Clinical and Translational Oncology (2020) 22:2253–2263 https://doi.org/10.1007/s12094-020-02366-y RESEARCH ARTICLE Study of the Spanish Society of Medical Oncology (SEOM) on the access to oncology drugs and predictive biomarkers in Spain A. Rodríguez‑Lescure1 · F. A. de la Peña2 · E. Aranda3 · A. Calvo4 · E. Felip5 · P. Garrido6 · R. Vera7 Received: 2 April 2020 / Accepted: 28 April 2020 / Published online: 12 June 2020 © The Author(s) 2020 Abstract Purpose The Spanish Society of Medical Oncology (SEOM) has carried out a study to analyse the conditions of access to oncology drugs in clinical practice in Spain. For the first time, the access of predictive biomarkers has also been analyzed. Methods A questionnaire was sent to 146 hospitals in Spain to collect information on the process of approval of 11 oncology drugs of an unquestionable clinical benefit and five predictive biomarkers of mandatory determination for specific treatments. Results Results highlight the still existing differences in the access of oncology drugs, as well as the newly identified dif- ferences in the access to predictive biomarkers between Autonomous Communities (AACC) in Spain, as well as between different hospitals within the same Autonomous Community. Conclusions The SEOM considers it necessary to reduce the differences identified, increase homogeneity, and improve conditions of access to oncology drugs and biomarkers, and makes proposals to address these issues. Keywords Oncology · Drug · Biomarker · Equity · Access · Barriers · Spain Introduction approximately 64% and to reach an estimate of 29.5 million new cases in 2040 [1]. Cancer is a primary health problem due to its high incidence, In Spain, an estimated total of 227,234 new cancer cases prevalence, and mortality rates. Worldwide in 2018, 18.1 were detected in 2019 [1], being the second leading cause of million new cases cancer were identified and a total of 9.5 mortality in the overall population following cardiovascular million cancer-associated deaths were registered. In the next disease, and the leading overall cause in the male popula- 20 years, the incidence of cancer is predicted to increase by tion [2]. 2 * A. Rodríguez‑Lescure Haematology and Medical Oncology Department, Hospital alescure@geicam.org Universitario Morales Meseguer, Murcia, Spain 3 F. A. de la Peña Oncology Department, Maimonides Institute of Biomedical frayalape@yahoo.es Research (IMIBIC), Reina Sofía Hospital, University of Córdoba, Spanish Cancer Network (RTICC), Instituto de E. Aranda Salud Carlos III, Madrid, Spain earandaa@seom.org 4 Medical Oncology Department, Hospital General A. Calvo Universitario Gregorio Marañón, Madrid, Spain aitanacalvo@hotmail.com 5 Medical Oncology Department, Hospital Universitario Vall E. Felip D’Hebron, Barcelona, Spain efelip@vhio.net 6 Medical Oncology Department, Hospital Universitario P. Garrido Ramón Y Cajal, Madrid, Spain pilargarridol@gmail.com 7 Medical Oncology Department, Complejo Hospitalario de R. Vera Navarra, Navarrabiomed, IdISNA, Pamplona, Spain ruth.vera.garcia@navarra.es 1 Medical Oncology Department, Hospital General Universitario de Elche, Elche, Spain 13 Vol.:(0123456789) 2254 Clinical and Translational Oncology (2020) 22:2253–2263 Nevertheless, the incidence and mortality trends in some how the situation has changed since 2015, and make new cancers are starting to level off, with some types of cancers proposals on ways of tackling the barriers and inequalities even beginning to show decreasing rates. This suggests an identified. increase in the efficacy of new therapeutic approaches as well as preventative policies, both at primary and second- ary levels [2]. In the past years, cancer survival rates have Materials and methods increased steadily in Europe, especially in some cancer types. In Spain, survival rates are on average 53% at 5 years, An electronic questionnaire was distributed via email to the which is comparable to those of similar countries [3–5]. Medical Oncology Services of 146 hospitals in Spain, cov- One of the main developments in the treatment of patients ering all 17 AACC and the Autonomous City of Ceuta. It with cancer is the possibility of making therapeutic deci- was elaborated by a group of medical oncologists belonging sions based on the genomic and molecular characteristics of to the SEOM, who also acted as the Panel of Experts (PE) each patient’s tumor. This approach is known as precision and are the authors of this article. They took part in work medicine and it allows patients to receive personalized treat- meetings throughout the project to monitor and evaluate ments, with a greater efficacy and a lower toxicity than the results, identify areas of improvement, and make subsequent conventional treatments [6, 7]. proposals. Advances in precision medicine go hand in hand with the The PE decided the drugs and biomarkers included in this identification and determination of new biomarkers. Never- study based on the following criteria: (1) unquestionable theless, many biomarkers are still not available in day-to-day clinical benefit, (2) funding granted in Spain between 2016 clinical practice due to the numerous barriers and threats and 2018, (3) drugs whose access issues could have a great that limit their accessibility [6, 7]. effect on the adequate treatment of patients, and (4) could An study on access to novel drugs for NSCLC carried out be representative of current access conditions in Spain. As in Central and Southeastern Europe (CEE) concluded that a result, the PE selected approved indications for 11 drugs the access to novel drugs was suboptimal in CEE countries and five predictive biomarkers mandatory for the prescrip- and that availability