Relevance of distinctions and parallels between the US and EU guidelines for determination of comparative effectiveness and safety of the orally inhaled drug products.

Approval of drug products for market registration warrants, among other data, evidence to support their safety and effectiveness in the target populations. The extent of investigations to provide the supporting evidence varies between the new innovator products and their follow-on versions generally referred to as Generic Drugs Products in the United States and Hybrids in the Europe. The new drug applications entail large data sets encompassing both nonclinical and clinical product developments. Safety and effectiveness in man is studied in sequentially phased clinical trials, including post marketing evaluations (Where applicable). However, for the generic/hybrid products the safety and effectiveness are established through determination of bioequivalence in head-to-head comparison between the originator and the follow-ons. Methods for documentation of bioequivalence for drug products that reach target site(s) through systemic circulation are aligned worldwide. However, establishing bioequivalence of orally inhaled drug products is complex as drug delivery to the local site(s) of action is independent of the systemic circulation. Documentation of bioequivalence gets further complicated due to the Drug-Device combination nature of these products. The guidelines for establishment of BE of locally acting orally inhaled drugs products vary among certain geographies. This article examines the scientific underpinning of distinctions and similarities between the US and EU guidelines.

Cardiovascular events of Bruton's tyrosine kinase inhibitors: A real-world study based on the United States Food and Drug Administration Adverse Event Reporting System database.

AIMS: Bruton's tyrosine kinase inhibitors (BTKIs), including first-generation ibrutinib, second-generation acalabrutinib and zanubrutinib, may be involved in the mechanisms of action related to adverse events (AEs) of the cardiovascular system. We aimed to characterize the cardiovascular AEs of BTKIs reported in the US Food and Drug Administration (FDA) Adverse Event Reporting System, and to compare the cardiovascular risks of BTKIs. METHODS: Across all indications of three FDA-approved BTKIs, primary suspect drugs were extracted over two periods: from January 2013 to December 2022 (after the approval of the first BTKI), and from January 2020 to December 2022 (all three BTKIs on the market). Disproportionality was measured by reporting odds ratios (RORs) and information components. Additional analyses were performed without incorporating patients with underlying cardiovascular disease (CVD). RESULTS: A total of 10 353 cases included the uses of ibrutinib, acalabrutinib and zanubrutinib. Ibrutinib was significantly associated with 47 cardiovascular AEs. Acalabrutinib was associated with new signals, including cardiac failure (ROR = 1.82 [1.13-2.93]), pulmonary oedema (ROR = 2.15 [1.19-3.88]), ventricular extrasystoles (ROR = 5.18 [2.15-12.44]), heart rate irregular (ROR = 3.05 [1.53-6.11]), angina pectoris (ROR = 3.18 [1.71-5.91]) and cardiotoxicity (ROR = 25.22 [17.14-37.10]). In addition, cardiovascular events had an earlier onset in acalabrutinib users. Zanubrutinib was only associated with atrial fibrillation. Acalabrutinib and zanubrutinib had lower ROR values than ibrutinib. The AE signals were generally consistent between the population receiving and not receiving CVD medications. CONCLUSIONS: Potential cardiovascular risks identified in this study were not clearly noted on the label of marketed acalabrutinib. Caution should be paid to the cardiovascular risks of BTKIs having been or being developed.

Pathogenesis of COVID19 and the applications of US FDA-approved repurposed antiviral drugs to combat SARS-CoV-2 in Saudi Arabia: A recent update by review of literature.

Still, there is no cure for the highly contagious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-caused coronavirus disease 2019 (COVID19). The COVID19 pandemic caused health emergencies which resulted in enormous medical and financial consequences worldwide including Saudi Arabia. Saudi Arabia is the largest Arab country of the Middle East. The urban setting of Saudi Arabia makes it vulnerable towards SARS-CoV-2 (SCV-2). Religious areas of this country are visited by millions of pilgrims every year for the Umrah and Hajj pilgrimage, which contributes to the potential COVID19 epidemic risk. COVID19 throws various challenges to healthcare professionals to choose the right drugs or therapy in clinical settings because of the lack of availability of newer drugs. Current drug development and discovery is an expensive, complex, and long process, which involves a high failure rate in clinical trials. While repurposing of United States Food and Drug Administration (US FDA)-approved antiviral drugs offers numerous benefits including complete pharmacokinetic and safety profiles, which significantly shorten drug development cycles and reduce costs. A range of repurposed US FDA-approved antiviral drugs including ribavirin, lopinavir/ritonavir combination, oseltamivir, darunavir, remdesivir, nirmatrelvir/ritonavir combination, and molnupiravir showed encouraging results in clinical trials in COVID19 treatment. In this article, several COVID19-related discussions have been provided including emerging variants of concern of, COVID19 pathogenesis, COVID19 pandemic scenario in Saudi Arabia, drug repurposing strategies against SCV-2, as well as repurposing of US FDA-approved antiviral drugs that might be considered to combat SCV-2 in Saudi Arabia. Moreover, drug repurposing in the context of COVID19 management along with its limitations and future perspectives have been summarized.

