European Medicines Agency Approval Research Articles

Continued cancer drug approvals in Japan and Europe after market withdrawal in the United States: A comparative study of accelerated approvals.

Regulatory authorities must balance ensuring evidence of efficacy and safety of new drugs. Various regulatory pathways, such as the accelerated approval program in the United States (US), allow authorities to quickly approve drugs for severely ill patients by granting market authorization based on surrogate end points and pending confirmatory trials. In this cross-sectional study, we considered 23 indications of cancer drugs that received accelerated approval by the US Food and Drug Administration (FDA) but were subsequently withdrawn as of April 2023. Our investigation extended to assessing the regulatory status of these accelerated approvals in the European Union (EU) and Japan, examining relevant regulatory documents and identifying factors contributing to the withdrawal in the United States. Comparing regions, we found that for 52% (12/23) and 30% (7/23) of withdrawn accelerated approvals in the United States, sponsors had also sought marketing authorization from the European Medicines Agency (EMA) and Japan's Pharmaceuticals and Medical Devices Agency (PMDA), respectively. As of the April 30, 2023 study cutoff date, 83% (10/12) of drug-indication pairs remained approved by the EMA, while the PMDA retained 100% (7/7). For these indications, the time from FDA withdrawal until the study cutoff date ranged from 0.23 years to 11.45 years for EMA approvals (median: 1.28 years) and 1.10 years to 11.45 years for PMDA approvals (median: 3.22 years). These findings highlight substantial regulatory discrepancies concerning cancer drugs with unconfirmed benefits. Addressing these discrepancies may involve requiring pharmaceutical companies to confirm clinical benefits using more robust end points and fostering international harmonization in regulators' assessment.

Sarcoma drug approvals in Latin America compared to the FDA and EMA: An analysis by the LACOG Sarcoma Group.

e13731 Background: Drug approval processes by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) often shape regulatory decisions globally. This study describes the particularities of drug approval of systemic therapies for sarcomas by the FDA and EMA and compares them with those of three Latin American regulatory authorities: Brazil's ANVISA, Argentina's ANMAT, and Mexico's COFEPRIS. The aim is to elucidate the similarities and differences in approval practices, which may inform future regulatory strategies in these regions. Methods: We conducted a comprehensive review of all cancer drugs approved by the FDA and EMA for the treatment of sarcoma over the past 15 years and matched to approvals in Brazil, Argentina, and Mexico. These countries were chosen due to their population size and the accessibility of their health agencies’ databases. The regulatory agencies’ websites were consulted for the registration of drugs approved between January 1st, 2009, and January 1st, 2024. We analyzed the characteristics of studies, availability of approvals based on randomized controlled trials (RCTs), overall survival (OS), and the interval between FDA and EMA approvals compared to each of the three assessed Latin American regulatory agencies. Additionally, we included drugs granted tissue-agnostic approval, recognizing the potential necessity for sarcoma treatments to be guided by biomarker-driven decisions. Results: Over the past 15 years, 19 drugs have been approved for by the FDA to treat sarcomas, and 13 by the EMA. The FDA led the approvals, granting authorization to 18 of these treatments first, with Trabectedin being the sole exception, approved earlier by the EMA and COFEPRIS. Mifamurtide is the only new drug against sarcoma licensed by the EMA but not by the FDA. During this period Argentina approved 8 of these drugs, Mexico 7, and Brazil 6. When comparing the median approval times, there was a 3.03-year interval from the FDA to the Latin American agencies (range: -6 to 5.7 years) and a 3.22-year interval from the EMA (range: -0.2 to 11.8 years). Phase 3 trial-based approvals constituted 83.3% for COFEPRIS, 75% for ANMAT, 66.7% for ANVISA, 61.5% for EMA, and 36.8% for FDA. Regarding approvals contingent on OS data, ANMAT had 37.5%, ANVISA: 33.3%, COFEPRIS 28.5%, compared to EMA 23%, and FDA 10.5%. Additionally, within this timeframe, 52.3% of FDA approvals were contingent on biomarkers, compared to 50% for EMA, 10.5% for ANVISA, and 5.2% for both ANMAT and COFEPRIS. Conclusions: The observed discrepancies in drug approval timelines and the lower number of drug approvals in Latin American countries, as compared to those by the FDA and EMA, may exacerbate disparities in treatment accessibility for sarcoma patients in these regions. Approvals of sarcoma drugs by regulatory agencies of Latin American countries were more frequently conditioned to phase 3 trials and overall survival benefit.

