Early Access Programs Research Articles

Early access programs for medical devices in France: Overview of recent reforms and outcomes (2015-2022)

The medical technology sector is characterised by a constant influx of innovations with the potential to revolutionise patient care. In France, there are several pathways for medical devices to enter the market, from diagnosis-related group tariffs to reimbursement lists. However, traditional regulatory pathways can delay market access for innovative technologies. In response, France has established Early Access Programs to expedite patient access to medical devices. This paper looks at three of these Early Access Programs for medical devices. Innovation Funding, introduced in its final version in 2015, provides temporary coverage for innovative devices and facilitates data collection for informed funding decisions. Transitional Coverage (PECT), established in 2021, targets CE-marked devices for rare or serious conditions. Transitional coverage for digital health applications (PECAN), introduced in 2022, covers digital medical devices, either therapeutic or for patient monitoring. Innovation funding has been granted to 16 technologies out of 35 applications (46%) since 2015. 6 technologies out of 11 (64%) applications benefit from PECT. PECAN, in its first year, has granted a telemonitoring solution with a favourable opinion. The French experience could provide valuable lessons for the development of a harmonised European framework to ensure that innovative medical technologies benefit those who need them, while maintaining high safety standards.

Early access programs for medicines: a reform proposal for the Italian National Health Service

The present paper illustrates a reform proposal on early access for medicines. In this proposal early access stands for patient’s access, outside of clinical trials and covered by the Italian National Health Service (Servizio Sanitario Nazionale, SSN), to a new medicine or an indication of an already approved medicine before the approval o in between the approval and the decision on price and reimbursement status. The proposal emerged from a multi-stakeholder working group within the Sixth Edition of the “Seminari di Mogliano Veneto”. The reform proposal is aimed at converting the current early access programs (mainly, the programs introduced with Laws 648/96 and 326/03) into a single program inspired by the one introduced in France in 2021. The proposal provides indications on eligibility criteria for drugs and patients, application procedure, evaluation process, economic safeguard clauses, data collection, issues derived from the circumstance that the drug/indication included into the early access program is not reimbursed afterwards and the actions to implement this program.

Linking an early access program (EAP) to the National Health Data System (NHDS) in France and assessing its performances and potential biases.

11137 Background: Early access programs (EAP) are a unique opportunity to document first use of innovative treatments in real-world settings. The French HTA body requires mandatory patients’ clinical data collection for EAP and since July 2021, has recommended anticipating linkage EAP to the National Health Data System (NHDS). Prior to drug initiation, the collected data is almost complete contrary to follow-up data. To the best of our knowledge, no other study has proposed a methodology to link EAP to the French Cancer cohort (FCC), an extract of the NHDS of over 8 million persons diagnosed or at high risk of cancer, and to assess its assets and downsides. Methods: This cohort study has reused data of informed French EAP patients treated with durvalumab from October 1st, 2017 to December 31st, 2018 (n=457) in locally advanced unresectable NSCLC and of patients who received durvalumab at the time of the EAP in the FCC (n=666). The linkage methodology consists in harmonizing available data across sources, defining matching, control and study variables, testing several indirect deterministic linkage algorithms and assessing their performances. Consistency and differences between data sources were described for the best performing algorithm. Results: Proposed linkage algorithms required matches on a combination of data among sex, birth year and month, treating hospital ID and department. Performance started at 80.9% (370/457) patients from the EAP cohort linked to eligible patients from FCC up to 85.3% (390/457) for the best performing algorithm. The consistency of linkage variables between the two sources was substantial (Cohen’s kappa > 0.8) or excellent (intraclass correlation > 0.9). It was the same for control variables. Comparisons between linked patients and unlinked patients from the EAP cohort showed no statistically significant difference on matching and control variables, except for few cases on history of chemotherapy and history of radiation therapy prior to durvalumab. Similarly, no statistically significant difference was found on matching and control variables between linked patients and unlinked patients from FCC, except for history of radiation therapy and treating hospital department. Median of time difference between foreseen date of first durvalumab administration in EAP versus the effective date in FCC was -1 (IQR = [-9 ; 0]) day. Lack of reported diagnosis related to prior radiation therapy administration in out-of-hospital settings refrained from using them as matching or control variables. Conclusions: The study illustrates the feasibility of matching EAP patients to the French NDHS with indirect deterministic linkage. Additional EAP linkages will be required to ensure the validation and reproducibility of such methodology. Further works in progress will document the adequacy of French NHDS data to address effectiveness.

Isatuximab plus pomalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma in real-world: The retrospective IMAGE study.

IMAGE is a retrospective cohort study of patients enrolled in early access programs (EAPs) in France with relapsed/refractory multiple myeloma (RRMM) receiving isatuximab with pomalidomide and dexamethasone (Isa-Pd). Patients aged ≥18 years with RRMM who received ≥1 dose of Isa under the EAPs between July 29, 2019 and August 30, 2020 were included. Effectiveness endpoints included progression-free survival (PFS) and response rates. Verbatim terms for adverse events (AEs) were coded using the Medical Dictionary for Regulatory Activities and not graded for severity. A total of 294 and 299 patients were included in the effectiveness and safety populations, respectively. IMAGE included patients who received one prior line of treatment (10.2%) and were daratumumab-refractory (19.1%). At median follow-up of 14.2 months, median PFS in the effectiveness population was 12.4 months (95% CI 9.0-15.0). Overall response and very good partial response rates were 46.3% and 27.9%, respectively. Subgroup analyses reflected similar results. In the safety population, 26.4% of patients reported at least one AE; the most common any-grade AE was neutropenia (9.4%). IMAGE demonstrated Isa-Pd had meaningful effectiveness in median PFS and depth of response and no new safety signals in a real-world context, consistent with clinical trial results.

