Received Marketing Authorization Research Articles

Traitements médicamenteux et psychothérapiques de l’alcoolodépendance

Despite what hospital nomenclature might seem to imply, treatment for alcohol dependence is not weaning; it is more comprehensive and mainly aimed at the overall phenomenon of addiction. Up until now, the objective of treatment has been to obtain total abstinence by any means. However, current treatments and research are aimed at enabling the dependent subject to learn to regain control over a disease defined precisely by the repeated impossibility of controlling behavior that persists notwithstanding his awareness of its deleterious consequences, be they physical, psychological, familial, professional and/or socio-environmental. Reestablishing control is by no means easy and the journey is fraught with pitfalls related to the person, the product and the environmental context. Insofar as none of these three factors prevail over the others, the therapeutic objective is necessarily triple. It is the patient himself who decides either to maintain alcohol abstinence or to attempt controlled consumption below thresholds for hazardous drinking. His choice may vary according to time and circumstances and it will in all likelihood entail a concrete psychotherapeutic approach associated with pharmacological treatment. Addiction to alcohol, a chronic and recurrent disease, requires first and foremost the setting of desired and achievable objectives that will orient psychotherapeutic actions accompanied by pharmacological treatments. To help the patient achieve his objectives, the addictologist will address abstinence (or control) as well as relapse, combat compensation phenomena and intervene with regard to co-addictions, psychiatric comorbidities and somatic comorbidities. Patients and therapists alike will be called upon to co-construct relapse prevention strategies and to develop psychotherapy taking into account the patient's initial pain and capacities for introspection. In France, four pharmacological treatments have received marketing authorization for abstinence maintenance, and two for controlled management.

Oral Therapies for Multiple Sclerosis.

Multiple sclerosis treatment faces tremendous changes owing to the approval of new medications, some of which are available as oral formulations. Until now, the four orally available medications, fingolimod, dimethylfumarate (BG-12), teriflunomide, and cladribine have received market authorization, whereas laquinimod is still under development. Fingolimod is a sphingosine-1-phosphate inhibitor, which is typically used as escalation therapy and leads to up to 60% reduction of the annualized relapse rate, but might also have neuroprotective properties. In addition, there are three more specific S1P agonists in late stages of development: siponimod, ponesimod, and ozanimod. Dimethylfumarate has immunomodulatory and cytoprotective functions and is used as baseline therapy. Teriflunomide, the active metabolite of the rheumatoid arthritis medication leflunomide, targets the dihydroorotate dehydrogenase, thus inhibiting the proliferation of lymphocytes by depletion of pyrimidines. Here we will review the mechanisms of action, clinical trial data, as well as data about safety and tolerability of the compounds.

Kyleena – another levonorgestrel IUS

A levonorgestrel (LNG) intrauterine system (IUS) known as Kyleena (Bayer PLC) received marketing authorisation from the European Medicines Agency in 2016.1 The device contains 19.5mg LNG and is licensed for...

VP23 The New Cancer Drugs Fund: The Future Model Of Oncology Reimbursement

Introduction:The Cancer Drugs Fund (CDF) was set up in 2011 in England to enable patients to access oncology therapies that are not routinely publicly funded. In April 2016, the CDF became a temporary reimbursement fund under the remit of the National Institute for Health and Care Excellence (NICE) with the aim of collecting observational data to inform subsequent technology appraisals. This study aims to evaluate how the reformed CDF has been utilized in the 18 months since this reform.Methods:NICE Final Appraisal Determinations for Single Technology Appraisals of oncology drugs from (29 July 2016 to 24 November 2017) were identified and key data extracted.Results:Seventy-four oncology drug:indication appraisals were identified, 54 (73 percent) were recommended/optimized, 10 (14 percent) were not recommended and 10 drug:indication pairings (14 percent: osimertinib, brentuximab vedotin, pembrolizumab, olaratumab, obinutuzumab, venetoclax, nivolumab [3 indications], and ibrutinib) were referred to the CDF. For most, the greatest uncertainty in their cost-effectiveness analyses related to their survival benefits, intended to primarily be resolved through subsequent clinical trial readouts. However, for venetoclax, ibrutinib and brentuximab, the main areas of uncertainty (relating to comparative survival benefit, pre-progression mortality, and rate of subsequent stem cell transplants, respectively) are expected to be resolved primarily through observational data collected under the CDF.Conclusions:The newly reformed CDF has been utilized in a minority of cases. Typically, the CDF acts as a temporary access mechanism for treatments that receive market authorization based on early/single-arm trial data until longer-term and/or Phase III data are available. However, venetoclax, brentuximab, and ibrutinib demonstrate how the CDF may address significant areas of uncertainty through the collection of uncontrolled observational data. For venetoclax, with only single-arm supportive clinical trial data, observational data of this intervention and appropriate comparator are to be collected, providing a potential case study of how to appropriately manage reimbursement in the face of significant clinical uncertainty.