Structure and function of therapeutic antibodies approved by the US FDA in 2023.

In calendar year 2023, the United States Food and Drug Administration (US FDA) approved a total of 55 new molecular entities, of which 12 were in the class of therapeutic antibodies. Besides antibody protein drugs, the US FDA also approved another five non-antibody protein drugs, making the broader class of protein drugs about 31% of the total approved drugs. Among the 12 therapeutic antibodies approved by the US FDA, 8 were relatively standard IgG formats, 3 were bivalent, bispecific antibodies and 1 was a trivalent, bispecific antibody. In 2023, no new antibody-drug conjugates, immunocytokines or chimeric antigen receptor-T cells were approved. Of the approved antibodies, two targeted programmed cell death receptor-1 (PD-1) for orphan indications, two targeted CD20 for diffuse large B cell lymphoma, two targeted different receptors (B-cell maturation antigen [BCMA] and G-coupled protein receptor class C, group 5, member D [GPRC5D]) for treatment of multiple myeloma, and one each that targeted amyloid-ß protofibrils for Alzheimer's disease, neonatal Fc receptor alpha-chain for myasthenia gravis, complement factor C5 for CD55 deficiency with hyper-activation of complement, angiopathic thrombosis and severe protein-losing enteropathy disease, interleukin (IL)-23p19 for severely active ulcerative colitis, IL-17A-F for plaque psoriasis and respiratory syncytial virus (RSV)-F protein for season-long RSV prophylaxis in infants.

A systematic review of real-world evidence (RWE) supportive of new drug and biologic license application approvals in rare diseases.

BACKGROUND: Real-world evidence (RWE) generated using real-world data (RWD) presents the potential to contextualize and/or supplement traditional clinical trials for regulatory approval of rare diseases (RDs). This systematic review evaluated the use of RWD for non-oncologic RD therapies with orphan drug designation (ODD) to support efficacy outcomes in regulatory application packages to the US Food and Drug Administration (FDA). New drug applications (NDAs) and biologic license applications (BLAs) submitted between January 2017 and October 2022 were obtained from publicly available FDA drug approval websites. NDAs and BLAs of non-oncologic RD therapies were screened, and manually reviewed using RWE-related keywords. Quantitative summary of number/proportion of study types was provided, whereas qualitative synthesis focused on key categories of output assessing the use of RWD in overall drug approval process, including agency's feedback on its strengths and key challenges. RESULTS: A total of 868 NDAs and BLAs were identified, of which 243 were screened for non-oncologic RDs with ODD, and 151 were subsequently reviewed for the RWD used to support efficacy outcomes. Twenty (12 NDAs, 8 BLAs) applications met the review inclusion criteria. Most (19; 95%) applications used only retrospective RWD, while one (5%) collected RWD both retrospectively and prospectively. RWD studies included natural history including registry-based/retrospective historical controls (14; 70%), retrospective medical chart-reviews (4; 20%), and external RWD controls from other studies (2; 10%). The FDA generally accepted RWD studies demonstrating a large effect size despite the noted concerns and criticisms. However, the agency expressed concerns about overall quality and comparability of RWD with trial data for some applications, including RWD study designs with respect to differences in patients' baseline characteristics, missing information, and potential bias and measurement errors. CONCLUSIONS: This systematic review highlights potential benefits of appropriately conducted RWE studies in RD, which can strengthen the clinical evidence for efficacy comparison and contextualization to support product approval efforts, particularly when a large magnitude of effect is observed for the new intervention. Nonetheless, quality and completeness of RWD and its comparability with trial data remain areas of concern that can serve as valuable learnings for advancing future science and regulatory approvals.

