scholarly journals Failures to further developing orphan medicinal products after designation granted in Europe: an analysis of marketing authorisation failures and abandoned drugs

BMJ Open ◽  
2017 ◽  
Vol 7 (9) ◽  
pp. e017358 ◽  
Author(s):  
Viviana Giannuzzi ◽  
Annalisa Landi ◽  
Enrico Bosone ◽  
Floriana Giannuzzi ◽  
Stefano Nicotri ◽  
...  
Keyword(s):  
Marketing Authorisation ◽  
Development Process ◽  
Developmental Process ◽  
Clinical Stage ◽  
Phase Iii ◽  
Marketing Approval ◽  
Medicinal Products ◽  
Safety Issues ◽  
Stage Of Development ◽  
Orphan Medicinal Products

ObjectivesThe research and development process in the field of rare diseases is characterised by many well-known difficulties, and a large percentage of orphan medicinal products do not reach the marketing approval.This work aims at identifying orphan medicinal products that failed the developmental process and investigating reasons for and possible factors influencing failures.DesignDrugs designated in Europe under Regulation (European Commission) 141/2000 in the period 2000–2012 were investigated in terms of the following failures: (1) marketing authorisation failures (refused or withdrawn) and (2) drugs abandoned by sponsors during development.Possible risk factors for failure were analysed using statistically validated methods.ResultsThis study points out that 437 out of 788 designations are still under development, while 219 failed the developmental process. Among the latter, 34 failed the marketing authorisation process and 185 were abandoned during the developmental process. In the first group of drugs (marketing authorisation failures), 50% reached phase II, 47% reached phase III and 3% reached phase I, while in the second group (abandoned drugs), the majority of orphan medicinal products apparently never started the development process, since no data on 48.1% of them were published and the 3.2% did not progress beyond the non-clinical stage.The reasons for failures of marketing authorisation were: efficacy/safety issues (26), insufficient data (12), quality issues (7), regulatory issues on trials (4) and commercial reasons (1). The main causes for abandoned drugs were efficacy/safety issues (reported in 54 cases), inactive companies (25.4%), change of company strategy (8.1%) and drug competition (10.8%). No information concerning reasons for failure was available for 23.2% of the analysed products.ConclusionsThis analysis shows that failures occurred in 27.8% of all designations granted in Europe, the main reasons being safety and efficacy issues. Moreover, the stage of development reached by drugs represents a specific risk factor for failures.

scholarly journals Orphan Medicinal Products for the Treatment of Pancreatic Cancer: Lessons Learned From Two Decades of Orphan Designation

2021 ◽  
Vol 11 ◽  
Author(s):  
Jorn Mulder ◽  
Tobias van Rossum ◽  
Segundo Mariz ◽  
Armando Magrelli ◽  
Anthonius de Boer ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Medicinal Product ◽  
Marketing Authorisation ◽  
Clinical Stage ◽  
Treatment Options ◽  
Lessons Learned ◽  
The European Union ◽  
Medicinal Products ◽  
Stage Of Development ◽  
Dismal Prognosis

Pancreatic cancer has a dismal prognosis and only a few treatment options are available. In the European Union, pancreatic cancer classifies as a rare disease, allowing drug developers to apply for orphan medicinal product (OMP) designation. The aim of this study was to provide more detail on OMPs for pancreatic cancer. All applications for OMP designation submitted to the EMA between 2000 and 2019 were identified. For each medicinal product that received an OMP designation, the mode of drug action, use of protocol assistance, and current life cycle status was determined. Fifty-two medicinal products received an OMP designation. At the time of submission, eighteen OMPs were at the non-clinical and 34 OMPs were at the clinical stage of development. At least fourteen kinds of mode of action were explored in the condition. For eighteen out of 52 OMPs protocol assistance was sought. At the time of data analysis, one OMP received marketing authorisation and 24 OMPs were ongoing in development. Many medicinal products for pancreatic cancer received an OMP designation and the majority of these products was already in the clinical stage of development. Nonetheless, the success rate of OMPs for pancreatic cancer that reach the market is low, and increasing this rate is something to aspire. Fortunately, development is still ongoing for a part of the OMPs, and a few developers are planning to submit a marketing authorisation application in the near future. This however does not guarantee success, as pancreatic cancer remains a difficult disease to treat. Developers are advised to make optimal use of incentives such as protocol assistance, establishing (early) dialogue between regulators and drug developers and to agree on important topics such as clinical trial design.

