Practical Considerations for the Implementation and Monitoring of Risk Minimisation Measures for High-Risk Teratogenic Medicines.

There is considerable societal interest in making medicines more affordable. A critical factor often inadequately considered early in the process of adding drugs to a company's product portfolio is that some products may require additional monitoring and complex, demanding and expensive additional risk minimisation measures (aRMMs). These aRMMs may have a sizeable impact on a company's commitment to that medicinal product throughout the product's entire life cycle. The teratogenic phthalimides were selected as an example of medicines that are recently being genericised and require a substantial commitment in terms of additional monitoring and aRMMs, most notably in the form of pregnancy prevention programmes (PPPs) with controlled distribution systems (CDSs). Implementing PPPs with CDSs is complex and demanding and encompasses all routine activities, aRMMs, local/regional Health Authority (HA) requirements, and commercialisation strategies. Considerations have been summarised that can support decision-making during due diligence processes, implementation and monitoring. Proactive, effective pharmacovigilance requires innovative, sustainable and flexible solutions to maintain high standards across the board. In particular, generic marketing authorisation holders operate with limited resources and may benefit appreciably from the following proposed suggestions and solutions such as early planning and preparation, knowledge-sharing, utilisation of new technologies and implementation of measures beyond HA-mandated requirements.

The evolution of pharmacovigilance ecosystems: Does Moore's law invite the use of Occam's razor?

AIMS: Moore's law predicts the doubling of complexity of integrated circuits every 2 years; Kryder's corollary assumes a doubling of data storage every 13 months. With the increasing volume of legislation, pharmacovigilance systems today are inherently complex, and the emphasis has shifted from reactive (responding to emerging risks) to planned, active, risk-proportionate approaches operating throughout the life cycle of medicines. METHODS: Exploration of the drivers for increasing complexity of pharmacovigilance systems, focusing on regulatory environment, data management and evaluation. RESULTS: Evaluation of postmarketing data plays an increasingly important role in pharmacovigilance. There is great interest on the part of all stakeholders in optimizing the use of these data. Innovative approaches, including pharmacogenetics and passive measures (sensors), will lead to increased complexity and volumes of data and inevitably to an increase in the volume of case reports. There is a multiplicity of regulations and guidelines on how to manage these data, with an inherent lack of harmonization. CONCLUSION: We summarize the current characterization of safety data types, sources and the classification of these data. Using this benchmark, we discuss the future requirements of an effective pharmacovigilance ecosystem, keeping the principle of parsimony in mind. In this complex, continuously and rapidly changing environment, there is a need for a return to simplicity and pragmatism. The application of Occam's razor could help to support the rapid provision of new, affordable medicines with a positive benefit to risk profile.

Implementation of a Pregnancy Prevention Programme (PPP) with a Controlled Distribution System (CDS) for the Generic Teratogenic Phthalimides Thalidomide, Lenalidomide and Pomalidomide.

Thalidomide (α-phthalimidoglutaride) was marketed in the 1950s and early 1960s; it was promoted as a sedative-hypnotic agent with minimal hangover. It was available in some countries as an over-the-counter medicine. Publications reporting profound teratogenic effects with thalidomide brought about major revisions to the monitoring of the safety of medicines. As a consequence of previously unrecognised teratogenic effects, it has been estimated that over 12,000 children were born with a range of defects and disabilities, including severe congenital anomalies. Notably, it has been hypothesised that around 40% of babies with thalidomide-induced malformations born during the 1950s and 1960s died in the neonatal period. The commonest causes of death were atresia of the small bowel, cardiac or renal malformations. Nevertheless, phocomelia (as a typical manifestation of thalidomide´s teratogenic effects) has been reported once again after thalidomide was approved for use in areas where leprosy is endemic. As a result, thalidomide embryopathy remains an important topic in countries such as Brazil. Nowadays thalidomide is approved around the world for the treatment of a wide range of conditions, including leprosy, Crohn's disease, multiple myeloma, and certain malignant solid tumours. Second-generation immunmodulatory drugs including lenalidomide and pomalidomide have received approval for use in the management of various forms of neoplastic disease. Based on clinical experience with thalidomide and its derivatives, learnings have been transferred to further research on a subset of substituted phthalimides each of which has a high risk of causing teratogenic effects. This group of phthalimides is classified within regulatory science as human teratogens. In order to gain approval, a Pregnancy Prevention Programme (PPP), along with a Controlled Distribution System (CDS) is required. The challenges of PPPs in particular for a generic manufacturer have been described, including Raising of awareness, and education; Special aspects of data collection and evaluation; Ethically and socially relevant aspects, and Utilising existing information technology and infrastructure. This paper highlights the risks of unplanned pregnancies, provides information on the regulatory background, and regulatory expectations. Our aim is to provide insights and practical learnings that have impacted operational risk management with the teratogenic phthalimides. Opportunities are presented that may support the implementation of harmonised approaches for PPP and CDS using existing IT-systems across countries and companies.

