Live biotherapeutic products and their regulatory framework in Italy and Europe.

In Italy and Europe, live microorganisms-containing products meant to be used by vulnerable or sick people for preventing or curing a disease are defined as live biotherapeutic products and are regulated as biological drugs. As such, they must undergo extensive quality, safety and efficacy testing and evaluation before receiving a marketing authorization. This review describes the regulatory framework of live biotherapeutic products with special focus on the European Pharmacopoeia monograph 3053 that set mandatory requirements for this kind of medicines, including verification of the number of live microorganisms and absence of certain contamination indicator microorganisms. The other product categories that may contain live microorganisms are also described, with brief references to the overlaps possibly occurring between the different categories.

Tratamientos y bioterapias para COVID-19 / Therapeutics and biotherapies for covid-19

INTRODUCCIÓN: Un nuevo brote de coronavirus surgió en 2019 en Wuhan, China, causando conmoción en el sistema sanitario de todo el mundo; el Comité Internacional de Taxonomía de Virus lo denominó SARS-CoV-2, agente causante de la enfermedad COVID-19.El espectro de gravedad de la enfermedad es muy amplio: la mayoría de los pacientes no presentan gravedad, pero otros pueden desarrollar neumonías, y la insuficiencia respiratoria aguda es la causa más frecuente de mortalidad. Objetivo: analizar y desarrollar las distintas alternativas terapéuticas aportadas por la Biotecnología para tratar los síntomas de aquellos pacientes con COVID-19. Metodología: se realizó una revisión de la bibliografía disponible, a partir de enero de 2020 en PubMed, acerca de los tratamientos que se encuentran aún en ensayos clínicos y aquellos que cuentan con aprobación bajo uso de emergencia para la enfermedad COVID-19. También se realizaron búsquedas a través de Google y Google Académico para publicaciones de organismos de Salud en referencia a políticas de salud establecidas para la terapéutica durante dicha pandemia. Resultados: este trabajo aborda las nuevas alternativas terapéuticas para COVID-19 derivadas de la Biotecnología, que se encuentran tanto en uso como en etapas de ensayos clínicos comprendidos dentro del segmento de los biofármacos y las bioterapias. Se incluye un breve resumen del estatus regulatorio de entidades de salud, el mecanismo de acción de dichas terapias y características generales de cada uno. Se incluyen novedosas bioterapias que se empezaron a implementar para afrontar la pandemia. Conclusiones: la pandemia de coronavirus está poniendo a prueba el sistema sanitario internacional, para brindar soluciones tanto desde el diagnóstico y prevención como para el tratamiento de la población a fin de disminuir la mortalidad. Esto incluyó, obviamente también, al área de la Biotecnología aplicada a la salud, que ha aportado en los tres aspectos mencionados; el presente trabajo se centra en las respuestas de tipo terapéutico que ha brindado y que están comercializadas o en fases clínicas. (AU)

INTRODUCTION: A new coronavirus outbreak emerged in 2019 in Wuhan, China, causing a shock to the healthcare system around the world; the International Committee on Taxonomy of Viruses named it SARS-CoV- 2, the infectious agent of the COVID-19 disease. The spectrum of severity of the disease is very wide, most patients are not serious, but others can develop pneumonia, with acute respiratory failure being the most frequent cause of mortality. Objective: to analyze and develop the different therapeutic alternatives provided by Biotechnology dedicated to Health, to treat the symptoms of those COVID-19 patients who require it, and thus reduce mortality.Methodology: a review of the available literature from January 2020 in PubMed of the treatments that are still in clinical trials and those that have been approved under emergency use for the disease COVID-19 was performed. Searches were also carried out through Google and Google Scholar for publications of Health organizations in reference to health policies established for therapeutics during the mentioned pandemic. Results: this work addresses the new therapeutic alternatives derived from Biotechnology, which are both in use and in stages of clinical trials, to treat patients who developed COVID-19 included within the segment of biopharmaceuticals and biotherapies. A brief summary of the regulatory status of health entities, the mechanism of action of said therapies and general characteristics of each one is included. Innovative biotherapies that began to be implemented to face the pandemic are included. Conclusions: The coronavirus pandemic has driven the international health system to the test, to provide solutions both from the diagnosis, prevention and treatment of the population to reduce the mortality of patients. This obviously also included the area of Biotechnology applied to health, which has contributed in the three aspects mentioned. The present work focuses on the therapeutic responses that it has provided and that are commercialized or in clinical phases. (AU)

British Rhinological Society Consensus Guidance on the use of biological therapies for chronic rhinosinusitis with nasal polyps.