Abstract PO4-04-14: Change of first-line treatment pattern in metastatic luminal breast cancer: Results from the Austrian AGMT_MBC-Registry

Abstract Background: For patients with HR+/HER2- (luminal) metastatic breast cancer (MBC), international guidelines recommend endocrine-based first-line therapy [ET] in combination with a CDK4/6 inhibitor for most patients. Only for patients with imminent organ failure, first-line chemotherapy should be considered. To clarify changing patterns of first-line treatments over time in an Austrian population of luminal MBC patients, we analyzed the data from the MBC registry of the Austrian Study Group for Medical Tumor Therapy (AGMT-MBC-Registry). Methods: The AGMT-MBC-Registry is an ongoing multicenter registry for MBC patients in Austria. Only patients with luminal MBC and sufficient outcome data were included in this analysis. Patients were assigned to one of the following groups according to the year of start of first-line treatment for MBC: 2001-2010, 2011-2013 (no CDK4/6i available for first-line in both periods), 2014-2016 (CDK4/6i available in early access programs and clinical trials for first-line only), 2017-2019, and 2020-2022 (CDK4/6i available in both periods). Time to first chemotherapy (TTC) defined as start of first-line treatment until first application of a cytotoxic agent, and overall survival (OS) defined as start of first-line treatment until death were calculated by the Kaplan-Meier method and compared using the log-rank test. OS analysis was adjusted for disease free survival (DFS) category (de novo, DFS < 24 month, DFS ≥ 24 month), menopausal status (pre-, postmenopausal, unknown), age at diagnosis of metastatic disease (continuous), number of metastatic sites at diagnosis (1, 2-3, > 3), visceral disease (no, yes), and Charlson comorbidity index at diagnosis (continuous). Results: As of May 16th 2023, 1,330 patients with HR+/HER2- disease receiving at least one treatment-line for MBC were evaluable. First-line treatments significantly changed over time (P < 0.001). In patients diagnosed between 2001 and 2010, 61.4% were treated with first-line chemotherapy compared to 10.0% in patients diagnosed between 2020 and 2022 (Table 1). Additionally, TTC also significantly increased over time (P < 0.001; Table 2). In contrast, the proportion of patients treated with a first-line CDK4/6i plus endocrine therapy combination increased over time from 4.4% in 2014-2016 up to 75.5% in the period of 2020-2022. Additionally, adjusted median overall survival estimates significantly increased over time (P < 0.001; Table 2). Conclusion: In our registry, the proportion of patients with luminal MBC treated with first-line chemotherapy significantly decreased over time, whereas the proportion or patients treated with first-line CDK4-6 inhibitors significantly increased. This is in line with the change of guideline recommendation as well as the availability of CDK4-6 inhibitors over the last 2 decades. The availability of new treatment options has significantly increased median overall survival over time. Table 1: First-line treatment pattern over time Period N ET ET plus CDK4/6i Chemotherapy Others* 2001-2010 220 84 (38.2%) 0 (0.0%) 135 (61.4%) 1 (0.5%) 2011-2013 238 116 (48.7%) 0 (0.0%) 110 (46.2%) 12 (5.0%) 2014-2016 318 174 (54.7%) 14 (4.4%) 99 (31.1%) 31 (9.7%) 2017-2019 293 60 (20.5%) 190 (64.8%) 36 (12.3%) 7 (2.4%) 2020-2022 249 22 (8.8%) 188 (75.5%) 25 (10.0%) 14 (5.6%) Overall 1,318 456 (34.6%) 392 (29.7%) 405 (30.7%) 65 (4.9%) Legend: N - number of patients, ET - endocrine therapy (tamoxifen, aromatase inhibitor and/or fulvestrant), CDK4/6i - CDK4/6 inhibitor; * e.g. endocrine treatment plus everolimus or investigational study treatment Table 2: Time to first chemotherapy (TCC) and overall survial (OS) over time Period Median TTC [months] Adjusted median OS [months] 2001-2010 0.0 (0.0 - 0.0) 49.4 (41.2 - 56.6) 2011-2013 4.3 (0.0 - 13.8) 48.2 (38.3 – 69.7) 2014-2016 20.0 (14.0 - 26.4) 60.3 (50.2 - 77.5) 2017-2019 40.1 (33.3 - 59.8) 60.8 (52.8 - NR) 2020-now 30.4 (27.6 - NR) NR (NR - NR) Legend: N - number of patients, NR - not reached Citation Format: Gabriel Rinnerthaler, Simon Gampenrieder, Angelika Pichler, Walter Herz, Andreas Petzer, Renate Pusch, Marija Balic, Christoph Suppan, Sonja Heibl, Lukas Scagnetti, Margit Sandholzer, Clemens Schmitt, August Zabernigg, Daniel Egle, Petra Pichler, Christopher Hager, Florian Roitner, Johannes Andel, Kathrin Strasser-Weippl, Rupert Bartsch, Michael Hubalek, Michael Knauer, Christian F. Singer, Richard Greil. Change of first-line treatment pattern in metastatic luminal breast cancer: Results from the Austrian AGMT_MBC-Registry [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-04-14.

