAin Track Life
FDA-EMARegistrationYears LostRegistrationFDA-EMAYears Lost
Austria115204318315081
Belgium140376516266995
Bulgaria89249338134053
Croatia72203275154662
Czech Republic15744059738114152
Estonia25709541418
Finland85234319185068
France85418032657150185336
Germany 112624663592219394613
Hungary11933445333100133
Ireland84234318174461
Italy60216912293143433576
Latvia3710414161925
Lithuania5515521182634
Netherlands292733102572194266
Norway1172733903194125
Poland50714161923127385512
Portugal164456621216384
Romania225632857364581
Serbia102287389226890
Slovakia92256349195877
Slovenia41113155113242
Spain5801545212679240318
Sweden23558381846132178
Switzerland136305440325789
United Kingdom117029884159200495695
Total life years lost722118,15225,373141834484867
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