OBJECTIVES: We set out to create Consensus Guidelines, based on current evidence and relative risks of adverse effects and the costs of different treatments, which reflect the views of the British Rhinological Society (BRS) Council on where the use of biologics should be positioned within treatment pathways for CRSwNP, specifically in the setting of the National Health Service (NHS). DESIGN: An expert panel of 16 members was assembled. A review of the literature and evidence synthesis was undertaken and circulated to the panel. We used the RAND/UCLA methodology with a multi-step process to make recommendations on the use of biologics. SETTING: N/A. PARTICIPANTS: N/A. RESULTS: Recommendations were made, based on underlying disease severity, prior treatments and co-morbidities. A group of patients for whom biologics were considered an appropriate treatment option for CRSwNP was defined. CONCLUSIONS: Although biologics are not currently available for the treatment of CRSwNP, the BRS Council have defined a group of patients who have higher rates of "failure" with current treatment pathways, higher resource use and are more likely to suffer with uncontrolled symptoms. We would urge NICE to consider approval of biologics for such indications without applying further restrictions on use.

Live biotherapeutic products: the importance of a defined regulatory framework.

Probiotics have been defined as "Live microorganisms that when administered in adequate amounts confer a health benefit on the host". This definition covers a wide range of applications, target populations and (combinations of) microorganisms. Improved knowledge on the importance of the microbiota in terms of health and disease has further diversified the potential scope of a probiotic intervention, whether intended to reach the market as a food, a food supplement or a drug, depending on the intended use. However, the increased interest in the clinical application of probiotics may require specific attention given their administration in a diseased population. In addition to safety, the impact of the type of product, in terms of quality, production method and, e.g., the acceptance of side effects, is now part of the current regulatory constraints for developers. In the European Union, foods are regulated by the European Food Safety Authority and drugs by the European Medicines Agency; in the United States, the Food and Drug Administration (FDA) deals with both categories. More recently, the FDA has defined a new "live biotherapeutic products" (LBP) category, clarifying pharmaceutical expectations. Since 2019, the quality requirements for this category of drug products have also been clarified by the European Pharmacopoeia (Ph. Eur.). Similar to all products intended to prevent or treat diseases, LBPs will have to be registered as medicinal products to reach the market in the US and in Europe. In this area, regulatory authorities and the pharmaceutical industry will routinely use guidelines of the "International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use" (ICH). Although ICH guidelines are not legally binding, they provide very important recommendations, recognized by almost all drug authorities in the world. In this review, we discuss some aspects of this regulatory framework, especially focusing on products with an intended use in a diseased or vulnerable target population.

ANCA-associated vasculitides: Recommendations of the French Vasculitis Study Group on the use of immunosuppressants and biotherapies for remission induction and maintenance.

Treatment of vasculitides associated with anti-neutrophil cytoplasm antibodies (ANCA) (AAVs) has evolved dramatically in recent years, particularly since the demonstration of rituximab efficacy as remission induction and maintenance therapy for granulomatosis with polyangiitis and microscopic polyangiitis. In 2013, the French Vasculitis Study Group (FVSG) published recommendations for its use by clinicians. Since then, new data have made it possible to better specify and codify prescription of rituximab to treat AAVs. Herein, the FVSG Recommendations Committee, an expert panel comprised of physicians with extensive experience in the treatment and management of vasculitides, presents its consensus guidelines based on literature analysis, the results of prospective therapeutic trials and personal experience.

A Six-Year Analysis of Biological Therapy for Severe Psoriasis in a Lithuanian Reference Centre of Dermatovenereology.

