Marketing Authorization Approval Research Articles

Pharmacological and Benefit-Risk Profile of Once-Weekly Basal Insulin Administration (Icodec): Addressing Patients' Unmet Needs and Exploring Future Applications.

Diabetes mellitus (DM) is a chronic metabolic disease affecting over 500 million people worldwide, which leads to severe complications and to millions of deaths yearly. When therapeutic goals are not reached with diet, physical activity, or non-insulin drugs, starting/adding insulin treatment is recommended by international guidelines. A novel recombinant insulin is icodec, a once-weekly insulin that successfully completed phase III trials and that has recently obtained the marketing authorization approval from the European Medicines Agency. This narrative review aims to assess icodec pharmacological and clinical features concerning evidence on benefit-risk profile, as compared to other basal insulins, addressing the potential impact on patients' unmet needs. Icodec is a full agonist, recombinant human insulin analogue characterized by an ultra-long half-life (196 h), enabling its use in once-weekly administration. Phase III randomized clinical trials involving more than 4000 diabetic patients, mostly type 2 DM, documented non-inferiority of icodec, as compared to currently available basal insulins, in terms of estimated mean reduction of glycated hemoglobin levels; a superiority of icodec, compared to control, was confirmed in insulin-naïve patients (ONWARDS 1, 3, and 5), and in patients previously treated with basal insulin (ONWARDS 2). Icodec safety profile was comparable to the currently available basal insulins. Once-weekly icodec has the potential to improve patients' adherence, thus positively influencing patients' treatment satisfaction as well as quality of life, especially in type 2 DM insulin-naïve patients. An improved adherence might positively influence glycemic target achievement, reduce overall healthcare costs and overcome some of the unmet patients' needs. Icodec has the potential to emerge as a landmark achievement in the evolution of insulin therapy, with a positive impact also for the National Health Services and the whole society.

Access to Innovative Medicines: Regulation Change and Factors Associated with Drug Approval Lag in Malaysia.

Drug approval lag is the time difference for new medicine to obtain marketing authorization approval in the study country compared to the first global approval. Drug approval lag delays the availability of innovative medicine to patients. This may lead to delay in treatment and severe public health implications. The study aimed to determine drug approval lag in Malaysia, the factors associated with drug approval lag (drug characteristics, regulatory factors and applicant type) and the association of the submission lag and review time with the regulation change. All new pharmaceutical products approved between January 2015 and March 2021 were examined (n = 136) using publicly available information. Factors associated with drug approval lag were determined using multiple linear regression. The median drug approval lag was 855days. Drug approval lag was associated with drug characteristics and regulatory factors. Median submission lag and median review time for products which fulfilled the requirement for the new regulations (Conditional Registration/ Facilitated Registration Pathway) were shorter compared to products which did not fulfil the requirement. Drug approval lag may delay the access of innovative medicine to patients, and this may lead to an increase in morbidity, mortality and healthcare costs. Good Regulatory Practices ensure efficient and transparent regulatory system which support the public health policy objectives in the most efficient way. The new regulations in Malaysia reduced the median submission lag and review time. The findings may be useful for regulators to consider for future policy development for medication access.

Analysing criteria for price and reimbursement of orphan drugs in Spain

ObjectiveThere are differences between countries regarding data requirements for orphan drug evaluation and it is also unknown which criteria might determine the price and reimbursement decision. This study aimed to identify the key criteria for price and reimbursement of orphan drugs in Spain, approved by the European Commission, between January 2012 and June 2018. MethodA descriptive analysis of the orphan drugs and its characteristics was performed. Outcomes criteria assessed were: therapeutic area, existence of alternative treatment, rarity of the disease, clinical trial outcomes and therapeutic positioning report assessment. Hypotheses for each variable regarding Spanish pricing and reimbursement were made and tested with two regression analyses. ResultsOut of 78 orphan drugs approved by the European Commission, 82.1% asked pricing and reimbursement in Spain. From this, 43.8% had pricing and reimbursement approved and 20.3% rejected. Mean time from Spanish marketing authorisation approval to pricing and reimbursement approval was 12.1 ± 5.1 months. Having a positive therapeutic positioning report and no therapeutic alternatives would be associated with a positive pricing and reimbursement in Spain. ConclusionsIt remains challenging to establish which are the driving criteria for pricing and reimbursement approval of orphan drugs in Spain. Further research should be done including other variables that might influence the pricing and reimbursement final decision in Spain.

