European Medical Agency Research Articles

Tolerability of duloxetine in elderly and in non-elderly adults: a protocol of a systematic review and individual participant data meta-analysis of randomized placebo-controlled trials

BackgroundDuloxetine is an antidepressant that benefits from a wide range of approval in the elderly population, while its safety for use compared to non-elderly is not clearly assessed. This protocol outlines a systematic review and individual participant data meta-analysis comparing the tolerability of duloxetine between elderly and non-elderly.MethodsSearches will be conducted in PubMed, ClinicalTrials.gov, Clinicaltrialsregister.eu, data sharing platforms, FDA drug approval packages, European public assessment reports and withdrawn applications from the EMA website. The review will be performed on studies available in electronic databases from their date of inception to the 31 March 2022. Only randomized controlled clinical trials, comparing duloxetine to placebo, will be included in this meta-analysis. The studies will be selected if they comprise both elderly and non-elderly adults, in conditions of use of duloxetine approved by the European Medical Agency (EMA) and the Food and Drug Administration (FDA). The primary outcome will be the rate ratio of serious adverse events under duloxetine compared to placebo, between participants at least 65 years old and non-elderly. Second, the number of any adverse events, clinical efficacy and quality of life will be compared between elderly and non-elderly under both interventions. The quality of evidence in the tolerability of duloxetine will be assessed using the GRADE system. A one or two-stage individual participant data random effect meta-analysis will be conducted depending on the availability of the data.DiscussionThis meta-analysis will investigate the tolerability safety of duloxetine in the elderly population across all conditions approved by European and American regulatory authorities. The results from this meta-analysis are intended to help prescribers to provide better care for the elderly population.Systematic review registrationThe protocol has been registered at the International Prospective Register of Systematic Reviews (PROSPERO; registration number: CRD42019130488).

Off-label use of omalizumab in a 6-year-old child with severe atopic dermatitis.

Background: Atopic dermatitis (AD) is a common chronic inflammatory skin disorder that affects up to 3% of adults and 15%-20% of children across the world. Although the mainstay of treatment is topical corticosteroids and/or calcineurin inhibitors, a majority of patients will not achieve a control of their condition and will need systemic treatment with steroids and immunosuppressants (1). Omalizumab is a humanized anti-IgE antibody licensed by the European Medical Agency for treatment of severe allergic asthma and spontaneous chronic urticaria in children older than 6 and 12 years, respectively; and a promising efficacy of omalizumab in the treatment of severe refractory AD has been shown by the ADAPT randomized clinical trial (2).Case report: A 6-year-old male patient being treated and followed at a pediatric dermatology clinic for a diagnosis of AD since the age of 3 years, showed unresponsive disease to different topical treatment options and non-pharmacological measures. The patient was referred to our clinic for systemic treatment when his SCORAD index was 70/103. At our immunology clinic, we did an extensive workup to unveil a comorbid or underlying disease. His labs showed high IgE levels at 2500 IU/mL, hypereosinophilia, and normal IgA, IgM, and lymphocyte subsets. We started him on different lines of immunosuppressants, including cyclosporine, prednisolone, tacrolimus, and intensive topical treatment; however, the patient did not show any noticeable response for 2 years. We then started him on omalizumab 300 mg twice weekly, and the SCORAD index dropped to 57 at 12 weeks and 55 at 18 weeks. The drug is still well tolerated, and we were able to stop systemic steroids at 15 weeks of treatment.Conclusion: Off-label use of omalizumab in a 6-year-old child with refractory severe AD was effective and safe in controlling the disease even though conventional systemic immunosuppressants proved ineffective.

Real-life experience with inotersen in hereditary transthyretin amyloidosis with late-onset phenotype: Data from an early-access program in Italy.