of drugs was not in accordance with tion of specific oncology drugs under Data Sheet require- their value scores, like the ESMO Magnitude of Clinical ments, to address the following conditions: non-microcytic Benefit Scale [8]. lung cancer (drugs: pembrolizumab, atezolizumab, and In Spain, after EU authorization, oncologic drugs must nivolumab; biomarkers: PDL-1, ALK, and ROS-1), breast first be approved by the Spanish Agency of Medicines and cancer (drugs: ribociclib and palbociclib), melanoma (drugs: Medical Products (AEMPS) and, after that, the Therapeutic dabrafenib + trametinib and cobimetinib + vemurafenib; bio- Positioning Report (IPT) is issued. This report serves as a marker: BRAF), and ovarian cancer (drug: olaparib; bio- reference for any action related to the acquisition and pro- marker: BRCA1/BRCA2) (Tables 1 and 2). motion of the rational use of the drug. The Inter-Ministerial The questionnaire requested descriptive data of each Commission for the Pricing of Medicines (CIPM) is then centre and information on the commissions and decision- responsable for establishing the Pricing and Reimbursement making bodies involved in the access. For each drug/indi- (PR) within the Spanish Public Health System (SNS) [9, 10]. cation, information requested included dates of application Afterwards, Autonomous Communities (AACC) will cover and approval/denial for use; approved usage conditions and the expense of the drugs as part of their regional budgets. any barriers or limitations. For each biomarker, information In this context, following the results obtained from the requested included availability of procedures for requesting 2015 study on the access of pharmaceutical drugs in Spain, their determination; in house or outsourced determination the Spanish Society of Medical Oncology (SEOM) has car- and response times; usage criteria; funding of the determina- ried out the present study to evaluate and follow up, 4 years tion in clinical practice; management and registering plat- later, the access conditions to oncology drugs in real clinical forms, and any barriers or limitations identified. The detail practice throughout the Spanish territory. Furthermore, for of the questions included is shown in Annexes 1, 2, and 3. the first time, the access conditions in clinical practice to The time taken from the EC authorization and from the predictive biomarkers mandatory by Data Sheet as a means fixing of PR conditions in Spain until the approval of each of selecting patients for some specific oncology drugs have drug /indication for its prescription in each individual hos- also been analyzed. pital was measured. The minimum, maximum, and median The aim of this study is to identify the different decision- times were also calculated. making mechanisms involved in the approval and access to A literature review was carried out on all relevant content oncology drugs and predictive biomarkers in clinical prac- published in the web pages of the EC, EMA, General Direc- tice in Spain, analyse the availability of approved drugs and torate of Pharmacy and Medicinal Products of the Spanish predictive biomarkers, as well as compare, where possible, Ministry of Health, the AEMPS, regional health services as 13 Clinical and Translational Oncology (2020) 22:2253–2263 2255 Table 1  Description of the drugs and indications analysed in this study Lung cancer Pembrolizumab 1. Monotherapy for the first-line treatment of metastatic Non-Small Cell Lung Carcinoma (NSCLC) in adults with tumours that express PD-L1 with a tumour maker proportion (TMP) ≥ 50% without positive tumour mutations o the EGFR or ALK genes 2. Monotherapy for the treatment of locally advanced or metastatic NSCLC in adults with tumours that express PD-L1 with a TPS ≥ 1% and that have received at least one previous chemotherapy treatment Atezolizumab Monotherapy for the treatment of adult patients with locally advanced or metastatic Non-Small Cell Lung Carcinoma (NSCLC) that have received prior treatment with chemotherapy Nivolumab Monotherapy for the treatment of adult patients with locally advanced or metastatic Non-Small Cell Lung Carcinoma (NSCLC) that have received prior treatment with chemotherapy Breast cancer Ribociclib In combination with an aromatase inhibitor as an initial hormonal treatment of post-menopausal women with locally advanced or metastatic breast cancer, positive for the Hormonal Receptor (HR), and negative for the Human Epidermal Growth Factor 2 (HER2) Palbociclib Treatment of metastatic or locally advanced Hormonal Receptor (HR) positive and Human Epidermal Growth Factor Receptor 2 (HER2) negative breast cancer Melanoma Dabrafenib y Trametinib Trametinib in combination dabrafenib for the treatment of adult patients with non-resectable or metastatic melanoma with a BRAF 600 mutation Cobimetinib y Vemurafenib Cobimetinib in combination with vemurafenib for the treatment of adult patients with non- resectable or metastatic melanoma with a BRAF V600 mutation Ovarian cancer OLAPARIB Monotherapy for the treatment of adult patients with BRCA-mutated (germline or somatic) advanced high-grade serous epithelial ovarian cancer, fallopian tube or primary peritoneal cancer, in relapse and sensitive to platinum, following first-line platinum-based chemotherapy (complete or partial response) Table 2  Description of the biomarkers and indications analysed in this study Lung cancer PD-L1 Expression of the PD-L1 predictive biomarker in response to the treatment of Non- Small-Cell Lung Carcinoma (NSCLC) ALK Rearrangement of ALK as a predictive biomarker in response to the treatment of NSCLC ROS-1 Translocation of ROS-1 as a predictive biomarker in response to the treatment of NSCLC