HTA172 Value of French Framework for Early Access Programs for the HTA Appraisal in the Rare Disease Space: The Example of Lanadelumab in Patients With Hereditary Angioedema

HTA172 Value of French Framework for Early Access Programs for the HTA Appraisal in the Rare Disease Space: The Example of Lanadelumab in Patients With Hereditary Angioedema

HTA97 Exploring the Value of RWD Collected From Early Access Programs to Support HTA Decision-Making

HTA97 Exploring the Value of RWD Collected From Early Access Programs to Support HTA Decision-Making

HPR43 Are There Any Common Denominators for Early Access Programs in Europe?

HPR43 Are There Any Common Denominators for Early Access Programs in Europe?

Isatuximab Plus Pomalidomide and Dexamethasone in Patients with Relapsed and/or Refractory Multiple Myeloma (RRMM) in Real-Life Context in France: IMAGE Subgroup Analysis Based on Prior Lines of Therapy and Refractory Status in Anti-CD38-Naïve Population

Introduction: Isatuximab, a CD38 monoclonal antibody (mAb), targets a specific CD38 epitope to induce myeloma cell death. Based on the results of the Phase 3 ICARIA-MM study, isatuximab (Isa) plus pomalidomide (P) and dexamethasone (d; Isa-Pd) is approved in adult patients (pts) with relapsed/refractory multiple myeloma (RRMM) who have received ≥2 prior therapies. Prior to Isa-Pd regulatory approval, Isa was available in France under early access programs (EAPs). IMAGE is a non-interventional, retrospective cohort study of pts treated with Isa-Pd under the French EAPs. In the IMAGE overall effectiveness population (median follow-up 14.2 months [mo]), median progression-free survival (mPFS) was 12.4 mo; overall response rate (ORR) was 46.3%; 27.9% of pts achieved a very good partial response (VGPR) and best response was VGPR for 60.3% of pts. In the current myeloma landscape, not all pts with RRMM have received a prior anti-CD38 mAb, particularly where access is difficult; thus, the real-world effectiveness of Isa in daratumumab (dara)-naïve pts needs to be assessed in light of the Phase 3 APOLLO and ICARIA-MM trials investigating dara-Pd and Isa-Pd in dara-naïve populations. Effectiveness results from the IMAGE subgroup analysis of dara-exposed and -refractory pts have been presented previously. Here, we describe results for dara-naïve pts based on prior lines of therapy (LOT) and lenalidomide (len)-refractory status. Methods: Data were collected from medical records of adult pts with RRMM who received ≥1 dose of Isa under the EAPs from 29 Jul 2019-1 Sep 2020. The effectiveness analysis was restricted to pts with ≥1 year of follow-up after Isa initiation. PFS was defined as the time from Isa-Pd initiation to date of disease progression or death. VGPR was defined as a ≥90% reduction in serum or urine M-protein, or in the difference between involved and non-involved free light chain. The description of adverse events (AEs; verbatim) was recorded as a reason for treatment temporary or permanent discontinuation or dose reduction. Data were recorded per the subject's medical file. No specific grading was performed. Results: The safety population included 299 pts who received ≥1 Isa dose under the EAPs; of these, 294 received ≥1 Isa dose and met all inclusion/exclusion criteria, thus comprising the effectiveness population. Within the overall effectiveness population, 216 (73.5%) pts were dara-naïve; among them, 13.4%, 58.8%, and 27.8% received 1, 2, and ≥3 prior LOT, respectively; 72.2% were len-refractory (median 2 prior LOT); and 54.2% were len-refractory at last prior LOT. At a median follow-up of 14.2 mo, mPFS (95% CI) in dara-naïve pts was not reached (NR; 14.6-NR), 15.0 mo (10.6-NR), and 14.8 mo (7.6-NR) with 1, 2, and ≥3 prior LOT, respectively; 13.2 mo (9.0-18.6) in those refractory to len; and 13.2 (9.0-NR) in those refractory to len at last prior LOT. ORR (of which, VGPR) was 41.4% (17.2%), 52.0% (34.6%), and 50.0% (31.7%) in pts with 1, 2, and ≥3 prior LOT, respectively; 49.4% (29.5%) in len-refractory pts; and 50.4% (29.9%) in len-refractory at last prior LOT pts (Table). At least 1 AE was reported in 53 (24.4%) pts in the dara-naïve safety population (n=217): 7 (24.1%), 32 (25.2%), and 14 (23.0%) in the 1, 2, and ≥3 prior LOT subgroups, respectively; 41 (26.1%) in the len-refractory subgroup; and 32 (27.4%) in the len-refractory at last prior LOT subgroup. AEs led to permanent Isa discontinuation in 3 (2.4%) pts with 2 prior LOT; 3 (1.9%) len-refractory pts; and 2 (1.7%) len-refractory at last prior LOT pts. The most common AEs were blood and lymphatic system disorders, occurring in 39 (18.0%) pts. Infections and infestations were reported in 2 (0.9%) pts: 1 had received 1 prior LOT and 1 had 2 prior LOT; both pts were len-refractory at last prior LOT. Conclusions: In the dara-naïve populations from APOLLO (dara-Pd) and ICARIA-MM (Isa-Pd), mPFS was 12.4 and 11.1 mo, respectively. This subgroup analysis of IMAGE provides real-world evidence of Isa effectiveness in dara-naïve subgroups: Isa-Pd demonstrated a high mPFS of 16.6 mo in dara-naïve pts and meaningful mPFS at first and subsequent relapse, including in difficult-to-treat len-refractory pts; mPFS was generally comparable to that of the overall effectiveness population. No new safety signals were observed compared with ICARIA-MM. However, the incidence of some AEs like infections was low, possibly due to the retrospective nature of the study. Funding: Sanofi.