scholarly journals eu Marketing Authorisation of Orphan Medicinal Products and Its Impact on Related Research

2017 ◽  
Vol 24 (5) ◽  
pp. 541-564 ◽  
Author(s):  
Sara Gerke ◽  
Shaun D. Pattinson
Keyword(s):  
Marketing Authorisation ◽  
Steady Increase ◽  
Marketing Approval ◽  
Medicinal Products ◽  
Market Exclusivity ◽  
Related Research ◽  
Orphan Medicinal Products ◽  
Potential Impact

Abstract Over the last 15 years, there has been a steady increase in the development of orphan medicinal products (omps). This raises an important question: What impact does the eu marketing authorisation of an omp have on related research? This article establishes that the key orphan incentive, namely the 10‑year market exclusivity provision laid down in Article 8 of the eu Regulation on omps (Regulation 141/2000), has a huge potential impact on related research. It is argued that this provision can make it too difficult for researchers/sponsors to attain marketing approval for closely related products. This article advances two proposals to address this problem. First, it argues for new principles for assessing similarity, so as to clarify and narrow the ambit of market exclusivity. Secondly, it argues for improved conditions for a demonstration of ‘clinical superiority’ for similar omps.

scholarly journals Orphan drug designation in Europe-Procedural guidance and challenges

2019 ◽  
Vol 7 (3) ◽  
pp. 1-7
Author(s):  
Christina Nicolodi
Keyword(s):  
Orphan Drug ◽  
Early Stage ◽  
Specific Treatment ◽  
Development Program ◽  
Orphan Drug Designation ◽  
Medicinal Products ◽  
Strategic Decisions ◽  
Stage Of Development ◽  
Orphan Medicinal Products ◽  
Legislative Framework

The European legislative framework on orphan medicinal products was implemented to stimulate the development of medicinal products against rare diseases and to ensure the patient’s adequate access to qualitative and specific treatment methods. Between 2000 and 2018 3210 orphan drug designation applications were submitted in Europe of which 2121 orphan designations have been issued by the European Commission. (1) Though the definitions for orphan medicinal products and the regulatory procedures are well defined, a high degree of regulatory knowledge is needed and strategic decisions on the development program must be considered at a very early stage of development: in fact, only 164 of the 2121 designated orphan development products have resulted in authorised orphan medicinal products since the orphan legislation was implemented. In this article, the requirements and procedures for the orphan designation application and maintenance at the time of marketing authorisation application are discussed in the context of the European Regulation.

scholarly journals Availability, accessibility and delivery to patients of the 28 orphan medicines approved by the European Medicine Agency for hereditary metabolic diseases in the MetabERN network

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Jean-Michel Heard ◽  
◽  
Charlotte Vrinten ◽  
Michael Schlander ◽  
Cinzia Maria Bellettato ◽  
...  
Keyword(s):  
Health Care ◽  
Health Care Providers ◽  
European Medicine Agency ◽  
Metabolic Diseases ◽  
Reference Network ◽  
Care Providers ◽  
Medicinal Products ◽  
Stage Of Development ◽  
Orphan Medicinal Products ◽  
Hereditary Metabolic Diseases