Detailed analysis of metastatic colorectal cancer patients who developed cardiotoxicity on another fluoropyrimidine and switched to S-1 treatment (subgroup analysis of the CardioSwitch-study).

The CardioSwitch-study demonstrated that patients with solid tumors who develop cardiotoxicity on capecitabine or 5-fluorouracil (5-FU) treatment can be safely switched to S-1, an alternative fluoropyrimidine (FP). In light of the European Medicines Agency approval of S-1 in metastatic colorectal cancer (mCRC), this analysis provides more detailed safety and efficacy information, and data regarding metastasectomy and/or local ablative therapy (LAT), on the mCRC patients from the original study. This retrospective cohort study was conducted at 12 European centers. The primary endpoint was recurrence of cardiotoxicity after switch. For this analysis, safety data are reported for 78 mCRC patients from the CardioSwitch cohort (N = 200). Detailed efficacy and outcomes data were available for 66 mCRC patients. Data for the safety of S-1 in mCRC patients were similar to the original CardioSwitch cohort and that expected for FP-based treatment, with no new concerns. Recurrent cardiotoxicity (all grade 1) with S-1-based treatment occurred in 4/78 (5%) mCRC patients; all were able to complete FP treatment. Median progression-free survival from initiation of S-1-based treatment was 9.0 months and median overall survival 26.7 months. Metastasectomy and/or LAT was performed in 33/66 (50%) patients, and S-1 was successfully used in recommended neoadjuvant/conversion or adjuvant-like combination regimens and schedules as for standard FPs. S-1 is a safe and effective FP alternative when mCRC patients are forced to discontinue 5-FU or capecitabine due to cardiotoxicity and can be safely used in the standard recommended regimens, settings, and schedules.

High Concordance of Different Assays in the Determination of Homologous Recombination Deficiency-Associated Genomic Instability in Ovarian Cancer.

Poly(ADP-ribose) polymerase inhibitors (PARPi) have shown promising clinical results in the treatment of ovarian cancer. Analysis of biomarker subgroups consistently revealed higher benefits for patients with homologous recombination deficiency (HRD). The test that is most often used for the detection of HRD in clinical studies is the Myriad myChoice assay. However, other assays can also be used to assess biomarkers, which are indicative of HRD, genomic instability (GI), and BRCA1/2 mutation status. Many of these assays have high potential to be broadly applied in clinical routine diagnostics in a time-effective decentralized manner. Here, we compare the performance of a multitude of alternative assays in comparison with Myriad myChoice in high-grade serous ovarian cancer (HGSOC). DNA from HGSOC samples was extracted from formalin-fixed paraffin-embedded tissue blocks of cases previously run with the Myriad myChoice assay, and GI was measured by multiple molecular assays (CytoSNP, AmoyDx, Illumina TSO500 HRD, OncoScan, NOGGO GISv1, QIAseq HRD Panel and whole genome sequencing), applying different bioinformatics algorithms. Application of different assays to assess GI, including Myriad myChoice, revealed high concordance of the generated scores ranging from very substantial to nearly perfect fit, depending on the assay and bioinformatics pipelines applied. Interlaboratory comparison of assays also showed high concordance of GI scores. Assays for GI assessment not only show a high concordance with each other but also in correlation with Myriad myChoice. Thus, almost all of the assays included here can be used effectively to assess HRD-associated GI in the clinical setting. This is important as PARPi treatment on the basis of these tests is compliant with European Medicines Agency approvals, which are methodologically not test-bound.

Added benefit and revenues of oncology drugs approved by the European Medicines Agency between 1995 and 2020: retrospective cohort study

ObjectivesTo evaluate the added benefit and revenues of oncology drugs, explore their association, and investigate potential discrepancies between added benefit and revenues across different approval pathways of the European Medicines...

Scientific Review of the Proarrhythmic Risks of Oligonucleotide Therapeutics: Are Dedicated ICH S7B/E14 Studies Needed for Low-Risk Modalities?