Current Challenges in Labelling for Generic Medicinal Products: Company Core Data Sheet (CCDS) Development and Maintenance.

Labelling of pharmaceutical products plays a vital role in the safe and effective use of approved medicinal products. This information may be provided to end-users including patients and/or prescribers, and it needs to be made available in multiple formats including printed forms (patient information leaflets, pack inserts, etc.) or web portals of the product, based on national authority guidelines. The Company Core Data Sheet (CCDS) serves as a key document representing the pharmaceutical company's position on the product and is used as a reference document for national labels. Content from national labels may differ from the CCDS for different reasons including implementation of national authority requirements in the serving market and findings from local markets. In the current article, we discuss the process, challenges and key concepts in creating and maintaining CCDS documents for generic products. We highlight key parameters that are worthy of process improvement in generic products' CCDS updates. In addition, we argue that labelling harmonisation across multiple regions, especially safety section-related information, plays a key role in promoting end-user safety and would help communicate risks. We also strongly believe that the topic is worthy of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) consideration, and propose that this is the key area that requires standardisation and harmonisation.

Longtime Neurologic Outcome of Extracorporeal Membrane Oxygenation and Non Extracorporeal Membrane Oxygenation Acute Respiratory Distress Syndrome Survivors.

Neurologic complications following acute respiratory distress syndrome (ARDS) are well described, however, information on the neurologic outcome regarding peripheral nervous system complications in critically ill ARDS patients, especially those who received extracorporeal membrane oxygenation (ECMO) are lacking. In this prospective observational study 28 ARDS patients who survived after ECMO or conventional nonECMO treatment were examined for neurological findings. Nine patients had findings related to cranial nerve innervation, which differed between ECMO and nonECMO patients (p = 0.031). ECMO patients had severely increased patella tendon reflex (PTR) reflex levels (p = 0.027 vs. p = 0.125) as well as gastrocnemius tendon reflex (GTR) (p = 0.041 right, p = 0.149 left) were affected on the right, but not on the left side presumably associated with ECMO cannulation. Paresis (14.3% of patients) was only found in the ECMO group (p = 0.067). Paresthesia was frequent (nonECMO 53.8%, ECMO 62.5%; p = 0.064), in nonECMO most frequently due to initial trauma and polyneuropathy, in the ECMO group mainly due to impairments of N. cutaneus femoris lateralis (4 vs. 0; p = 0.031). Besides well-known central neurologic complications, more subtle complications were detected by thorough clinical examination. These findings are sufficient to hamper activities of daily living and impair quality of life and psychological health and are presumably directly related to ECMO therapy.

Differential immunomodulation in human monocytes versus macrophages by filarial cystatin.

Parasitic nematodes have evolved powerful immunomodulatory molecules to enable their survival in immunocompetent hosts by subverting immune responses and minimizing pathological processes. One filarial molecule known to counteract host immune responses by inducing IL-10 and regulatory macrophages in mice is filarial cystatin. During a patent filarial infection monocytes encounter microfilariae in the blood, an event that occurs in asymptomatically infected filariasis patients that are immunologically hyporeactive. The microfilarial larval stage was formerly shown to induce human regulatory monocytes and macrophages. Thus, here we aim was to determine how filarial cystatin of the human pathogenic filaria Brugia malayi (BmCPI-2) contributes to immune hyporesponsiveness in human monocytes and macrophages elicited by microfilaria. For this purpose, filarial cystatin was depleted from microfilarial lysate (Mf). Detecting the immunomodulatory potential of cystatin-depleted Mf revealed that IL-10, but not IL-8 and IL-6 induction in monocytes and macrophages is dependent on the presence of cystatin. In addition, the Mf-induced expression of the regulatory surface markers PD-L1 and PD-L2 in human monocytes, but not in macrophages, is dependent on cystatin. While Mf-treated monocytes result in decreased CD4+ T-cell proliferation in a co-culture assay, stimulation of T-cells with human monocytes treated with cystatin-depleted Mf lead to a restoration of CD4+ T-cell proliferation. Moreover, IL-10 induction by cystatin within Mf was dependent on p38 and ERK in macrophages, but independent of the ERK pathway in monocytes. These findings indicate that filarial nematodes differentially trigger and exploit various signaling pathways to induce immunomodulation in different myeloid cell subsets.