How does the vaccine approval procedure affect COVID-19 vaccination intentions?

People's willingness to vaccinate is critical to combating the COVID-19 pandemic. We devise a representative experiment to study how the design of the vaccine approval procedure affects trust in newly developed vaccines and consequently public attitudes towards vaccination. Compared to an Emergency Use Authorization, choosing the more thorough Conditional Marketing Authorization approval procedure increases vaccination intentions by 13 percentage points. The effects of the increased duration of the approval procedure are positive and significant only for Emergency Use Authorization. Treatment effects do not differ between relevant subgroups, such as respondents who had (did not have) COVID-19, or between vaccinated and unvaccinated respondents. Increased trust in the vaccine is the key mediator of treatment effects on vaccination intentions.

Expert opinion on the treatment of vulvovaginal atrophy with ospemifene based on new evidence

Vulvovaginal atrophy (VVA) is an underdiagnosed and undertreated chronic condition resulting in physiological and histological changes in the genitourinary tract of postmenopausal women. Treatment of moderate to severe VVA includes local estrogens, dehydroepiandrosterone (DHEA) and oral ospemifene, a third-generation selective estrogen receptor modulator (SERM). Due to venous thromboembolism (VTE) safety concerns classically associated with the SERM class, and as part of its original marketing authorization approval (MAA), the European Medicines Agency (EMA) requested the performance of a 5-year post-authorization safety study (PASS) to study the incidence rate of VTE among women receiving ospemifene. The results have led to important regulatory changes to ospemifene’s labeling, extending its indication and eliminating concerted risk management measures. A panel of experts discussed and reached consensus on the impact of these regulatory changes on clinical practice, reflecting on the reassurance of ospemifene’s benefit–risk balance and recommending its positioning as a first-line pharmacological treatment option for moderate to severe VVA together with local therapies. In a scenario where different treatments present similar efficacy and safety profiles, a shared decision between clinician and patient, according to her needs and preferences over time, is fundamental to improve adherence and persistence with sequential treatment, contributing to the achievement of health outcomes.

Hemophilia “A” gene therapy: Lost in translation

Successful gene therapy for hemophilia A had been considered as one of the “holy grails” in the gene therapy field. An important milestone toward realizing this goal had been achieved (https://www.ema.europa.eu/en/news/first-gene-therapy-treat-severe-haemophilia) following the first conditional marketing authorization approval in the European Union for an adeno-associated virus type 5 (AAV5)-based gene therapy strategy.1 Most of the treated patients remained off prophylaxis and bleed-free 2 years after dosing and up to 5 years in a supporting trial.

Current Regulatory Requirements for Biosimilars in Six Member Countries of BRICS-TM: Challenges and Opportunities.

