Proposal for a new classification of orphan and/or rare conditions based on clinical characteristics that determine the applicability of different research methods to their study

Antecedents: Les malalties rares són aquelles que afecten a un petit nombre de persones i tenen una prevalença particularment baixa en comparació amb la població general. Si bé individualment aquestes entitats són poc comuns, com a grup, són una important causa de malaltia crònica, discapacitat i de mort prematura en nens i adults. La Unió Europea considera que una malaltia és rara quan afecten a no més de 5 de cada 10.000 persones. Metodologies destinades a augmentar l'eficiència dels estudis clínics en poblacions petites han estat poc aplicades en el desenvolupament clínic de nous medicaments orfes. La manca de referències i guies pot explicar la reticència a utilitzar metodologies alternatives. Actualment l’existència d’una guia específica que engloba informació general és poc pràctica donat al gran nombre de condicions òrfenes existents. Un enfocament sistemàtic per a l'agrupació de condicions mèdiques en base als seus requeriments metodològics pot ser útil per permetre la generalització de recomanacions per tipus de condicions, en lloc de per condicions individuals. Hipòtesi: Les condicions òrfeness es poden agrupar a través d'un enfocament sistemàtic en funció dels seus requeriments metodològics, i l'agrupació resultant pot esdevenir una eina eficaç per a establir recomanacions específiques per a l'estudi dels grups de condicions en lloc de per condicions individuals. Aquesta eina pot facilitar un enfocament més estructurat en el desenvolupament i la presa de decisions regulatòries. Objectiu: Proposar una agrupació de condicions òrfenes en base als seus requeriments metodològics, amb l'objectiu de proporcionar una guia pel desenvolupament de nous tractaments i la presa de decisions regulatòries per a medicaments orfes. Mètodes: S’ha identificat les característiques clíniques que poden ser rellevants en el disseny d’un estudi i en la presa de decisions de regulatòries per a medicaments orfes. S’ha seleccionat un nombre de condicions rares descrites en detall mitjançant aquestes característiques clíniques, i s’han emprat per a crear una base de dades que ha estat analitzada a través d’un Anàlisis de Correspondències Múltiples (MCA) per a identificar grups de condicions. Els grups de condicions obtinguts han estat refinats i validats des d'un punt de vista clínic i regulatori. La validació clínica va incloure una reunió amb especialistes clínics amb experiència reconeguda en el camp de les malalties òrfenes, per tal de conèixer la seva opinió envers la classificació proposada. Resultats: Es proposen sis grups de condicions mèdiques que comparteixen aplicabilitat metodològica similar pel seu estudi: episodi agut únic, episodis aguts repetits, condició lenta / no progressiva, condició on intervé un òrgan o un sistema, progressiva multidimensional multi-orgànica i d’evolució per estadis. Un total de 125 indicacions mèdiques amb dictàmens favorables emesos per l'EMA per a medicament orfes han estat testats per a provar l'aplicabilitat de les inferències metodològiques derivades de cada grup. Les enquestes lliurades en la validació clínica als especialistes van concloure que l’aproximació proposada resulta útil per a guiar la decisió metodològica de la indústria, dels reguladors i també dels investigadors. Conclusions: Es proposa una nova agrupació de condicions en base als seus requeriments metodològics com a guia pel desenvolupament de nous tractaments i per a la presa de decisions regulatòries envers als medicaments orfes.Background: Rare diseases are those that affect a small number of people and have a particularly low prevalence compared to the general population. While individually these entities are uncommon, as a group they are an important cause of chronic illness, disability and premature death in both children and adults. The European Union considers diseases to be rare when they affect not more than 5 in 10000 individuals. Methodologies aimed to increase efficiency of clinical studies in small populations have been only scarcely applied to the clinical development of new orphan medicinal products (OMP). The lack of references and guidance may explain reluctance to alternative methodologies, but specific guidance is impractical due to the huge number of existing orphan conditions. A systematic approach to grouping medical conditions based on their methodological requirements may be useful to allow generalisation of recommendations to type conditions, rather than to single disease models. Hypothesis: Orphan conditions can be grouped through a systematic approach based on their methodological requirements, and the resulting clustering can be an effective tool for establishing specific recommendations for the study of groups of conditions rather than for individual conditions, that would facilitate a more structured approach to regulatory development and decision making. Objective: To propose a clustering of medical conditions based on their methodological requirements, with the aim to provide a framework for guidance on treatment development and regulatory decision making on OMP. Methods: The characteristics of medical conditions which may be relevant to study design and regulatory decision making have been identified, and a number of sample conditions have been described in detail for these characteristics and used to produce a database that has been analysed through Multiple Correspondence Analysis (MCA) to identify clusters of conditions. These have been refined and validated from a clinical and regulatory perspective which included a meeting with clinical specialists with recognised expertise in the field of orphan diseases, in order to know their opinion towards the proposed classification and to get insights on potential weaknesses of the approach. Results: Six groups of medical conditions are proposed which share applicability of similar methodologies to their study: single acute episode, repeated acute episodes, slow/non progressive, progressive led by one organ or system, progressive multidimensional multi-organ and staged condition. A total of 125 medical indications with positive opinions issued by the EMA on OMP applications have been clustered to test applicability of inferences. The methodological inferences to the different established clusters implied a first step of listing the variables that had a high discriminative value for each cluster, and a second step to make detailed descriptions of these determinants in relation to aspects required to define clinical study designs. This was done in order to test the validity of the proposed clusters to their main purpose as issuing common recommendations on product development for a given group of conditions. The results of the surveys given to members of the clinical board were collected and summarised. Clinicians agreed on the fact that current methods in clinical research have room for a more structured approach and that would help to the access to new treatments urgently needed, and considered it would be useful to guide methodological decision for industry and regulators, also to investigators and health technology assessment. Conclusions: A new clustering of conditions based on their methodological requirements is proposed as a framework for guidance on treatment development and regulatory decision making on OMP