Oligonucleotide therapeutics (ONTs) represent a new modality with unique pharmacological and chemical properties that modulate gene expression with a high degree of target specificity mediated by complementary Watson-Crick base pair hybridization. To date, the proarrhythmic assessment of ONTs has been influenced by International Conference on Harmonization (ICH) E14 and S7B guidance. To document current hERG/QTc evaluation practices, we reviewed US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) Approval Packages (source: PharmaPendium.com) and collated preclinical and clinical studies for 17 marketed ONTs. In addition, clinical QTc data from 12 investigational ONTs were obtained from the literature. Of the marketed ONTs, eight were tested in the hERG assay with no inhibitory effect identified at the top concentration (range: 34-3,000 μM) tested. Fourteen of the ONTs were evaluated in nonhuman primate cardiovascular studies with 11 of them in dedicated telemetry studies. No effect on QTc intervals were observed (at high exposure multiples) in all studies. Clinically, four ONTs were evaluated in TQT studies; an additional six ONTs were assessed by concentration-QTc interval analysis, and six by routine safety electrocardiogram monitoring. None of the clinical studies identified a QTc prolongation risk; the same was true for the 12 investigational ONTs. A search of the FDA Adverse Event Database indicated no association between approved ONTs and proarrhythmias. Overall, the collective weight of evidence from 29 ONTs demonstrate no clinical proarrhythmic risk based on data obtained from ICH S7B/E14 studies. Thus, new ONTs may benefit from reduced testing strategies because they have no proarrhythmic risk, a similar cardiac safety profile as monoclonal antibodies, proteins, and peptides.

Differences and Common Ground in 177Lu-PSMA Radioligand Therapy Practice Patterns: International Survey of 95 Theranostic Centers.

177Lu-labeled prostate-specific membrane antigen (PSMA) radioligand therapy effectively treats metastatic castration-resistant prostate cancer. Patients requiring treatment, and consequently the number of theranostic centers, are expected to increase significantly after Food and Drug Administration and European Medicines Agency approval. This requires standardization or harmonization among theranostic centers. The aim of this study was to assess operational differences and similarities among 177Lu-PSMA treatment centers. Methods: A questionnaire comprising 62 items, designed by a core team of 5 physicians and externally reviewed by international experts, was developed. Study participants were asked to provide answers about their center, patient selection, radiopharmaceuticals, clinical assessment before and after 177Lu-PSMA treatments, laboratory values, treatment discontinuation, posttreatment imaging, and general information. An invitation e-mail to participate in the study was sent in June 2022. Duplicates were removed to allow for only one valid response per center. Results: Ninety-five of 211 (45%) contacted centers completed the questionnaire. Most participating centers were in Europe (51%), followed by America (22%) and Asia (22%). During the 12 mo before this study, a total of 5,906 patients received 177Lu-PSMA therapy at the 95 participating centers. Most of these patients were treated in Europe (2,840/5,906; 48%), followed by Asia (1,313/5,906; 22%) and Oceania (1,225/5,906; 21%). PSMA PET eligibility for 177Lu-PSMA was determined most frequently using 68Ga-PSMA-11 (77%). Additional pretherapy imaging included 18F-FDG PET/CT, CT, renal scintigraphy, and bone scintigraphy at 41 (49%), 27 (32%), 25 (30%), and 13 (15%), respectively, of the 84 centers for clinical standard of care, compassionate care, or local research protocols and 11 (26%), 25 (60%), 9 (21%), and 28 (67%), respectively, of the 42 centers for industry-sponsored trials. PSMA PET eligibility criteria included subjective qualitative assessment of PSMA positivity at 33% of centers, VISION criteria at 23%, and TheraP criteria at 13%. The mean standard injected activity per cycle was 7.3 GBq (range, 5.5-11.1 GBq). Sixty-two (65%) centers applied standardized response assessment criteria, and PSMA PET Progression Criteria were the most applied (37%). Conclusion: Results from this international survey revealed interinstitutional differences in several aspects of 177Lu-PSMA radionuclide therapy, including patient selection, administered activity, and the response assessment strategy. Standardization or harmonization of protocols and dedicated training are desirable in anticipation of increasing numbers of patients and theranostic centers.

Pediatric Market Access: A Qualitative Study.

This qualitative study aims to analyze current PM regulation and market access requirements and proposes potential solutions to mitigate current challenges. Twenty-two semi-structured interviews were conducted with experts from pharmaceutical industry, regulatory authorities, national health technology assessment (HTA) bodies, pediatricians, and academia from the Netherlands (NL), Germany (DE), the United Kingdom (UK), and France (FR) to get insight into the pediatric research, the regulatory and reimbursement processes, challenges, and solutions. Themes for further testing were developed on how to facilitate pediatric market access. Atlas.ti 9 was used to analyze the findings. Heterogeneity in requirements for the European Medicines Agency (EMA) and HTA approvals are noted. By example, DE grants direct reimbursement after regulatory approval, the other countries require additional reimbursement which generate delays and challenges in patient access after marketing authorization. Key components in facilitating PM market access include multi-stakeholder collaboration, transparency, patient representatives, informed consent guidance, real-world evidence, and appropriate clinical trial designs. Pricing models based on the economic capabilities of individual countries could further reduce delays and challenges in market access. The additional specific pediatric incentives should be taken as best practice to encourage innovation in pediatric conditions. This study highlights differences in requirements for regulatory and reimbursement approval, along with international differences in pricing and reimbursement procedures for pediatric market access.