Background: The aim of the study was to identify, interpret, and compare the current perspectives of regulatory agencies in six member countries of BRICS-TM (Brazil, Russia, India, China, South Africa, Turkey, and Mexico) on the different criteria used for biosimilar development and marketing authorisation process.Methods: A semi-quantitative questionnaire was developed covering the organisation of agency, biosimilar development criteria and marketing authorisation process and sent to seven regulatory agencies covering the BRICS-TM countries. All data was kept anonymous and confidential. Data processing and analysis was carried out; descriptive statistics were used for quantitative data and content analysis was employed to generate themes for qualitative data.Results: Out of the seven regulatory agencies included in the study, six representatives provided the responses. The perspectives of these six regulatory agencies varied on a number of aspects relating to the review criteria for biosimilar development and licencing process. The most prevalent model for data assessment is the “full review” of a marketing authorisation application. There is lack of a standard approach across the agencies on sourcing of the reference biological product, in vivo toxicity studies and confirmatory clinical studies. Most agencies restrict interaction with biosimilar developers and any scientific advice is non-binding. The marketing authorisation approval depends on scientific assessment of the dossier, sample analysis and GMP certification. The agencies do not issue any public assessment report specifying the summary basis of biosimilar approval.Conclusion: Regulatory agencies across the six emerging economies are steadily improving the regulatory mechanism in the area of biosimilars. However, there remains scope for increasing the effectiveness and efficiency of the processes by encouraging open and transparent interaction with developers, adopting a flexible approach toward accepting advanced analytical data in lieu of clinical studies and enhancing regulatory reliance amongst agencies. This will help to simplify the new biosimilar development programmes and make them more cost-effective.

A question of information mismatch in the SPC and PIL on the effect of ADHD stimulant medications on tourette's syndrome

AimsTo assess the quality of information provided by pharmaceutical companies to patients and doctors regarding the impact of stimulant medications indicated for the treatment of Attention Deficit Hyperactive Disorder (ADHD) on Tourette's syndrome(TS) and tics in children and its implication on treatment.BackgroundIt is estimated that between 35% to 90% of TS patients also have ADHD. However, there remains a pervasive belief that the use of stimulants to treat ADHD symptoms in children with comorbid tic disorders is contraindicated because of concerns about possible tic exacerbation. Recent studies has disproved this, which is reflected in United Kingdom(UK) and European ADHD and TS guidelines. Pharmaceutical companies are legally required to provide a Summary of Product Characteristic (SPC) and Patient Information Leaflet (PIL) for each medicine as it is an integral part of the marketing authorisation approval. The SPC contains vital information for the usage and prescription of a drug for use by healthcare professionals. The PIL included in the medication packaging is a patient-friendly version of the SPC.MethodThe available stimulant medications licenced for use in paediatric patients with ADHD in the UK were identified through the Medicines & Healthcare products regulatory Agency (MHRA) website. The SPC and PIL were then accessed from the Electronic Medicines Compendium (EMC) website. Those not on the site were obtained directly from the marketing authorisation holder. Any direct mention of tics or Tourette's in the contraindication, warning and caution, or side effect section were documented. The information was then tabulated and compared.ResultOf the three stimulant drug types, 17 variations are currently available for use in the UK. There were inconsistencies found between the SPC and PIC in reference to the impact of these drugs on tics and TS in all 17 licensed medication. Most discrepancy was found in regard to TS as a side effect (16/17) and also tics (15/17). TS is also listed as a contraindication in the SPC and PIL for all available variety of Dexamphetamine class drugs. This is inconsistent with current clinical evidence and guidelines.ConclusionThe disparities in information regarding the impact of stimulant medications on tics and TS can have wide ranging effects. Outcomes could include poor patient adherence, or prevention of initiation of potentially beneficial treatment. It would benefit to standardize the information between these two documents to minimize inconsistencies in understanding between doctor and patient.

PCN259 How Accelerated Is Patients' Access to New Oncology Products in the New Era of the Cancer Drugs Fund in England, Considering the IMPACT of the 2018 New Technology Appraisal Process