Background and purposeHereditary transthyretin (TTR) amyloidosis (ATTRv) is a dominantly inherited, adult‐onset, progressive, and fatal disease caused by mutations in the transthyretin gene. Therapeutic agents approved for this disease include the TTR stabilizer tafamidis and the gene‐silencing drugs patisiran and inotersen. Inotersen is an antisense oligonucleotide that suppresses the hepatic production of transthyretin. After European Medical Agency approval in 2018, an early‐access program was opened in Italy, and in this article, we present the long‐term outcome of a cohort of Italian ATTRv patients who received inotersen within this program.MethodsThis is a multicenter, observational, retrospective study of patients affected by ATTRv that started inotersen during the early‐access program. The primary end point was safety. Secondary end points included change from baseline in familial amyloid polyneuropathy (FAP) stage, Polyneuropathy Disability, Neuropathy Impairment Scale, Compound Autonomic Dysfunction Test, Norfolk Quality of Life–Diabetic Neuropathy, troponin, N‐terminal pro–brain natriuretic peptide, interventricular septum thickness, and body mass index.ResultsIn total, 23 patients were enrolled. No patient permanently discontinued the treatment because of thrombocytopenia, and no cases of severe thrombocytopenia were observed. Five patients discontinued the treatment permanently because of voluntary withdrawal (two patients), renal failure after infective pyelonephritis, not related to inotersen, drug‐related hypotension, and amyloid‐negative crescentic glomerulonephritis. In seven patients, dosing frequency was reduced to every 2 weeks due to recurrent thrombocytopenia. Considering the FAP stage, only two patients worsened, whereas the other 21 patients remained stable until the last follow‐up available.ConclusionsThe long‐term safety profile of inotersen is favorable. Neurologic disease severity at baseline is the main factor associated with progression.

Comparison of Fluoroquinolones and Other Antibiotic Prophylaxis Regimens for Preventing Complications in Patients Undergoing Transrectal Prostate Biopsy.

Our study aimed to compare the incidence of infective complications after transrectal ultrasound-guided prostate biopsy (TRUSBx) when adopting different antimicrobial prophylaxis regimens. A multi-institutional cohort of 1150 patients who underwent TRUSBx was retrospectively analyzed. Procedures were performed between 2017 and 2019 (before and after the EMA warning about the use of fluoroquinolones for the antibiotic prophylaxis of patient candidates to TRUSBx). The primary endpoint was the occurrence of infective complications, including sepsis and/or fever. The population was stratified according to the antibiotic prophylaxis adopted: fluoroquinolones (levofloxacin, ciprofloxacin, prulifloxacin), cephalosporins (cefixime, ceftriaxone) or trimethoprim/sulfamethoxazole. Univariable and multivariable binomial logistic regression models were used to assess the odds ratio (OR) with 95% confidence interval (CI) testing of the risk of infective complication after adjusting for each prebiopsy covariate. In total, 478 (41.6%) patients received fluoroquinolone-based prophylaxis. Among these, 443 (38.5%), 25 (2.2%) and 10 (0.9%) patients received levofloxacin prophylaxis, ciprofloxacin and prulifloxacin, respectively while 14.6% received cefixime, 20.7% received the comedication of ceftriaxone/fosfomycin and 23.1% received trimethoprim/sulfamethoxazole. The trimethoprim/sulfamethoxazole and fluoroquinolone regimens were significantly associated with a lower risk of infective complications (OR 0.15, 95% CI 0.03–0.48, p = 0.003 and OR 0.17, 95% CI 0.06–0.43, p < 0.001, respectively). The ceftriaxone/fosfomycin (OR 0.21, 95% CI 0.04–0.92, p = 0.04) and fluoroquinolone (OR 0.07, 95% CI 0.00–0.70, p = 0.048) prophylaxis were associated with a lower risk of infective sequelae. Fluoroquinolone-based prophylaxis was associated with a lower risk of infective complications after TRUSBx compared to other prophylaxis regimens although its clinical application was recently forbidden by European Medical Agency restrictions.

Alloreactivity of Allogeneic Mesenchymal Stem/Stromal Cells and Other Cellular Therapies: A Concise Review.

