Medicamentos huérfanos

Orphan drugs are intended for the treatment of diseases of low prevalence, also known as rare diseases. Research and development into new therapies for this heterogeneous group of diseases presents a number of well-recognized difficulties. One of these is that the small number of patients affected jeopardizes the economic return on the investment made by the pharmaceutical industry. For this reason, in the year 2000 the European Union brought out a specific European Regulation to promote and encourage the development of these therapies. After more than a decade, the results reveal a positive effect of the approval of that regulation. Currently, more than 1300 compounds have been designated orphan drugs, of which over 90 have already obtained marketing authorization. The voice of the patient has been key to producing this change and programs and research consortia promoted by the EU promise an even brighter future.Los medicamentos huérfanos son aquellos fármacos destinados al tratamiento de enfermedades de baja prevalencia, también conocidas como enfermedades raras. La investigación y desarrollo de nuevas terapias para este conjunto heterogéneo de enfermedades presenta una serie de dificultades que están bien reconocidas. Entre ellas, el reducido número de afectados compromete el retorno económico de la inversión realizada por parte de la industria farmacéutica. Por ello la Unión Europea en el año 2000 aprobó un Reglamento Europeo específico para favorecer e incentivar el desarrollo de estas terapias. Transcurrida más de una década, los resultados muestran el efecto positivo que la entrada en vigor de dicho Reglamento ha provocado. Actualmente se han designado más de 1300 compuestos, de los cuales más de 90 ya han obtenido la autorización de comercialización. La voz de los pacientes ha sido clave para el devenir de este cambio y los programas y consorcios promovidos por la UE prometen todavía un futuro más esperanzador

Pathways of economically relevant demersal species in the Ibiza channel from a lagrangian backtracking approach

This work studies the most probable spatial origin of demersal species that eventually reach the Ibiza Channel after a dispersion stage, a region where water masses with different characteristics choke. Demersal species are assumed to be in a planktonic stage in which they behave as passive particles, being only advected by the dominant ocean currents. To find the origin we have performed a set of backward Lagrangian simulations using a high-resolution model of currents. As a result, we obtain the preferred pathways of dispersion for demersal species. A careful analysis of pathways provides useful information on the spatiotemporal variability of demersal and their origin weeks ago before they reach the Ibiza Channel. This information is very valuable from a conservation standpoint to determine the key regions that should be protected as eggs and larvae exportation areas.Peer Reviewe

Applicability and added value of novel methods to improve drug development in rare diseases

The ASTERIX project developed a number of novel methods suited to study small populations. The objective of this exercise was to evaluate the applicability and added value of novel methods to improve drug development in small populations, using real world drug development programmes as reported in European Public Assessment Reports. The applicability and added value of thirteen novel methods developed within ASTERIX were evaluated using data from 26 European Public Assessment Reports (EPARs) for orphan medicinal products, representative of rare medical conditions as predefined through six clusters. The novel methods included were 'innovative trial designs' (six methods), 'level of evidence' (one method), 'study endpoints and statistical analysis' (four methods), and 'meta-analysis' (two methods) and they were selected from the methods developed within ASTERIX based on their novelty; methods that discussed already available and applied strategies were not included for the purpose of this validation exercise. Pre-requisites for application in a study were systematized for each method, and for each main study in the selected EPARs it was assessed if all pre-requisites were met. This direct applicability using the actual study design was firstly assessed. Secondary, applicability and added value were explored allowing changes to study objectives and design, but without deviating from the context of the drug development plan. We evaluated whether differences in applicability and added value could be observed between the six predefined condition clusters. Direct applicability of novel methods appeared to be limited to specific selected cases. The applicability and added value of novel methods increased substantially when changes to the study setting within the context of drug development were allowed. In this setting, novel methods for extrapolation, sample size re-assessment, multi-armed trials, optimal sequential design for small sample sizes, Bayesian sample size re-estimation, dynamic borrowing through power priors and fall-back tests for co-primary endpoints showed most promise - applicable in more than 40% of evaluated EPARs in all clusters. Most of the novel methods were applicable to conditions in the cluster of chronic and progressive conditions, involving multiple systems/organs. Relatively fewer methods were applicable to acute conditions with single episodes. For the chronic clusters, Goal Attainment Scaling was found to be particularly applicable as opposed to other (non-chronic) clusters. Novel methods as developed in ASTERIX can improve drug development programs. Achieving optimal added value of these novel methods often requires consideration of the entire drug development program, rather than reconsideration of methods for a specific trial. The novel methods tested were mostly applicable in chronic conditions, and acute conditions with recurrent episodes. The online version of this article (10.1186/s13023-018-0925-0) contains supplementary material, which is available to authorized users

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Estudi de caracterització del disseny d’assajos clínics realitzats amb medicaments orfes. Study to characterize the designs of clinical trials conducted with orphan medicinal products.