Background and Objectives: Biological therapy is widely used for the treatment of severe psoriasis. The objective of this study was to evaluate the efficacy and safety of biological therapy for patients with severe psoriasis. Materials and Methods: A retrospective study of 79 patients with severe psoriasis, who have been treated with biological therapy between 2012 and 2018, was conducted. During this study, the following data were collected and evaluated: sex, age, body mass index (BMI), duration of illness, the results of treatment with biological therapy, concomitant therapy, Psoriasis Area and Severity Index (PASI) and adverse events. Results: In total, 74.7% (n = 59) of subjects were male. Their overall average age was 47.4 ± 11.4 (range: 18-73) years. Their baseline BMI was 27.6 ± 5.9, which increased to 29.6 ± 4.5 after 6 years of treatment. The mean duration of psoriasis was 25.7 ± 12.5 years. In total, 39.2% (n = 31) of subjects received infliximab, 36.7% (n = 29)-etanercept, 24.1% (n = 19)-ustekinumab. The treatment duration for infliximab, etanercept and ustekinumab was 201.6 ± 86.8, 156.2 ± 137.4 and 219.1 ± 95.7 weeks (p < 0.01), respectively. Overall, 65.8% (n = 52) of subjects were also on methotrexate; 30.8% (n = 16) of them discontinued it due to clinical improvement (31.3% (n = 5)), impaired liver function (31.3% (n = 5)), and intolerance (25% (n = 4)). Baseline PASI was 20.8 ± 8.8. PASI 50 was achieved by 96.2% (n = 76) of patients at week 11, PASI 75 by 86.1% (n = 68) at week 16, PASI 90 by 54.4% (n = 43) at week 35, and PASI 100 by 13.9% (n = 11) at week 33. The overall incidence rate of adverse events was 0.362 per patient year of follow-up. Conclusion: Biological therapy is an effective and safe treatment for patients with severe psoriasis.

Approach to Latent Tuberculosis Infection Screening Before Biologic Therapy in IBD Patients: PPD or IGRA?

The use of biological agents for the treatment of chronic inflammatory conditions such as inflammatory bowel diseases (IBD) has been on the rise.1,2 Current biological therapies include antitumor necrosis factor-α (anti-TNF-α), anti-interleukin-12/23, and anti-integrin agents. Before initiation of biological drugs, screening for Mycobacterium tuberculosis infection is required to avoid reactivation or worsening of disease after immunosuppression. It has been shown that anti-TNF-α treated patients have a 14-fold increased risk of tuberculosis (TB) infection/reactivation compared with healthy controls.3 The methods for screening for TB have evolved over time and vary from region to region.

The Brazilian Society of Rheumatology guidelines for axial spondyloarthritis - 2019.

Spondyloarthritis is a group of chronic inflammatory systemic diseases characterized by axial and/or peripheral joints inflammation, as well as extra-articular manifestations. The classification axial spondyloarthritis is adopted when the spine and/or the sacroiliac joints are predominantly involved. This version of recommendations replaces the previous guidelines published in May 2013.A systematic literature review was performed, and two hundred thirty-seven studies were selected and used to formulate 29 recommendations answering 15 clinical questions, which were divided into four sections: diagnosis, non-pharmacological therapy, conventional drug therapy and biological therapy. For each recommendation the level of evidence supporting (highest available), the strength grade according to Oxford, and the degree of expert agreement (inter-rater reliability) is informed.These guidelines bring evidence-based information on clinical management of axial SpA patients, including, diagnosis, treatment, and prognosis.

Changes in Manufacturing Processes of Biologic Therapies Can Alter the Immunogenicity Profile of the Product.

Manufacturing process changes may alter the characteristics of a protein therapeutic. In 2009, somatropin (version 1.0), a recombinant human growth hormone therapeutic, underwent a manufacturing update (version 1.1). The immunogenicity of somatropin version 1.1 as a daily subcutaneous injection was evaluated in 2014 in a prospective, open-label, single-arm clinical study of treatment-naive pediatric patients with idiopathic human growth hormone deficiency for 1 year. The primary end point was the proportion of patients who developed antidrug antibodies (ADAs) after treatment. Eighty-two patients were enrolled. The mean (SD) treatment duration was 347 (53) days. The incidence of ADAs was 3.7%. No neutralizing antibodies were observed in the three patients with ADA-positive samples. Two patients (2.6%) had growth attenuation, but they were not ADA positive. The manufacturing changes for somatropin version 1.1 resulted in a similar safety and efficacy profile compared with somatropin version 1.0 and a different immunogenicity profile with a lower incidence of ADAs.

[Consensus of infectious complications in patients treated with selected biological therapies: first Part]. / Consenso sobre riesgo de complicaciones infecciosas en pacientes usuarios de medicamentos biológicos seleccionados. Parte I.