Cosmétiques et médicaments topiques dans l’acné : où est la frontière ?

Acne is a chronic disease that may cause sequels such as atrophic or hypertrophic scars or post-inflammatory hyperpigmentation. Topical and systemic medications with proven pharmacologic activity and which have received marketing authorization are the key actors in the treatment of acne. However, these topical or systemic treatments frequently cause adverse effects related to impairment of the skin barrier, and cosmetics must therefore be used in combination to help protect the skin barrier. Nowadays, new cosmetic products containing active ingredients tested in vitro or in a small number of subjects have changed the world of cosmetics. In being described as "dermo-cosmetic" and in integrating active ingredients in their formulations, these cosmetics are now being presented as being specifically adapted for a given disease, and no longer limited to skin care and hygiene but suitable as an adjunctive or even an alternative to current medications. The aim of this article is to provide a better understanding of the respective roles of medications and cosmetics in the management of acne.

BIOBOARD

SINGAPORE – Asia Pacific Medical Technology Association (APACMed) Announces Partnership with Duke-NUS Medical School’s Centre of Regulatory Excellence (CoRE), Pledging Joint Commitment to Promote Regulatory Convergence and Capacity Building Across the Region. SINGAPORE – Guardian Partners with MyDoc to Address Singapore’s Population Health Needs through Integrating Technology and Self-Care. SINGAPORE & UNITED STATES – CellMax Life’s Precision, Non-Invasive Cancer Testing Now Available throughout Southeast Asia through Asia Genomics. UNITED STATES – 3-D Printed Models Could Improve Patient Outcomes in Heart Valve Replacements. UNITED STATES – Promising Target to Protect Bone in Patients with Diabetes. UNITED STATES – New Antibody Appears to Re-Activate Immune System in Cancer Therapy. UNITED STATES – Combo Immunotherapy May Herald New Standard of Care for Kidney Cancer. JAPAN – Chugai’s Bispecific Antibody “Emicizumab” Global Phase III Data in Patients with Haemophilia A with Inhibitors Published in The New England Journal of Medicine Online. RUSSIA & INDIA – BIOCAD’s Rituximab Biosimilar to Receive Market Authorization Soon in India.

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.

Antibody-Drug Conjugates (ADCs) for Personalized Treatment of Solid Tumors: A Review.

Attaching a cytotoxic “payload” to an antibody to form an antibody–drug conjugate (ADC) provides a mechanism for selective delivery of the cytotoxic agent to cancer cells via the specific binding of the antibody to cancer-selective cell surface molecules. The first ADC to receive marketing authorization was gemtuzumab ozogamicin, which comprises an anti-CD33 antibody conjugated to a highly potent DNA-targeting antibiotic, calicheamicin, approved in 2000 for treating acute myeloid leukemia. It was withdrawn from the US market in 2010 following an unsuccessful confirmatory trial. The development of two classes of highly potent microtubule-disrupting agents, maytansinoids and auristatins, as payloads for ADCs resulted in approval of brentuximab vedotin in 2011 for treating Hodgkin lymphoma and anaplastic large cell lymphoma, and approval of ado-trastuzumab emtansine in 2013 for treating HER2-positive breast cancer. Their success stimulated much research into the ADC approach, with >60 ADCs currently in clinical evaluation, mostly targeting solid tumors. Five ADCs have advanced into pivotal clinical trials for treating various solid tumors—platinum-resistant ovarian cancer, mesothelioma, triple-negative breast cancer, glioblastoma, and small cell lung cancer. The level of target expression is a key parameter in predicting the likelihood of patient benefit for all these ADCs, as well as for the approved compound, ado-trastuzumab emtansine. The development of a patient selection strategy linked to target expression on the tumor is thus critically important for identifying the population appropriate for receiving treatment.