Introducció: La recerca i el desenvolupament de nous medicaments orfes ha estat limitada per la manca de coneixement sobre les malalties, la previsible manca de retorn de la inversió realitzada en absència d’incentius, i la manca de metodologies específiques per utilitzar en poblacions petites. Deu anys després de l’aprovació de la Regulació Europea sobre Medicaments Orfes (ER 141/2000), el nombre de medicaments destinats al tractament de malalties minoritàries ha augmentat significativament. L’anàlisi del tipus d’evidència científica i els assajos clínics duts a terme per recolzar l’autorització de comercialització de medicaments orfes a Europa permetrà analitzar el grau d’utilització de metodologies alternatives destinades a incrementar l’eficiència dels assajos clínics en poblacions petites, disposar d’una referència per explorar l’aplicabilitat d’aquestes metodologies alternatives, i comparar els mètodes actualment utilitzats per dur a terme assajos clínics en el camp de les malalties minoritàries en relació amb els mètodes alternatius proposats. Objectius: Analitzar les característiques dels assajos clínics principals duts a terme amb els medicaments orfes autoritzats a Europa des de l’entrada en vigor de la Regulació Europea sobre Medicaments Orfes a l’any 2000, amb l’objectiu d’explorar si hi ha oportunitats per a l’aplicació de metodologies alternatives en el disseny d’assajos clínics. Mètodes: Es va dur a terme una revisió de les característiques administratives, farmacològiques, reguladores i clíniques pels primers 100 medicaments orfes aprovats a Europa des de l’entrada en vigor de la Regulació europea específica (ER 141/2000) a l’any 2000 i fins a Desembre de 2014. La informació recollida va ser posteriorment sistematitzada i analitzada. Resultats: Des de l’entrada en vigor de la Regulació Europea sobre Medicaments Orfes a l’any 2000 i fins a Desembre de 2014, 100 medicaments orfes diferents han estat autoritzats a Europa per a 125 indicacions terapèutiques, cobrint fins a 84 malalties diferents. La oncologia és l’àrea amb un major nombre de medicaments autoritzats. Les metodologies alternatives rarament s’han utilitzat. En general, les dades suggereixen que la robustesa metodològica de l’evidència científica que recolza l’aprovació d’indicacions terapèutiques per medicaments orfes és usualment baixa. El grau de raresa i el tipus de condicions mèdiques van influenciar en les característiques dels assajos clínics duts a terme. Conclusions: Les característiques dels assajos clínics principals duts a terme amb medicaments orfes a Europa des de l’entrada en vigor de la Regulació Europea sobre Medicaments Orfes a l’any 2000 suggereixen que hi ha espai per explorar la possible aplicació de metodologies alternatives en la realització d’assajos clínics en el camp de les malalties minoritàries.Introducción: La investigación y el desarrollo de nuevos medicamentos huérfanos han estado limitados por la falta de conocimiento sobre las enfermedades, la previsible falta de retorno de la inversión realizada en ausencia de incentivos, y la ausencia de metodologías específicas para aplicar en poblaciones pequeñas. Diez años después de la aprobación de la Regulación Europea sobre Medicamentos Huérfanos (ER 141/2000), el número de medicamentos destinados al tratamiento de enfermedades raras ha aumentado significativamente. El análisis del tipo de evidencia científica y los ensayos clínicos llevados a cabo para apoyar la autorización de comercialización de medicamentos huérfanos en Europa permitirá analizar el grado de utilización de metodologías alternativas destinadas a incrementar la eficiencia de los ensayos clínicos en poblaciones pequeñas, disponer de una referencia para explorar la aplicabilidad de estas metodologías alternativas, y comparar los métodos actualmente utilizados para llevar a cabo ensayos clínicos en el campo de las enfermedades raras en relación con los métodos alternativos propuestos. Objetivos: Analizar las características de los ensayos clínicos principales llevados a cabo con los medicamentos huérfanos autorizados en Europa desde la entrada en vigor de la Regulación Europea sobre Medicamentos Huérfanos en el año 2000, con el objetivo de explorar si hay espacio para la aplicación de metodologías alternativas en el diseño de ensayos clínicos. Métodos: Se llevó a cabo una revisión de las características administrativas, farmacológicas, reguladoras y clínicas para los primeros 100 medicamentos huérfanos aprobados en Europa desde la entrada en vigor de la Regulación europea específica (ER 141/2000) en el año 2000 y hasta Diciembre de 2014. La información recogida fue posteriormente sistematizada y analizada. Resultados: Desde la entrada en vigor de la Regulación Europea sobre Medicamentos Huérfanos en el año 2000 y hasta Diciembre de 2014, 100 medicamentos huérfanos diferentes han sido autorizados en Europa para 125 indicaciones terapéuticas, cubriendo hasta 84 enfermedades diferentes. La oncología es el área con un mayor número de medicamentos autorizados. Las metodologías alternativas raramente se han utilizado. En general, los datos sugieren que la robustez metodológica de la evidencia científica que apoya la aprobación de indicaciones terapéuticas para medicamentos huérfanos es usualmente baja. El grado de rareza y el tipo de condiciones médicas influenciaron en las características de los ensayos clínicos llevados a cabo. Conclusiones: Las características de los ensayos clínicos llevados a cabo con medicamentos huérfanos en Europa desde la entrada en vigor de la Regulación Europea sobre Medicamentos Huérfanos en el año 2000 sugieren que hay espacio para explorar la posible aplicación de metodologías alternativas en la realización de ensayos clínicos en el campo de las enfermedades raras.Background: Research and development of new orphan medicinal products has been limited because of lack of knowledge on the diseases, anticipated lack of return of investment in absence of incentives, and lack of methodologies to deal with small populations. Ten years after the European Orphan Drug Regulation (141/2000) the number of medicines for orphan diseases has increased significantly. The analysis of the type of scientific evidence and clinical trials conducted to support the marketing authorisation of orphan medicines in Europe will allow to analyse if alternative methodologies aimed to increase efficiency of clinical studies in small populations are applied, to have a reference to explore the applicability of such methodologies, and to compare the current methods used to conduct clinical trials in the rare diseases field versus the alternative methods proposed. Objective: To analyse the characteristics of the main clinical trials conducted with the orphan drugs authorised in Europe since the European regulation on orphan medicinal products entered in force in year 2000, in order to explore if there is room for application of alternative methodologies in the conduction of clinical trials. Methods: A review of administrative, pharmacological, regulatory and clinical data for the first 100 orphan medicinal products approved in Europe since the entry into force of the specific European regulation (ER 141/2000) to December 2014 has been conducted and systematized. Results: Since the European regulation on orphan medicinal products entered in force in year 2000 and up to December 2014, 100 orphan medicinal products have been approved for 125 indications in Europe covering 84 different diseases. Oncology is the area with higher number of orphan medicines authorised. Alternative methodological designs are seldom used. Overall, data suggest that the current methodological robustness of the evidence supporting approval of indications for orphan medicinal products is generally low. The rareness degree and the type of conditions influenced the characteristics of clinical trials conducted. Conclusions: The characteristics of the main clinical trials conducted with the orphan drugs authorised in Europe since the European regulation on orphan medicinal products entered in force in year 2000 suggest that there is room to explore the application of alternative methodologies in the conduction of clinical trials in rare diseases