Melanoma BRAF Mutation of BRAF as a predictive biomarker in response to the treatment of Melanoma Ovarian cancer BRCA1/BCRA2 Mutation in the BRCA1/BRCA2 genes as predictive biomarkers in response to the treat- ment of Ovarian Cancer well as the Official Gazettes of each Autonomous Commu- 200,000 and 300,000 inhabitants, and 22% to areas below nity, regarding the approval and use of biomarkers, as well 200,000 inhabitants. as the access to oncology drugs. This study started in December 2018 and ended in May 2019. Oncology drugs Commissions and decision‑making bodies Results that affect the access The questionnaire was completed by 84 hospitals (58% of According to the responses, in 51% of cases, decisions the centres contacted). Of these, 80 are public hospitals and regarding the access of the drugs are taken at hospital/health four are private hospitals, one of these being an associated Area; in 42% of cases, decisions are made at Autonomous private centre. The participating centres represent all 17 Community level; and in 5% of cases, decisions are made at AACC as well as the Autonomous City of Ceuta. Accord- a combination of levels. Results show there are clear vari- ing to the responses, 62% of the centres are of level 3 com- ations between AACC. In Asturias, Baleares, Cantabria, plexity, 29% are of level 2 complexity, and 9% are of level C. Valenciana, Galicia, La Rioja, Navarra, and País Vasco, 1 complexity; 56% of the participant centres correspond to decisions are always made at Autonomous Community level; areas of over 300,000 inhabitants, 22% of areas between whereas in Castilla La Mancha and Madrid, decisions are 13 2256 Clinical and Translational Oncology (2020) 22:2253–2263 always made at a hospital/health Area level. In the remaining in ascending order are the following: 13 months for AACC, responses obtained vary between hospitals. atezolizumab (7–23 months); 16.5 months for palboci- No information was provided on the commissions in 58% clib (12–24 months); 17 months for pembrolizumab 1st of the answers, either because it is not publically available NSCLC (7–25 months), 17 months for pembrolizumab (31%) or because it is unknown (27%). 2nd NSCLC (7–32 months), and 21 months for nivolumab In cases where participants have information about the (5–40 months). decision-making commission, they have indicated that at Table 3 shows the median time from the designation of least one medical oncologist participates in it. the PR until the authorization at each Autonomous Com- munity, as well as the minimum, maximum, and global Conditions for the use and the need for additional median for each of the drugs/indication. The time taken approvals from the EC authorization until PR is also shown. A total of 60% of the responses indicate that, despite having been authorised by the AEMPS and having fixed PR condi- Barriers to the access of oncology drugs tions, the use of the drugs requires an additional authoriza- tion by the Hospital´s Pharmacotherapy Commission (HPC). In 43% of the centres, barriers to the access and use have A total of 20% of responses indicate that at least one of been detected for at least one of the drugs analyzed. These the drugs/indications included in this study had not been barriers primarily consist of: delays and slowness of the approved (15%) or were pending approval (5%). It must be approval process; requirement of a supporting report for noted that this questionnaire was carried out during the first each patient, which means additional delays and can result 4 months of 2019 and that the drugs/indications included in in the denial of the request; use criteria more restrictive the study were designated PR conditions between January than those established for the drug commercialization in 2016 and April 2018. Spain; selection of other drugs with the same indication There are differences in the responses obtained regarding and a different mechanism of action for use in the cen- the criteria which govern the use of the drugs. These criteria tre; non-approval or a pending approval of the drug in the are specified by, amongst others, regional reports, hospital centre. reports developed by the HPC, and positioning reports of the SEOM. Furthermore, the criteria established for their use are not always the same as those established for their commercialization in Spain. Biomarkers Analysis of authorization times for the approval Commissions and decision‑making bodies of prescriptions (Table 3) Responses to the questionnaire and the bibliographic review According to the responses, the time taken from the designa- show that there are no standardized criteria for the imple- tion of PR until approval for prescription within the differ- mentation of biomarkers in clinical practice in Spain. ent hospitals shows great variability, ranging between 0 and According to the answers, in most AACC, there are great 36 months. For palbociclib, the median was of 5 months, variations between hospitals regarding how and where the (ranging from 1 to 12 months); 5.75 months for ribociclib decisions for the approval of biomarkers are made. (2–13 months); 6.5 months for atezolizumab in NSCLC In 84% of centres, there is no established commission or (1–16 months); 7 months for cobimetinib + vemurafenib decision-making body responsible for making decisions on (0 to 24 months); 10 months for dabrafenib + trametinib the access of predictive biomarkers or there is no informa- (5–30 months); 10.5 months for pembrolizumab 1st L tion in this regard. NSCLC (1 to 18 months); 11 months for pembrolizumab In the majority of centres that do have a decision-mak- in 2ndL NSCLC (1–26 months); 13 months for olaparib ing body, such decisions are made in one of the following: (1–35 months); and 17 months for nivolumab in NSCLC Tumour or Molecular Pathology Committee; Tumours or (1 to 36 months). Genetic Committee. Timescales from the EC authorization until the Some participants have indicated that, at the end date of approval for prescription at different hospitals ascend up the study (May 2019), some of the AACC were implement- to 48 months (olaparib), with medians ranging between ing, or starting to work on the implementation of mecha- 87.5 months (ribociclib between 5 and 18 months) and nisms for the management of biomarkers determination in 26 months (olaparib between 14 and 18 months). For clinical practice and on their possible inclusion in the port- the remaining drugs/indications, median timescales folio of services offered by the region. 