Why We Fail: An Analysis of Terminated Interventional Clinical Trials in Lymphoma

Introduction: Clinical trials serve as the cornerstone for advancing therapeutic and clinical strategies in Lymphoma. Learning from prematurely terminated trials provides valuable insights for researchers and drug developers. This study analyses interventional clinical trials in lymphoma terminated between 2010 and 2023, aiming to identify common factors contributing to their failure and improve future research in Lymphoma. Methods The study identified clinical trials in Lymphoma registered in the US between 01/01/2010, and 01/07/2023, using the InovaSight platform. The analysis included trials investigating drugs in phases I-III with at least one recruited patient. Phase 4 studies, early access programs, and trials examining medical devices were excluded, as were trials terminated early due to positive efficacy signals. Natural language processing (NLP) & classification algorithms were used to categorize trials into distinct phases of clinical development and were also applied to identify reasons for trial termination from official registrations and relevant publications. These reasons were then characterized using the InovaSight trial ontology for thematic analysis. Enriching features, including mechanism of action information, design characteristics, target enrolment, and inclusion criteria, were generated and linked for each eligible trial. The analysis was conducted using the InovaSight drug development platform, which employs responsible artificial intelligence to expedite the development of novel therapeutics for haematological malignancies. Results: A total of 306 trials met the inclusion criteria, with phase II trials being most frequently withdrawn (49.3%), followed by phase I (42.5%) and phase III (8.2%). The trials spanned from 2010-01-31 to 2021-12-15. Among terminated studies, single-arm trials were most frequent (64%), followed by two-armed designs (21.2%) and three or more arms (14.7%). A concentration of mechanisms of action were observed across all phases (further described in poster). Reasons for early termination included enrolment issues, sponsor decisions, lack of efficacy, safety concerns, funding withdrawal, investigator-related issues, study irrelevance, drug supply problems, COVID-19, and unspecified reasons. The most common reason for early termination was enrolment issues in Phase I and Phase II studies, and sponsor decisions in Phase III studies. Detailed results are presented in Figure 1. Discussion: Our analysis identified a total of 306 trials that met the inclusion criteria, encompassing different phases of clinical development. Interestingly, phase II trials were the most frequently withdrawn, followed by phase I and phase III trials. This observation suggests that a considerable number of trials face challenges during the intermediate stages of development, which could be attributed to various factors such as safety concerns, lack of efficacy, or financial constraints. Our analysis revealed a concentration of similar mechanisms of action across all trial phases. This finding suggests that certain therapeutic areas or drug targets may be more prone to early termination. Exploring the underlying reasons for this pattern could provide valuable insights for future trial planning and design (This is further elucidated in the full presentation). Among the various reasons for early termination, enrolment issues emerged as the most common factor in both Phase I and Phase II studies. This highlights the critical need for in depth and principled approaches to study feasibility assessment routed in an evidence-based methodology. In contrast, sponsor decisions were the leading cause of termination in Phase III trials. This finding suggests that late-stage trials are more susceptible to decisions made by the trial sponsors, which could be influenced by factors such as financial considerations or market dynamics. The results underscore the importance of careful trial planning, patient recruitment strategies, and effective collaboration between sponsors, investigators, and regulatory bodies. Understanding the challenges and factors contributing to trial termination can aid in optimizing future trial designs, mitigating risks, and improving the efficiency of drug development processes.

Программы раннего доступа лекарственных препаратов: опыт БРИКС, Европейского Союза, Соединенных Штатов Америки

Timely accessibility of effective and safe medicinal products is one of the main tasks of healthcare. The goal of the present review is to assess various approaches that provide an early access to medicinal products within the BRICS group (list of participants as of 01.10.2023), European Union and United States of America. The stage of the life cycle of medicinal products is closely associated with their further movement in the market, patient access rate, and partially with the issues of their financing and reimbursement, which directly influence their affordability for population. The article contains data about the specifics of expanded access to unregistered medicinal products used on a compassionate basis and presenting therapy under early access programs financed by pharmaceutical companies; it also describes approaches to accelerated registration and registration of medicinal products in case of limited clinical data. Experience of the reviewed countries in early access programs is described.

Differences in time to patient access to innovative cancer medicines in six European countries.

Patients across Europe face inequity regarding access to anticancer medicines. While access is typically evaluated through reimbursement status or sales data, patients can receive first access through early access programs (EAPs) or off-label use. This study aims to assess the time to patient access at the hospital level, considering different indications and countries. (Pre-)registered access to six innovative medicines (Olaparib, Niraparib, Ipilimumab, Osimeritinib, Nivolumab and Ibritunib) was measured using a cross-sectional survey. First patient access to medicines and indications were collected using the hospital databases. Nineteen hospitals from Hungary, Italy, the Netherlands, Belgium, Switzerland and France participated. Analysis showed that some hospitals achieved patient access before national reimbursement, primarily through EAPs. The average time from EMA-approval to patient access for these medicines was 2.1 years (Range: -0.9-7.1 years). Hospitals in Italy and France had faster access compared to Hungary and Belgium. Variation was also found within countries, with specialized hospitals (x̄: -0.9 years; SD: 2.0) more likely to provide patient access prior to national reimbursement than general hospitals (x̄: 0.4 years; SD: 2.9). Contextual differences were observed, with EAPs or off-label use being more prevalent in Switzerland than Hungary. Recent EMA-approved indications and drug combinations reached patients at a later stage. Substantial variation in patient access time was observed between and within countries. Improving pricing and reimbursement timelines, fostering collaboration between national health authorities and market authorization holders, and implementing nationally harmonized, data-generating EAPs can enhance timely and equitable patient access to innovative cancer treatments in Europe.