Estudi de caracterització del disseny d'assajos clínics realitzats amb medicaments orfes = : Study to characterize the designs of clinical trials conducted with orphan medicinal products /

Introducció: La recerca i el desenvolupament de nous medicaments orfes ha estat limitada per la manca de coneixement sobre les malalties, la previsible manca de retorn de la inversió realitzada en absència d'incentius, i la manca de metodologies específiques per utilitzar en poblacions petites. Deu anys després de l'aprovació de la Regulació Europea sobre Medicaments Orfes (ER 141/2000), el nombre de medicaments destinats al tractament de malalties minoritàries ha augmentat significativament. L'anàlisi del tipus d'evidència científica i els assajos clínics duts a terme per recolzar l'autorització de comercialització de medicaments orfes a Europa permetrà analitzar el grau d'utilització de metodologies alternatives destinades a incrementar l'eficiència dels assajos clínics en poblacions petites, disposar d'una referència per explorar l'aplicabilitat d'aquestes metodologies alternatives, i comparar els mètodes actualment utilitzats per dur a terme assajos clínics en el camp de les malalties minoritàries en relació amb els mètodes alternatius proposats. Objectius: Analitzar les característiques dels assajos clínics principals duts a terme amb els medicaments orfes autoritzats a Europa des de l'entrada en vigor de la Regulació Europea sobre Medicaments Orfes a l'any 2000, amb l'objectiu d'explorar si hi ha oportunitats per a l'aplicació de metodologies alternatives en el disseny d'assajos clínics. Mètodes: Es va dur a terme una revisió de les característiques administratives, farmacològiques, reguladores i clíniques pels primers 100 medicaments orfes aprovats a Europa des de l'entrada en vigor de la Regulació europea específica (ER 141/2000) a l'any 2000 i fins a Desembre de 2014. La informació recollida va ser posteriorment sistematitzada i analitzada. Resultats: Des de l'entrada en vigor de la Regulació Europea sobre Medicaments Orfes a l'any 2000 i fins a Desembre de 2014, 100 medicaments orfes diferents han estat autoritzats a Europa per a 125 indicacions terapèutiques, cobrint fins a 84 malalties diferents. La oncologia és l'àrea amb un major nombre de medicaments autoritzats. Les metodologies alternatives rarament s'han utilitzat. En general, les dades suggereixen que la robustesa metodològica de l'evidència científica que recolza l'aprovació d'indicacions terapèutiques per medicaments orfes és usualment baixa. El grau de raresa i el tipus de condicions mèdiques van influenciar en les característiques dels assajos clínics duts a terme. Conclusions: Les característiques dels assajos clínics principals duts a terme amb medicaments orfes a Europa des de l'entrada en vigor de la Regulació Europea sobre Medicaments Orfes a l'any 2000 suggereixen que hi ha espai per explorar la possible aplicació de metodologies alternatives en la realització d'assajos clínics en el camp de les malalties minoritàries.Introducción: La investigación y el desarrollo de nuevos medicamentos huérfanos han estado limitados por la falta de conocimiento sobre las enfermedades, la previsible falta de retorno de la inversión realizada en ausencia de incentivos, y la ausencia de metodologías específicas para aplicar en poblaciones pequeñas. Diez años después de la aprobación de la Regulación Europea sobre Medicamentos Huérfanos (ER 141/2000), el número de medicamentos destinados al tratamiento de enfermedades raras ha aumentado significativamente. El análisis del tipo de evidencia científica y los ensayos clínicos llevados a cabo para apoyar la autorización de comercialización de medicamentos huérfanos en Europa permitirá analizar el grado de utilización de metodologías alternativas destinadas a incrementar la eficiencia de los ensayos clínicos en poblaciones pequeñas, disponer de una referencia para explorar la aplicabilidad de estas metodologías alternativas, y comparar los métodos actualmente utilizados para llevar a cabo ensayos clínicos en el campo de las enfermedades raras en relación con los métodos alternativos propuestos. Objetivos: Analizar las características de los ensayos clínicos principales