13 Table 3  Time taken in months from the PR fixation of an indication until the approval for its use Autonomous community Pembrolizumab 1L Pembrolizumab 2L Atezolizumab Nivolumab Ribociclib Med Min Max N Med Min Max N Med Min Max N Med Min Max N Med Min Max N Andalucía 12 8 16 12 11 1 14 11 4 1 8 12 20 3 36 12 6.5 2 13 10 Aragón – – – – – – – – – – – – – – – – 4 4 4 – Asturias 10 10 10 1 – – – – 0 0 0 1 – – – – – – – – Baleares 10.5 6 15 2 17.5 13 22 2 7 7 7 2 24 24 24 2 5 5 5 2 C. de Madrid 9 1 14 9 13 1 18 9 7 3 8 9 20.5 1 29 9 4 3 12 7 C. La Mancha 15 15 15 5 22 22 26 6 7 7 7 6 12 10 13 6 – – – 5 C. Valenciana 13 13 13 6 9.5 3 16 6 5 5 5 6 8 4 12 6 3,5 2 5 6 Canarias – – – – – – – – – – – – – – – – – – – – Cantabria 0 0 0 1 – – – – – – – – 19 19 19 1 – – – Castilla y León 6 6 6 4 10 10 10 4 8 8 8 4 14 13 17 5 – – – – Clinical and Translational Oncology (2020) 22:2253–2263 Cataluña 8 5 9 11 13.5 0 16 11 2 0 16 9 15 2 26 10 7 4 9 10 Ceuta 13 13 13 1 – – – – – – – – 33 33 33 1 – – – Extremadura – – – – –– – – – – – – – 1 1 1 1 – – – – Galicia 18 18 18 4 – – – – 3 3 3 4 – – – – – – – – La Rioja 0 0 0 1 – – – – 6 6 6 1 – – – – – – – – Murcia 15 15 15 2 1 1 1 2 4 4 4 2 13 10 16 2 7 7 7 2 Navarra 9 9 9 1 5 5 5 1 7 7 7 1 – – – – – – – – País Vasco 3.5 3 4 3 11 11 11 3 8 8 8 2 23 23 23 2 6.5 6 7 3 Global Median (months) 10 11 6 17 6 Pembrolizumab 1L Pembrolizumab 2L Atezolizumab Nivolumab Ribociclib Date of approval by the EC 27/01/2017 29/07/2016 21/09/2017 28/10/2015 22/08/2017 Date of PR fixing for the indication 01/08/2017 01/01/2017 01/04/2018 01/02/2016 01/11/2017 Autonomous community Palbocilib Dabrafenib and trametinib Cobimetinib and vemurafenib Olaparib Med Min Max N Med Min Max N Med Min Max N Med Min Max N Andalucía 7.5 5 11 11 9 5 22 11 6 0 16 11 28 14 35 10 Aragón 4 4 4 3 – – – – – – – – – – – 3 Asturias 0 0 0 1 11 11 11 1 5 5 5 1 13 13 13 1 Baleares 5 5 5 2 – – – – – – – – 29 29 29 2 C. de Madrid 4 3 10 10 19 14 25 8 16 16 19 7 13 1 33 6 C. La Mancha 11 1 12 6 9 9 9 5 7 3 11 5 – – – 4 C. Valenciana 2 2 2 7 14 14 14 5 12 12 12 5 0 0 0 6 Canarias – – – – 10 10 10 1 3 3 3 1 32 32 32 1 Cantabria – – – – 21 21 21 1 21 21 21 1 – – – 1 Castilla y León 7 7 7 4 18 18 18 4 12 12 12 5 20 20 20 3 13 2257 2258 Clinical and Translational Oncology (2020) 22:2253–2263 Access to biomarkers 10 N 2 2 1 1 4 1 Max In 96% of the participating centres, it is possible to request the determination of the predictive biomarkers included in 10 23 12 1 1 5 – – this study (93–98% depending on the biomarker). There is great diversity about the criteria followed for Min 10 23 12 the access. In 32% of the responses, the criteria estab- 1 1 0 – – 16/12/2014 01/01/2016 lished in the drug´s Data Sheet are followed; in 26%, the Olaparib Olaparib consensus reports of the SEOM-SEAP (Spanish Society Med 13 10 23 12 for Pathologic Anatomy) or the clinical guidelines are fol- 1 1 – 3 – lowed; in 20%, the guidelines of the IPTs are followed; and 12% follow reports of the corresponding Autonomous N 3 2 1 – 4 6 – - Cobimetinib and Vemurafenib Community. Cobimetinib and vemurafenib The determination of the biomarkers included in this Max study is outsourced to other centres in the following vary- 12 10 24 – 2 – – 3 ing percentages: 29% for PDL-1, 36% for BRAF, 37% for ALK, 47% for ROS-1, and 63% for BRCA1/BRCA2. In the Min 12 remaining cases, determinations are carried out in house. 0 – 2 – 3 8 – 01/10/2016 Med n/a 12 16 5 7 – 2 – – 3 Biomarkers funding Responses regarding the source of funding for each bio- N 1 3 – 2 6 – – 4 marker vary between AACC, as well as between hospitals Dabrafenib and Trametinib Dabrafenib and trametinib within a given Autonomous Community and between differ- Max 18 15 30 ent biomarkers within a given hospital. 0 – – 9 – In more than 50% of the participating centres, pharma- ceutical companies are the source funding for the determina- Min 18 5 – 0 – 9 0 – 01/04/2016 tion for clinical purposes of at least one of the biomarkers included in the study. In the remaining centers, the source Med median, Min minimum, Max maximum, N number of centres that have answered Med of funding, public or private, cannot be determined due to 9.5 n/a 10 18 6 0 9 – – - the type of answers obtained. A vast majority of the centres indicate that they do not employ any computer platform to manage and register the N 1 3 1 2 9 – – 5 determination of predictive biomarkers. These kinds of reg- istries are used when determinations are outsourced to other Max 11 7 2 4 4 8 – – centres and are funded by pharmaceutical companies. Min 11 2 4 6 2 – – 1 09/11/2016 01/11/2017 Time taken from the request until results Palbocilib Palbocilib Med 2.5 5.5 The average estimated time taken from the request of the 11 5 2 4 6 – – determination for the predictive biomarkers until the attain- ment of results varies between biomarkers, AACC and Date of PR fixing for the indication hospitals. Median times