ALS Clinical Trials Review: 20 Years of Failure. Are We Any Closer to Registering a New Treatment?

Amyotrophic lateral sclerosis (ALS) is a devastating condition with an estimated mortality of 30,000 patients a year worldwide. The median reported survival time since onset ranges from 24 to 48 months. Riluzole is the only currently approved mildly efficacious treatment. Riluzole received marketing authorization in 1995 in the USA and in 1996 in Europe. In the years that followed, over 60 molecules have been investigated as a possible treatment for ALS. Despite significant research efforts, the overwhelming majority of human clinical trials (CTs) have failed to demonstrate clinical efficacy. In the past year, oral masitinib and intravenous edaravone have emerged as promising new therapeutics with claimed efficacy in CTs in ALS patients. Given their advanced phase of clinical development one may consider these drugs as the most likely near-term additions to the therapeutic arsenal available for patients with ALS. In terms of patient inclusion, CT with masitinib recruited a wider, more representative, less restrictive patient population in comparison to the only successful edaravone CT (edaravone eligibility criteria represents only 18% of masitinib study patients). The present manuscript reviews >50 CTs conducted in the last 20 years since riluzole was first approved. A special emphasis is put on the analysis of existing evidence in support of the clinical efficacy of edaravone and masitinib and the possible implications of an eventual marketing authorisation in the treatment of ALS.

OP136 Clinical Benefit Of Oncological Therapies At The Time Of Approval

INTRODUCTION:In the last decade an increasing number of high-priced, new cancer treatments received marketing authorization in Europe. What is actually known about the clinical benefit of those therapies at the time of approval needs to be elucidated in order to inform decisions about the use and reimbursement of these novel treatment options. Thus, the aim of the current analysis was to systematically investigate oncological therapies approved between January 2009 and April 2016. We extracted, as well as quantified the level of knowledge of the clinical benefit at the time of marketing authorization.METHODS:To assess the benefit of new interventions as well as expanded indications, we extracted the median gain of the two study endpoints: progression-free survival (PFS) and overall survival (OS). Information is based on approval documents provided by the European Medicines Agency (EMA) and assessments from the Austrian Horizon Scanning programme (HSO). We included all cancer therapies approved in Europe between 1 January 2009 and 15 April 2016.RESULTS:Cancer drugs for 134 new indications approved since 2009 were identified. In the case of thirty-seven indications (27 percent), no data was available for PFS or for OS. A positive difference in median overall survival was reached by seventy-six licensed indications (55.5 percent); twenty-two (16 percent) of them showed a difference of more than three months. Regarding the study endpoint progression-free survival, an improvement was shown in ninety indications (65.2 percent).CONCLUSIONS:Scarce knowledge regarding the clinical benefit of anti-cancer therapies is available at the time of approval. In addition, the survival benefit of the approved indications is less than three months in the majority of approved therapies.

Between January 2009 and April 2016, 134 novel anticancer therapies were approved: what is the level of knowledge concerning the clinical benefit at the time of approval?

ObjectiveIn the last decade an increasing number of high-priced, new cancer treatments received marketing authorisation in Europe. What is actually known about the clinical benefit of those therapies at the time of approval needs to be elucidated in order to inform decisions about the use and reimbursement of these novel treatment options. Thus, the aim of the current analysis was to systematically investigate oncological therapies approved between January 2009 and April 2016 and extract as well as quantify the level of knowledge of the clinical benefit at the time of marketing authorisation.MethodsTo assess the benefit of new interventions as well as expanded indications, we extracted the median gain of the two study end points: progression-free survival (PFS) and overall survival (OS). Information is based on approval documents provided by the European Medicines Agency and assessments from the Austrian Horizon Scanning programme. We included all cancer therapies approved in Europe between 2009 (January 1) and 2016 (April 15).ResultsCancer drugs for 134 new indications approved since 2009 were identified. In the case of 37 indications (27%), no data were available for PFS or for OS. A positive difference in median OS was reached by 76 licensed indications (55.5%); 22 (16%) of them showed a difference of more than 3 months. Regarding the study end point PFS, an improvement was shown in 90 indications (65.2%).ConclusionScarce knowledge regarding the clinical benefit of anticancer therapies is available at the time of approval. In addition, the survival benefit of the approved indications is less than 3 months in the majority of approved therapies.