Cellular therapies, deemed live medicine, have brought a wave of new generation biological therapies to treat previously untreatable diseases such as cancers and degenerative diseases like osteoarthritis. These cellular therapies have gained significant recognition in clinical research. The area has been further strengthened with the approval of Chimeric Antigen Receptor added on T cells (CAR-T) therapies by the regulatory authorities USA's Food and Drugs Administration (FDA), European Medical Agency (EMA), the Australian Therapeutic Goods Administration (TGA), and in many countries in 2017 to treat hematological cancers. Another milestone was achieved when allogeneic Mesenchymal Stem Cell- (MSC-) based therapy was approved by the EMA to treat Chrohn's disease in 2018. Allogeneic donor-derived MSC therapies in particular hold great promise and real hope because of their ‘off-the shelf' availability and accessibility for patients in need of urgent treatment. So far, thousands of clinical trials have explored the safety and efficacy of both autologous and allogeneic cell therapies, deeming them safe, however with varying degrees of efficacy. In the current pandemic, clinical trials have begun in many parts of the world to treat severe cases of COVID with MSCs. However, the risk of tissue rejection and the development of undesirable effects due to alloreactivity of allogeneic cells are currently not adequately addressed. Therefore, this warrants careful investigation and detailed reporting of such events by clinical researchers. This review aims at discussing the current landscape of approved allogeneic MSCs along with a few other cellular therapies. We explore any possible reactivity reported to inform the readers of any safety concern and on the efficacy of such therapies.

Interpreting the efficacy of secukinumab on patient-reported outcomes in psoriatic arthritis

In 2022, many treatment options are available for psoriatic arthritis, and the magnitude of effect of the different drugs appears quite close.1 This similarity between drugs makes the development of a treatment algorithm difficult, as can be seen by the divergences between recent recommendations for disease management.2–4 Patient-reported outcomes reflect the patient perspective and are considered important by scientific societies, the US Food and Drug administration, the European Medical Agency, health-care providers, and patients alike.

Is Molecular Mimicry between hPF4 and SARS-CoV-2 Spike Protein a Potential Basis for Autoimmune Responses in Vaccinated and Naturally Infected Patients?

Vaccination against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) will hopefully terminate the pandemic of coronavirus disease 2019 (COVID-19) and several vaccines are now available. The European Medical Agency has approved four vaccines[1] for the prevention of symptomatic COVID-19: two messenger RNA (mRNA)–based vaccines (mRNA BNT162b2-BioNTech/Pfizer and mRNA-1273-Moderna) encoding the spike protein antigen of SARS-CoV-2 and two recombinant adenoviral vector–based vaccines (ChAdOx1-AstraZeneca and Ad26.COV2.S -Janssen) encoding the spike glycoprotein of SARS-CoV-2.

Post-SSRI Sexual Dysfunction (PSSD): Biological Plausibility, Symptoms, Diagnosis, and Presumed Risk Factors.

Post-SSRI sexual-dysfunction (PSSD) is an iatrogenic syndrome, the underlying neurobiological mechanisms of which are unclear. Symptom onset follows cessation of serotonergic antidepressants i.e. Selective Serotonin and Norepinephrine Reuptake Inhibitors (SSRI's, SNRI's), and Tricyclic antidepressants (TCA's). PSSD symptoms include genital anesthesia, erectile dysfunction and orgasmic/ejaculatory anhedonia, and should be differentiated from depression-related sexual-dysfunction. Recently, accumulated data of numerous case-reports suggest additional non-sexual symptoms including, anhedonia, apathy, and blunted affect. PSSD gained official recognition after the European medical agency concluded that PSSD is a medical condition that persists after discontinuation of SSRI's and SNRI's. To review possible underlying neurobiological mechanisms of this syndrome, update information on the pathophysiology, present a list of potential risk-factors and discuss potential management options for PSSD. Extensive literature review on the main symptom-patterns of this disorder was undertaken using PubMed. It includes introductory explications of relevant neurobiology with the objective of generating hypothesis. Precipitating factors for PSSD include previous exposure to certain drugs, genetic predisposition, psychological stress or chemical stressful reaction to antidepressants along pre-existing medical conditions affecting neuroplasticity. Different theories have been proposed to explain the pathophysiology of PSSD: epigenetic gene expression, dopamine-serotonin interactions, serotonin neurotoxicity and hormonal changes. The diagnosis of PSSD is achieved by excluding all other etiologies of sexual-dysfunction. Treatment is challenging, and many strategies have been suggested without definitive outcomes. We offer the contours of a future neurobiological research agenda, and propose several underlying mechanisms for the various symptoms of PSSD which could be the foundation for a future treatment algorithm. There is a need for well-designed neurobiological research in this domain, as well as in the prevalence, pathophysiology, and treatment of PSSD. Practitioners should be alert to the distinctive features of PSSD. Misdiagnosing this syndrome might lead to harmful treatments including reinstatement of medications which generated PSSD. Sexual Medicine Reviews. Peleg LC, Rabinovitch D, Lavie Y, et al. Post-SSRI Sexual Dysfunction (PSSD): Biological Plausibility, Symptoms, Diagnosis, and Presumed Risk Factors. Sex Med Rev 2022;10:91-98.

