Directrices de la OMS sobre gestión de la sangre y los componentes sanguíneos como medicamentos esenciales. Anexo 3 del sexagésimo sétimo informe del Comité de Expertos de la OMS en Patrones Biológicos

La OMS define los medicamentos esenciales como aquellos productos medicinales que satisfacen las necesidades sanitarias de la mayoría de la población. Por consiguiente, deben estar disponibles en todo momento, en cantidad suficiente y en las formulaciones adecuadas, y con calidad y asequibilidad garantizadas. Estas directrices de la OMS tienen por objeto proporcionar un marco de referencia para establecer la supervisión reguladora de la sangre y los componentes sanguíneos destinados a transfusión como medicamentos esenciales. El concepto subyacente es que tales sangre y componentes sanguíneos son productos terapéuticos biológicos de origen humano, cuya preparación debe estar sujeta a normalización y supervisión reguladoras para garantizar su calidad, seguridad y eficacia. El marco proporcionado en estas directrices es parecido al que se aplica ampliamente para la regulación de los medicamentos producidos bajo las buenas prácticas de preparación actuales, pero adaptado para abordar los atributos específicos de la sangre y los componentes sanguíneos para transfusión, que los distinguen de los productos medicinales derivados del plasma y de los medicamentos (o productos farmacéuticos) en general. En las jurisdicciones donde los marcos jurídicos en vigor para los medicamentos fabricados con arreglo a las buenas prácticas de preparación actuales de las preparaciones farmacéuticas no se apliquen a la sangre y los componentes sanguíneos, la regulación paralela basada en el modelo proporcionado por las presentes directrices incluiría la aplicación de las buenas prácticas de preparación análogas para tales productos.

A Trans-Governmental Collaboration to Independently Evaluate SARS-CoV-2 Serology Assays.

The emergence of SARS-CoV-2 created a crucial need for serology assays to detect anti-SARS-CoV-2 antibodies, which led to many serology assays entering the market. A trans-government collaboration was created in April 2020 to independently evaluate the performance of commercial SARS-CoV-2 serology assays and help inform U.S. Food and Drug Administration (FDA) regulatory decisions. To assess assay performance, three evaluation panels with similar antibody titer distributions were assembled. Each panel consisted of 110 samples with positive (n = 30) serum samples with a wide range of anti-SARS-CoV-2 antibody titers and negative (n = 80) plasma and/or serum samples that were collected before the start of the COVID-19 pandemic. Each sample was characterized for anti-SARS-CoV-2 antibodies against the spike protein using enzyme-linked immunosorbent assays (ELISA). Samples were selected for the panel when there was agreement on seropositivity by laboratories at National Cancer Institute's Frederick National Laboratory for Cancer Research (NCI-FNLCR) and Centers for Disease Control and Prevention (CDC). The sensitivity and specificity of each assay were assessed to determine Emergency Use Authorization (EUA) suitability. As of January 8, 2021, results from 91 evaluations were made publicly available (https://open.fda.gov/apis/device/covid19serology/, and https://www.cdc.gov/coronavirus/2019-ncov/covid-data/serology-surveillance/serology-test-evaluation.html). Sensitivity ranged from 27% to 100% for IgG (n = 81), from 10% to 100% for IgM (n = 74), and from 73% to 100% for total or pan-immunoglobulins (n = 5). The combined specificity ranged from 58% to 100% (n = 91). Approximately one-third (n = 27) of the assays evaluated are now authorized by FDA for emergency use. This collaboration established a framework for assay performance evaluation that could be used for future outbreaks and could serve as a model for other technologies. IMPORTANCE The SARS-CoV-2 pandemic created a crucial need for accurate serology assays to evaluate seroprevalence and antiviral immune responses. The initial flood of serology assays entering the market with inadequate performance emphasized the need for independent evaluation of commercial SARS-CoV-2 antibody assays using performance evaluation panels to determine suitability for use under EUA. Through a government-wide collaborative network, 91 commercial SARS-CoV-2 serology assay evaluations were performed. Three evaluation panels with similar overall antibody titer distributions were assembled to evaluate performance. Nearly one-third of the assays evaluated met acceptable performance recommendations, and two assays had EUAs revoked and were removed from the U.S. market based on inadequate performance. Data for all serology assays evaluated are available at the FDA and CDC websites (https://open.fda.gov/apis/device/covid19serology/, and https://www.cdc.gov/coronavirus/2019-ncov/covid-data/serology-surveillance/serology-test-evaluation.html).