How to shorten the market entry innovation in a highly regulated market. The case of Early access programs in the pharmaceutical industry

Government regulation impacts deeply on the innovation process. Regulatory frameworks influence firms’ innovativeness. This study aims to provide an exploratory investigation of Early Access programs as a tool to shorten the time to place innovation in highly regulated markets. Thus, our research question is: How do institutional actors push the entry of innovation in highly regulated markets? To address the research question, a qualitative analysis was conducted using the multiple case study method among different countries. The analysis practised an inductive approach. The results provide an inductive conceptual framework to identify different configurations of Early Access programs based on three characterizing dimensions: (1) authorities involved, (2) eligibility criteria and (3) applicant. This study provides implications for both theory and practice. Future research will be needed to investigate the emerging aspects further and make the model generalisable.

Temporal trends of atypical drug access at an academic oncology unit: The Verona University Hospital experience.

e13651 Background: In Italy, patient (pt) access to oncological drugs is almost exclusively provided by the NHS, following authorization by the European Medicines Agency (EMA) and negotiation with the Italian Medicines Agency (AIFA) for specific indications. However, regulatory delays (with respect to the availability of scientific evidence) and the need for rapid access to innovative drugs, particularly in the context of orphan and rare diseases, have prompted the utilization of atypical drug access pathways. In addition to enrollment in clinical trials, atypical drug access pathways are expected to be increasingly used in the context of a Precision Oncology practice. Methods: We explored trends in atypical drug access at the Oncology Section of the Verona University and Hospital Trust, by interrogating Oncology and Pharmacy databases and regional registries of rare diseases and reviewing AIFA registries records. Data on atypical drug access were also correlated with the use of NGS-based molecular profiling. Results: Between January 2016 and December 2022, a total of 355 atypical drug access requests for the treatment of cancer pts were recorded, with a peak in 2017 and no discernible temporal trend. Over this period, the two most common atypical access schemes were compassionate (including named patient and early access programs, 61%) and off-label (21%) use. The latter steadily increased over time (from 8% in 2017 to 39% in 2021). Overall, the type of drugs requested through atypical access were almost equally distributed between classical cytotoxic agents (CHT, 36%), immuno-oncology drugs (IO, 29%) and molecularly targeted agents (TT, 35%). Temporal trends in the usage of different classes of drugs are shown. Interestingly, TT requests decreased between 2016 and 2018 and stabilized at approximately 50% of total requests since 2019. Between 2019 and 2021, atypical drug access requests triggered by NGS-based extended molecular profiling significantly increased from 2.8% to 23.1% (p=0.0007). Conclusions: Although atypical drug access did not increase overall during the observation period, a trend towards increased off-label use of TT was identified, especially from 2019 onwards; figures for 2022 are being analyzed and will be presented at the Meeting. Since 2019, NGS-informed requests have significantly increased to constitute almost 1/4 of all atypical drug access requests, clearly identifying a trend towards implementation of Precision Oncology in routine clinical practice and evolving towards the implementation of Molecular Tumor Board case discussions. [Table: see text]

IMPRESS-Norway: Improving public cancer care by implementing precision cancer medicine in Norway.

e15188 Background: Precision cancer medicine is evolving rapidly, with new drugs and biomarkers being developed. Advanced molecular diagnostics is a prerequisite for using some of the drugs, which might be approved on small or large subsets of patients. Drugs targeting a specific pathway or gene aberration, might be efficient in other tumour types harbouring the same molecular alteration, but not yet tried in randomized trials due to limited number of patients. This indicates that patients might benefit drugs that are on the market, not available for patients outside the existing indication. Methods: In this national-wide, investigator-initiated, prospective, open-label, non-randomized combined basket- and umbrella-trial, patients are enrolled into multiple parallel treatment cohorts. Patients with progressive disease on standard therapy, are eligible. Each cohort is defined by the patient’s tumour type, molecular profile, and study drug. Treatment outcome in each cohort is assessed by using a Simon two-stage-like ‘admissible’ monitoring plan to identify evidence of clinical activity. All drugs available in IMPRESS-Norway have regulatory approval and are funded by pharmaceutical companies. Currently, 21 drugs are provided by six different pharmaceutical companies, and we are in process to acquire additional drugs for patients in this study. Molecular diagnostics with the TSO-500 gene panel are funded by the public health care system. In addition, patients included are offered analyses of circulating tumour DNA (ctDNA). The primary objective is to evaluate clinical benefit of treatment at 16 weeks of treatment, defined as complete response, partial response, or stable disease. Results: IMPRESS-Norway opened for accrual at April 1st 2021. As of January 24, 2023, tumour cells from 791 patients with advanced cancer, have been analysed with TSO-500, and 662 patients had been discussed at the national molecular tumour board. 150 patients (23%) were allocated to therapy in different treatment-cohorts in IMPRESS-Norway, and 11% were referred to other ongoing clinical studies or early access programs. Extended and updated data and frequency of targetable molecular alteration will be presented. Conclusions: Patients with advanced cancer progressing on standard treatment are referred to treatment in IMPRESS-Norway after advanced molecular diagnostics. Genetic alterations indicating benefit of the drugs currently available in the study, are detected in 23% of 662 evaluated patients. Clinical trial information: NCT04817956 .