Abstract Background The European Medicine Agency granted marketing approval to 164 orphan medicinal products for rare diseases, among which 28 products intended for the treatment of hereditary metabolic diseases. Taking advantage of its privileged connection with 69 healthcare centres of excellence in this field, MetabERN, the European Reference Network for hereditary metabolic diseases, performed a survey asking health care providers from 18 European countries whether these products are available on the market, reimbursed and therefore accessible for prescription, and actually delivered in their centre. Results Responses received from 52 centres (75%) concerned the design of treatment plans, the access to marketed products, and the barriers to delivery. Treatment options are always discussed with patients, who are often involved in their treatment plan. Most products (26/28) are available in most countries (15/18). Among the 15 broadly accessible products (88.5% of the centres), 9 are delivered to most patients (mean 70.1%), and the others to only few (16.5%). Among the 10 less accessible products (40.2% of the centres), 6 are delivered to many patients (66.7%), and 4 are rarely used (6.3%). Information was missing for 3 products. Delay between prescription and delivery is on average one month. Beside the lack of availability or accessibility, the most frequent reasons for not prescribing a treatment are patients’ clinical status, characteristic, and personal choice. Conclusions Data collected from health care providers in the MetabERN network indicate that two-third of the orphan medicines approved by EMA for the treatment of hereditary metabolic diseases are accessible to treating patients, although often less than one-half of the patients with the relevant conditions actually received the approved product to treat their disease. Thus, in spite of the remarkable achievement of many products, patients concerned by EMA-approved orphan medicinal products have persistent unmet needs, which deserve consideration. The enormous investments made by the companies to develop products, and the high financial burden for the Member States to purchase these products emphasize the importance of a scrupulous appreciation of treatment value involving all stakeholders at early stage of development, before marketing authorization, and during follow up.

Determinants for successful marketing authorisation of orphan medicinal products in the EU

2012 ◽  
Vol 17 (7-8) ◽  
pp. 352-358 ◽  
Author(s):  
Michelle Putzeist ◽  
Harald E. Heemstra ◽  
Jordi Llinares Garcia ◽  
Aukje K. Mantel-Teeuwisse ◽  
Christine C. Gispen-De Wied ◽  
...  
Keyword(s):  
Marketing Authorisation ◽  
Medicinal Products ◽  
Orphan Medicinal Products ◽  
The Eu

scholarly journals Current Approaches to Planning and Conducting Clinical Trials of Medicinal Products for the Treatment of Crohn's Disease

2020 ◽  
Vol 10 (2) ◽  
pp. 111-120
Author(s):  
А. N. Bogdanov ◽  
E. V. Gorbunova ◽  
D. V. Goryachev ◽  
E. V. Petraneva
Keyword(s):  
Clinical Trials ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Clinical Research ◽  
Therapeutic Effect ◽  
Marketing Authorisation ◽  
Methodological Approach ◽  
Phase Iii ◽  
Medicinal Products ◽  
Conducting Phase

Accumulation of knowledge on Crohn’s disease, and development of biological products intended for the treatment of its underlying cause formed the basis for the development of objective methods for assessing the intensity of the pathological process, which in turn affected scientific approaches to the planning of clinical trials in this field. To date, many international recommendations related to planning, conduct of clinical trials, and analysis of their results, have been updated. Considerable experience has been gained with clinical trials of medicines intended for the treatment of Crohn’s disease. Therefore, the methodological approach to the planning of pivotal clinical studies needs to be reviewed. The aim of the study was to develop requirements for planning and expert evaluation of clinical trials conducted with the aim of obtaining marketing authorisation for medicinal products for the treatment of Crohn’s disease. The paper analyses regulations, recommendations, and scientific literature on the treatment of Crohn’s disease and describes the methodology for planning clinical trials. It describes the evolution of approaches to clinical research planning since biological medicines appeared. The authors substantiate the need for an integrated concept of clinical research, which covers goals, estimated therapeutic effect, design, and choice of the statistical analysis method. They also provide scientific arguments in favour of a combined primary endpoint including endoscopic remission and the assessment of treatment results by the patient. The paper lists patient eligibility criteria in terms of “inducing and/or maintaining remission of the disease”. The authors analyse the main intercurrent events, their influence on the therapeutic effect, and propose approaches to the planning of endpoints, including assessment of intercurrent events. The paper highlights the fact that the principles of planning and conducting Phase III clinical trials need to be consistent with the evidence-based strategies of reducing the risk of incorrect assessment of efficacy and safety of new medicines, and that the obtained results have to meet the requirements of the regulatory authorities at the stage of marketing authorisation.