Systematic Literature Review and Meta-Analysis of Comparative Clinical Evidence Investigating Daratumumab, Lenalidomide, and Dexamethasone (DRd) Versus Bortezomib, Lenalidomide, and Dexamethasone (VRd) As First-Line Treatment for Transplant-Ineligible Newly Diagnosed Multiple Myeloma

Background: Daratumumab in combination with lenalidomide and dexamethasone (DRd) and bortezomib in combination with lenalidomide and dexamethasone (VRd) are currently the only guideline-recommended preferred regimens for primary treatment of transplant-ineligible (TIE) patients with newly diagnosed multiple myeloma (NDMM). The lack of direct head-to-head trials comparing these two preferred regimens makes it difficult for the treating physicians to select optimal frontline treatment for TIE NDMM patients. A number of network meta-analyses comparing the existing therapies in this patient population have been published; however, these studies have certain limitations such as not sufficiently accounting for heterogeneity among trials (MAIA trial included TIE patients only while SWOG S0777 had a mix of TIE and transplant not intended patients), variable duration of follow-up, inclusion of treatments not used in routine clinical practice in the US, and use of aggregate level data from the pivotal trials. Therefore, the current systematic literature review and meta-analysis (MA) aims to identify and aggregate clinical evidence specifically comparing DRd versus VRd as first-line (1L) treatment for TIE patients with NDMM across a wider evidence base, including indirect treatment comparisons and real-world evidence studies. Methods: The protocol was developed in alignment with the PRISMA for systematic review protocols (PRISMA-P) statement. The Population, Intervention, Comparator, Outcome, Study design (PICOS) framework was used to develop the search strategy and structure the reporting of the eligibility criteria. The search strategy was developed by a medical information specialist and peer reviewed. Ovid MEDLINE ®, Embase, and the Cochrane Library databases were searched from January 2019 to June 2023 along with key congresses (International Myeloma Society, American Society of Hematology, European Hematology Association, American Society of Clinical Oncology) from January 2018 to June 2023. These dates were implemented to identify recent literature and to align with the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) approvals of DRd for TIE NDMM. Study eligibility was assessed according to pre-specified criteria. Randomized clinical trials (RCTs) and adequately adjusted, non-randomized comparative studies comparing DRd versus VRd for treatment of adult TIE patients with NDMM were identified for inclusion. The primary outcome of interest was progression-free survival (PFS). Risk of bias was assessed using the National Institute for Health and Care Excellence (NICE) checklist. The feasibility of conducting a MA of the included studies was assessed. A frequentist approach was conducted for the MA considering the unit of analysis, varying treatment effects, and risk of bias. The study protocol is available on PROSPERO (CRD42023435119). Results: Of 863 records screened, 4 were included (1 publication and 3 conference abstracts), representing 3 unique studies. Two studies were indirect treatment comparisons and 1 was a retrospective chart review. In each study, TIE NDMM patients treated with DRd had a significantly lower risk of progression/death compared to those treated with VRd (Table 1). After qualitatively reviewing the evidence base and assessing between-trial clinical and methodological heterogeneity, it was considered feasible to conduct a MA of PFS including all 3 identified studies. Results from the MA (Figure 1) suggest that patients treated with DRd had a lower risk of progression/death compared to those treated with VRd (hazard ratio: 0.59, 95% confidence interval: [0.42-0.82]). Conclusions: Findings from the MA indicate that DRd is associated with a lower risk of disease progression/death compared to VRd as 1L treatment for TIE patients with NDMM. These findings could help inform the selection of optimal 1L treatment for these patients in the absence of head-to-head clinical trials.