Early access programs for medicines: comparative analysis among France, Italy, Spain, and UK and focus on the Italian case

Early access programs (EAPs) generally refer to patient access to medicines/indications before marketing authorization, possibly extended to price and reimbursement approval. These programs include compassionate use, which is usually covered by pharmaceutical companies, and EAPs reimbursed by third-party payers. This paper aims at comparing EAPs in four European countries (France, Italy, Spain, UK) and providing empirical evidence on EAPs in Italy. The comparative analysis was conducted through a literature review (including scientific and grey literature), complemented by 30-min semi-structured interviews with local experts. The Italian empirical analysis employed data available on the National Medicines Agency website. Although EAPs are very different across countries, they exhibit some common features: (i) eligibility criteria refer to the absence of valid therapeutic alternatives and a presumed favourable risk–benefit profile; (ii) payers do not allocate a pre-determined budget to these programs; (iii) total spending on EAPs is unknown. The French EAPs seem to be the most structured, financed through social insurance, covering pre-marketing, post-marketing and pre-reimbursement phases and providing for data collection. Italy’s approach to EAPs has been varied, with several programs covered by different payers, including the cohort-based 648 List (for both early access and off-label use), the nominal-based 5% Fund, and Compassionate Use. Most applications to EAPs are from the Antineoplastic and immunomodulating drug class (ATC L). Some 62% of indications in the 648 List are either not under clinical development or have never been approved (pure off-label use). For those subsequently approved, most approved indications coincide with those covered through EAPs. Only the 5% Fund provides data on economic impact (€ 81.2 million in 2021; average cost per patient € 61.5K). Diverse EAPs are a possible source of inequalities in access to medicines across Europe. A harmonization of these programs, though difficult to achieve, could be modelled on the French EAPs and provide key advantages, not least of which a common effort to collect real-world data in parallel with clinical trials and clear separation between EAPs and off-label use programs.

Compassionate drug uses in Italy. Analysis of regional and local diffusion.

Compassionate drugs are provided to patients with a specific disease and no further treatment option, most frequently via Early (or Expanded) Access Programs. In Italy, it often occurs that compassionate uses concern medicines whose price has not been negotiated yet (and therefore unavailable on the market), although their use has been approved in Europe. Thus, compassionate drug uses turn out to be a way to expedite the access to new innovative drugs with demonstrated efficacy. This study aims to investigate how widespread is the use of compassionate drugs throughout the Country. We analyzed data from 20 early access programs implemented by 2 pharmaceutical companies in the last few years. Data were analyzed by the number of patients and centers in each Region and province, and a correlation was established between patients and centers in each Region and the resident population. A further analysis was carried out with the same criteria on the subpopulation of oncology patients, including more than 80% of total study population. In our sample, 7529 patients received compassionate drug treatments in 348 centers throughout Italy. A significant correlation exists between the resident population in each Region and the number of requesting centers (r2=0.877) and patients treated (r2=0.844) in the Region. Taking the value of the linear regression slope as the expected one, certain Regions show a better "performance", in terms of more patients treated than expected, namely Umbria, Emilia-Romagna, Lazio, Lombardy, Tuscany, Liguria and Friuli Venezia-Giulia. In this study we showed that the use of compassionate drugs in Italy is diffused in a manner closely related to the population of each Region. A number of Regions - mostly but not exclusively from the South and Island areas - show a performance below the expectations, in terms of patients treated.

Isatuximab Plus Pomalidomide and Dexamethasone in Patients with Relapsed and/or Refractory Multiple Myeloma in Real-Life Context in France: IMAGE Subgroup Analysis Based on Prior Lines of Therapy and Refractory Status