Essential light chain S195 phosphorylation is required for cardiac adaptation under physical stress.

AIMS: Regulatory proteins of the sarcomere are pivotal for normal heart function and when affected by mutations are frequently causing cardiomyopathy. The exact function of these regulatory proteins and how mutations in these translate into distinct cardiomyopathy phenotypes remains poorly understood. Mutations in the essential myosin light chain (ELC) are linked to human cardiomyopathy characterized by a marked variability in disease phenotypes and high incidences of sudden death. Here we studied the role of the highly conserved S195 phosphorylation site of ELC using heterozygous adult zebrafish lazy susan (laz(m647)) in regulating contractile function in normal physiology and disease. METHODS AND RESULTS: Echocardiography revealed signs of systolic dysfunction in otherwise phenotypically unremarkable heterozygote mutants. However, after physical stress, heart function of laz heterozygous zebrafish severely deteriorated causing heart failure and sudden death. Mechanistically, we show that upon physical stress, ELCs become phosphorylated and lack of S195 dominant-negatively impairs ELC phosphorylation. In vitro motility analysis with native myosin from adult heterozygous hearts demonstrates that S195 loss, specifically following physical stress, results in altered acto-myosin sliding velocities and myosin binding cooperativity, causing reduced force generation and organ dysfunction. CONCLUSION: Using adult heterozygous zebrafish, we show that ELC S195 phosphorylation is pivotal for adaptation of cardiac function to augmented physical stress and we provide novel mechanistic insights into the pathogenesis of ELC-linked cardiomyopathy.

Kinematic motion analysis of the joints of the forelimbs and hind limbs of dogs during walking exercise regimens.

OBJECTIVE: To assess forelimbs and hind limb joint kinematics in dogs during walking on an inclined slope (uphill), on a declined slope (downhill), or over low obstacles (cavaletti) on a horizontal surface and compare findings with data acquired during unimpeded walking on a horizontal surface. ANIMALS: 8 nonlame dogs (mean +/- SD age, 3.4 +/- 2.0 years; weight, 23.6 +/- 4.6 kg). PROCEDURES: By use of 10 high-speed cameras and 10 reflecting markers located on the left forelimbs and hind limbs, joint kinematics were recorded for each dog during uphill walking, downhill walking, and walking over low obstacles or unimpeded on a horizontal surface. Each exercise was recorded 6 times (10 s/cycle); joint angulations, angle velocities and accelerations, and range of motion for shoulder, elbow, carpal, hip, stifle, and tarsal joints were calculated for comparison. RESULTS: Compared with unimpeded walking, obstacle exercise significantly increased flexion of the elbow, carpal, stifle, and tarsal joints and extension in the carpal and stifle joints. Only uphill walking caused increased hip joint flexion and decreased stifle joint flexion; downhill walking caused less flexion of the hip joint. During obstacle exercise, forward angle velocities in the elbow and stifle joints and retrograde velocity in the tarsal joint changed significantly, compared with unimpeded walking. Joint angle acceleration of the elbow joint changed significantly during all 3 evaluated exercises. CONCLUSIONS AND CLINICAL RELEVANCE: These evidence-based data indicated that each evaluated exercise, except for downhill walking, has a specific therapeutic value in physical therapy for dogs.

Correlation of surface electromyography of the vastus lateralis muscle in dogs at a walk with joint kinematics and ground reaction forces.