Structural-based Study to Identify the Repurposed Candidates Against Bacterial Infections.

BACKGROUND: Microbial infections are mostly caused by Gram-positive as well as Gram-negative bacteria affecting millions of people worldwide. There is an urgent need to explore existing molecules or discover new chemical entities (NCEs) against bacterial infection. OBJECTIVE: The main objective of the current investigation is to explore recently US-FDA- approved drugs (2019-2023) against various targets of Gram-positive and Gram-negative bacteria using high-performance computational studies. AIM: The current study aims to find out the potential drugs of recently US-FDA-approved drugs as repurposing candidates against bacterial infections. METHODS: The targets of Gram-positive and Gram-negative bacteria were identified using literature studies whereas ligands were selected from the FDA-approved drug lists of the last 5 years. Further, the drugs and targets were prepared through the LigPrep and Protein Preparation Wizard modules of Schrödinger (release 2023-1) respectively. The GlideDock and Desmond modules of Schrödinger were used for the molecular docking study and molecular dynamics simulation respectively. RESULTS: A total of 202 drugs were found in the FDA lists which were approved in the last five years. Out of them, 77 drugs were selected for docking study based on their properties. A total of 21 drugs have shown energetically favored binding conformation of drugs in the active site of bacterial targets. The interaction of these drugs was studied in detail using molecular dynamics (MD) simulation. The MD simulation results have shown stable dynamic conformation of triclabendazole (anti-helminthic) with topoisomerase II of gram-negative bacteria whereas solriamfetol (for obstructive sleep apnea) has shown stable dynamic conformation in the active site of restriction endonuclease of gram-positive bacteria. CONCLUSION: The identified drugs can be repurposed against Gram-positive and Gramnegative bacterial infections. However, further experimental studies are required to confirm their antibacterial potential.

Recapitulation of human pathophysiology and identification of forensic biomarkers in a translational model of chlorine inhalation injury.

Chlorine gas (Cl2) has been repeatedly used as a chemical weapon, first in World War I and most recently in Syria. Life-threatening Cl2 exposures frequently occur in domestic and occupational environments, and in transportation accidents. Modeling the human etiology of Cl2-induced acute lung injury (ALI), forensic biomarkers, and targeted countermeasures development have been hampered by inadequate large animal models. The objective of this study was to develop a translational model of Cl2-induced ALI in swine to understand toxico-pathophysiology and evaluate whether it is suitable for screening potential medical countermeasures and to identify biomarkers useful for forensic analysis. Specific pathogen-free Yorkshire swine (30-40 kg) of either sex were exposed to Cl2 (≤240 ppm for 1 h) or filtered air under anesthesia and controlled mechanical ventilation. Exposure to Cl2 resulted in severe hypoxia and hypoxemia, increased airway resistance and peak inspiratory pressure, and decreased dynamic lung compliance. Cl2 exposure resulted in increased total leucocyte and neutrophil counts in bronchoalveolar lavage fluid, vascular leakage, and pulmonary edema compared with the air-exposed group. The model recapitulated all three key histopathological features of human ALI, such as neutrophilic alveolitis, deposition of hyaline membranes, and formation of microthrombi. Free and lipid-bound 2-chlorofatty acids and chlorotyrosine-modified proteins (3-chloro-l-tyrosine and 3,5-dichloro-l-tyrosine) were detected in plasma and lung tissue after Cl2 exposure. In this study, we developed a translational swine model that recapitulates key features of human Cl2 inhalation injury and is suitable for testing medical countermeasures, and validated chlorinated fatty acids and protein adducts as biomarkers of Cl2 inhalation.NEW & NOTEWORTHY We established a swine model of chlorine gas-induced acute lung injury that exhibits several features of human acute lung injury and is suitable for screening potential medical countermeasures. We validated chlorinated fatty acids and protein adducts in plasma and lung samples as forensic biomarkers of chlorine inhalation.

Agents at the Peak of US FDA Approval for the Treatment of Alzheimer's Disease.