Introduction: Isatuximab (Isa) plus pomalidomide (P) and dexamethasone (d; Isa-Pd) is approved in patients with relapsed/refractory multiple myeloma (RRMM) who have received ≥2 prior therapies, based on the Phase 3 ICARIA-MM study (NCT02990338). Prior to Isa-Pd regulatory approval, Isa was available in France under early access programs (EAPs). In the non-interventional, retrospective IMAGE study, we analyzed the progression-free survival (PFS) and safety among French pts with RRMM treated with Isa-Pd under the EAPs. Here, we report results from the interim subgroup analysis of the IMAGE study based on prior lines of therapy (LOT) and refractory status. Methods: The IMAGE study was conducted based on medical records of adult patients with RRMM who received ≥1 dose of Isa under the EAPs. The analysis of effectiveness endpoints was restricted to patients with ≥1 year of follow-up after Isa initiation. PFS was defined as the time from start of Isa-Pd to date of disease progression or death. Refractoriness was defined per IMWG criteria. Adverse events (AEs) were not graded for severity. Verbatim terms for AEs were coded using the Medical Dictionary for Regulatory Activities. Results: Across 62 study sites in France, 299 patients who had received ≥1 Isa dose under the EAPs from 29 Jul 2019 -1 Sep 2020 were included in the safety population; the effectiveness population included 294 pts who met all inclusion/exclusion criteria. In contrast to ICARIA-MM, the IMAGE study included daratumumab-refractory patients and patients who had received only 1 prior LOT. In the effectiveness population, 10.2%, 49.0%, 40.8% received 1, 2, and ≥3 prior LOT, respectively; 96.3% had lenalidomide; 26.5% had daratumumab; 73.1% were lenalidomide-refractory; and 19.1% were daratumumab-refractory. At a median follow-up of 14.2 months (mo), median PFS (mPFS) of the overall effectiveness population was 12.4 (95% CI 9.0-15.0) mo (Table) with a median 2 prior LOT; this is similar to that reported for daratumumab plus Pd (12.4 mo) in the APOLLO study and for Isa-Pd (11.1 mo) in the ICARIA-MM study, where patients received a median of 2 and 3 prior LOT, respectively. Median PFS was not reached (NR; 95% CI 9.6-NR), 13.6 (95% CI 10.2-NR), and 7.6 (95% CI 4.4-11.8) mo among patients with 1, 2, and ≥3 prior LOT, respectively; 9.0 (95% CI 6.4-12.4) mo in lenalidomide-refractory subgroup; and 10.6 (95% CI 6.8-15.0) mo in lenalidomide-refractory at last prior LOT (Table). Within the lenalidomide-refractory subgroup, mPFS (95% CI) was NR (6.8-NR), 10.6 (6.8-NR), and 5.0 (3.2-7.8) mo with 1, 2, and ≥3 prior LOT, respectively. Among daratumumab-naïve patients, median PFS (95% CI) was 16.6 (13.2-NR) mo. Patients exposed to daratumumab had a median washout period of 6.5 mo between last daratumumab injection and Isa initiation. Patients exposed and refractory to daratumumab had a mPFS of 3.0 (2.4-4.8) mo with a median washout period of 4.0 mo, while patients who were exposed to daratumumab but were not refractory had a mPFS of 8.4 (95% CI 2.8-NR) mo and a median washout period of 9.5 mo. At least 1 AE was reported in 8 (26.7%), 38 (26.4%), and 33 (26.4%) patients in 1, 2, and ≥3 prior LOT subgroups; 60 (27.5%) in lenalidomide-refractory subgroup; and 43 (30.7%) in lenalidomide-refractory at last prior LOT subgroup. AEs led to permanent Isa discontinuation in 3 (2.1%) patients with 2 prior LOT, 1 (0.8%) patient with ≥3 prior LOT, 4 (1.8%) patients in lenalidomide-refractory subgroup, and 3 (2.1%) patients in lenalidomide-refractory at last prior LOT subgroup. Conclusions: In this subgroup analysis of the IMAGE study based on prior LOT and refractory status, Isa-Pd demonstrated meaningful mPFS with a manageable safety profile at first and second relapse and in the difficult-to-treat lenalidomide-refractory subgroups. Importantly, a high mPFS of 16.6 mo was reported for daratumumab-naïve patients. In the APOLLO and ICARIA-MM trials investigating daratumumab plus Pd and Isa-Pd in a daratumumab-naïve population, mPFS was 12.4 and 11.1 mo respectively. The IMAGE study shows daratumumab-refractory patients do not respond well to Isa-Pd. However, as PFS outcomes were favorable in patients who were exposed to but not daratumumab-refractory, anti-CD38 antibody sequencing in successive therapies may be a good alternative in real-world practice when patients may be exposed to daratumumab but not refractory. Funding: Sanofi. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Effectiveness and Safety of Belantamab Mafodotin in Patients with Relapsed or Refractory Multiple Myeloma in Real-Life Setting: The ALFA Study