vary from 7 days in PD-L1 in advanced Date of approval by the EC NSCLC (from 2 to 21 days) to 29 days for BRCA1/BRCA2 Autonomous community Global median (months) in advanced ovarian cancer (from 1 to 240 days). The median Table 3  (continued) time for BRAF in metastatic melanoma is 8 days (from 1 to 31 days); whilst in ALK and ROS1 in advanced NSCLC is Extremadura País Vasco of 10 days (from 2 to 30 days). Cataluña La Rioja Navarra Galicia Murcia In centres which outsource these determinations, the time Ceuta taken until obtaining a response is notably greater than in 13 Clinical and Translational Oncology (2020) 22:2253–2263 2259 those where the determination is carried out in house. In the composition of commissions and other decision-making some cases, these differences can be of up to 90 days. bodies is either not publically accessible or that there is no information available in this regard. When this information Barriers and limitations to the determination is available, participants indicate that such commissions of the biomarkers include at least one medical oncologist, while 9.7% of hos- pitals indicated that no medical oncologist formed part of Amongst the primary barriers and/or limitations to the them in the study carried out in 2015. access to the biomarkers included in this study, partici- The period to access to drugs of unquestionable therapeu- pants have stated: the lack of standardized authorization tic value is excessively long and, above all, there are signifi- procedures and of clear decision-making mechanisms; the cant differences at a regional level, and even at a hospital dependency on the pharmaceutical industry for funding level within a given region. Without a doubt, this is a source and, on occasions, for the designation of reference centres; of significant inequalities in the health system. Furthermore, in some cases, a lack of access to the determination; the 43% of the participant oncologists identify access barriers to time until the attainment of results, which is, in many cases, the use of, at least, one of the drugs analyzed. In the study related to the outsourcing of the determination. In private carried out in 2015, 37.8% of participants identified barriers hospitals, the primary barrier is the lack of coverage by pri- or limitations for the access to the oncology drugs analyzed. vate insurance companies. With regards to the access of biomarkers, in Spain, there is neither standardized procedure nor regulatory frame- work for the evaluation, implementation, and funding of Discussion biomarkers that predict the efficacy of specific oncology drugs in a given patient. These biomarkers are not included The SEOM, from its commitment towards excellence in the in the national portfolio of health services and, therefore, care of cancer patients, carried out an initial study in 2015 are authorised at regional or hospital levels following very to identify the difficulties and differences in the access to different criteria and with varying approval timeframes. In oncology drugs between hospitals and AACC in Spain [11]. fact, 84% of the centres included in this study do not have a With this present study, SEOM wanted to analyse the cur- commission or decision-making body responsible for man- rent situation, 4 years later, as well as to include in the study aging the access of predictive biomarkers, or at least the an analysis of the access to predictive biomarkers, essential participants have no information in this regard. tools for precision medicine. In fact, SEOM, together with Other relevant areas of inequality include the funding of the Spanish Society for Pathological Anatomy (SEAP) and predictive biomarker determinations and the selection of the Spanish Society for Hospital Pharmacists (SEFH), has hospital centres where such determinations are carried out. defended the need to develop a National Precision Medicine This study shows that pharmaceutical companies play a sig- Strategy [12]. nificant role in the funding, and, thus, in the organization of The SEOM acknowledges of the existing need for a resources and the access to the biomarkers/indications that health system planning based both on the quality of care have been analyzed. as on equal access and still considers it a priority to iden- Concerning response times, the estimated time from the tify inequalities and issue proposals for improvement with request for the determination of the biomarkers/indications the aim of guaranteeing the accessibility of pharmaceutical until the availability of a result varies significantly between drugs and biomarkers in equitable conditions throughout the biomarkers, AACC, and hospitals. The time taken is nota- national territory, without affecting the measures taken by bly greater in centres that outsource the determination than AACC to rationalize use of drugs and health products, as where the determination is carried out in house. established in the modification of Article 88.1 of December The differences in the access to oncology drugs and pre- 2014 of Law 29/2006 on Guaranties and Rational Use of dictive biomarkers could impact on the health outcomes, Drugs and Health Products. even though this impact has not been measured in this study The results show that there are significant differences due to the limitations in its scope. between AACC regarding the scope of which decisions Given this situation, the SEOM expresses its concern relevant to drug accessibility are made. Nevertheless, this regarding the variability in the access to oncology drugs as analysis shows a tendency towards a greater centralization well as to biomarkers which are necessary for the correct of decisions at an autonomic level. The responses indicate selection of certain treatments that have an unquestionable that in 51% of cases, decisions are made at a hospital/health clinical benefit, in the different AACC and in different hos- área level (65.3% of cases in 2015), and that in 42% of cases, pital centres within the same Autonomous Community. decisions are made at a regional level (27.8% of cases in The SEOM, therefore, considers it necessary to imple- 2015). In 58% of all responses, the participants indicate that ment initiatives with the following objectives: 13 2260 Clinical and Translational Oncology (2020) 22:2253–2263 1. Include biomarkers in the portfolio of common services means that biomarkers are introduced differently in the of the Spanish National Health System (SNS). different AACC and in different hospitals. 