Imaging Prostate Cancer: Clinical Utility of Prostate-Specific Membrane Antigen.

PURPOSE: Our goal was to review the pathway and pertinent materials leading to approval of prostate-specific membrane antigen (PSMA) scanning by the U.S. Food and Drug Administration (FDA). MATERIALS AND METHODS: Beginning with the pivotal trials and working backward, we summarize the evolution of PSMA scanning, beginning with the discovery of the molecule, the mechanism of action to identify prostate cancer, the route to the present-day test and some of the major publications leading to each step of the sequence. From the thousands of PSMA articles listed on PubMed®, the present review is focused on the 4 large U.S. trials incorporating university studies of the gallium-68 compound and commercial studies of the fluorine-18 compound. The review further focuses on the role of PSMA scanning for both initial staging of prostate cancer and diagnosis of recurrent prostate cancer. RESULTS: PSMA is a transmembrane-bound glycoprotein which is overexpressed by 100-1,000-fold in prostate cancer cells. Preclinical PSMA studies at Cornell and Johns Hopkins in the 1990s were followed by early human studies in Germany in the early 2010s, then pivotal clinical trials at University of California, Los Angeles and University of California, San Francisco, leading to the first FDA approval in December 2020 (68Ga-PSMA-11). In January 2021, a commercially available product (18F-DCFPyL) was approved on the basis of multisite registration trials (CONDOR and OSPREY). Sensitivity and specificity of PSMA scanning exceeds that of any other imaging method currently available for initial staging of prostate cancer and diagnosis of recurrent disease. The accuracy of PSMA scanning is attributed to the great image contrast (high signal-to-noise ratio), a property deriving from the high PSMA tracer uptake by prostate cancer cells. That property can be estimated quantitatively by a metric, the standardized uptake value. A follow-on PSMA compound, the theranostic lutetium-177, is currently pending FDA approval for treatment of metastases. CONCLUSIONS: PSMA scanning is a disruptive technology that promises to transform the way prostate cancer is initially staged, recurrence is diagnosed and some advanced cases are treated.

Palpable breast lumps an age-based approach to evaluation and diagnosis

A palpable breast lump is a common presentation of breast disease to a general practitioner. Fortunately, investigation of most of these lumps will lead to a benign diagnosis. It is essential to have a clear and systematic approach when investigating a palpable breast lump to avoid over investigation with the resultant increase in healthcare cost and anxiety. This article will discuss an approach to evaluating and diagnosing a palpable breast lump in the primary care setting

Facteurs de risque et prise en charge de la rupture utérine dans une structure de 1ere référence du Mali: cas du district sanitaire de Bougouni / Risk factors and management of uterine rupture in a 1st reference structure in Mali: case of the Bougouni health district

L'objectif était d'évaluer les facteurs de risque de la RU et de proposer les aspects thérapeutiques. Matériels et méthodes : Nous avons réalisé une étude cas-témoins au centre de santé de Référence de Bougouni en 2019. Résultats : De janvier au 31 décembre 2019; sur 1161 accouchements 43 RU ont été enregistrées soit 3,7% correspondant à une RU pour 27 accouchements. Les patientes de 35 ans et plus ont été plus touchée par la RU (44,2%) avec ORaIC95%= 6,3 [1,5 - 26,3]. Les évacuations obstétricales avaient un ORaIC95%=25,6 [7,8- 83,7]. La totalité des patientes étaient des femmes au foyer (97,7%) des cas versus (82,3%) des témoins avec ORaIC95%= 8,9 (1,1-69). Les Paucipares et multipares avaient respectivement un ORaIC95%= 6,2 [1,8 - 20,3] et 4,1[1,3 - 12,9]. La cicatrice utérine (20,9%) des cas contre 8,1 % les témoins avait un ORaIC95%= 2,9 [1,1 - 8,7]. En effet l'absence de CPN étaient un facteur de risque, ORaIC95%= 3,0 [1,3 ­ 6,9]. Le délai de la RU était ˂ 6 heures chez 95%. En effet 34 RU complètes (79,1%) et 9 RU incomplètes (20,9%) ont été notées. Seulement 2,3 % des cas avaient accouché par voie basse. Le traitement de la RU reposait sur la chirurgie (100%) complétée par celui du choc (51,2%) des cas et de l'infection (100%) des cas. Conclusion: La RU est fréquente dans nos pays sous médicalisés. Sa prévention efficace passe par des stratégies visant à agir sur les facteurs de risque