Comparison between European Medicines Agency and US Food and Drug Administration in Granting Accelerated Marketing Authorizations for Covid-19 Medicines and their Utilized Regulations

BackgroundPrompted by the Covid-19 pandemic and the need to ensure timely and safe access to medicines during a pandemic, the aim of this study was to compare and contrast the EU and US regulations, processes, and outcomes pertaining to the granting of accelerated Marketing Authorizations (MAs) for COVID-19 vaccines and treatments with a view to determining how effective these regulations were in delivering safe medicines in a timely manner.MethodsMAs for medicines approved for Covid-related indications in the first two pandemic years (March 2020–February 2022) were identified using the European Medicines Agency (EMA) and US Food and Drug Administration (FDA) websites. Authorization reports and utilized regulations were reviewed to determine and compare approval timelines, facilitated pathways, accepted clinical evidence, and effectiveness of the regulations by assessing them against time and safety standards.ResultsBy the end of February 2022, the EMA and FDA had granted 12 and 14 MAs, respectively. Two EU and two US approvals were issued in relation to new indications for already-approved treatments; the remaining ones were first-time approvals of novel vaccines and treatments. The median time to approval was 24 days for the EMA’s conditional MAs and 36 days for the USFDA’s Emergency Use Authorizations (EUA) for all Covid-19 medicines. This is compared with 23 and 28 days, respectively, specifically for first-time novel vaccines and treatments authorized by both USFDA and EMA. The USFDA and EMA differed markedly in terms of the time taken to approve new indications of already-approved treatment; the USFDA took 65 days for such approval, compared with 133 days for the EMA. Where MAs were issued by both authorities, USFDA approvals were issued before EMA approvals; applications for approval were submitted to the FDA before submission to the EMA. Three EU and two US MAs were based on data from two or more phase 3 clinical trials; the remaining ones were based on single trial data. Only six EU and four US trials had been completed by the time of authorization. This was in line with regulations. While the applicable regulations shared many similarities, there were marked differences. For instance, the EU’s conditional MA regulation pertains only to first approvals of new treatments. It does not cover new indications of already-approved treatments. This contrasts with the US, where the EUA regulation applies to both types of applications, something that may have impacted approval timelines.Overall, both EU and US utilized regulations were considered to be effective. For most cases, utilizing such regulations for Covid-19 MAs resulted in faster approval timelines compared to standard MAs. They were flexible enough to manage the process of granting emergency approvals while maintaining strict requirements and allowing comprehensive reviews of the supporting evidence.ConclusionUS and EU regulations were effective in ensuring timely accelerated market access to Covid-19 medicines during the pandemic without compromising the approval standards related to safety or efficacy. The population in both regions will receive comparable access to medicines during a pandemic if sponsors submit their applications to both authorities in parallel.

The characteristics and regulations of adaptive designs from 2008 to 2020: An overview of European Medicines Agency approvals.

The aim of this study was to identify and characterize all European Medicines Agency (EMA) approvals derived from adaptive designs in clinical trials and to provide an update of the current status of these drugs. Relevant files were identified in the EMA database for annual reports for the period between 2008 and 2020 using a list of suitable keywords related to adaptive designs. We recorded trial characteristics from drug approvals and used Fisher exact test to compare the characteristics. A total of 1,054 EMA approvals were identified, and the percentage of EMA approvals planned with adaptive trial designs increased from 1.85% in the period 2008-2012 to 6.19% in between 2017-2020. A total of 41 approvals were identified among 91 original EMA files that contained adaptive designs. The types of adaptive designs used in clinical trials increased after 2017 where the most common type used was the most common (17/41). Most approvals (32/41) comprised pivotal trials, and most assessments had not been accelerated (38/41). Of 32 confirmatory trials planned with adaptive designs, the proportion of those with additional monitoring (AM) increased significantly (p<0.0001) from 0% in the 2008-2012 period to 90.48% in the 2017-2020 period. The percentage of approved antitumor drugs in approved drugs in ongoing clinical trials was 82.35%, compared to 20.83% in trials that were completed (p=0.0001). The proportion of drug approved but where clinical trials were still ongoing in companies requiring post-authorization safety studies (PASSs) or post-authorization efficacy studies (PAESs) or who were granted conditional marketing authorization (CMA) significantly differed from the group of drugs approved where clinical trials were completed (p=0.0230). A trend showing an increased number of EMA approvals related to adaptive designs was observed for the period from 2008 to 2020. Different types of adaptive trial designs could be encouraged for the designation of clinical trials, especially for antitumor drugs; meanwhile, more stringent monitoring regulations seemed to be conducted for ongoing trials of antitumor drugs with adaptive design.