2. Develop a standardized procedure and a regulatory This situation could directly affect patients, whose framework for the implementation and funding of the access to certain drugs and predictive biomarkers depends biomarkers. on the region and on the centre where they are being 3. Determine which biomarkers should be carried out in treated. house and which must be carried out in reference cen- For this reason, the SEOM expresses its concern and con- tres. siders it necessary to implement initiatives to (a) reduce the 4. Reduce the identified differences and increase homoge- detected differences to ensure equity in drug access, regard- neity in the access to drugs in Spain, demanding that the less of the patients´ place of residence, and reduce delays in same conditions apply throughout the Spanish territory the time taken from the EC authorization until use in hospi- and that the competent decision-making bodies approve tals, (b) include biomarkers in the basic portfolio of drugs these common conditions. and services of the SNS, and (c) measure health outcomes   To achieve this, there is a need to: to understand the real impact of introducing new treatments and biomarkers. • Ensure total transparency in the composition and The SEOM would like to offer itself as a collaborative decisions of commissions and other decision-making partner for the Spanish health authorities in promoting ini- bodies tiatives aimed at ensuring equity and the optimal access of • Eliminate barriers at a regional level (AACC) and oncology drugs and biomarkers, regardless of a patients´ hospital level place of residence. 5. Reduce existing delays between the date of approval of drugs for their commercialization in Spain and the date Acknowledgements The authors would like to thank the entire team of medical oncologists that took part in the study for their time and of approval for their prescription to patients. commitment. Their participation has been crucial for the undertaking   To achieve this, there is a need to: of this study. • Limit the time taken for the inclusion of new drugs in Funding This study was funded by SEOM. the AACC following the authorization by the Span- ish Ministry of Health. Compliance with ethical standards • Eliminate bureaucratic procedures, such as addi- tional supporting reports following the attainment of Conflict of interest A Rodríguez-Lescure has received consultant, published IPTs as well as Scientific Society reports advisory, or speaker fees or travel and accommodation for attending prepared by experts. symposia from Roche, Pfizer, Novartis, Lilly, Kern, Astrazeneca, Ei- sai, and Mylan. F Ayala de la Peña has received honoraria for speak- ing at symposia and educational meetings from Astrazeneca, Celgene, Measure health outcomes to understand the real impact of Eisai, Novartis, Roche, Pfizer, Pierre Fabre; research grant/funding introducing a new drug, using the tools designed in collabo- from Celgene and Roche; meeting travel expenses from Roche, Pfizer, ration with the General Directorate of Basic Portfolio of Ser- Celgene, Eisai, Pierre Fabre, and MSD, and financial support for edu- vices of the Spanish National Health System and Pharmacy, cational programs or advisory boards from MSD, Pfizer, and Roche. E Aranda has received fees for advisory role from Amgen, Bayer, Cel- and that these be used in every Autonomous Community gene, Merck, Roche, and Sanofi. A. Calvo has received speaking, advi- with the same criteria. sory, travel, or grant support from Lilly, Merck, BMS, Amgen, Servier, Boehringer-Ilgenheim, and Roche. E. Felip has received honoraria for advisory, consultancy, speaker bureau or expert testimony from Pfizer, Roche, Boehringer Ingelheim, Astrazeneca, BMS, Guardant Health, Conclusions Novartis, Takeda, Abbvie, Blue Print medicines, Lilly, Merck KGaA, MSD, Janssen, Samsung, Medscape, Prime oncology, and Touchtime; research grant funding from Fundación Merck Salud (Grant for oncol- This study shows that there are still variations in the access ogy innovation). P Garrido has received honoraria for speaker or advi- of drugs as well as of biomarkers that predict the efficacy of sory from Roche, Astrazeneca, BMS, Guardant Health, MSD, Pfizer, different oncology drugs between different AACC as well as Janssen, Boehringer Ingelheim, Novartis, Gilead, Rovi, Abbvie, Lilly, Takeda, Sysmex, Blueprint medicines, and Bayer. R Vera has received at a hospital level within a given Autonomous Community. honoraria and non-financial support from Roche, Merck, MSD, Sanofi, In addition to the significant differences in the deci- Servier, and BMS. sion-making process, access times for these drugs are still worrisome, not only due to its length, but also due to the Ethical approval This article does not contain any studies with human participants or animals performed by any of the authors. notable differences between AACC and between hospitals for a given drug. Additionally, the fact that biomarkers are Informed consent Informed consent was obtained from all individual not included in the basic portfolio of services of the SNS participants included in the study. 