llevados a cabo con los medicamentos huérfanos autorizados en Europa desde la entrada en vigor de la Regulación Europea sobre Medicamentos Huérfanos en el año 2000, con el objetivo de explorar si hay espacio para la aplicación de metodologías alternativas en el diseño de ensayos clínicos. Métodos: Se llevó a cabo una revisión de las características administrativas, farmacológicas, reguladoras y clínicas para los primeros 100 medicamentos huérfanos aprobados en Europa desde la entrada en vigor de la Regulación europea específica (ER 141/2000) en el año 2000 y hasta Diciembre de 2014. La información recogida fue posteriormente sistematizada y analizada. Resultados: Desde la entrada en vigor de la Regulación Europea sobre Medicamentos Huérfanos en el año 2000 y hasta Diciembre de 2014, 100 medicamentos huérfanos diferentes han sido autorizados en Europa para 125 indicaciones terapéuticas, cubriendo hasta 84 enfermedades diferentes. La oncología es el área con un mayor número de medicamentos autorizados. Las metodologías alternativas raramente se han utilizado. En general, los datos sugieren que la robustez metodológica de la evidencia científica que apoya la aprobación de indicaciones terapéuticas para medicamentos huérfanos es usualmente baja. El grado de rareza y el tipo de condiciones médicas influenciaron en las características de los ensayos clínicos llevados a cabo. Conclusiones: Las características de los ensayos clínicos llevados a cabo con medicamentos huérfanos en Europa desde la entrada en vigor de la Regulación Europea sobre Medicamentos Huérfanos en el año 2000 sugieren que hay espacio para explorar la posible aplicación de metodologías alternativas en la realización de ensayos clínicos en el campo de las enfermedades raras.Background: Research and development of new orphan medicinal products has been limited because of lack of knowledge on the diseases, anticipated lack of return of investment in absence of incentives, and lack of methodologies to deal with small populations. Ten years after the European Orphan Drug Regulation (141/2000) the number of medicines for orphan diseases has increased significantly. The analysis of the type of scientific evidence and clinical trials conducted to support the marketing authorisation of orphan medicines in Europe will allow to analyse if alternative methodologies aimed to increase efficiency of clinical studies in small populations are applied, to have a reference to explore the applicability of such methodologies, and to compare the current methods used to conduct clinical trials in the rare diseases field versus the alternative methods proposed. Objective: To analyse the characteristics of the main clinical trials conducted with the orphan drugs authorised in Europe since the European regulation on orphan medicinal products entered in force in year 2000, in order to explore if there is room for application of alternative methodologies in the conduction of clinical trials. Methods: A review of administrative, pharmacological, regulatory and clinical data for the first 100 orphan medicinal products approved in Europe since the entry into force of the specific European regulation (ER 141/2000) to December 2014 has been conducted and systematized. Results: Since the European regulation on orphan medicinal products entered in force in year 2000 and up to December 2014, 100 orphan medicinal products have been approved for 125 indications in Europe covering 84 different diseases. Oncology is the area with higher number of orphan medicines authorised. Alternative methodological designs are seldom used. Overall, data suggest that the current methodological robustness of the evidence supporting approval of indications for orphan medicinal products is generally low. The rareness degree and the type of conditions influenced the characteristics of clinical trials conducted. Conclusions: The characteristics of the main clinical trials conducted with the orphan drugs authorised in Europe since the European regulation on orphan medicinal products entered in force in year 2000 suggest that there is room to explore the application of alternative methodologies in the conduction of clinical trials in rare diseases