Enfortumab Vedotin in Metastatic Urothelial Carcinoma: Survival and Safety in a European Multicenter Real-world Patient Cohort

BackgroundTreatment options for patients with urothelial cancer (UC) refractory to platinum and immunotherapy are limited and survival is short. Enfortumab vedotin (EV) is a monoclonal anti-NECTIN4 antibody conjugated to monomethyl auristatin. It was recently approved because of superior survival in comparison to standard-of-care (SOC) chemotherapy. Real-world patients, however, often have worse characteristics than patients included in clinical trials. ObjectiveTo analyze the efficacy and safety of EV in a cohort of real-world patients. Design, setting, and participantsRetrospective data were collected from 23 hospitals and private practices for patients with metastatic and previously treated UC who received EV either when reimbursed by their insurance company before European Medicines Agency (EMA) approval, within a compassionate use program, or as SOC treatment after EMA approval. Imaging and therapy management were in accordance with local standards. Outcome measurements and statistical analysisAdverse events (AEs) were reported according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 criteria. Objective responses were evaluated according to Response Evaluation Criteria in Solid Tumors version 1.1. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Results and limitationsThe median age for the 125 eligible patients was 66 yr (range 31–89). The Eastern Cooperative Oncology Group performance status (ECOG PS) was 0–1 for 76.0%, 2–4 for 13.6%, and unknown for 10.4% of patients. EV was administered in the fourth or later line for 44.8% of patients. The overall response rate was 41.6% (partial response 39.2%, complete response 2.4%). Median OS was 10.0 months (mo) (95% confidence interval 7.20–12.80) and median PFS was 5.0 mo (95% confidence interval 4.34–5.67). For patients with ECOG PS of 0–1, median OS was 14 mo. Any-grade AEs were observed in 67.2% and CTCAE grade ≥3 AEs in 30.4%. The most common AEs were peripheral sensory neuropathy and skin toxicity. Three fatal events (pneumonia, pneumonitis) occurred. Limitations include the retrospective design and short follow-up. ConclusionsAdministration of EV for real-world patients was feasible with an acceptable toxicity profile. No new safety signals were reported. Antitumor activity in our cohort was comparable to data previously reported for trials. In summary, our results support the use of EV in patients with metastatic UC. Patient summaryEnfortumab vedotin is a medication that improved the survival of patients with bladder cancer in comparison to standard chemotherapy in clinical trials. However, patients included in clinical trials are highly selected and results for toxicities and improvements in survival do not always transfer to the real-world setting. We analyzed data for 125 patients who were treated with enfortumab vedotin. Our results are comparable to the outcomes from clinical trials regarding the safety and efficacy of this treatment.

Process of drug registration in Israel: the correlation between the number of discussions within the Ministry of Health and postapproval variations by EMA and/or FDA

ObjectivesUS FDA and EMA allow facilitated regulatory pathways to expedite access to new treatments. Limited supportive data may result in major postapproval variations. In Israel, partly relying on Food and...

The therapeutic value of treatment for multiple sclerosis: analysis of health technology assessments of three European countries.

In accordance with European regulation, medicines containing a new active substance to treat neurodegenerative diseases as well as autoimmune and other immune dysfunctions must be approved by the European Medicines Agency (EMA) through the centralized procedure before they can be marketed. However, after EMA approval, each country is responsible for national market access, following the assessment performed by health technology assessment (HTA) bodies with regard to the therapeutic value. This study aims to provide a comparative analysis of HTA recommendations issued by three EU countries (France, Germany, and Italy) for new drugs for multiple sclerosis (MS) following EMA approval. In the reference period, we identified 11 medicines authorized in Europe for MS, including relapsing forms of MS (RMS; n = 4), relapsing-remitting MS (RRMS; n = 6), secondary progressive MS (SPMS; n = 1), and the primary progressive form (PPMS; n = 1). We found no agreement on the therapeutic value (in particular, the "added value" compared to the standard of care) of the selected drugs. Most evaluations resulted in the lowest score ("additional benefit not proven/no clinical improvement"), underlining the need for new molecules with better efficacy and safety profiles for MS, especially for some forms and clinical settings.