Where Alzheimer's disease (AD) is becoming a global health issue, the present anti-AD medications have also been exposed to produce only symptomatic outcomes. The pathological factors, like neuronal transmission impairment, amyloidal-tau constituents, oxidative damage, neuro-inflammation, synaptic dysfunction, infectious agents, and impairment of gut microbiota and vitamins' levels; all favor the disease's progression and sustainability. The researchers have investigated several drugable molecules against these factors; however, no treatment could have been discovered yet to prevent the disease's progression rather than anti-amyloidal antibodies. After a comprehensive review of the literature and the clinical registry (clinicaltrials.gov), the authors of this manuscript have explored drug molecules that are under phase-3 of clinical trials and at the peak of getting approval for the management of AD. The inclusion and exclusion criteria for clinical trials were decided by considering the basis of a drug's approval. We included only the clinical trials were found in stages of Enrolling-by-Invitation, Recruiting, Not Recruiting (But active), and Not Recruiting (Not active) while excluding Completed, Terminated, Suspended, Withdrawn, or the trials of Unknown Status. We have found many potent drug molecules reached the clinical trials in phase-3 that could be futuristic anti-AD agents. This review article aims to provide an update on the prospective potential anti-AD medicines and to reveal the therapeutic targets of great significance for designing further a possible drug development strategy against AD pathology.

Unveiling the potential of recently FDA-approved drugs as quorum sensing inhibitors against P. Aeruginosa using high-performance computational techniques.

Through cell-to-cell communication, activation of efflux pumps, formation of biofilms, and other mechanisms, pseudomonas aeruginosa's quorum sensing systems (QSS), notably the lasl/las-r system, contribute a vital role in the development of anti-microbial resistance (AMR). Identifying potential drugs against these targets could have significant implications for combating pseudomonal infections. The current study aims to identify promising recently FDA-approved drugs against lasl/las-r proteins. The ligands were selected from the FDA-approved drug lists of the last 5 years. Out of 202, 78 drugs were checked for interaction with lasl/las-r protein and 4 drugs revealed top binding conformations characterized by favorable energetic profiles within the active site of the las-r protein which were further assigned for 250-ns molecular dynamics (MD) simulation. The MD analysis confirmed the dynamical stability of brexanolone and oteseconazole with las-r protein. The root mean square deviation (RMSD), radius of gyration (Rg) and solvent-accessible surface area (SASA) analysis have indicated less deviation, more compactness of protein and less exposure of protein ligand complex to its surroundings as compared to the reference ligand-protein complex. The hydroxyl group in the oteseconazole whereas hydroxyl and ketone group in the brexanolone were responsible for hydrogen bonds with the active site residue of las r ptotein as indicated by ligand-protein contacts diagram. The binding energies per residue analysis revealed TYR-47 as the most contributing amino acid residue for interaction with oteseconazole and brexanolone. The identified drugs may be potential repurposing candidates against pseudomonal infections through inhibition of las-r protein.Communicated by Ramaswamy H. Sarma.

Identification of Novel Signals Associated with US-FDA Approved Drugs (2013) Using Disproportionality Analysis.

BACKGROUND: Drugs are related with various adverse drug reactions (ADRs), however, many unexpected ADRs of drugs are reported through post-marketing surveillance. AIM: The current study's goal is to uncover potential signals connected with FDA-approved medications in the United States (2013). METHODOLOGY: Open Vigil 2.1-MedDRA-v24 (data 20004Q1-2021Q3) was used as a tool to query the FAERS data. To find possible signals, disproportionality measures such as Proportional Reporting Ratio (PRR 2) with associated Chi-square value, Reporting Odds Ratio (ROR 2) with 95% confidence interval, and case count (3) were calculated. RESULTS: A total of eight potential signals were identified with five drugs. Positive signals were found with pomalidomide, canagliflozin, dolutegravir sodium, macitentan and ibrutinib. CONCLUSION: However, further causality assessment is required to confirm the association of these drugs with identified potential signals.

Vosoritide, a miracle drug, covering unmet need in achondroplasia: A regulatory update.

Dwarfism is a rare condition characterized by small stature. Achondroplasia is predominantly considered the leading cause of dwarfism. Although the condition is not life-threatening, it dramatically impacts the social life of the patient. The United States Food and Drug Administration (US FDA) first approved the drug Voxzogo (vosoritide) for achondroplasia. The drug also received approval from the European Medicines Agency (EMA) via the centralized procedure. The drug is associated with a decrease in blood pressure, a severe adverse event. However, this adverse event/risk has been overcome by benefits, i.e. fulfilling of unmet medical need. In the United States, the drug received accelerated approval as it satisfied the criteria of rare pediatric disease. This review includes a detailed orphan drug approval process with particular reference to vosoritide, which is considered a milestone for the treatment of achondroplasia.