This research provides an update on a poster presented at ISPOR Europe 2018 reviewing the accelerated appraisal timetable proposed in April 2016 by National Health Service England (NHSE) and National Institute for Health and Care Excellence (NICE) to publish final guidance within 90-days of an oncology drug indication receiving its’ marketing authorisation (MA), following reforms to the Cancer Drugs Fund (CDF) in 2016. To reassess the time taken from MA to publication of final NICE guidance for new oncology Technology Appraisals (TA) against the NICE target of 90-days. Of interest is the new appraisal process (post-April 2018) which aims to streamline appraisal and regulatory timelines by introducing a ‘Technical Engagement’ step to remove issues before the Appraisal Committee Meeting (ACM). The NICE website was methodically searched to include all TAs with final guidance published before 20th May 2020 and having an ACM post 1st April 2016. Only newly licensed indications/products with MA granted by EMA before the cut-off date were included. Multiple technology appraisals (MTAs) and transition drugs which were previously in the CDF, have been excluded. Ninety-one TAs were identified across 14 cancer categories; thirteen were appraised under the new process. In total, seven (7.7%) TAs had guidance produced within 90-days of MA; two (15.4%) under post-2018 and five (6.4%) under pre-2018 process. From the 79 TAs recommending new products/indications for routine commissioning or the CDF (46 and 33 respectively), final guidance was published on average 269 days post-MA. Following MA approval, on average, patients will gain access to innovative cancer therapies within 8.4 months to improve their health outcomes. The post-2018 process has a higher proportion (54%) of final recommendations made after one ACM compared to pre-2018 process (17%). Further exploration is required to understand the barriers in meeting the 90-day post-MA target.

PNS266 Collecting EARLY Access Real World Evidence DATA for a Successful Reimbursement Appraisal

In France, patients benefit from early access to innovation, ahead of the marketing authorization approval, via the compassionate use program (ATU). Medicinal products indicated in a severe, rare and/or chronic disease are likely to be eligible mainly when there is no suitable treatment available and when both efficacy and safety are relevant. ATU approval is associated with a data collection protocol (PUT). Real world data (RWD) have to be collected during ATU. HTA agency is resquesting ATU data during the reimbursement assessment. We investigate how ATU data are valuated by the Transparency Commission (TC) in France. We performed a retrospective analysis of TC assessments published on the HAS website in 2019. We read and collected information about how these ATU data were value in the reimbursement appraisal. Amongst the 130 TC evaluations reviewed, 18 products were available in an ATU program (50% being onco-hematology drugs). For 90% of the products, the TC concluded clinically relevant comparator(s) exist(s). 78% of the ATU products were valued with a medical improvement rating (ASMR IV [minor] or better). The median target population was very low: 51 years (min-max: 0-1679) The data valued by the TC were: patients’ characteristics and clinical outcome, efficacy, safety and prescription data (treatment line, prescribers, etc.). All of these data were displayed for only 2 products. For these 2 products, the TC valued the data collected. Collecting ATU data allows to gather early real world evidence data, which are an asset for successful market access. Those data are considered as valuable by TC and mentioned in the apraisal. The challenge is to optimize the collection of relevant ATU data for market access considering the short time available to set up an ATU, and TC dossier submission mandatory deadlines.

Eyes on New Product Development.

Eyes on New Product Development.

Authoring a periodic adverse drug experience report…here's what you need to know!

Aggregate reporting involves preparation and submission of safety reports for a given medicinal product to worldwide regulatory agencies and constitutes an essential part of safety monitoring of a medicinal product. There are specific aggregate safety reports required for a molecule in development called development safety update reports while Periodic Adverse Drug Experience Reports (PADERs) and Periodic Safety Update Reports/Periodic Benefit-risk Evaluation Reports (PBRERs) are submitted for products with marketing authorization. Based on the periodic analysis of worldwide safety reports, product label is updated to optimize safe use of a medicinal product. PADERs are aggregate safety reports to be submitted to the Food and Drug Administration (FDA) for products approved for marketing in the United States (US). PADER submission starts once marketing authorization approval is received for a medicinal product by the sponsor. Quarterly and annual PADERs should be submitted within 30 and 60 days of data lock point, respectively. PADERs mainly involve presentation of case reports with serious unlisted events (15-day alert reports) in the form of narratives or in a tabular format. The present article focuses on the background, scope, structure of a PADER, and its submission timelines; lists differences between PADER and PBRER; and describes the knowledge, skills, and attitudes required for a PADER writer.