A Review of Labeling Based on Patient-Reported Outcome Endpoints for New Oncology Drugs Approved by the European Medicines Agency (2017-2021)

ObjectiveA review of new oncology indications approved by the European Medicines Agency (EMA) for 2012-2016 showed that 33% of new drugs had labeling based on patient-reported outcomes (PROs). We reviewed labeling text based on PRO endpoints for new oncology indications approved during 2017-2021. MethodsNew oncology drugs approved by EMA to treat indications of cancers during 2017-2021 were identified from the EMA website. PRO-related language reported in EMA summaries of product characteristics (SmPCs) were summarized and compared with similar findings reported for oncology indications approved during 2012-2016. ResultsReview documents by the EMA during 2017-2021 were available for 49 new oncology drugs for 70 cancer indications. Submissions for 52 (74.3%) of the 70 indications included PRO data for EMA review. Of all submissions, 14 (20.0%) approvals contained PRO-related language in the SmPC. Broad concepts such as health-related quality of life were most common and found in 8 of 14 (57.1%) PRO-related labels. ConclusionPRO-related language appeared in SmPCs for 20% of all indications of new oncology drugs approved by EMA during 2017-2021 compared with approximately 33% of EMA approvals during 2012-2016. PRO-related labeling during the same periods showed a greater decline (from 47% to 27%) for indications of new oncology drugs that also included PRO data. One possible reason for this decline may be the increase in open-label studies from 62% between 2012 and 2016 to approximately 79% between 2017 and 2021.

Financing and Reimbursement of Approved Advanced Therapies in Several European Countries

ObjectivesThe uncertainty in the cost-benefit of advanced therapy medicinal products (ATMPs) is a current challenge for their reimbursement in health systems. This study aimed to provide a comparative analysis of the National Health Authorities (NHAs) reimbursement recommendations issued in different European countries. MethodsThe NHA reimbursement recommendations for the approved ATMPs were compared among 8 European Union (EU) Countries (EU8: Ireland, England/Wales, Scotland, The Netherlands, France, Germany, Spain, and Italy). The search was carried out until December 31, 2021. ResultsA total of 19 approved ATMPs and 76 appraisal reports were analyzed. The majority of the ATMPs were reimbursed, although with uncertainty in added therapeutic value. No relationship between the type of the European Medicines Agency approval and reimbursement was found. Managed entry agreements, such as payment by results, were necessary to ensure market access. The main issue during the evaluation was to base the cost-effectiveness analyses on assumptions because of the limited long-term data. The estimated incremental cost-effectiveness ratio among countries reveals high variability. Overall, the median time to NHA recommendation for the EU8 is in the range of 9 to 17 months. ConclusionsTransparent, harmonized, and systematic assessments across the EU NHAs in terms of cost-effectiveness, added therapeutic value, and grade of innovativeness are needed. This could lead to a more aligned access, increasing the EU market attractiveness and raising public fairness in terms of patient access and pricing.

Recurrent laryngeal papillomatosis

Human papillomaviruses (HPV)6 and11 cause 90% of recurrent laryngeal papillomatosis (RLP). It is unclear whether recurrences are caused by new infections or the spread of infected cells. Symptomatic and sometimes curative treatment is laser surgery or conventional microsurgical removal. RLP surgery aims to relieve shortness of breath and improve the voice. Patients (especially children) are affected by voice problems, repetitive surgeries, pulmonary manifestations, and psychological trauma. Vaccination with Gardasil9 (Merck & Co., Rahway, NJ, USA) prevents new infections with HPV6, 11, 16, 18, 31, 33, 45, 52, and58 and induces vaccine antigen-specific antibodies and CD4+ Thelper cells. According to current studies, RLP can be avoided with prophylactic vaccination. The treatment is associated with ageneral vaccination risk (European Medicines Agency approval: girls and boys from 9years). Studies also show that the vaccine after removal of HPV-associated neoplasia/papilloma prevents recurrences. Extension of the vaccination recommendation to prevent recurrences of HPV-associated diseases in men may promote applicability and herd immunity. For rare and treatment-refractory cases with laryngotracheal involvement, systemic therapy with bevacizumab (e.g. Avastin; Genentech, San Francisco, CA, USA), aVEGF antibody, is apromising adjuvant treatment option.

Value assessment of medicinal products by the Italian Medicines Agency (AIFA) and French National Authority for Health (HAS): Similarities and discrepancies.