Proposal for a new classification of orphan and/or rare conditions based on clinical characteristics that determine the applicability of different research methods to their study

Antecedents: Les malalties rares són aquelles que afecten a un petit nombre de persones i tenen una prevalença particularment baixa en comparació amb la població general. Si bé individualment aquestes entitats són poc comuns, com a grup, són una important causa de malaltia crònica, discapacitat i de mort prematura en nens i adults. La Unió Europea considera que una malaltia és rara quan afecten a no més de 5 de cada 10.000 persones. Metodologies destinades a augmentar l'eficiència dels estudis clínics en poblacions petites han estat poc aplicades en el desenvolupament clínic de nous medicaments orfes. La manca de referències i guies pot explicar la reticència a utilitzar metodologies alternatives. Actualment l'existència d'una guia específica que engloba informació general és poc pràctica donat al gran nombre de condicions òrfenes existents. Un enfocament sistemàtic per a l'agrupació de condicions mèdiques en base als seus requeriments metodològics pot ser útil per permetre la generalització de recomanacions per tipus de condicions, en lloc de per condicions individuals. Hipòtesi: Les condicions òrfeness es poden agrupar a través d'un enfocament sistemàtic en funció dels seus requeriments metodològics, i l'agrupació resultant pot esdevenir una eina eficaç per a establir recomanacions específiques per a l'estudi dels grups de condicions en lloc de per condicions individuals. Aquesta eina pot facilitar un enfocament més estructurat en el desenvolupament i la presa de decisions regulatòries. Objectiu: Proposar una agrupació de condicions òrfenes en base als seus requeriments metodològics, amb l'objectiu de proporcionar una guia pel desenvolupament de nous tractaments i la presa de decisions regulatòries per a medicaments orfes. Mètodes: S'ha identificat les característiques clíniques que poden ser rellevants en el disseny d'un estudi i en la presa de decisions de regulatòries per a medicaments orfes. S'ha seleccionat un nombre de condicions rares descrites en detall mitjançant aquestes característiques clíniques, i s'han emprat per a crear una base de dades que ha estat analitzada a través d'un Anàlisis de Correspondències Múltiples (MCA) per a identificar grups de condicions. Els grups de condicions obtinguts han estat refinats i validats des d'un punt de vista clínic i regulatori. La validació clínica va incloure una reunió amb especialistes clínics amb experiència reconeguda en el camp de les malalties òrfenes, per tal de conèixer la seva opinió envers la classificació proposada. Resultats: Es proposen sis grups de condicions mèdiques que comparteixen aplicabilitat metodològica similar pel seu estudi: episodi agut únic, episodis aguts repetits, condició lenta / no progressiva, condició on intervé un òrgan o un sistema, progressiva multidimensional multi-orgànica i d'evolució per estadis. Un total de 125 indicacions mèdiques amb dictàmens favorables emesos per l'EMA per a medicament orfes han estat testats per a provar l'aplicabilitat de les inferències metodològiques derivades de cada grup. Les enquestes lliurades en la validació clínica als especialistes van concloure que l'aproximació proposada resulta útil per a guiar la decisió metodològica de la indústria, dels reguladors i també dels investigadors. Conclusions: Es proposa una nova agrupació de condicions en base als seus requeriments metodològics com a guia pel desenvolupament de nous tractaments i per a la presa de decisions regulatòries envers als medicaments orfes.Background: Rare diseases are those that affect a small number of people and have a particularly low prevalence compared to the general population. While individually these entities are uncommon, as a group they are an important cause of chronic illness, disability and premature death in both children and adults. The European Union considers diseases to be rare when they affect not more than 5 in 10000 individuals. Methodologies aimed to increase efficiency of clinical studies in small populations have been only scarcely applied to the clinical development of new orphan medicinal products (OMP). The lack of references and guidance may explain reluctance to alternative methodologies, but specific guidance is impractical due to the huge number of existing orphan conditions. A systematic approach to grouping medical conditions based on their methodological requirements may be useful to allow generalisation of