13 Clinical and Translational Oncology (2020) 22:2253–2263 2261 Open Access This article is licensed under a Creative Commons Attri- • ☐ Hospital bution 4.0 International License, which permits use, sharing, adapta- • ☐ Group of hospitals tion, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, • ☐ Health area provide a link to the Creative Commons licence, and indicate if changes • ☐ Province were made. The images or other third party material in this article are • ☐ Autonomous Community included in the article’s Creative Commons licence, unless indicated • ☐ Unknown otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not • ☐ No binding decisions are made at any level permitted by statutory regulation or exceeds the permitted use, you will 7. In your centre, is there a Commission or any other need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat​iveco​mmons​.org/licen​ses/by/4.0/. decision-making body responsible for making deci- sions regarding the access to predictive biomarkers of response to treatment with oncology drugs? Appendix • ☐ Yes (please indicate which) • ☐ No ☐ Unknown Appendix 1. Descriptive data requested for each centre   If the selected answer is “YES”, is the information on its existence and means of operation publically avail- 1. Select your province (MANDATORY) able? 2. Select the level of your hospital 8. Additional comments 3. Select the number of inhabitants of your reference popu- lation Appendix 2. Requested data on the access 4. Select the scope of influence of the Pharmacotherapy of the drugs and indications analysed (for each Commission where binding decisions regarding the drug/indication) drug access in your centre are made: (Please select one option) 1. Has the request for the use of the drug in your centre • ☐ Hospital been presented to the Pharmacotherapy Commission? • ☐ Group of hospitals • ☐ Yes • ☐ Health area • ☐ No • ☐ Province • ☐ No, approval is granted by the regional Commis- • ☐ Autonomous Community sion where presenting the drug is not necessary • ☐ Unknown • ☐ Unknown   Do you know the number of members that form the   If the answer is “No”, what was the primary previously mentioned Commission? motive for not presenting a request? • ☐ Yes • ☐ Unofficial negative response • ☐ No • ☐ Excessive delay   If the chosen answer is “YES”, please indicate the • ☐ Excessive burocracy following: • ☐ It does not affect my prescription   Number of members in the previously mentioned Commission: 2. Has the drug been approved for clinical use for the given   Number of medical oncologists that take part in the indication in your hospital? commission: • Yes ☐   Is this information publically available? • No ☐ • ☐ Yes • Pending evaluation ☐ (indicate date) • ☐ No ☐Unknown   If the chosen answer is “YES”, please indicate the date of approval (month/year) 5. Are there any electronic prescription mechanisms avail-   If the chosen answer is “NO”, have patients been able? Please indicate. derived to other centres that have access to the drug? 6. Select the level that decisions regarding the determina-   If the chosen answer is “NO”, are there any alter- tion of predictive biomarkers of response to treatment native prescription mechanisms in place that grant with oncology drugs are made: access to the drug?  Yes ☐ (Please indicate) No ☐ 13 2262 Clinical and Translational Oncology (2020) 22:2253–2263 3. If the use of the drug has been approved in the hospital Appendix 3. Requested data on the access for the given indication, is its use governed by/depend- to the analysed biomarkers (for each biomarker/ ent on the criteria established in…? Please select one or indication) more of the following options: • ☐ Data Sheet (Ficha Técnica, FT) 1. In your centre, is it possible to request the determi- • ☐ It has been approved under the same conditions as nation of the biomarker as a predictive biomarker of response to the treatment of the given indication? the Data Sheet (FT) • ☐ It has been approved under more restrictive condi- • ☐ Yes tions than those of the Data sheet (FT) • ☐ No • ☐ It has been approved under less restrictive condi- tions than those of the Data Sheet (FT) • ☐ Therapeutic Positioning Report (Informe de Posi- 1.1 If the chosen answer is “YES”, since when has the cionamiento Terapéutico, IPT) use of the biomarker been possible (month and • ☐ It has been approved under the same conditions as year)? the Therapeutic Positioning Report (IPT)   Multiple choice: • ☐ It has been approved under more restrictive con- 1.2 If the chosen answer is “NO”, what is the reason for ditions than those of the Therapeutic Positioning its inaccessibility? Report (IPT) • ☐ It has been approved under less restrictive con-   Multiple choice: ditions than those of the Therapeutic Positioning Report (IPT) • ☐ Negative response from the decision-making bod- • ☐ Regional Report (Autonomous Community) ies • ☐ Hospital Report prepared by the Pharmacotherapy • ☐ Delay in the response Commission • ☐ Procedures for presenting the request are • ☐ SEOM Evaluation Report unknown/inexistent • ☐ Genesis Evaluation Report • ☐ Other motives. Please specify which. Click here • ☐ The drug is not available in the centre to type text. • ☐ Others Please specify 4. Can you identify any barriers / limitations to the access 2. Is the use of the biomarker as a predictive biomarker of the drug for the given indication in your center?: of response to treatment for a different type of cancer  No ☐ Yes ☐ included in the