Pilot Equivalence Study Comparing Different Batches of Topical 0.025% Capsaicin Emulsion: Product Microstructure, Release, and Permeation Evaluation.

The European Medical Agency (EMA) has issued a draft guideline on the quality and equivalence of topical products. The equivalence for complex semisolid formulations involves several steps: the same quantitative content, the same microstructure, the same release, and permeation profile. In this paper, several batches of a low strength topical product, which we used as a reference/comparator product, were evaluated according to the recommendations of the EMA draft guideline. The batches were 0.025% capsaicin emulsions from the same manufacturer that were evaluated in terms of droplet size, X-ray diffraction patterns, rheology, release, and permeation profile. The generated data revealed a large batch-to-batch variability, and if the EMA guideline was applied, these batches would not be considered equivalent, although they were produced by the same manufacturer. The result of this work illustrates the difficulties in obtaining equivalence according to the current draft guidelines. It also highlights that the equivalence guidelines should consider the variability of the comparator product, and in our opinion, the guidelines should allow for claiming equivalence by comparing the limits in the variability of the data generated for the comparator product with the limits in the variability of the data generated for the intended equivalence product.

Efficacy and Safety of Lurasidone in Children and Adolescents: Recommendations for Clinical Management and Future Research.

Lurasidone is a novel azapirone derivative and atypical antipsychotic agent with a high binding affinity for dopaminergic (D2), serotoninergic (5-HT2A), and 5-HT7 receptors (antagonist), a moderate affinity for 5- HT1A receptors (partial agonist), and no appreciable affinity for histaminergic (H1) and muscarinic (M1) receptors. It was recently included by the European Medication Agency among the in-label pharmacological treatments for children and adolescents affected by early onset schizophrenia. As a dopamine and serotonin antagonist, lurasidone acted on a variety of receptors and showed its efficacy both as an antipsychotic and an activating compound. Administered with food or within 30 minutes from a meal, it presents sufficient bioavailability and does not interact with most of the other drugs during metabolism. With little effects on hormones and weight gain, potential procognitive profile due to its 5-HT7 antagonism, and reduced extrapyramidal side effects, lurasidone could be a good choice in terms of both effectiveness and tolerability, particularly for patients headed towards a long-term treatment. This article aims to summarize the available scientific evidence from the literature on the use of lurasidone in children and adolescents and to provide recommendations for clinical management and future research.

The Utility of Remote Inspections During the COVID-19 Health Emergency and in the Postpandemic Setting