Evidence supporting regulatory-decision making on orphan medicinal products authorisation in Europe : methodological uncertainties

To assess uncertainty in regulatory decision-making for orphan medicinal products (OMP), a summary of the current basis for approval is required; a systematic grouping of medical conditions may be useful in summarizing information and issuing recommendations for practice. A grouping of medical conditions with similar characteristics regarding the potential applicability of methods and designs was created using a consensus approach. The 125 dossiers for authorised OMP published between 1999 and 2014 on the EMA webpage were grouped accordingly and data was extracted from European Public Assessment Reports (EPARs) to assess the extent and robustness of the pivotal evidence supporting regulatory decisions. 88% (110/125) of OMP authorizations were based on clinical trials, with 35% (38/110) including replicated pivotal trials. The mean (SD) number of pivotal trials per indication was 1.4 (0.7), and the EPARs included a median of three additional non-pivotal supportive studies. 10% of OMPs (13/125) were authorised despite only negative pivotal trials. One-third of trials (53/159) did not include a control arm, one-third (50/159) did not use randomisation, half the trials (75/159) were open-label and 75% (119/159) used intermediate or surrogate variables as the main outcome. Chronic progressive conditions led by multiple system/organs, conditions with single acute episodes and progressive conditions led by one organ/system were the groups where the evidence deviated most from conventional standards. Conditions with recurrent acute episodes had the most robust datasets. The overall size of the exposed population at the time of authorisation of OMP − mean(SD) 190.5 (202.5) − was lower than that required for the qualification of clinically-relevant adverse reactions. The regulatory evidence supporting OMP authorization showed substantial uncertainties, including weak protection against errors, substantial use of designs unsuited for conclusions on causality, use of intermediate variables, lack of a priorism and insufficient safety data to quantify risks of relevant magnitude. Grouping medical conditions based on clinical features and their methodological requirements may facilitate specific methodological and regulatory recommendations for the study of OMP to strengthen the evidence base. The online version of this article (10.1186/s13023-018-0926-z) contains supplementary material, which is available to authorized users