Pathways to faster access to medicines

Before a medicine can be marketed in the UK, marketing authorisation approval is needed from the European Medicines Agency (EMA) or the Medicines and Healthcare products Regulatory Agency (MHRA). However,...

Ocrelizumab for multiple sclerosis

▼Ocrelizumab (Ocrevus - Roche Registration GmbH) has received marketing authorisation approval from the European Medicines Agency (EMA) for the treatment of adults with multiple sclerosis.1,2 It is the first drug...

Rationale and design of the DARWIN-T2D (DApagliflozin Real World evIdeNce in Type 2 Diabetes): A multicenter retrospective nationwide Italian study and crowdsourcing opportunity

BackgroundRandomized controlled trials (RCTs) in the field of diabetes have limitations inherent to the fact that design, setting, and patient characteristics may be poorly transferrable to clinical practice. Thus, evidence from studies using routinely accumulated clinical data are increasingly valued. AimsWe herein describe rationale and design of the DARWIN-T2D (DApagliflozin Real World evIdeNce in Type 2 Diabetes), a multicenter retrospective nationwide study conducted at 50 specialist outpatient clinics in Italy and promoted by the Italian Diabetes Society. Data synthesisThe primary objective of the study is to describe the baseline clinical characteristics (particularly HbA1c) of patients initiated on dapagliflozin from marketing authorization approval to the end of 2016. Secondary and exploratory objectives will evaluate the changes in glycaemic and extraglycaemic efficacy parameters after initiation of dapagliflozin or after initiation of comparator glucose lowering medications (DPP-4 inhibitors, gliclazide extended release, and long-acting GLP-1 receptor agonists). An automated software will extract relevant data from the same electronic chart system at all centres, thereby minimizing data treatment and human intervention. ConclusionThe study is expected to collect an enormous dataset of information on dapagliflozin- and comparator-using patients. After study completion, the Italian Diabetes Society will launch an open crowdsourcing call on the DARWIN-T2D database, challenging diabetes researchers to apply their ideas and approaches to address new unmet needs and knowledge gaps in diabetes. We believe this will move DARWIN-T2D to the next generation of real world studies.

Understanding clinical development of chimeric antigen receptor T cell therapies

Background aimsIn the past decade, many clinical trials with gene- and cell-based therapies (GCTs) have been performed. Increased interest in the development of these drug products by various stakeholders has become apparent. Despite this growth in clinical studies, the number of therapies receiving marketing authorization approval (MAA) is lagging behind. To enhance the success rate of GCT development, it is essential to better understand the clinical development of these products. Chimeric antigen receptor (CAR) T cells are a GCT product subtype with promising efficacy in cancer treatment which are tested in many clinical trials, but have not yet received MAA. MethodsWe generated an overview of the characteristics of CAR T-cell clinical development in the United States, Canada and Europe. Subsequently, the characteristics of clinical trials with CAR T-cell products that proceeded to a subsequent clinical trial, used as a proxy for success, were compared with those that did not proceed. ResultFrom the U.S. and European Union clinical trial databases, 106 CAR T-cell trials were selected, from which 49 were linked to a subsequent trial and 57 were not. The majority of the trials had an academic sponsor from which most did not proceed, whereas most commercially sponsored trials were followed by another clinical trial. Furthermore, trials with a subsequent trial more frequently recruited large patient cohorts and were more often multicenter compared with trials that were not followed up. DiscussionThese characteristics can be used by investigators to better design clinical trials with CAR T cells. We encourage sponsors to plan clinical development ahead for a higher efficiency of product development and thereby achieving a higher success rate of development towards MAA.

Oral Teicoplanin as an Alternative First-Line Regimen in Clostridium difficile Infection in Elderly Patients: A Case Series.