PurposeThe COVID-19 pandemic has affected the management and operation of regulatory agencies and the pharmaceutical industry around the world. It has prompted regulatory authorities to consider new ways of working and introduced, among others, remote inspections to validate the integrity of the regulatory data submitted by companies, to evaluate the quality of production and manufacturing sites, and to ensure the conformity with Good Regulatory Practices with the overall goal of guaranteeing patient safety during the crisis.MethodThis article summarizes and discusses remote inspection guidelines and other related information made available by the Therapeutic Goods Administration (Australia), the European Medicines Agency (EMA), the Pharmaceutical and Medical Devices Agency (Japan), the Medicines and Healthcare Products Regulatory Agency (United Kingdom), and the US Food and Drug Administration (FDA). We also analyze the effect of the pandemic on inspections conducted by the inspectorates of the EMA and the FDA.FindingsThe regulatory authorities that we studied all recognized the importance of implementing regulatory policies on remote inspections in response to the COVID-19 pandemic. The remote inspection guidelines from the 5 selected regulatory authorities aimed at mitigating the impact of the pandemic but, while providing valuable advice to the pharmaceutical companies and being similar in intent, were not always aligned in terms of approach and solutions.ImplicationsOn-site inspections are likely to continue to be the norm and the preferred standard for the foreseeable future. However, health authorities will need to further adopt a risk-based inspection approach and stimulate the increased uptake of inspection reliance as proposed by the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme not to overwhelm the pharmaceutical companies with repeat and redundant inspections. Remote inspections have proven to be a new inspection tool, but health authorities should align on their approach to remote inspections in terms of methods applied and documentation requested.

Prescription Patterns of Sodium-Glucose Cotransporter 2 Inhibitors and Cardiovascular Outcomes in Patients with Diabetes Mellitus and Heart Failure.

The benefit of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with heart failure (HF) with reduced ejection fraction (HFrEF) and type 2 diabetes mellitus (T2DM) has been unequivocally proven in randomized, controlled trials. However, real-world evidence assessing the implementation of SGLT2i in clinical practice and their benefit in HF outside of highly selected study populations is limited. Patients with HF and T2DM admitted to the cardiology ward of the Medical University of Vienna between 01/2014 and 04/2020 were included in the present analysis. All first-time prescriptions of SGLT2i were identified. The outcome of interest was cardiovascular mortality. The median follow-up time was 2.3years. Out of 812 patients with T2DM and HF (median age 70.4 [IQR 62.4-76.9] years; 70.3% males), 17.3% received an SGLT2i. The frequency of SGLT2i prescriptions significantly increased over the past 6years (+ 36.6%, p < 0.001). In propensity score-adjusted pairwise analyses, SGLT2i treatment was inversely associated with long-term cardiovascular mortality in patients with HFrEF presenting with an adjusted HR of 0.33 (95%CI: 0.13-0.86; p = 0.024). Despite large outcome trials showing a cardiovascular benefit, SGLT2i remain underutilized in clinical practice in patients with T2DM and HF. National and European Medical Agency remuneration regulations would allow more patients at high risk to receive these cardiovascular protective drugs. Most importantly, an SGLT2i therapy was associated with a survival benefit in patients with HFrEF.

A comparison of regulatory approval of clinical trial protocol with different countries

&lt;p class="abstract"&gt;In present scenario, different countries must follow different regulatory requirements for protocol approval process of new drug application. Present study, we studied the regulatory requirements, timelines of approval and guidelines according to central drug standard control organization (CDSCO), therapeutic goods administration (TGA), food and drug administration (FDA) and European medical agency (EMA). The objective was to compare the regulatory approval of clinical trial protocol process. A comparative observational study was undertaken among the clinical trials and regulatory bodies of India (CDSCO), Australia (TGA), US (USFDA), Europe (EMA). The study specified various regulatory guidelines and safety requirements for conduct and inspection of clinical trial. Clinical trial protocol guidelines the essential documents are determined, and various timelines are being identified. And compared with the fees with other countries. Indian payments were compared with other countries. Timelines with safety reporting were compared with other 3 countries (Europe, Australia and US). The regulatory guidelines in the clinical trial different between countries. There is different timelines and requirements of clinical trial application approval process for each regulatory body. This study methodology has enabled comparisons to be made both within agencies and between different authorities and has identified differences in the timelines that applications spend in different stages of the review.&lt;/p&gt;&lt;p&gt; &lt;/p&gt;

Assessing Nigrostriatal Dopaminergic Pathways via 123I-FP-CIT SPECT in Dementia With Lewy Bodies in a Psychiatric Patient Cohort