The evaluation of pharmaceutical innovation and therapeutic value is an increasingly complex exercise for which different approaches are adopted at the national level, despite the need for standardisation of processes and harmonisation of public health decisions. The objective of our analysis was to compare the approaches of the AIFA (Agenzia Italiana del Farmaco) and the HAS (Haute Autorité de Santé) in assessing the same medicinal products. In Italy, the 1525/2017 AIFA Deliberation introduces a transparent scheme for the evaluation of innovative status (innovative, conditional, not innovative) based on the therapeutic added value (TAV), therapeutic need, and quality of evidence. In contrast, in France, the HAS makes judgements using the effective clinical benefit (Service Médical Rendu) and improvement of effective clinical benefit (Amélioration du Service Médical Rendu, ASMR). This analysis focused on medicinal products evaluated both by the AIFA and by the HAS from July 2017 to September 2021. Similarities between AIFA and HAS evaluations were investigated in terms of the TAV, recognition of innovativeness, and the ASMR. Both total and partial agreements were considered relevant. Therefore, raw agreement, Cohen's kappa (weighted and unweighted), and Bangdiwala's B-statistic were estimated. A total of 102 medicinal products were included in this study. Out of these, 38 (37.2%) were orphan drugs, while 56 (54.9%) had a clinical indication for the treatment of cancer. The AIFA and HAS reached a higher level of agreement on the innovativeness status compared with the TAV. A moderate total agreement emerged in the recognition of innovativeness (k = 0.463, p-value ≤0.0001), and partial agreement was substantial (equal weight k = 0.547, squared k = 0.638), while a lack of agreement resulted in a comparison of the TAV according to the AIFA and the ASMR recognised by the HAS. Indeed, whereas the AIFA determined the TAV to be important, the HAS considered it to be moderate. In addition, whereas the AIFA identified a bias towards a moderate TAV, the HAS identified a bias towards a minor ASMR. A higher level of agreement was reached, both on the TAV and on innovative status, for less critical medical products (non-cancer-related, or non-orphan, or with a standard European Medicines Agency approval). These results underline the importance of implementing European procedures that are more broadly aligned in terms of value definition criteria.

1693P Incidence of NTRK genes fusion in adult brain tumours: A prospective cohort of 140 patients with cerebral gliomas and brain metastases

Oncogenic fusion of neurotrophin receptor tyrosine kinase NTRK1, NTRK2, or NTRK3 genes have been found in different types of solid tumours. Nevertheless, the incidence of NTRK gene fusions in these cancers remains quite unexplored. The treatment of patients with TRK fusion cancer with a first-generation TRK inhibitor (such as larotrectinib or entrectinib) is associated with high response rates (>75%), regardless of tumour histology and presence of metastases, and acceptable toxicity profile. Due to the efficacy of TRK inhibitor therapy and the recent Food and Drug Administration and European Medicines Agency approval of larotrectinib and entrectinib, it is clinically important to identify patients accurately and efficiently with TRK fusion cancer.

Large Predominance of Off-Label Prescriptions of C1-Inhibitor Concentrates and Icatibant in a Real-Life Setting: A Retrospective Clinical Study.

C1-inhibitor (C1INH) concentrates and the selective bradykinin B2 receptor antagonist icatibant are approved only for treating hereditary angioedema with C1INH deficiency. Yet, they are regularly prescribed off label in other types of bradykinin-mediated angioedema including angiotensin-converting enzyme inhibitor (ACEi)-related and undetermined angioedema. We conducted a retrospective chart review of inpatient prescriptions of C1INH concentrates and icatibant between 2016 and 2020 in the University Hospital of Angers. The first outcome was the proportion of prescriptions with explicit indication. Then, we determined the compliance of prescriptions with European Medicines Agency approvals and the French bradykinin-mediated angioedema reference center guidelines. Finally, we estimated the economic impact of inappropriate prescribing. The therapeutic indication was explicit in 90.4% of prescriptions (n=66/73). Only 17.8% of prescriptions were for hereditary angioedema with C1INH deficiency, while 31.5% were for ACEi-related and 28.7% for undetermined angioedema. However, most off-label prescriptions were consistent with the French bradykinin-mediated angioedema reference center guidelines (73.3%). We estimated that 13% of drug expenditures were potentially excessive. The predominance of off-label prescriptions may be explained by the infrequency of hereditary angioedema and the absence of approved alternatives in other types of bradykinin-mediated angioedema. Most attacks were related to ACEis. Epinephrine was rarely prescribed as first-line therapy in attacks of unknown origin. Given the high prices of these drugs, we advocate the development of a readily available management algorithm of angioedema to reduce inappropriate prescriptions in our center. In addition, we think that the drug prescription circuit should be redesigned to ensure the traceability of prescribed vials in the dispensing areas.