scholarly journals Environmental fate and effects assessment of human pharmaceuticals: lessons learnt from regulatory data

2021 ◽  
Vol 33 (1) ◽  
Author(s):  
Simon Schwarz ◽  
Daniela Gildemeister ◽  
Arne Hein ◽  
Patrick Schröder ◽  
Jean Bachmann
Keyword(s):  
Environmental Fate ◽  
Environmental Risks ◽  
Marketing Approval ◽  
Current Guideline ◽  
The European Union ◽  
Medicinal Products ◽  
Effect Data ◽  
Assessment Approach ◽  
Biotic Degradation ◽  
High Sorption

AbstractHuman pharmaceuticals are extensively studied and assessed before marketing approval. Since 2006, this also includes an assessment of environmental risks. In the European Union, this is based on the guideline on the environmental risk assessment of medicinal products for human use (EMEA/CHMP/SWP/4447/00 corr 2), which is currently under revision. For Germany, the German Environment Agency (UBA) is tasked with the evaluation of environmental risks of human pharmaceuticals. Applicants seeking approval of medicinal products need to submit fate and effect data, in case predicted environmental concentrations (PECs) exceed 10 ng/L in surface waters, or the substance is of specific concern through its mode of action or physico-chemical characteristics.Over the last decade, this regulatory work resulted in an internal agency database containing effect data on approximately 300 active pharmaceutical ingredients (APIs). A considerable part of this data is currently not publicly available due to property rights held by the respective applicants. The database was evaluated to draw conclusions on how the current assessment approach may be improved.The evaluation of aquatic effect data shows considerable variation in ecotoxic effect concentrations, but supports the current use of 10 ng/L as PEC action limit. For endocrine-active substances and antibiotics, a clear sensitivity profile was observed, which allows a more targeted assessment in the future. The conclusions drawn from terrestrial effect data are less clear, as the database itself is biased because information is only available for substances with high sorption. Further adaptations of the terrestrial assessment strategy, including action triggers, appear necessary. Fate data show a high persistence of many APIs: approximately 43% of all APIs are classified as very persistent; 12% of these show DT50 values in a range where abiotic or biotic degradation is not expected.Overall, the evaluation has shown that improvements of the current guideline are possible.

Taube nuss is a novel gene essential for the survival of pluripotent cells of early mouse embryos

Development ◽  
2000 ◽  
Vol 127 (24) ◽  
pp. 5449-5461 ◽  
Author(s):  
A.K. Voss ◽  
T. Thomas ◽  
P. Petrou ◽  
K. Anastassiadis ◽  
H. Scholer ◽  
...  
Keyword(s):  
Cell Population ◽  
Developmental Process ◽  
Inner Cell Mass ◽  
Chromatin Condensation ◽  
Cell Mass ◽  
Adult Brain ◽  
Stem Cell Population ◽  
Novel Gene ◽  
Stage Of Development ◽  
Short Period