Elderly patients are more susceptible to Clostridium difficile infections (CDIs). Despite existing guidelines, there is no specific treatment for CDI in geriatrics. Vancomycin is commonly used in the treatment of CDI. Teicoplanin is an alternative glycopeptide which recently received marketing authorization approval for CDI in Europe. Evaluate the potential interest of oral teicoplanin and assess whether such treatment could potentially become an alternative treatment in mild to severe CDIs in elderly patients. A prospective monocentric study was conducted over 10 months (from December 2015 to October 2016) in a geriatric unit (Sainte Périne, AP-HP, Paris, France). According to the remote infectious disease specialist, some hospitalized patients suffering from CDI and aged over 65 years received oral teicoplanin 200 mg twice a day (highest dose recommended). The clinical response to teicoplanin and relapses after treatment were evaluated. Patients were monitored up to 90 days after teicoplanin administration, and analyzed in non-responder imputation analysis. Eleven patients received teicoplanin among 19 CDIs during the study time period. In non-responder imputation analysis, 90.9% (n = 10) successfully responded to oral teicoplanin. The rate of relapse observed after a 90-day follow-up was 36.4%. Patients reported no drug-related adverse effects. Oral teicoplanin is a glycopeptide that could be proposed as an alternative to other recommended drugs for CDI. In our case series, teicoplanin seems to be an effective therapy as a first-line regimen for CDI in geriatrics. Such treatment has good acceptability in geriatrics, considering it can be taken orally twice a day.

Hurdles in clinical implementation of academic advanced therapy medicinal products: A national evaluation

BackgroundSince the implementation of the European Union (EU) regulation for advanced therapy medicinal products (ATMPs) in 2009, only six ATMPs achieved marketing authorization approval in the EU. Recognizing the major developments in the ATMP field, starting mostly in academic institutions, we investigated which hurdles were experienced in the whole pathway of ATMP development towards clinical care. MethodsQuality interviews were executed with different stakeholders in The Netherlands involved in the ATMP development field, e.g. academic research groups, national authorities and patient organizations. Based on the hurdles mentioned in the interviews, questionnaires were subsequently sent to the academic principal investigators (PIs) and ATMP good manufacturing practice (GMP) facility managers to quantify these hurdles. ResultsBesides the familiar regulatory routes of marketing authorization (MA) and hospital exemption (HE), a part of the academic PIs perceived that ATMPs should become available by the Tissues and Cells Directive or did not anticipate on the next development steps towards implementation of their ATMP towards regular clinical care. The main hurdles identified were: inadequate financial support, rapidly evolving field, study-related problems, lacking regulatory knowledge, lack of collaborations and responsibility issues. DiscussionCreating an academic environment stimulating and planning ATMP development and licensing as well as investing in expanding the relevant regulatory knowledge in academic institutions seems a prerequisite to develop ATMPs from bench to patient.

Clinical development of gene- and cell-based therapies: overview of the European landscape

In the last decade, many clinical trials with gene- and cell-based therapies were performed and increasing interest in the development was established by (national) authorities, academic developers, and commercial companies. However, until now only eight products have received marketing authorization (MA) approval. In this study, a comprehensive overview of the clinical development of gene- and cell-based therapies in Europe is presented, with a strong focus on product-technical aspects. Public data regarding clinical trials with gene- and cell-based therapies, obtained from the European Union (EU) clinical trial database (EudraCT) between 2004 and 2014 were analyzed, including product-technical variables as potential determinants affecting development. 198 unique gene and cell therapy products were identified, which were studied in 278 clinical trials, mostly in phase 1/2 trials and with cell therapies as major group. Furthermore, most products were manufactured from autologous starting material mostly manufactured from stem cells. The majority of the trials were sponsored by academia, whereas phase 3 trials mostly by large companies. Academia dominated early-stage development by mainly using bone marrow derived products and stem cells. Conversely, commercial sponsors were more actively pursuing in vivo gene therapy medicinal product development, and cell therapies derived from differentiated tissue in later-stage development.

Developments in the management of idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF), a chronic progressive fibrotic interstitial lung disease (ILD) of unknown origin,1 has seen significant change in its management over the last 15 years.2 In addition, two...