Background(123)-I-2-ß-carbomethoxy-3ß-(4-iodophenyl)-N-(3-fluoropropyl) nortro- pane single photon emission computed tomography (123I-FP-CIT SPECT) was validated to distinguish Alzheimer’s dementia from dementia with Lewy Bodies (DLB) by European medical agencies. Little evidence exists that validates 123 I-FP-CIT SPECT as a supplementary method to diagnose probable DLB in a psychiatric cohort of patients with psychiatric symptomatology and suspected DLB. We aim to elucidate differences in the clinical phenotype of DLB between those patients with and those without a positive 123 I-FP-CIT SPECT indicating a nigrostriatal deficit.MethodsTo investigate this, we included 67 patients from the Department of Psychiatry and Psychotherapy at University Medical Center Göttingen (UMG) in our study who had undergone 123I-FP-CIT SPECT in the Department of Nuclear Medicine (UMG) by evaluating their patient files.Results55% with a positive-123I-FP-CIT SPECT and probable DLB after the 123I-FP-CIT SPECT exhibited psychiatric features. The number of probable DLB patients in those exhibiting psychiatric symptoms was higher post-123I-FP-CIT SPECT than pre-123I-FP-CIT SPECT assessed cross-sectionally over a 6-year period (p < 0.05). In addition, prodromal DLB and prodromal DLB patients with a psychiatric-phenotype yielded higher numbers post-123I-FP-CIT SPECT than pre-123I-FP-CIT SPECT (p < 0.05). Furthermore, we discovered no phenotypical differences between those DLB patients with a positive and those with a negative 123I-FP-CIT SPECT. 123I-FP-CIT SPECT-positive DLB patients in our psychiatric cohort revealed a psychiatric onset more often (52%); DLB was less often characterized by an MCI onset (26%) (p < 0.005).ConclusionsOur findings support 123I-FP-CIT SPECT as an adjuvant tool for improving the diagnosis of probable DLB and prodromal DLB in a cohort of psychiatric patients with often concomitant psychiatric symptomatology. The psychiatric-onset is more frequent than an MCI-onset in DLB patients presenting nigrostriatal dysfunction, giving us an indication of the relevance of deep clinical phenotyping in memory clinics that includes the assessment of psychopathology.

Regulatory advances and prospects of variation filing for the registered parenteral products in USA and Europe

Drug Regulatory Affairs (DRA) is a vital unit in a pharmaceutical company. It is concern about the healthcare product lifecycle, it provide strategic, tactical and operational direction and support for working within regulations to expedite the development and delivery of safety and efficacy in pharmaceuticals, veterinary medicines, medical devices, cosmetics and complementary medicines, healthcare products to individuals around the world. Regulatory affairs (RA) professionals are employed in pharmaceutical industry, government, academic research and clinical institutions. As India is growing very rapidly in pharmaceutical sector, there is a need of regulatory affairs professionals to cater the current needs of industries for the global competition. Regulatory affairs professionals are the link between pharmaceutical industries and worldwide regulatory agencies. A regulatory affair is a somewhat new profession which has developed from the desire of governments to defend public health. Substantial documentation and data are required in these types of submissions, resulting in large, complex applications. Today 35 member countries along with 11 candidate countries and 4 international agencies have joined together to create the Pharmaceutical Inspection Cooperation Scheme (PIC/S) to promote a globally accepted GMP. Current constrain of Regulatory Affairs reveals diverse countries need to follow different regulatory requirements for marketing authorization Application (MAA) approval of new drugs. In this present exertion, study expresses the drug approval process and regulatory requirements according to US Food and Drug Administration (UDFDA), European Medical Agency (EMA) and Central Drug Standard Control Organization (CDSCO).

