Patient-reported, observer-reported and performance outcomes in qualification procedures at the European Medicines Agency 2013-2018.

AIMS: To describe characteristics of applicant, tool, outcomes, regulatory responses and general learnings from European Medicines Agency (EMA) Qualification Procedures on patient-reported outcomes (PROs), observer-reported outcomes (ObsROs) and performance outcomes (PerfOs) finalized between January 2013 and December 2018. METHODS: Descriptive analysis, and qualitative review of the regulatory outcomes of the study procedures. RESULTS: Seventeen qualification programmes for PROs, 6 for ObsRO tools and 11 for PerfO tools were submitted by consortia, large and small/medium companies. Gastroenterology and neurology were the most frequent therapeutic areas. There was a high level of regulators' partial agreement (above 70%) with applicant's approaches with constructive input; EMA published Letters of Support for PRO (6), ObsRO (2) and PerfO (4) tools, and Qualification Opinions on PROs (2) and PerfOs (1). General issues related to Qualification Procedures on PROs raised by EU regulatorsincluded: population, appropriate studies to demonstrate ability to detect change, tool validation in interventional trials, anchoring, identification of the minimally important difference, item selection, weighting, and multiple domains. In addition, specific issues for ObsROs and PerfO tools validation are identified. CONCLUSIONS: Regulators discussed principles and challenges of validation tailored to specific setting in tool development, providing constructive feedback. Regulatory outputs supportive of further development were published in over one-third of programs. We encourage applicants intending to use or develop novel PRO, ObsRO and PerfO tools that will generate evidence for regulatory submissions on medicines to consider Qualification procedures for novel methods to seek feedback on the development and validation of these tools.

The same annual dose of 292000 IU of vitamin D (cholecalciferol) on either daily or four monthly basis for elderly women: 1-year comparative study of the effects on serum 25(OH)D concentrations and renal function.

OBJECTIVE: Daily dosing of vitamin D supplements may be difficult among older people. Infrequent administration of 'megadoses' controlled by health care personnel may overcome adherence problem. We compared the efficacy and safety of two oral dosages (800 IU daily or 97333 IU four monthly) of vitamin D(3) resulting in the equal annual dose of 292000 IU. DESIGN: Randomized, double-blind, double-dummy parallel group comparison. Patients Forty women aged 69.3-78.8 years. INTERVENTIONS: Vitamin D(3) 400 IU twice daily (D group) or vitamin D(3) oil 97333 IU every 4 months (4 M group) for 1 year. All received 1 g of calcium daily. MEASUREMENTS: Serum 25-hydroxyvitamin D(3) [25(OH)D(3)] in relation to the target levels of 50-75 nmol/l, PTH, serum type I procollagen aminoterminal propeptide (PINP), serum and urine calcium, renal function. RESULTS: A quantity of 25OHD(3) increased more in D group than in 4 M group (P < 0.0001). All participants in D group and 67% in 4 M group had 25(OH)D(3) above 50 nmol/l at 12 months; the target level of 75 nmol/l was reached by 47% and 28% respectively. PTH did not show any seasonal perturbation in either group. PINP declined and urinary calcium rose similarly in the study groups over time (P < 0.0001). Renal function did not worsen in either group. CONCLUSIONS: In terms of serum 25(OH)D(3) concentrations, 800 IU daily was more efficient than a 97333 IU every 4 months. However, to increase adherence, the latter is still worth developing. Both treatments increased urinary excretion of calcium, but did not worsen renal function.

European Medicines Agency support mechanisms fostering orphan drug development.

A legislative framework introducing European public health measures on orphan medicinal products came into force in the European Union in April 2000. The aim of the orphan legislation is to stimulate research and development of medicinal products for rare diseases by providing incentives to the sponsors. Incentives include, among others, an unreserved access to the centralized procedure with a 10-year period of market exclusivity and fee reductions including free scientific advice for drug development. Nine years after the implementation of the orphan legislation, more than 690 products have been designated and 58 have received marketing authorizations in Europe. The orphan designations granted to date cover a wide variety of diseases for which there are either no authorized treatments or only limited treatment options with a need for improvement. At the dawn of the tenth anniversary of the orphan legislation, the aim of this article is to review how the European Medicines Agency has supported the mechanisms fostering development of orphan medicines in the E.U. since 2000.

Marketing authorisation of orphan medicines in Europe from 2000 to 2013.

An analysis was performed on a data set of 157 orphan designated medicines with an outcome for marketing authorisation application (MAA) between 2000 and 2013. The intention was to understand the factors associated with marketing authorisation success, the challenges developers face regarding orphan medicine development, and how scientific advice (SA) is used during development. The results demonstrated that orphan medicines have a lower success rate compared with non-orphan medicines and that determinants for marketing authorisation success were company size and compliance with SA. Compliance with SA could help orphan medicine developers overcome clinical development challenges.

Establishing medical plausibility in the context of orphan medicines designation in the European Union.

In the European Union, sponsors have the responsibility to demonstrate the "intention to diagnose, prevent or treat" a serious and rare condition before the Committee of Orphan Medicinal Products (COMP), for a medicinal product to meet the criteria for Orphan Designation. This requirement is commonly referred to as "medical plausibility" and the justification of this intention is assessed on the merits of each application by the COMP, which deliberates over the scientific evaluation of the evidence submitted. The scientific assessment of the applications for orphan designation by the Committee is based on the review of non-clinical (such as in vitro and in vivo) and/or clinical data submitted by the sponsor. Several challenges regarding the evidence provided emerge when the sponsor is applying for a designation at an early stage of development. Herein we discuss specific examples from the experience of the COMP, in order to elaborate on the type and level of evidence generally considered necessary for the purpose of justification of the intention to treat an orphan condition. Importantly, it is pointed out that bridging of data from other products, irrespectively of how comparable they may be, or from settings not directly associated with the condition as applied for designation, is by and large not a successful exercise and may only be exceptionally considered. It is further exemplified that, as reflected in the updated 'Guideline on the format and context of the applications for designation' and the guidance document 'Recommendation on elements required to support the medical plausibility and the assumption of significant benefit for an orphan designation' available on the EMA website, the sponsor should provide data with the specific product as applied for in specific models of the condition or in patients affected by the same condition subject of each application.

Use of biomarkers in the context of orphan medicines designation in the European Union.

The use of biomarkers within the procedures of the Committee of Orphan Medicinal Products (COMP) of the European Medicines Agency (EMA) is discussed herein. The applications for Orphan Medicinal Product designation in the EU are evaluated at two stages. At the time of orphan designation application, the file undergoes an assessment to establish whether the proposed condition is a distinct and serious condition affecting not more than 5 in 10,000 people in the EU, and whether the product is plausible as a therapy for that condition. In cases where therapies already exist, the significant benefit of the candidate product over existing therapies is also evaluated. The orphan criteria are reassessed at the time of marketing authorisation, so that marketing exclusivity for the product in the orphan medical condition can be granted. Within this context, biomarkers have been used in submissions in order to define an orphan condition and to justify that the criteria for orphan designation are met. The current work discusses specific examples from the experience of the COMP, where biomarkers have played a decisive role. Importantly, it identifies the proposal of sub-sets of non-rare conditions based on biomarkers as a challenging issue in the evaluation of applications. In particular two specific requirements for the candidate orphan medicines in relation to the biomarker-based subsets are highlighted: the "plausible link to the condition" and the "exclusion of effects outside the subset".

European regulation on orphan medicinal products: 10 years of experience and future perspectives.

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 850 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 60 orphan drugs have received marketing authorization in Europe. Here, stimulated by the tenth anniversary of the COMP, we reflect on the outcomes and experience gained in the past decade, and contemplate issues for the future, such as catalysing drug development for the large number of rare diseases that still lack effective treatments.