The objective was to assess the risk factors for and to suggest therapeutic aspects. Materials and methods: We carried out a case-control study at the Bougouni Reference health center in 2019. Results: From January to December 31, 2019; out of 1161 deliveries, 43 uterine rupture were recorded, 3.7% corresponding to one uterine rupture for 27 deliveries. Patients 35 years and older were more affected by uterine rupture (44.2%) with ORaIC95% = 6.3 [1.5 - 26.3]. Obstetric evacuations had an ORaIC95% = 25.6 [7.8-83.7]. All of the patients were housewives (97.7%) versus (82.3%) controls with ORaIC95% = 8.9 (1.1-69). Pauciparous and multiparous had an ORaIC95% = 6.2 [1.8 - 20.3] and 4.1 [1.3 - 12.9], respectively. The uterine scar (20.9%) of cases versus 8.1% of controls had a 95% ORaIC95% = 2.9 [1.1 - 8.7]. Indeed the absence of ANC was a risk factor, ORaIC95% = 3.0 [1.3 - 6.9]. The time to uterine rupture was ˂ 6 hours in 95%. In fact 34 complete uterine rupture (79.1%) and 9 incomplete uterine rupture (20.9) were noted. Only 2.3% of cases gave birth vaginally. Treatment of uterine rupture was based on surgery (100%) supplemented by shock (51.2%) of cases and infection (100%) of cases. Conclusion: Uterine rupture is common in our countries under medical care. Its effective prevention involves strategies aimed at acting on risk factors.

Autoantibody Discovery, Assay Development and Adoption: Death Valley, the Sea of Survival and Beyond.

Dating to the discovery of the Lupus Erythematosus (LE) cell in 1948, there has been a dramatic growth in the discovery of unique autoantibodies and their cognate targets, all of which has led to the availability and use of autoantibody testing for a broad spectrum of autoimmune diseases. Most studies of the sensitivity, specificity, commutability, and harmonization of autoantibody testing have focused on widely available, commercially developed and agency-certified autoantibody kits. However, this is only a small part of the spectrum of autoantibody tests that are provided through laboratories world-wide. This manuscript will review the wider spectrum of testing by exploring the innovation pathway that begins with autoantibody discovery followed by assessment of clinical relevance, accuracy, validation, and then consideration of regulatory requirements as an approved diagnostic test. Some tests are offered as "Research Use Only (RUO)", some as "Laboratory Developed Tests (LDT)", some enter Health Technology Assessment (HTA) pathways, while others are relegated to a "death valley" of autoantibody discovery and become "orphan" autoantibodies. Those that achieve regulatory approval are further threatened by the business world's "Darwinian Sea of Survival". As one example of the trappings of autoantibody progression or failure, it is reported that more than 200 different autoantibodies have been described in systemic lupus erythematosus (SLE), a small handful (~10%) of these have achieved regulatory approval and are widely available as commercial diagnostic kits, while a few others may be available as RUO or LDT assays. However, the vast majority (90%) are orphaned and languish in an autoantibody 'death valley'. This review proposes that it is important to keep an inventory of these "orphan autoantibodies" in 'death valley' because, with the increasing availability of multi-analyte arrays and artificial intelligence (MAAI), some can be rescued to achieve a useful role in clinical diagnostic especially in light of patient stratification and precision medicine.

Predictive biomarkers and clinical evidence.

Predictive biomarkers play an important role in our efforts to individualize pharmacotherapy, and within recent years, a number of different types of assays have been introduced. These biomarkers may potentially support the selection and dosage of specific drugs in order to maximize efficacy and minimize adverse reactions in the individual patient. However, in many instances, the scientific and clinical evidence is insufficient to support the prescribing decision. When predictive biomarkers are used to guide pharmacotherapy, it is important to secure that decisions are based on solid clinical evidence. Here, the regulatory authorities, especially the FDA, have been at the forefront in relation to regulate this type of biomarker assay in order to secure patient safety. The approval process for companion diagnostics is an example of this effort, where the scientific validity of the biomarker and assay is in focus. With the approaching implementation of the new IVD Regulation, greater attention will also be paid to analytical and clinical validity of biomarker assays in the EU. For any type of predictive biomarker assay, including pharmacogenetic and tumour profiling tests, the clinical evidence needs to be in place before they are used routinely in the clinic.

Cancer Immunotherapy Update: FDA-Approved Checkpoint Inhibitors and Companion Diagnostics.

Immune checkpoint inhibitors (ICIs) are considered a new standard-of-care across many cancer indications. This review provides an update on ICIs approved by the Food and Drug Administration (FDA), with focus on monoclonal antibodies that target the programmed cell death 1 (PD-1) or its ligand, PD-1 ligand 1 (PD-L1), including information on their clinical indications and associated companion diagnostics. The information is further discussed with strategies for identifying predictive biomarkers to guide the clinical use of PD-1/PD-L1-targeted therapies.

AI-based smartphone apps for risk assessment of skin cancer need more evaluation and better regulation.

Smartphone applications ("apps") with artificial intelligence (AI) algorithms are increasingly used in healthcare. Widespread adoption of these apps must be supported by a robust evidence-base and app manufacturers' claims appropriately regulated. Current CE marking assessment processes inadequately protect the public against the risks created by using smartphone diagnostic apps.

Herpes Simplex Virus-1 and -2 Rapid Detection in Whole Blood.

BACKGROUND: Disseminated herpes simplex virus (HSV) infection has high morbidity and mortality, particularly in neonates, and requires rapid diagnosis for proper treatment. Currently, there are no US FDA-approved assays available to perform HSV testing on blood. OBJECTIVES: Our goal was to evaluate the analytical sensitivity and clinical performance of an available sample-to-answer real-time polymerase chain reaction (PCR) platform used as a laboratory-developed test (LDT) for the detection of HSV-1 and -2 in whole blood (WB). METHODS: A clinical comparison study comparing a real-time PCR reference assay to a LDT based on the DiaSorin Simplexa Direct assay kit was performed. Analytical sensitivity studies comparing WB to the FDA-approved specimen type, cerebrospinal fluid (CSF), were also conducted with contrived quantified HSV-1 and -2 samples in WB and CSF matrix. RESULTS: In total, 102 samples were tested using the LDT and reference assay for the clinical correlation study, with 91 negative and 10 positive results for HSV-1 (n = 7) and HSV-2 (n = 3), exhibiting 100% concordance with comparator results. The overall limit of detection (LoD) for HSV-1 and HSV-2 in WB was comparable to that seen in CSF, with the calculated 95% LoD for blood being 1489 ± 16 copies/ml for HSV-1 and 1187 ± 18 copies/ml for HSV-2 and for CSF being 1168 ± 17 copies/ml for HSV-1 and 953 ± 21 copies/ml for HSV-2. CONCLUSIONS: The performance of the LDT for detection of HSV-1 and HSV-2 in WB specimens is adequate for clinical use. The LoD for HSV-1 and HSV-2 is comparable to that in CSF, the FDA-approved specimen type.

Rapid diagnostic tests for infectious diseases in the emergency department.