Regulatory claims made by US businesses engaged in direct-to-consumer marketing of purported stem cell treatments and exosome therapies.

Aim: This study investigated whether US businesses engaged in direct-to-consumer online marketing of purported stem cell therapies and stem cell-derived exosome products made claims concerning the regulatory status of these interventions. Methods: We used data mining and content analysis of company websites to examine regulatory-related representations made by US businesses marketing stem cell treatments and exosome therapies. Results: More than two thirds of such businesses did not make explicit representations about the regulatory status of their marketed products. Businesses that made claims about the regulatory status of the stem cell and exosome products they sold used range of representations concerning the legal standing of these interventions. Conclusion: The absence of information addressing the regulatory status of stem cell interventions and exosome products and the use of what appeared to be inaccurate information concerning the regulatory status of numerous products likely complicates efforts by customers to make informed health-related decisions.

Scientific considerations in the regulatory approval of generic (or biosimilar) version of enoxaparin sodium - A lifesaving carbohydrate polymer.

Enoxaparin sodium (Clexane®/Klexane®/Lovenox®) is one amongst the few drugs that have assumed a central role as drug of treatment and/or prevention against thromboembolic complications during COVID-19. The increase in demand resulting in many generic (or biosimilar) versions entering the market has increased the risks of quality and safety (including immunogenicity) related issues. Under the circumstances, development of stringent regulatory approaches has received much attention as investigation of new drug delivery systems for improved therapeutic activity. As one of the measures to increase quality testing and ensure uninterrupted supply of this life-saving drug globally, determination of enoxaparin molecular weight (MW) has been added in the United States Pharmacopoeia (USP) monograph for enoxaparin sodium. In addition, the presence of a unique 1,6-anhydro-ring structure at the reducing end of about 15-25% of the poly (oligo) saccharide chains of the generic (or biosimilar) product has been set as a mandatory requirement. This article presents an overview of the scientific considerations in the quality manufacturing and testing of the generic (or biosimilar) enoxaparin for regulatory review and approval. In certain cases of strong analytical similarity (structural and functional), abandonment of in vivo testing in animals and humans represents a major advancement in the approval of generic (or biosimilar) version of innovator enoxaparin sodium (lovenox®, injections).

Assessing Visual Outcomes: A Comparative Study of US-FDA Premarket Approval Data for Multifocal and EDOF Lens Implants in Cataract Surgery.

This study compares the efficacy, safety, and patient-reported outcomes of three intraocular implants (IOL): Tecnis Synergy IOL, AcrySof IQ PanOptix Trifocal, and Tecnis Symfony EDOF IOL. Participants achieving 20/20 or better uncorrected binocular visual acuity were as follows: Synergy-67% distance, 64% intermediate, and 47% near; PanOptix-73% distance, 73% intermediate, and 50% near; and Symfony-63% distance, 75% intermediate, and 22% near. Symfony demonstrated superior intermediate visual acuity compared to Synergy (p = 0.0182) for those achieving 20/25 or better. Both Synergy and PanOptix showed superiority over Symfony for near visual acuity (p < 0.0001). Halos were statistically more common in Synergy participants compared to PanOptix (p = 0.0013) and Symfony (p < 0.0001). Each trial lens outperformed its monofocal IOL in terms of independence from glasses or contacts, with Synergy and PanOptix showing statistical significance over Symfony. Comparing contrast sensitivities and defocus curves was challenging due to data variance and as such, standardization of United States Food and Drug Administration (US-FDA) data reporting is key for better comparison of outcomes among different IOL platforms.

US regulatory considerations for low field magnetic resonance imaging systems.