The use of biological therapies has meant a great improvement in the management of several conditions like autoimmune, neoplastic or others diseases. Although its use has implied significant improvements in the prognosis of these diseases, it is not exempt from complications: infectious diseases as one of them. The objective of this consensus was to evaluate, from an infectious viewpoint, the safeness of the most frequently used biological therapies and give recommendations for the prevention of infections in patients treated with these drugs. These recommendations were based on the highest quality evidence available for the selected biologics. The consensus counts of two manuscripts. This first part details the risks of developing infectious complications depending on the type of biological used for a certain pathology. This evaluation included a broad search in MEDLINE and Epistemonikos of systematic reviews and meta-analyzes of controlled clinical trials and casecontrol examining post-treatment infections with anti-TNF alpha, anti-CD20, anti-CD52, CTLA4-Ig and anti-integrins. The research was complemented by a review of: multicentre cohorts of biological users, the MMWR of the CDC, Atlanta, U.S.A., and national registers and scientific societies in which infectious complications derived from the use of biological therapies were mentioned.

Consenso sobre riesgo de complicaciones infecciosas en pacientes usuarios de medicamentos biológicos seleccionados. Parte I / Consensus of infectious complications in patients treated with selected biological therapies: first Part

Resumen La incorporación de terapias biológicas ha significado un gran avance en el manejo de diversas patologías de origen autoinmune, neoplásico u otros. Si bien su uso ha implicado mejoras significativas en el pronóstico de estas enfermedades, no está exento de complicaciones, entre estas, las infecciosas. El objetivo de este consenso fue evaluar el perfil de seguridad, desde la mirada infectológica, de las terapias biológicas de uso más frecuente y dar recomendaciones para la prevención de infecciones en pacientes tratados con ellas, basándose en la evidencia de mayor calidad disponible para los biológicos seleccionados. El consenso cuenta de dos manuscritos. Esta primera parte detalla los riesgos de desarrollar complicaciones infecciosas dependiendo del tipo de biológico utilizado para determinada patología. La revisión incluyó búsqueda amplia en MEDLINE y Epistemonikos de revisiones sistemáticas y meta-análisis de estudios clínicos controlados y caso/control que examinaban infecciones posteriores al tratamiento con anti-TNF alfa, anti-CD20, anti-CD52, CTLA4-Ig y anti-integrinas. Esta búsqueda se complementó con revisión de cohortes multicéntricas de usuarios de biológicos, del MMWR del CDC, Atlanta, E.U.A. y de registros nacionales y/o de sociedades científicas en la que se hiciera mención a complicaciones infecciosas derivadas del uso de biológicos.

The use of biological therapies has meant a great improvement in the management of several conditions like autoimmune, neoplastic or others diseases. Although its use has implied significant improvements in the prognosis of these diseases, it is not exempt from complications: infectious diseases as one of them. The objective of this consensus was to evaluate, from an infectious viewpoint, the safeness of the most frequently used biological therapies and give recommendations for the prevention of infections in patients treated with these drugs. These recommendations were based on the highest quality evidence available for the selected biologics. The consensus counts of two manuscripts. This first part details the risks of developing infectious complications depending on the type of biological used for a certain pathology. This evaluation included a broad search in MEDLINE and Epistemonikos of systematic reviews and meta-analyzes of controlled clinical trials and casecontrol examining post-treatment infections with anti-TNF alpha, anti-CD20, anti-CD52, CTLA4-Ig and anti-integrins. The research was complemented by a review of: multicentre cohorts of biological users, the MMWR of the CDC, Atlanta, U.S.A., and national registers and scientific societies in which infectious complications derived from the use of biological therapies were mentioned.

Development of quality measures for use of self-injectable biologic therapy in inflammatory bowel disease: An integrated specialty pharmacy initiative.

PURPOSE: The development of a tool to measure medication safety, therapeutic efficacy, and other quality outcomes in patients receiving self-injectable biologic therapy for the management of inflammatory bowel disease (IBD) at a health-system specialty pharmacy is described. SUMMARY: Through a collaborative initiative by pharmacists, gastro-enterologists, and representatives of a pharmacy benefit manager and a pharmaceutical company, a set of clinical and specialty pharmacy quality measures was developed. The clinical measures are intended for use in assessing patient safety, disease status, treatment efficacy, and healthcare resource utilization during 3 assessments (pre-treatment, on-treatment, and longitudinal). The specialty pharmacy measures can be used to assess medication adherence, medication persistence, specialty pharmacy accreditation, and patient satisfaction. The proposed quality measures provide a foundation for evaluating the quality of IBD care and improving patient outcomes within a health-system specialty pharmacy. Future efforts to validate and implement the tool in clinical practice are planned. CONCLUSION: The proposed quality measures provide a foundation for future inquiry regarding the appropriateness and feasibility of integrating the measures into clinical care. Further work is needed to implement and validate these quality measures and determine their impact in optimizing health outcomes.

Platelet-Rich Fibrin and its Emerging Therapeutic Benefits for Musculoskeletal Injury Treatment.

New therapies that accelerate musculoskeletal tissue recovery are highly desirable. Platelet-rich fibrin (PRF) is a leukocyte- and platelet-rich fibrin biomaterial that acts as a binding site for both platelets and growth factors. Through increasing the local concentration of growth factors at specific tissues, PRF promotes tissue regeneration. PRF has been frequently used in combination with bone graft materials to reduce healing times and promote bone regeneration during maxillofacial surgery. However, its benefits during muscle repair and recovery are less well-documented. Here, we perform a narrative review on PRF therapies and muscle injuries to ascertain its beneficial effects. We reviewed the factors that contribute to the biological activity of PRF and the published pre-clinical and clinical evidence to support its emerging use in musculoskeletal therapy. We include in vitro studies, in vivo animal studies and clinical articles highlighting both the success and failures of PRF treatment. PRF can promote the healing process when used in a range of orthopaedic and sports-related injuries. These include cartilage repair, rotator cuff surgery and anterior cruciate ligament surgery. However, conflicting data for these benefits have been reported, most likely due to inconsistencies in both PRF preparation protocols and dosing regimens. Despite this, the literature generally supports the use of PRF as a beneficial adjuvant for a range of chronic muscle, tendon, bone or other soft tissue injuries. Further clinical trials to confirm these benefits require consistency in PRF preparation and the classification of a successful clinical outcome to fully harness its potential.

Reliable LC-MS Multiattribute Method for Biotherapeutics by Run-Time Response Calibration.

A major challenge of a mass-spectrometry-based quantitative multiattribute method (MAM) for biotherapeutics is its high variability between instruments. For reproducible attribute measurements, not only is a similar instrument model required, but the instruments must also be tuned to the same condition. This poses great long-term challenges, considering the rapid development of new instrumentations. In addition, differences in digestion efficiency, peptide recovery, and artificial modifications during sample preparation also contribute to variability between laboratories. To overcome these challenges, new mathematical methods are developed to calculate the attribute abundance in the sample, using the reference standard (RS) material as calibrant. Most quality attributes in the RS remain constant throughout the life of the standard, and therefore, the RS can serve as a calibrant to correct for the difference between instruments or sample preparation procedures. Because RS data are usually collected in a MAM assay, no additional work is required from the analyst. Data from a large number of attributes demonstrated that these methodologies greatly reduced instrument-to-instrument and sample preparation variabilities. With these methodologies, a consistent instrument model and sample preparation procedure is no longer a requirement. As a result, changes in digestion procedure and advances in instrumentations will not significantly affect the assay result.

Addressing Reproducibility in Stem Cell and PRP Therapies.

Stem cell and platelet-rich plasma (PRP) therapies are promising breakthroughs in the treatment of multiple conditions. However, the lack of reproducibility due to inaccurate reporting of the protocols used to obtain these biologics can hinder their therapeutic progress. A reporting guideline for biological therapies is required to address this issue.

White paper on microbial anti-cancer therapy and prevention.