Introduction: Although the therapeutic landscape for multiple myeloma (MM) has expanded, MM is an incurable disease and treatment of patients (pts) with relapsed or refractory multiple myeloma (RRMM) remains challenging. Pts triple refractory to immunomodulators (IMIDs), proteasome inhibitors (PIs), and anti-CD38 antibodies have few therapeutic alternatives and poor prognosis. Belantamab mafodotin (blmf) is a first-in-class antibody-drug conjugate targeting B-cell maturation antigen (BCMA) and showed promising results in the DREAMM-2 trial. The aim of the ALFA study is to describe blmf effectiveness and safety in pts with RRMM in a real-life setting. Methods: ALFA is a non-interventional, retrospective study of pts with RRMM initiating blmf in 46 centers in France during early access programs from April 27, 2020, to June 30, 2021. Pts characteristics, overall response rate (ORR, ≥partial response [PR]), clinical benefit rate (CBR, ≥minimal response [MR]), ≥very good PR (VGPR) rate, progression-free survival (PFS), overall survival (OS), and safety were assessed. Subgroup analyses for PFS and OS were performed according to best response, CBR, cytogenetic risk, renal failure, age at blmf initiation, previous penta-exposition (at least 2 PIs, 2 IMIDs, and 1 anti-CD38 exposition), and number of prior lines of treatment. Results: Between April 2020 and June 2021 (median duration of follow-up 7.8 months [mo]), 184 pts initiated blmf. Median time from MM diagnosis to initiation of blmf was 6 years, and 107 pts (58%) had received ≥5 prior lines of therapy. At initiation, 53% were male, median age was 70 years with 30% of pts aged of 75 years or older; 49% had renal failure; 79% were penta-exposed; and 8% had extramedullary disease. Among pts with available data (n=156), 36.5% had an ECOG PS ≥2. Cytogenetic profiles at initial diagnosis were available for 87 pts (47%), among whom 27 (33%) had high cytogenetic risk defined as pts presenting either t(4;14) or del(17p) or t(14;16); 40% had ophthalmological history (cataract in 53%). Blmf was delivered by intravenous infusion in 21-days cycles according to SmPC. Median dose at initiation was 2.5 mg/kg (min max 1.6-3.0). The median number of blmf cycles received was 3 (Q1-Q3 2-7). The ORR was 35% (≥VGPR 21%, PR 14%) and 59 pts (39%) achieved clinical benefit; 25% had stable disease (SD) and 37% had progressive disease (PD). The median PFS (mPFS) for the whole population was 2.7 mo (95 CI% 1.9-3.3), and median OS (mOS) was 9.5 mo (95 CI% 7.2-11.9). For both OS and PFS, no differences were found in subgroups according to cytogenetic risk, renal failure, age at blmf initiation, penta-exposition, and number of prior lines. According to best response, mPFS was 20.6 mo (95 CI% 13.1 to not reached) in pts with ≥VGPR, 6.6 mo (95 CI% 5.1-7.7) in pts with PR or MR and 2.8 mo (95 CI% 2.1-3.7) in pts with SD; P<0.01 (Figure 1). mOS was not reached in pts with ≥VGPR (1-year survival rate 96.7% [95 CI% 90.2-100.0]), 17.5 mo (95 CI% 9.8 to not reached) in pts with PR or MR, 9.5 mo (95 CI% 5.4-12.2) in pts with SD, and 3.3 mo (95 CI% 2.5-5.8) in pts with PD; P<0.01 (Figure 2). In pts with a clinical benefit, mPFS was 9.7 mo (95 CI% 7.5-14.9) and mOS was not reached. Safety findings were consistent with the known profile of blmf. Adverse events (AEs) were reported in 159 pts (86.4%). Most frequent reported AEs were ocular AEs in 56.0% of pts (n=103), among whom 70 pts had keratitis/keratopathy, and thrombocytopenia in 13.0% of pts. Infusion reaction was reported in 2.7% of pts. Permanent discontinuation due to AEs occurred in 12.5% of pts. Ocular AEs led to dose modification, temporary interruption, and permanent discontinuation in 19.6%, 11.4%, and 12.0% of pts, respectively. Conclusions: The ALFA study confirms the results of belantamab mafodotin as reported in the DREAMM-2 trial. In the overall population, the ORR was 35% (21% with ≥VGPR), CBR was 39%, mPFS was 2.7 mo, and mOS was 9.5 mo. In patients with a clinical benefit, mPFS was 9.7 mo and mOS was not reached. No new safety concerns were identified. These data presented from the largest real-life study conducted to our knowledge confirm previous results. Funding: GSK (214820) Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Impact of FDA-Approved Novel Agents for Steroid-Refractory Chronic Graft-Vs. Host Disease on Treatment Patterns and Outcomes - a Single Center Longitudinal Cohort Analysis

Background - Chronic graft vs host disease (cGVHD), explicitly steroid-refractory disease, is associated with substantial morbidity and mortality in patients undergoing allogeneic hematopoietic cell transplantation (HCT). Since 2018, access to novel immunosuppressive therapies (IST) for steroid-refractory GVHD have become available via clinical studies, early-access programs and private insurances. We aimed to analyze changes in treatment pattern and thus outcomes during the last decade in this population. Methods - We included all patients above the age of 18 years who developed cGVHD after first allogeneic transplantation performed between 2012 and 2020 in the Tel Aviv Sourasky Medical Center. We divided the patient cohort into 3 treatment periods according to clinical trials available/FDA approved drugs - 2012-2014 (group 1), 2015-2017 (group 2), and 2018-2020 (group 3). The NIH 2004 criteria was used to define chronic GVHD. All patients were managed by the same medical team with a well-established long-term survival program. Data was extracted on July, 2022. Results - between 2012 and 2020, 301 patients underwent HCT, of them 222 survived more than 3 months and 91 (41%) developed chronic GVHD and fulfilled the inclusion criteria. Median follow-up was 51 (range, 13-97) months. There was no statistically significant differences in patient characteristics between the 3 groups, except of older age and greater employment of reduced intensity conditioning in patients included in group 3, Table 1a. All patients, except 1, received GCSF-moblized peripheral blood stem cells and all patients receiving matched-unrelated donor allografts, were given anti-thymocyte globulin. 92% of patients were managed with steroids as first line treatment for cGVHD. Patients in the second and third group, compared to the first, received lower mean cumulative dose of steroids/kg/day (p=.008) and fewer mean number of treatment days for cGVHD (p=.042). However, there was no difference between the groups in the proportion of number of steroids treatment days/total days of treatment of cGVHD (p=0.72), Table 1b. The median IST-free survival was 79 (95% CI 54-94) months, with a higher percentage of patients in group 3 able to discontinue IST at 3 years from GVHD onset, though this did not reach statistical significance (p=0.1). Regarding long-term complications, patients in cohort 2/3 had better diabetes control (p<0.001), a trend for lower cardiovascular complications, and a higher bone density (p=0.06). A significantly higher proportion of patients returned to work in cohort 2 and 3 (56% and 43%, respectively) compared to cohort 1 (20%) in a shorter period of time from HCT (p=0.05 and p=0.01). There was no difference in the incidence of depression/anxiety. There was no difference in 3-year relapse incidence (p=0.54), non-relapse mortality (p=0.69) and overall survival (0.68). Cox regression analysis identified lower platelets at the onset of cGVHD and the employment of reduced intensity regimen, as being associated with shorter survival (P=.005, HR-1.1 and p=.049, HR-3.5, respectively), while patient's group, sex, age and eosinophil count ,did not impact survival. Conclusions - this real-world data clearly show that incorporation of FDA-approved novel agents for the management of cGVHD is associated with reduced overall steroid consumption and a better control of metabolic long-term complications. While these effects significantly improve some aspects of quality of life, these modifications in therapy are yet to be translated to survival advantage. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal