Inherited retinal dystrophies and orphan designations in the European Union.

Inherited Retinal Dystrophies (IRD) are diverse rare diseases that affect the retina and lead to visual impairment or blindness. Research in this field is ongoing, with over 60 EU orphan medicinal products designated in this therapeutic area by the Committee for Orphan Medicinal Products (COMP) at the European Medicines Agency (EMA). Up to now, COMP has used traditional disease terms, like retinitis pigmentosa, for orphan designation regardless of the product's mechanism of action.

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.

Regulatory and health technology assessment advice on postlicensing and postlaunch evidence generation is a foundation for lifecycle data collection for medicines.

The understanding of the benefit risk profile, and relative effectiveness of a new medicinal product, are initially established in a circumscribed patient population through clinical trials. There may be uncertainties associated with the new medicinal product that cannot be, or do not need to be resolved before launch. Postlicensing or postlaunch evidence generation (PLEG) is a term for evidence generated after the licensure or launch of a medicinal product to address these remaining uncertainties.

European regulators' views on a wearable-derived performance measurement of ambulation for Duchenne muscular dystrophy regulatory trials.

Development of novel therapies for Duchenne muscular dystrophy (DMD) are driving the need for more efficient ways of detecting changes in disease- progression in DMD [1]. However, medicines' approval must be based on outcome measures that are acceptable from a regulatory perspective. In this article, European regulators provide an update on the recent regulatory consideration of a new endpoint (Stride Velocity 95th Centile (SV95C)) that could be used in therapeutic DMD trials.

Development of a Retinopathy of Prematurity Activity Scale and Clinical Outcome Measures for Use in Clinical Trials.

Importance: To facilitate drug and device development for neonates, the International Neonatal Consortium brings together key stakeholders, including pharmaceutical companies, practitioners, regulators, funding agencies, scientists, and families, to address the need for objective, standardized clinical trial outcome measurements to fulfill regulatory requirements. Retinopathy of prematurity (ROP) is a disease that affects preterm neonates. The current International Classification of Retinopathy of Prematurity does not take into account all of the characteristics of ROP and does not adequately discriminate small changes in disease after treatment.

The impact of parallel regulatory-health technology assessment scientific advice on clinical development. Assessing the uptake of regulatory and health technology assessment recommendations.

Aims: The parallel regulatory-health technology assessment scientific advice (PSA) procedure allows manufacturers to receive simultaneous feedback from both EU regulators and health technology assessment (HTA) bodies on development plans for new medicines. The primary objective of the present study is to investigate whether PSA is integrated in the clinical development programmes for which advice was sought.

Methods: Contents of PSA provided by regulators and HTA bodies for each procedure between 2010 and 2015 were analysed.

Biomarkers and Surrogate Endpoints in Drug Development: A European Regulatory View.

Purpose: To give a European regulatory overview of the requirements on and the use of biomarkers or surrogate endpoints in the development of drugs for ocular disease.

Methods: Definitions, methods to validate new markers, and circumstances where surrogate endpoints can be appropriate are summarized.

Results: The key endpoints that have been used in registration studies so far are based on visual acuity, signs, and symptoms, or on surrogate endpoints.

How aligned are the perspectives of EU regulators and HTA bodies? A comparative analysis of regulatory-HTA parallel scientific advice.

Background: In 2010, the European Medicines Agency (EMA) initiated a pilot project on parallel scientific advice with Health Technology Assessment bodies (HTABs) that allows manufacturers to receive simultaneous feedback from both the European Union (EU) regulators and HTABs on their development plans for medicines.

Aims: The present retrospective qualitative analysis aimed to explore how the parallel scientific advice system is working and levels of commonality between the EU regulators and HTABs, and among HTABs, when applicants obtain parallel scientific advice from both a regulatory and an HTA perspective.

Methods: We analysed the minutes of discussion meetings held at the EMA between 2010, when parallel advice was launched, and 1 May 2015, when the cutoff date for data extraction was set.

Parathyroid hormone-related protein protects against mammary tumor emergence and is associated with monocyte infiltration in ductal carcinoma in situ.

Parathyroid hormone-related protein (PTHrP) is required for mammary gland development and promotes the growth of breast cancer metastases within bone. However, there are conflicting reports of the prognostic significance of its expression in primary breast cancers. To study the role of PTHrP in early breast cancer, the effect of conditional deletion of PTHrP was examined in the context of neu-induced mammary tumorigenesis.

The effects of an infant-feeding classroom activity on the breast-feeding knowledge and intentions of adolescents.

This study examined the impact of an infant-feeding classroom activity on the breast-feeding knowledge and intentions of adolescents living in Nova Scotia, Canada. One hundred twenty-one students attending two high schools were administered one pretest and two posttest questionnaires. Students were arbitrarily assigned to a control or intervention group.

Effects of uteroplacental insufficiency and reducing litter size on maternal mammary function and postnatal offspring growth.