2.4 - Regulation Of Orphan Medicinal Products In Europe: History Trends And Challenges

In 2000, regulation on orphan medicinal products was adopted in the European Union with the aim of benefiting patients who suffer from serious, rare conditions for which there is currently no satisfactory treatment. Since then, more than 1000 orphan drug designations have been granted by the European Commission based on a positive opinion from the Committee for Orphan Medicinal Products (COMP), and more than 100 orphan drugs have received marketing authorization in Europe. The COMP has dealt with innovation in several forms including cutting-edge therapies and for many years acted as the “gate-opener” at the EMA for innovative and medically plausible research. Although the market exclusivity granted for an orphan product lasts for 10 years (with a 2 years extension for paediatric development), the knowledge gained during the development process is eternal. To face the growing challenges resulting from the advancements in science, strengthened interactions between all stakeholders were necessary, providing more innovative approaches to the development of orphan medicines, thereby bringing science into regulation and regulation into science. The result of this scientific role of EMA in the field of orphan medicines can be translated into a shift of the products under assessment by the Committee of Human Medicinal Products, so that a significant number of orphan medicines are requesting marketing authorization. This undeniably represents the commitment of all stakeholders to providing further scientific innovation and more treatment options for patients affected by rare diseases. In order to translate more research into treatment, a structured responsive capacity to the continuous evolution occurring in the interface of science and regulation is expected aligned with the aim of having more, better, efficacious, and safer orphan medicines in the years to come.

The Evolving Biosimilar Landscape: Approval of the First Etanercept Biosimilar in Europe, An Interview With Emilio Martín-Mola

On January 14th 2016, SB4 (Benepali®) received marketing authorisation application approval from the European Commission (EC). It is the first biosimilar to etanercept available in Europe as well as the first subcutaneous anti-tumour necrosis factor biosimilar. Benepali® was approved for the treatment of rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis (ankylosing spondylitis and non-radiographic spondyloarthritis), and plaque psoriasis. SB4 adds to the available biologic armamentarium of biosimilars in rheumatology, which also includes two infliximab biosimilars; one under the brand names Remsima® and Inflectra®, and the other under the brand name Flixabi®. Unlike infliximab biosimilar, which is a chimeric monoclonal antibody, SB4 is a fusion protein. We aimed to review the current European Medicines Agency (EMA) requirements for the approval of biosimilars and how these products can integrate into daily clinical practice in rheumatology. To that effect, we recently discussed with Dr Emilio Martín-Mola about the European framework for approval of biosimilars and the controversies that may surround this new category of medicinal products. We discussed how the advent of biosimilars in rheumatology has the potential to truly be a game-changer for both physicians and patients.

Tunable phosphatase-sensitive stable prodrugs of 5-aminolevulinic acid for tumor fluorescence photodetection

5-Aminolevulinic acid (5-ALA) has been at the forefront of small molecule based fluorescence-guided tumor resection and photodynamic therapy. 5-ALA and two of its esters received marketing authorization but suffer from several major limitations, namely low stability and poor pharmacokinetic profile. Here, we present a new class of 5-ALA derivatives aiming at the stabilization of 5-ALA by incorporating a phosphatase sensitive group, with or without self-cleavable linker. Compared to 5-ALA hexyl ester (5-ALA-Hex), these compounds display an excellent stability under acidic, basic and physiological conditions. The activation and conversion into the 5-ALA is controlled and can be structure-tailored. The prodrugs display reduced acute toxicity compared to 5-ALA-Hex with superior dose response profiles of protoporphyrin IX synthesis and fluorescence intensity in human glioblastoma cells in vitro. Clinically relevant fluorescence kinetics in vivo shown in U87MG glioblastoma spheroid tumor model in chick embryos provide a solid basis for their further development and translation to clinical fluorescence guided tumor resection and photodynamic therapy.