Ertugliflozin + metformin as a treatment option for Type 2 Diabetes

Introduction: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduce blood glucose and glycosylated haemoglobin (HbA1c), the risk of hospitalization for heart failure (HF) and the incidence of serious adverse kidney function events (chronic kidney disease, CKD) in patients with type 2 diabetes mellitus (T2DM). Ertugliflozin is the last SGLT2i approved by Food and Drug Administration (FDA) in the USA and European Medical Agency (EMA) in Europe for the treatment of T2DM alone or in combination with other drugs. Areas covered: The authors critically discuss in this drug evaluation the safety and efficacy of the ertugliflozin + metformin combination in patients with T2DM without complications, those with CKD, or those with heart failure (HF). Furthermore, the authors discuss the results of the VERTIS CV trial (MK-8835-004), the trials NCT01986881 and NCT01986855 and other smaller studies. Expert opinion: The ertugliflozin + metformin combination is safe and effective in patients with T2DM with renal impairment, HF of any kind, or those without diabetic complications. These have practical implications that will help diabetologists, cardiologists, internists, nephrologists and general practitioners in selecting the proper combination of SGLT2i on top of metformin, if needed.

PND1 The CARS Scale to Assess Pharmacological Therapies in Autism Spectrum Disorder: A Targeted Literature Review

The Childhood Autism Rating Scale (CARS) is a standardized, comprehensive, and reliable observational rating scale of Autism Spectrum Disorder (ASD). It has been cited by the European Medical Agency (EMA) as a scale used for assessment of symptoms in ASD and a potential scale to measure treatment-related changes in the ASD core symptoms. This study aims at documenting how the CARS has been used to assess clinically relevant response to investigational drug treatments in clinical trials and observational studies.

Molecular enhancement of fracture healing - Is there a role for Bone Morphogenetic Protein-2, parathyroid hormone, statins, or sclerostin-antibodies?

Enhancement of fracture healing has been a hot topic over the last two decades. This narrative review article is aimed to provide an update on current clinical use and evidence on four clinically available agents in the treatment of fracture healing: bone morphogenetic proteins-2 (BMP-2), parathyroid hormone, statins and sclerostin-antibodies. After first promising results from animal and clinical studies in the early 2000s, BMP-2 was studied mainly in open tibia shaft fractures treated with intramedullary nailing. There are conflicting results from different randomized clinical trials (RCTs) regarding fracture healing time and complications compared to BMP-2 free control treatment in open tibia fractures, as BMP-2 could not show significant differences in patients treated with reamed nails compared to BMP-2 free control treatment with reamed nailing only. Given that fact, its official use was limited in Europe to open tibia shaft fractures treated with unreamed tibial nailing by the European Medical Agency (EMA). Another more recent RCT failed to show equivalence of BMP- 2 together with allograft versus autograft for the treatment of tibia fractures with critical size defects. Recombinant human parathyroid hormone has proven anabolic effects on bone metabolism and is commonly used in treatment of severe osteoporosis. Different animal trials suggested an enhancement effect in fracture healing by PTH. In several clinical trials, PTH seems to have a stimulative effect for lower limb fractures. Statins, commonly used in treatment of dyslipidemia, could also enhance fracture healing in animal trials, especially when they were applied locally at the fracture site. For statins, there is only one RCT that failed to show significant effects for the oral administration of statins in undisplaced distal radius fractures. The role of sclerostin in fracture healing has more and more been understood. Application of sclerostin antibodies has been shown to be beneficial for fracture healing in animal trials. However, no RCTs on the effect of sclerostin antibodies on fracture healing have been performed yet. In conclusion, the "magic bullet" for molecular enhancement of fracture healing has not been identified yet, at least not with its optimal dosage and delivery method.

Thrombosis with Thrombocytopenia Syndrome associated with viral vector COVID-19 vaccines

On March 11 2021, the European Medical Agency highlighted two relevant issues, after the decision by the Danish Health Authority to temporarily suspend its vaccination campaign with Vaxzevria (the COVID-19 vaccine by AstraZeneca) following the reports of thromboembolic events (TE) associated with the administration of the vaccine: 1) lack of evidence of a cause/effect relationship between the vaccine and TE; 2) the number of reported TE (30 in around 5,000,000 vaccinated people) was no higher than that expected [1].

(Ultra-)long-acting insulin analogues for people with type 1 diabetes mellitus.

(Ultra-)long-acting insulin analogues for people with type 1 diabetes mellitus.