hospital´s portfolio of available ser-   If the chosen answer is yes, please select one or more vices? of the following options regarding the barriers to access the drug in your centre: • ☐ Yes. Please specify • ☐ No. • ☐ The requirements established by the centre are more restrictive than those included in the Data 3. What are the available techniques for the determination Sheet of the biomarker as a predictive biomarker in response • ☐ Drafting of a supporting report specific to each to the treatment of the given indication? patient is required 4. Who is responsible for carrying out the determination • ☐ Expenditure capping systems have been imple- of the biomarker as a predictive biomarker in response mented to the treatment of the given indication? • ☐ No medical oncologists take part in the Pharma-   The hospital itself ☐ Outsourced ☐ cotherapy Commission   Do other centres outsource their determinations to • ☐ Lack of hospital budget your centre? • ☐ A different drug with the same indication but a lower price has been approved • ☐ Yes. Please specify which centres. Click here to • ☐ The sequence of treatments for the same indication type text. are not permitted • ☐ No. • ☐ Other barriers to the use. Please specify which • ☐ Unknown.   If determinations are outsourced, please specify to 5. Please add any other relevant comments. which centre 13 Clinical and Translational Oncology (2020) 22:2253–2263 2263 5. Is the use of the biomarker as a predictive biomarker in 2. REDECAN 2019. Available at https​://redec​an.org/es/. Accessed response to the treatment of the given indication gov- May 2020. 3. Instituto Nacional de Estadística. National Statistical Institute of erned by/ dependant on the criteria established in…? Spain. Defunciones según causa de muerte. Año 2083. Publicado Please select one or more of the following options: el 19 de diciembre de 2019. Available at: https:​ //www.ine.es/prens​ a/edcm_2018.pdf. Accessed May 2020. • ☐ Therapeutic Positioning Report (IPT) Please spec- 4. Galceran J, Ameijide A, Carulla M, Mateos A, Quirós JR, Alemán A et al. Estimaciones de la Incidencia y la superviven- ify which drug cia del cáncer en España y su situación en Europa. Informe de • ☐ Data Sheet (FT) Please specify which drug la Red Española de Registros de Cáncer (Redecan); octubre • ☐ Regional Report (Autonomous Community) de 2014. https​: //funca​. cat/redec​a n/redec​a n.org/es/pagec​c 61. • ☐ Hospital Report html?id=102&title​=regis​tro-de-cance​r-de-tarra​gona. 5. Las cifras del cáncer en España 2019. SEOM. Depósito Legal: • ☐ Clinical Guidelines / SEOM Consensus Reports M-3800–2019. https​://seom.org/seomc​ms/image​s/stori​es/recur​ • ☐ Unknown sos/Las_cifra​s_del_cance​r_en_Esp_2017.pdf. • ☐ The biomarker is not available in the centre 6. Página web SEOM. Available at https​://seom.org/infor ​macio​ • ☐ Other Please specify n-sobre​-el-cance​r/ique-es-la-medic​ina-de-preci​sion. Accessed May 2020. 7. Mordente A, Meucci E, Martorana GE, Silvestrini A. Cancer bio- 6. Who is responsible for funding the biomarker determi- markers discovery and validation: state of the art, problems and nation for the purpose of predictive care for the indica- future perspectives. Adv Exp Med Biol. 2015;867:9–26. tion in your hospital? 8. Cufer T, Ciuleanu TE, Berzinec P, Galffy G, Jakopovic M, Jassem J, Jovanovic D, Mihaylova Z, Ostoros G, Thallinger C, Zemanova M, Zielinski C. Access to novel drugs for non-small cell lung can- • ☐ Regional Health Services / Regional Ministries cer in central and southeastern europe: a central European coop- • ☐ The Hospital erative oncology group analysis. Oncol. 2020;25:e598–e601. https​ • ☐ Pharmaceutical Industry ://doi.org/10.1634/theon​colog​ist.2019-0523. 9. Cómo se regulan los Medicamentos y Productos Sanitarios en • ☐ Research funds España. Agencia Española de Medicamentos y Productos Sani- • ☐ Other. Please specify tarios. 2014. Available at: https​://www.aemps​.gob.es/publi​cacio​ nes/publi​ca/regul​acion​_med-PS/home.htm. Accessed on 14 Dec 7. Do you use any IT platform to manage and register the 2015. 10. Propuesta de colaboración para la elaboración de los informes de determination of a biomarker as a predictive biomarker posicionamiento terapéutico de los medicamentos. Agencia Espa- in response to the treatment of a given indication? ñola de Medicamentos y Productos Sanitarios. 2014. Available at: https​://www.aemps​.gob.es/medic​ament​osUso​Human​o/infor​ • ☐ Yes, please specify mesPu​blico​s/docs/propu​esta-colab​oraci​on-infor​mes-posic​ionam​ iento​-terap​eutic​o.pdf. Accesed on 22 Apr 2019. • ☐ No 11. Salvador J, Aparicio J, Barón FJ, García-Campelo R, García- Carbonero R, Lianes P, Garrido P. Equity, barriers and cancer 8. What is the average response time from the application disparities: study of the Spanish Society of Medical Oncology on for the determination until de availability of the result? the access to oncologic drugs in the Spanish Regions. Clin Transl Oncol. 2017;19(3):341–56. 9. Can you identify any barriers/limitations in your cen- 12. Garrido P, Aldaz A, Calleja MA, de Alava E, Lamas MJ, Martín tre to the access of the biomarker as a predictive bio- M, Matias-Guiu X, Palacios J, Vera R (2017) Farmacia hospita- marker in response to the treatment of the given indica- laria: órgano oficial de expresión científica de la Sociedad Espa- tion? ñola de Farmacia Hospitalaria 41(6):688–691.  Yes ☐ please specify No ☐ Publisher’s Note Springer Nature remains neutral with regard to 10. Please add any other relevant comments. jurisdictional claims in published maps and institutional affiliations. Reference 1. GLOBOCAN 2018. Available at: https​://gco.iarc.fr/tomor​row/. Accessed May 2020. 13