Human intrauterine growth restriction is often associated with uteroplacental insufficiency and a decline in nutrient and oxygen supply to the fetus. This study investigated the effects of uteroplacental insufficiency and intrauterine growth restriction (Restricted) or reducing litter size for normally grown pups (Reduced Litter) on maternal mammary development and function, milk composition, offspring milk intake, and their resultant effects on postnatal growth. Uteroplacental insufficiency was surgically induced by bilateral uterine vessel ligation on day 18 of gestation in the Wistar Kyoto rat.

Bringing theory to life: engaging nursing students in a collaborative population-based screening project.

A collaborative population-based project for bowel cancer prevention provided an ideal opportunity to involve nursing students in applying theory to practice. In this article, described is how the engagement of students and subsequent application of a population health template contributed to a community-based bowel cancer education and screening campaign. The campaign was a valuable teaching-learning experience for students and contributed to the goal of reducing and reporting on the number of bowel cancer deaths in the local area.

Tumor-specific expression of alphavbeta3 integrin promotes spontaneous metastasis of breast cancer to bone.

Introduction: Studies in xenograft models and experimental models of metastasis have implicated several beta3 integrin-expressing cell populations, including endothelium, platelets and osteoclasts, in breast tumor progression. Since orthotopic human xenograft models of breast cancer are poorly metastatic to bone and experimental models bypass the formation of a primary tumor, however, the precise contribution of tumor-specific alphavbeta3 to the spontaneous metastasis of breast tumors from the mammary gland to bone remains unclear.

Methods: We used a syngeneic orthotopic model of spontaneous breast cancer metastasis to test whether exogenous expression of alphavbeta3 in a mammary carcinoma line (66cl4) that metastasizes to the lung, but not to bone, was sufficient to promote its spontaneous metastasis to bone from the mammary gland.

Testing and implementing signal impact analysis in a regulatory setting: results of a pilot study.

Background And Aim: Statistical signal detection methods such as proportional reporting ratios (PRRs) detect many drug safety signals when applied to databases of spontaneous suspected adverse drug reactions (ADRs). Impact analysis is a tool that was developed as an aid to prioritisation of such signals. This paper describes a pilot project whereby impact analysis was simultaneously introduced into practice in a regulatory setting and tested in comparison with the existing approach.

Impact analysis of signals detected from spontaneous adverse drug reaction reporting data.

This paper describes a new method of prioritising signals of potential adverse drug reactions (ADRs) detected from spontaneous reports that is called impact analysis. This is an interim step between signal detection and detailed signal evaluation. Using mathematical screening tools, large numbers of signals may now be detected from spontaneous ADR databases.

Upregulated MT1-MMP/TIMP-2 axis in the TSU-Pr1-B1/B2 model of metastatic progression in transitional cell carcinoma of the bladder.

Muscle invasive transitional cell carcinoma (TCC) of the bladder is associated with a high frequency of metastasis, resulting in poor prognosis for patients presenting with this disease. Models that capture and demonstrate step-wise enhancement of elements of the human metastatic cascade on a similar genetic background are useful research tools. We have utilized the transitional cell carcinoma cell line TSU-Pr1 to develop an in vivo experimental model of bladder TCC metastasis.

Genomic analysis of a spontaneous model of breast cancer metastasis to bone reveals a role for the extracellular matrix.

A clinically relevant model of spontaneous breast cancer metastasis to multiple sites, including bone, was characterized and used to identify genes involved in metastatic progression. The metastatic potential of several genetically related tumor lines was assayed using a novel real-time quantitative RT-PCR assay of tumor burden. Based on this assay, the tumor lines were categorized as nonmetastatic (67NR), weakly metastatic to lymph node (168FARN) or lung (66cl4), or highly metastatic to lymph node, lung, and bone (4T1.

Uteroplacental restriction in the rat impairs fetal growth in association with alterations in placental growth factors including PTHrP.

During pregnancy, parathyroid hormone-related protein (PTHrP) is one of many growth factors that play important roles to promote fetal growth and development, including stimulation of placental calcium transport. Angiotensin II, acting through the AT(1a) receptor, is also known to promote placental growth. We examined the effects of bilateral uterine artery and vein ligation (restriction), which mimics placental insufficiency in humans, on growth, intrauterine PTHrP, placental AT(1a), and pup calcium.

Risk management : a European regulatory perspective.

Risk management for European regulators means the detection and assessment of risks, the development and selection of measures to reduce risk, and monitoring of the effectiveness of risk control; all aspects of pharmacovigilance intended to minimise risk to European Union citizens associated with use of medicinal substances. This incorporates earlier and better planning of pharmacovigilance through formal product risk-management plans, better use of information tools to protect public health and routine audit of effectiveness of regulatory action.

Co-expression of parathyroid hormone-related protein (PTHrP) and PTH/PTHrP receptor in cartilaginous tumours: a marker for malignancy?

Aim: Parathyroid hormone-related protein (PTHrP) is one of the critical factors for the differentiation and growth of chondrocytes. We examined the correlation between the co-expression of PTHrP and PTH/PTHrP receptor and the grade of malignancy in cartilaginous tumours.

Methods: We analysed PTHrP and PTH/PTHrP receptor expression in chondrosarcoma by immunohistochemistry and compared specific staining with the expression in benign cartilaginous tumours.