recommendations to type conditions, rather than to single disease models. Hypothesis: Orphan conditions can be grouped through a systematic approach based on their methodological requirements, and the resulting clustering can be an effective tool for establishing specific recommendations for the study of groups of conditions rather than for individual conditions, that would facilitate a more structured approach to regulatory development and decision making. Objective: To propose a clustering of medical conditions based on their methodological requirements, with the aim to provide a framework for guidance on treatment development and regulatory decision making on OMP. Methods: The characteristics of medical conditions which may be relevant to study design and regulatory decision making have been identified, and a number of sample conditions have been described in detail for these characteristics and used to produce a database that has been analysed through Multiple Correspondence Analysis (MCA) to identify clusters of conditions. These have been refined and validated from a clinical and regulatory perspective which included a meeting with clinical specialists with recognised expertise in the field of orphan diseases, in order to know their opinion towards the proposed classification and to get insights on potential weaknesses of the approach. Results: Six groups of medical conditions are proposed which share applicability of similar methodologies to their study: single acute episode, repeated acute episodes, slow/non progressive, progressive led by one organ or system, progressive multidimensional multi-organ and staged condition. A total of 125 medical indications with positive opinions issued by the EMA on OMP applications have been clustered to test applicability of inferences. The methodological inferences to the different established clusters implied a first step of listing the variables that had a high discriminative value for each cluster, and a second step to make detailed descriptions of these determinants in relation to aspects required to define clinical study designs. This was done in order to test the validity of the proposed clusters to their main purpose as issuing common recommendations on product development for a given group of conditions. The results of the surveys given to members of the clinical board were collected and summarised. Clinicians agreed on the fact that current methods in clinical research have room for a more structured approach and that would help to the access to new treatments urgently needed, and considered it would be useful to guide methodological decision for industry and regulators, also to investigators and health technology assessment. Conclusions: A new clustering of conditions based on their methodological requirements is proposed as a framework for guidance on treatment development and regulatory decision making on OMP

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

Successful Integration of Clinical Pharmacists in an OPAT Program : A Real-Life Multidisciplinary Circuit

Outpatient parenteral antimicrobial therapy (OPAT) programs encompass a range of healthcare processes aiming to treat infections at home, with the preferential use of the intravenous route. Although several barriers arise during the implementation of OPAT circuits, recent cumulative data have supported the effectiveness of these programs, demonstrating their application in a safe and cost-effective manner. Given that OPAT is evolving towards treating patients with higher complexity, a multidisciplinary team including physicians, pharmacists, and nursing staff should lead the program. The professionals involved require previous experience in infectious diseases treatment as well as in outpatient healthcare and self-administration. As we describe here, clinical pharmacists exert a key role in OPAT multidisciplinary teams. Their intervention is essential to optimize antimicrobial prescriptions through their participation in stewardship programs as well as to closely follow patients from a pharmacotherapeutic perspective. Moreover, pharmacists provide specialized counseling on antimicrobial treatment technical compounding. In fact, OPAT elaboration in sterile environments and pharmacy department clean rooms increases OPAT stability and safety, enhancing the quality of the program. In summary, building multidisciplinary teams with the involvement of clinical pharmacists improves the management of home-treated infections, promoting a safe self-administration and increasing OPAT patients' quality of life