OBJECTIVE: To describe the activity pattern of the vastus lateralis muscle in dogs at walk measured by surface electromyography (EMG) in relation to kinematics and kinetics of the pelvic limb. STUDY DESIGN: Experimental. ANIMALS: Malinois dogs (n=11). METHODS: Dogs (mean +/- SD age, 5.5 +/- 2.9 years; weight, 27.3 +/- 3.8 kg; shoulder height, 62.7 +/- 3.3 cm) walked on a treadmill system with integrated force plates, which allowed simultaneous analysis of kinematics, kinetics, and EMG data from all limbs. The maxima, minima, and their time of occurrence in the motion cycle of the EMG and the pelvic limb kinematics and kinetics were calculated; correlations between joint movement patterns, ground reaction forces (GRF), and activity pattern of the muscle group were investigated. RESULTS: The vastus lateralis muscle had an activity pattern with 2 peaks and a close positive correlation with GRF. The 1st peak occurred in early stance, followed by a decrease in activity during mid-stance. The 2nd peak occurred directly before the quick activity decrease in late stance phase, reaching its minimum early in swing phase. CONCLUSIONS: These results suggest that the vastus lateralis muscle supports the vertical position and elevation of the pelvis during stance and push-off. During early stance, the muscle acts as a coantagonist to the hamstring muscle group and the gastrocnemius muscle, and restrains flexion during the late stance. CLINICAL RELEVANCE: Results of this study could enhance diagnosis of locomotor system disorders and facilitate monitoring effects of treatments (e.g., therapeutic exercises) on gait ability and muscle function.

Prevalence of mental disorders in acromegaly: a cross-sectional study in 81 acromegalic patients.

OBJECTIVE: Emotional and behavioural alterations have been described in acromegalic patients. However, the nature and psychopathological value of these changes remained unclear. We examined whether acromegalic patients have an increased prevalence of comorbid DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th Version) mental disorders in comparison to subjects with or without chronic somatic disorders. DESIGN/PATIENTS: A cross-sectional study was conducted at the Max-Planck Institute of Psychiatry and the Ludwig-Maximilians-University Munich. Eighty-one acromegalic patients were enrolled. Control subjects with (n = 3281) and without chronic somatic (n = 430) disorders were drawn from a representative sample of the German adult general population as part of the Mental Health Supplement of the German Health Interview and Examination Survey. Lifetime and 12-month prevalences of DSM-IV mental disorders were assessed with face-to-face interviews using the standardized German computer-assisted version of the Composite International Diagnostic Interview. RESULTS: Acromegalic patients had increased lifetime rates of affective disorders of 34.6% compared to 21.4% in the group with chronic somatic disorders (OR = 2.0, 95% CI 1.2-3.2) and to 11.1% in the group without chronic somatic disorders (OR = 4.4, 95% CI 2.3-8.7). Affective disorders that occurred significantly more often than in the control groups began during the putative period of already present GH excess. Higher rates of DSM-IV mental disorders were reported in those patients with additional treatment after surgery. CONCLUSION: Acromegaly is associated with an increased prevalence and a specific pattern of affective disorders. Greater emphasis on diagnosing and treatment of mental disorders in acromegalic patients might improve the disease management.

Fourier analysis of vertical ground reaction forces in dogs with unilateral hind limb lameness caused by degenerative disease of the hip joint and in dogs without lameness.

OBJECTIVE: To evaluate the applicability of Fourier analysis for assessment of ground reaction forces (GRFs) and differentiation between dogs with unilateral hind limb lameness caused by degenerative joint disease of the hip (DJD-H) and dogs without lameness. ANIMALS: 37 dogs with or without unilateral DJD-H. PROCEDURES: Data were obtained from other studies and analyzed retrospectively. Among the 37 dogs, 20 had unilateral DJD-H and 9 (non-Belgian Malinois breeds) had no lameness; another 8 were nonlame Belgian Malinois (radiographically confirmed Fédération Cinologique International classification A [ie, no hip dysplasia or DJD-H]). Gait data acquisition was performed as dogs walked on a treadmill with integrated force platforms. The peak vertical force, mean vertical force, and vertical impulse were compared among the 3 groups. Fourier analysis was performed on the force-time curves for the vertical GRF, and calculated Fourier coefficients were compared within and between groups. RESULTS: Lameness in the hind limbs with DJD-H was detectable via conventional analysis of the GRF as well as via Fourier analysis. However, subtle gait aberrations in the forelimbs of the dogs with DJD-H were detected solely via Fourier analysis of GRFs and remained undetected via conventional analysis. CONCLUSIONS AND CLINICAL RELEVANCE: Results support the applicability of Fourier analysis for evaluation of force-time curves of GRFs. Fourier analysis can reveal subtle alterations of gait that might otherwise remain inapparent; however, further investigation is necessary before this method can be routinely applied for lameness detection in dogs.