A mirror image study of the utility of long acting aripiprazole

Aims and backgroundAblify Maintena (AM) is a long acting injection of aripiprazole that received marketing authorisation in the UK in January 2014. It is costly compared to first generation antipsychotics (FGAs) LAIs and there are no robust trials comparing AM with FGAs. We examined the effectiveness and use of AM in a mental health trust.MethodsWe identified all patients prescribed AM in North Staffordshire (population: 470,000) since launch and examined records for demography, diagnosis, bed and medication use. We examined the effectiveness of AM using a mirror image design.ResultsThirty patients received AM in a time frame allowing a 1-year follow-up. Sixty-nine percent were male and the mean age was 39 years. Over half were detained under the 1983 Mental Health Act and 30% were inpatients on a psychiatric intensive care unit when AM was started. Twenty-eight patients had a psychotic diagnosis. There was a significant reduction in bed occupancy (63 v 6 days, P = 0.0001) and admissions (1.6 v 0.5, P = 0.0001). The median dose was 400 mg. Lack of effectiveness/poor adherence with prior treatments were the main reason for starting AM in 84%. Eighty-six percent of patients clinically improved on AM. Blood parameters were in the normal range.DiscussionWithin the limitations of the methodology, our results show a reduction in psychiatric bed use in the year following AM initiation on an intention to treat basis. The reduction in bed use equates to a minimum annual saving of £14,250 per patient. AM at the median study dose costs £2645 per year.Disclosure of interestThe authors have not supplied their declaration of competing interest.

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.

Management of stage 1 TTR FAP: French experience

Transthyretin Familial Amyloid Polyneuropathy (TTR-FAP) is a worldwide autosomal dominant disease due to point mutation of TTR gene. The main endemic area is Portugal, associated with V30M variant and an early onset (EO) (mean age 30 yo). Phenotype is a progressive length dependent small fiber polyneuropathy with autonomic dysfunction and cardiac conduction disorders; the median survival is 12 years. France is a prototypic non endemic country, characterized by sporadic cases in 50%, a late onset (LO>50 yo) in 75%, a genetic heterogeneity (41 variants ; V30M in 55%). Liver transplantation (LT) is the gold standard treatment allows to stop progression of the neuropathy in EO V30M patients and to prolonge significantly the survival. Tafamidis, a TTR kinetic stabilizer, received marketing authorization in Europe for stage 1 FAP (walking unaided) allowing to slow progression of the neuropathy. Aims of the study was to assess the place of tafamidis in the management of TTR-FAP.

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...

Plasmid Biopharmaceuticals.

Plasmids are currently an indispensable molecular tool in life science research and a central asset for the modern biotechnology industry, supporting its mission to produce pharmaceutical proteins, antibodies, vaccines, industrial enzymes, and molecular diagnostics, to name a few key products. Furthermore, plasmids have gradually stepped up in the past 20 years as useful biopharmaceuticals in the context of gene therapy and DNA vaccination interventions. This review provides a concise coverage of the scientific progress that has been made since the emergence of what are called today plasmid biopharmaceuticals. The most relevant topics are discussed to provide researchers with an updated overview of the field. A brief outline of the initial breakthroughs and innovations is followed by a discussion of the motivation behind the medical uses of plasmids in the context of therapeutic and prophylactic interventions. The molecular characteristics and rationale underlying the design of plasmid vectors as gene transfer agents are described and a description of the most important methods used to deliver plasmid biopharmaceuticals in vivo (gene gun, electroporation, cationic lipids and polymers, and micro- and nanoparticles) is provided. The major safety issues (integration and autoimmunity) surrounding the use of plasmid biopharmaceuticals is discussed next. Aspects related to the large-scale manufacturing are also covered, and reference is made to the plasmid products that have received marketing authorization as of today.

Planning operations before market launch for balancing time-to-market and risks in pharmaceutical supply chains

Shorter product life cycles and the resulting increase in new product introductions boost the importance of product launch operations. In the pharmaceutical sector, product launch operations are of particular importance, as companies seek to reduce time-to-market to better exploit patent protection. Large volumes of product need to be ready to fill the downstream supply chain immediately at market launch. Building up the required inventory is, however, connected to several risks. In addition to the risk associated with the lack of demand information for a new product, there are several risks unique to the pharmaceutical sector. After approval by central authorities such as the FDA or EMA, a new drug still needs to receive market authorization, which is in most cases granted by some local authorities – in Europe, for example, by more than 30 national and regional bodies. The duration of these different market authorization processes as well as their outcomes (e.g. price and reimbursement levels, requirements of label or leaflet changes) are highly uncertain. We develop a two-stage stochastic model to support market launch preparation decisions. It trades off the costs of accepting these risks, for example by risk packaging before authorization, against the lost revenue caused by risk-averse operations. The model is applied to a case based on an empirical study. Our approach results in significant savings compared to current practices. We hereby provide an example of how quantitative methodology can provide valuable decision support for product launch operations, even when complex regulatory affairs need to be considered.