In this White Paper, we discuss the current state of microbial cancer therapy. This paper resulted from a meeting ('Microbial Based Cancer Therapy') at the US National Cancer Institute in the summer of 2017. Here, we define 'Microbial Therapy' to include both oncolytic viral therapy and bacterial anticancer therapy. Both of these fields exploit tumor-specific infectious microbes to treat cancer, have similar mechanisms of action, and are facing similar challenges to commercialization. We designed this paper to nucleate this growing field of microbial therapeutics and increase interactions between researchers in it and related fields. The authors of this paper include many primary researchers in this field. In this paper, we discuss the potential, status and opportunities for microbial therapy as well as strategies attempted to date and important questions that need to be addressed. The main areas that we think will have the greatest impact are immune stimulation, control of efficacy, control of delivery, and safety. There is much excitement about the potential of this field to treat currently intractable cancer. Much of the potential exists because these therapies utilize unique mechanisms of action, difficult to achieve with other biological or small molecule drugs. By better understanding and controlling these mechanisms, we will create new therapies that will become integral components of cancer care.

WHO informal consultation on development of guidelines on procedures and data requirements for changes to approved biotherapeutic products, Seoul, Republic of Korea, 27-28 April 2017.

In April 2017, WHO convened an informal consultation to develop WHO guidelines on procedures and data requirements for changes to approved biotherapeutic products. The objective of the meeting was to review the draft of WHO guidelines and the comments received from the public consultation. The guidelines were recognized by the participants as a tool for regulatory convergence and harmonization. Regulation of changes to approved biotherapeutic products is a key in ensuring that products of consistent quality, safety and efficacy are distributed after they receive authorization or licensure. Participants agreed that the guidelines would contribute to assuring the continued quality, safety and efficacy throughout the life-cycle of biotherapeutics as well as continuity in supply and access. In the meeting, participants further requested WHO should assist national regulatory authorities in improving technical expertise in the evaluation of biotherapeutics and their post-approval changes by organizing implementation workshops and developing case studies and e-training modules on various technical topics. At its meeting in October 2017, the WHO Expert Committee on Biological Standardization formally adopted the WHO guidelines on procedures and data requirements for changes to approved biotherapeutic products.

Recommendations by the Spanish Society of Rheumatology on the Use of Biological Therapies in Axial Spondyloarthritis. / Recomendaciones de la Sociedad Española de Reumatología sobre el uso de terapias biológicas en espondiloartritis axial.

OBJECTIVE: Recent data published on biological therapy in axial spondyloarthritis (axSpA) since the last publication of the recommendations of the Spanish Society of Rheumatology (SER) has led to the generation of a review of these recommendations based on the best possible evidence. These recommendations should be a reference for rheumatologists and those involved in the treatment of patients with axSpA. METHODS: Recommendations were drawn up following a nominal group methodology and based on systematic reviews. The level of evidence and grade of recommendation were classified according to the model proposed by the Centre for Evidence Based Medicine at Oxford. The level of agreement was established through the Delphi technique. RESULTS: In this review, we did an update of the evaluation of disease activity and treatment objectives. We included the new drugs with approved therapeutic indication for axSpA. We reviewed both the predictive factors of the therapeutic response and progression of radiographic damage. Finally, we drafted some recommendations for the treatment of patients refractory to anti-tumor necrosis factor, as well as for the possible optimization of biological therapy. The document also includes a table of recommendations and a treatment algorithm. CONCLUSIONS: We present an update of the SER recommendations for the use of biological therapy in patients with axSpA.

A View on the Importance of "Multi-Attribute Method" for Measuring Purity of Biopharmaceuticals and Improving Overall Control Strategy.

Today, we are experiencing unprecedented growth and innovation within the pharmaceutical industry. Established protein therapeutic modalities, such as recombinant human proteins, monoclonal antibodies (mAbs), and fusion proteins, are being used to treat previously unmet medical needs. Novel therapies such as bispecific T cell engagers (BiTEs), chimeric antigen T cell receptors (CARTs), siRNA, and gene therapies are paving the path towards increasingly personalized medicine. This advancement of new indications and therapeutic modalities is paralleled by development of new analytical technologies and methods that provide enhanced information content in a more efficient manner. Recently, a liquid chromatography-mass spectrometry (LC-MS) multi-attribute method (MAM) has been developed and designed for improved simultaneous detection, identification, quantitation, and quality control (monitoring) of molecular attributes (Rogers et al. MAbs 7(5):881-90, 2015). Based on peptide mapping principles, this powerful tool represents a true advancement in testing methodology that can be utilized not only during product characterization, formulation development, stability testing, and development of the manufacturing process, but also as a platform quality control method in dispositioning clinical materials for both innovative biotherapeutics and biosimilars.