The cells of the inner cell mass constitute the pluripotent cell population of the early embryo. They have the potential to form all of the tissues of the embryo proper and some extra-embryonic tissues. They can be considered a transient stem cell population for the whole of the embryo, and stem cells maintaining the same capacity can be isolated from these cells. We have isolated, characterised and mutated a novel gene, taube nuss (Tbn), that is essential for the survival of this important cell population. The taube nuss protein sequence (TBN) was highly conserved between human, mouse, Xenopus laevis, Drosophila melanogaster, Caenorhabditis elegans and Arabidopsis thaliana, particularly in a domain that is not present in any published proteins, showing that TBN is the founding member of a completely new class of proteins with an important function in development. The Tbn gene was expressed ubiquitously as early as E2. 5 and throughout embryonic development. It was also expressed in adult brain with slightly higher levels in the hippocampus. The Tbn mutant embryos developed normally to the blastocyst stage and contained inner cell masses. They hatched from the zonae pellucidae, implanted and induced decidual reactions, but failed to develop beyond E4.0. At this time the trophoblast cells were viable, but inner cell masses were not detectable. At E3.75, massive TUNEL-positive DNA degradation and chromatin condensation were visible within the inner cell masses, whereas the cell membranes where intact. Caspase 3 was expressed in these cells. In vitro, the inner cell mass of mutant embryos failed to proliferate and died after a short period in culture. These results indicate that the novel protein, taube nuss, is necessary for the survival of the inner cell mass cells and that inner cell mass cells died of apoptosis in the absence of the taube nuss protein. As cell pruning by apoptosis is a recognised developmental process at this stage of development, the taube nuss protein may be one of the factors regulating the extent of programmed cell death at this time point.

PROSPER: Phase III RandOmized Study Comparing PERioperative nivolumab versus observation in patients with renal cell carcinoma (RCC) undergoing nephrectomy (ECOG-ACRIN EA8143).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS4596-TPS4596
Author(s):  
Mohamad E. Allaf ◽  
Se Eun Kim ◽  
Viraj A. Master ◽  
David F. McDermott ◽  
Sabina Signoretti ◽  
...  
Keyword(s):  
Immune System ◽  
Clinical Outcomes ◽  
Clinical Stage ◽  
Randomized Study ◽  
Standard Of Care ◽  
Phase Iii ◽  
Perioperative Therapy ◽  
Tumor Biopsy ◽  
Care Surgery ◽  
Metastatic Rcc

TPS4596 Background: There is no standard adjuvant systemic therapy that increases overall survival (OS) over surgery alone for non-metastatic RCC. Anti-PD-1 nivolumab (nivo) improves OS in metastatic RCC and is well tolerated. In mouse models, priming the immune system prior to surgery with anti-PD-1 results in superior OS compared to adjuvant dosing. Remarkable pathologic responses have been seen with neoadjuvant PD-1 in multiple ph 2 studies in bladder, lung and breast cancers. Phase 2 neoadjuvant RCC trials of nivo show preliminary feasibility and safety with no surgical delays. PROSPER RCC seeks to improve clinical outcomes by priming the immune system with neoadjuvant nivo prior to nephrectomy followed by continued immune system engagement with adjuvant blockade in patients (pts) with high risk RCC compared to standard of care surgery alone. Methods: This global, unblinded, phase 3 National Clinical Trials Network study is accruing pts with clinical stage ≥T2 or TanyN+ RCC of any histology planned for radical or partial nephrectomy. Select oligometastatic disease is permitted if the pt can be rendered ‘no evidence of disease’ within 12 weeks of nephrectomy (≤3 metastases; no brain, bone or liver). In the investigational arm, nivo is administered 480mg IV q4 weeks with 1 dose prior to surgery followed by 9 adjuvant doses. The control arm is nephrectomy followed by standard of care surveillance. There is no placebo. Baseline tumor biopsy is required only in the nivo arm but encouraged in both. Randomized pts are stratified by clinical T stage, node positivity, and M stage. 805 pts provide 84.2% power to detect a 14.4% absolute benefit in recurrence-free survival at 5 years assuming the ASSURE historical control of ̃56% to 70% (HR = 0.70). The study is powered to evaluate a significant increase in OS (HR 0.67). Critical perioperative therapy considerations such as safety, feasibility, and quality of life metrics are integrated. PROSPER RCC embeds a wealth of translational studies to examine the contribution of the baseline immune milieu and neoadjuvant priming with anti-PD-1 on clinical outcomes. As of February 10, 2021, 704 patients have been enrolled (N = 805). Clinical trial information: NCT03055013.

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