BACKGROUND: Rapid diagnostic tests (RDTs) for infectious diseases, with a turnaround time of less than 2 hours, are promising tools that could improve patient care, antimicrobial stewardship and infection prevention in the emergency department (ED) setting. Numerous RDTs have been developed, although not necessarily for the ED environment. Their successful implementation in the ED relies on their performance and impact on patient management. OBJECTIVES: The aim of this narrative review was to provide an overview of currently available RDTs for infectious diseases in the ED. SOURCES: PubMed was searched through August 2019 for available studies on RDTs for infectious diseases. Inclusion criteria included: commercial tests approved by the US Food and Drug Administration (FDA) or Conformité Européenne (CE) in vitro diagnostic devices with data on clinical samples, ability to run on fully automated systems and result delivery within 2 hours. CONTENT: A nonexhaustive list of representative commercially available FDA- or CE-approved assays was categorized by clinical syndrome: pharyngitis and upper respiratory tract infection, lower respiratory tract infection, gastrointestinal infection, meningitis and encephalitis, fever in returning travellers and sexually transmitted infection, including HIV. The performance of tests was described on the basis of clinical validation studies. Further, their impact on clinical outcomes and anti-infective use was discussed with a focus on ED-based studies. IMPLICATIONS: Clinicians should be familiar with the distinctive features of each RDT and individual performance characteristics for each target. Their integration into ED work flow should be preplanned considering local constraints of given settings. Additional clinical studies are needed to further evaluate their clinical effectiveness and cost-effectiveness.

Considerations for diagnostic COVID-19 tests.

During the early phase of the coronavirus disease 2019 (COVID-19) pandemic, design, development, validation, verification and implementation of diagnostic tests were actively addressed by a large number of diagnostic test manufacturers. Hundreds of molecular tests and immunoassays were rapidly developed, albeit many still await clinical validation and formal approval. In this Review, we summarize the crucial role of diagnostic tests during the first global wave of COVID-19. We explore the technical and implementation problems encountered during this early phase in the pandemic, and try to define future directions for the progressive and better use of (syndromic) diagnostics during a possible resurgence of COVID-19 in future global waves or regional outbreaks. Continuous global improvement in diagnostic test preparedness is essential for more rapid detection of patients, possibly at the point of care, and for optimized prevention and treatment, in both industrialized countries and low-resource settings.

Ravaging SARS-CoV-2: rudimentary diagnosis and puzzling immunological responses.

INTRODUCTION: In December 2019, the first COVID-19 case, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was reported in Wuhan, China. The SARS-CoV-2 rapidly disseminated throughout the world via community spread, acquiring pandemic status with significant fatality. OBSERVATIONS: Rapid SARS-CoV-2 diagnosis was soon perceived critical for arresting community spread and effective therapy development. Human SARS-CoV-2 infection can be diagnosed either by nucleic acid identification or specific antibody detection. Contrary to nucleic acid identification confirmed active SARS-CoV-2 infection; antibody detection confirms a past infection, even in asymptomatic subjects. SARS-CoV-2 specific antibodies augment the ability to effectively counter the virus. A crucial hurdle limiting the steadfast implementation of antibody detection is the time required for threshold B lymphocyte population generation. This process is dependent on precise antigen recognition and MHC class I molecules presentation. CONCLUSIONS: Thus, nucleic acid and antibody dependent tests complement each other in identifying human SARS-CoV-2 infection and shaping up subsequent immunological responses. This article discusses the complimentary association of nucleic acid identification (corresponding to an active infection) and antibody testing (the yester CoV-2 infection vulnerability) as the diagnostic and screening measures of SARS-CoV-2 infection. Highlights Nucleic acid (RNA) identification and specific antibody detection against SARS-CoV-2 are the noted diagnostic mechanisms for screening human SARS-CoV-2 infection. While nucleic acid identification screens prevailing SARS-CoV-2 infection, detection of SARS-CoV-2 specific antibodies signifies a past infection, even in asymptomatic subjects. Antibodies against SARS-CoV-2 provide a potential therapeutic option via transfer from antibody rich plasma of a recovered subject to an infected individual. Nucleic acid identification may not absolutely confirm the infection because of frequent SARS-CoV-2 genome mutations and possible technical errors, while specific antibody detection also needs at least (8-14) days for detectable screening of B-cell generated antibodies. Nucleic acid and antibody tests are complementary to each other as an early stage diagnostic assay for SARS-CoV-2 infection and possible therapy (antibodies). Sufferers with a high clinical suspicion but negative RT-PCR screening could be examined via combined imaging and repeated swab test.