Although there has been a resurgence of interest in low field magnetic resonance imaging (MRI) systems in recent years, low field MRI is not a new concept. FDA has a long history of evaluating the safety and effectiveness of MRI systems encompassing a wide range of field strengths. Many systems seeking marketing authorization today include new technological features (such as artificial intelligence), but this does not fundamentally change the regulatory paradigm for MR systems. In this review, we discuss some of the US regulatory considerations for low field magnetic resonance imaging (MRI) systems, including applicability of existing laws and regulations and how the U.S. Food and Drug Administration (FDA) evaluates low field MRI systems for market authorization. We also discuss regulatory considerations in the review of low field MRI systems incorporating novel AI technology. We foresee that MRI systems of all field strengths intended for general diagnostic use will continue to be evaluated for marketing clearance by the metric of substantial equivalence set forth in the premarket notification pathway.

The Impact of US Medical Product Regulatory Complexity on Innovation: Preliminary Evidence of Interdependence, Early Acceleration, and Subsequent Inversion.

PURPOSE: Is the complexity of medical product (medicines and medical devices) regulation impacting innovation in the US? If so, how? METHODS: Here, this question is investigated as follows: Various novel proxy metrics of regulation (FDA-issued guidelines) and innovation (corresponding FDA-registrations) from 1976-2020 are used to determine interdependence, a concept relying on strong correlation and reciprocal causality (estimated via variable lag transfer entropy and wavelet coherence). RESULTS: Based on the observed interdependence, a mapping of regulation onto innovation is conducted and finds that regulation seems to accelerate then supports innovation until on or around 2015; at which time, an inverted U-curve emerged. CONCLUSIONS: If empirically evidentiary, an important innovation-regulation nexus in the US has been reached; and, as such, stakeholders should (re)consider the complexity of the regulatory landscape to enhance US medical product innovation. Study limitations, extensions, and further thoughts complete this investigation.

Integrated the embedding delivery system and targeted oxygen scavenger enhances free radical scavenging capacity.

World trends in oil crop growing area, yield, and production over the last 10 years exhibited an increase of 48 %, 82 %, and 240 %, respectively. Concerning reduced shelf-life of oil-containing food products caused by oil oxidation and the demand for sensory quality of oil, the development of methods the improvement oil quality is urgently required. This critical review presented a concise overview of the recent literature related to the inhibition ways of oil oxidation. The mechanism of different antioxidants and nanoparticle delivery systems on oil oxidation was also explored. The current review provides scientific findings on control strategies: (i) design oxidation quality assessment model; (ii) packaging by antioxidant coatings and eco-friendly film nanocomposite: ameliorate physicochemical properties; (iii) molecular investigations on inhibitory effects of selected antioxidants and underlying mechanisms; (iv) explore the interrelationship between the cysteine/citric acid and lipoxygenase pathway in the progression of oxidative/fragmentation degradation of unsaturated fatty acid chains.

Evaluation of the dual effects of antiviral drugs on SARS-CoV-2 receptors and the ACE2 receptor using structure-based virtual screening and molecular dynamics simulation.

The use of US FDA-approved drugs is preferred due to the need for lower costs and less time. In in silico medicine, repurposing is a quick and accurate way to screen US FDA-approved medications to find a therapeutic option for COVID-19 infection. Dual inhibitors possess dual inhibitory activity, which may be due to the inhibition of two different enzymes, and are considered better than combination therapy from the developmental and clinical perspectives. In this study, a molecular docking simulation was performed to identify the interactions of antiviral drugs with the critical residues in the binding site of the main SARS-CoV-2 protease, spike glycoprotein, and papain-like protease receptors compared to the angiotensin-converting enzyme-related carboxypeptidase (ACE2) receptor of host cells. Each of the receptors was docked with 70 US FDA-approved antiviral drugs using AutoDock Vina. A molecular dynamics (MD) simulation study was also used for 100 ns to confirm the stability behaviour of the ligand receptor complexes. Among the drugs that had the strongest interaction with the SARS-CoV-2 main protease, spike glycoprotein and papain-like protease receptors, and host cell ACE2 receptors, Simeprevir, Maraviroc and Saquinavir had dual inhibitory effects. The MD simulation study confirmed the stability of the strongest interactions between the antiviral drugs and the main protease, ACE2, spike glycoprotein, and papain-like protease receptors to 100 ns. However the results of MMPBSA analysis showed that the bond between Saquinavir and the ACE2 receptor was weak. Simeprevir and Maraviroc drugs had acceptable binding energies with dual receptors, especially the Simeprevir.Communicated by Ramaswamy H. Sarma.