Evidence supporting regulatory-decision making on orphan medicinal products authorisation in Europe : methodological uncertainties

BACKGROUND: To assess uncertainty in regulatory decision-making for orphan medicinal products (OMP), a summary of the current basis for approval is required; a systematic grouping of medical conditions may be useful in summarizing information and issuing recommendations for practice. METHODS: A grouping of medical conditions with similar characteristics regarding the potential applicability of methods and designs was created using a consensus approach. The 125 dossiers for authorised OMP published between 1999 and 2014 on the EMA webpage were grouped accordingly and data was extracted from European Public Assessment Reports (EPARs) to assess the extent and robustness of the pivotal evidence supporting regulatory decisions. RESULTS: 88% (110/125) of OMP authorizations were based on clinical trials, with 35% (38/110) including replicated pivotal trials. The mean (SD) number of pivotal trials per indication was 1.4 (0.7), and the EPARs included a median of three additional non-pivotal supportive studies. 10% of OMPs (13/125) were authorised despite only negative pivotal trials. One-third of trials (53/159) did not include a control arm, one-third (50/159) did not use randomisation, half the trials (75/159) were open-label and 75% (119/159) used intermediate or surrogate variables as the main outcome. Chronic progressive conditions led by multiple system/organs, conditions with single acute episodes and progressive conditions led by one organ/system were the groups where the evidence deviated most from conventional standards. Conditions with recurrent acute episodes had the most robust datasets. The overall size of the exposed population at the time of authorisation of OMP - mean(SD) 190.5 (202.5) - was lower than that required for the qualification of clinically-relevant adverse reactions. CONCLUSIONS: The regulatory evidence supporting OMP authorization showed substantial uncertainties, including weak protection against errors, substantial use of designs unsuited for conclusions on causality, use of intermediate variables, lack of a priorism and insufficient safety data to quantify risks of relevant magnitude. Grouping medical conditions based on clinical features and their methodological requirements may facilitate specific methodological and regulatory recommendations for the study of OMP to strengthen the evidence base

Applicability and added value of novel methods to improve drug development in rare diseases

BACKGROUND: The ASTERIX project developed a number of novel methods suited to study small populations. The objective of this exercise was to evaluate the applicability and added value of novel methods to improve drug development in small populations, using real world drug development programmes as reported in European Public Assessment Reports. METHODS: The applicability and added value of thirteen novel methods developed within ASTERIX were evaluated using data from 26 European Public Assessment Reports (EPARs) for orphan medicinal products, representative of rare medical conditions as predefined through six clusters. The novel methods included were 'innovative trial designs' (six methods), 'level of evidence' (one method), 'study endpoints and statistical analysis' (four methods), and 'meta-analysis' (two methods) and they were selected from the methods developed within ASTERIX based on their novelty; methods that discussed already available and applied strategies were not included for the purpose of this validation exercise. Pre-requisites for application in a study were systematized for each method, and for each main study in the selected EPARs it was assessed if all pre-requisites were met. This direct applicability using the actual study design was firstly assessed. Secondary, applicability and added value were explored allowing changes to study objectives and design, but without deviating from the context of the drug development plan. We evaluated whether differences in applicability and added value could be observed between the six predefined condition clusters. RESULTS AND DISCUSSION: Direct applicability of novel methods appeared to be limited to specific selected cases. The applicability and added value of novel methods increased substantially when changes to the study setting within the context of drug development were allowed. In this setting, novel methods for extrapolation, sample size re-assessment, multi-armed trials, optimal sequential design for small sample sizes, Bayesian sample size re-estimation, dynamic borrowing through power priors and fall-back tests for co-primary endpoints showed most promise - applicable in more than 40% of evaluated EPARs in all clusters. Most of the novel methods were applicable to conditions in the cluster of chronic and progressive conditions, involving multiple systems/organs. Relatively fewer methods were applicable to acute conditions with single episodes. For the chronic clusters, Goal Attainment Scaling was found to be particularly applicable as opposed to other (non-chronic) clusters. CONCLUSION: Novel methods as developed in ASTERIX can improve drug development programs. Achieving optimal added value of these novel methods often requires consideration of the entire drug development program, rather than reconsideration of methods for a specific trial. The novel methods tested were mostly applicable in chronic conditions, and acute conditions with recurrent episodes