RESUMEN
PURPOSE: Pharmacy chains can differ with respect to the characteristics of their patient populations as well as their nonprescription products, services, and practices, and thus may serve as a surrogate for potential unmeasured confounding in observational studies of prescription drugs. This study evaluates whether a single-source drug can have different patient outcomes based on the dispensing pharmacy chain. METHODS: Separate analyses for two anticoagulant drugs, rivaroxaban and apixaban, were conducted using Medicare Fee-for-Service claims evaluating the association between dispensing pharmacy chain and outcomes of acute myocardial infarction, ischemic stroke, intracranial hemorrhage, gastrointestinal (GI) bleeding, all-cause mortality, and major GI bleeding. Inverse probability of treatment weighting (IPTW) was used to balance baseline covariates across pharmacy chain cohorts, and outcome association was assessed with a Cox Proportional Hazards model. RESULTS: We observed no differences in outcomes across pharmacy chains for apixaban recipients. Rivaroxaban recipients from pharmacy chain C, however, had lower rates of GI bleeding (adjusted HR 0.83; 95% CI 0.69-1.00) and ischemic stroke (adjusted HR 0.57; 95% CI 0.38-0.87) as compared to chain A in primary analyses with a 3-day grace period. The results moved closer to the null when 14- and 30-day grace periods were implemented. CONCLUSIONS: These results suggest that dispensing pharmacy chains may have the potential to act as a confounder of associations between drug exposure and outcome in some observational studies. Additional studies of potential confounding by pharmacy chain are needed. Further evaluation of potential pharmacy chain effects on safe use would be of value.
Asunto(s)
Fibrilación Atrial , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Anciano , Humanos , Estados Unidos , Anticoagulantes/efectos adversos , Rivaroxabán/efectos adversos , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/prevención & control , Accidente Cerebrovascular/complicaciones , Dabigatrán/uso terapéutico , Fibrilación Atrial/tratamiento farmacológico , Medicare , Hemorragia Gastrointestinal/inducido químicamente , Hemorragia Gastrointestinal/epidemiología , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Piridonas/uso terapéutico , Estudios RetrospectivosRESUMEN
Neutralizing antibodies to the SARS CoV-2 spike proteins have been issued Emergency Use Authorizations and are a likely mechanism of vaccines to prevent COVID-19. However, benefit of treatment with monoclonal antibodies has only been observed in clinical trials in outpatients with mild to moderate COVID-19 but not in patients who are hospitalized and/or have advanced disease. To address this observation, we evaluated the timing of anti SARS-CoV-2 antibody production in hospitalized patients with the use of a highly sensitive multiplexed bead-based immunoassay allowing for early detection of antibodies to SARS-CoV-2. We found significantly lower levels of antibodies to the SARS-CoV-2 spike protein in the first week after symptom onset in patients who expired as compared to patients who were discharged. We also developed a model to characterize the relationship between each patient's individual antibody level trajectory and eventual COVID 19 outcome which can be adapted into a prediction model with more data.
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Anticuerpos Antivirales/sangre , COVID-19/inmunología , COVID-19/mortalidad , SARS-CoV-2/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Especificidad de Anticuerpos , Antígenos Virales/inmunología , Femenino , Humanos , Inmunoglobulina G/sangre , Modelos Lineales , Masculino , Persona de Mediana Edad , Modelos Inmunológicos , Pandemias , Pronóstico , Glicoproteína de la Espiga del Coronavirus/inmunología , Factores de Tiempo , Estados Unidos/epidemiologíaRESUMEN
With the passage of the Biologics Price Competition and Innovation Act of 2009, the US Food and Drug Administration established an abbreviated pathway for developing and licensing biosimilar and interchangeable biological products. The regulatory framework and the technical requirements of the US biosimilars program involve a stepwise approach that relies heavily on analytical methods to demonstrate through a "totality of the evidence" that a proposed product is biosimilar to its reference product. By integrating analytical, pharmacological, and clinical data, each of which has limitations, a high level of confidence can be reached regarding clinical performance. Although questions and concerns about the biosimilars pathway remain and may slow uptake, a robust scientific program has been put in place. With three biosimilars already licensed and numerous development programs under way, clinicians can expect to see many new biosimilars come onto the US market in the coming decade. [Note added in proof: Since the writing of this article, a fourth biosimilar has been approved.].
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Biosimilares Farmacéuticos , Aprobación de Drogas/legislación & jurisprudencia , Anticuerpos Monoclonales , Biosimilares Farmacéuticos/normas , Etiquetado de Medicamentos/legislación & jurisprudencia , Sustitución de Medicamentos , Humanos , Control de Calidad , Estados Unidos , United States Food and Drug AdministrationRESUMEN
A network of regulatory innovations brings a holistic approach to improving the submission, assessment, and lifecycle management of pharmaceutical quality information in the U.S. This dedicated effort in the FDA's Center for Drug Evaluation and Research (CDER) aims to enhance the quality assessment of submissions for new drugs, generic drugs, and biological products including biosimilars. These regulatory innovations include developing or contributing: (i) the Knowledge-Aided Assessment and Structured Application (KASA), (ii) a new common technical document for quality (ICH M4Q(R2)), (iii) structured data on Pharmaceutical Quality/Chemistry, Manufacturing and Controls (PQ/CMC), (iv) Integrated Quality Assessment (IQA), (v) the Quality Surveillance Dashboard (QSD), and (vi) the Established Conditions tool from the ICH Q12 guideline. The innovations collectively drive CDER toward a more coordinated, effective, and efficient quality assessment. Improvements are made possible by structured regulatory submissions, a systems approach to quality risk management, and data-driven decisions based on science, risk, and effective knowledge management. The intended result is better availability of quality medicines for U.S. patients.
RESUMEN
BACKGROUND: The mechanism for anaphylaxis following mRNA COVID-19 vaccination has been widely debated; understanding this serious adverse event is important for future vaccines of similar design. A mechanism proposed is type I hypersensitivity (i.e., IgE-mediated mast cell degranulation) to polyethylene glycol (PEG). Using an assay that, uniquely, had been previously assessed in patients with anaphylaxis to PEG, our objective was to compare anti-PEG IgE in serum from mRNA COVID-19 vaccine anaphylaxis case-patients and persons vaccinated without allergic reactions. Secondarily, we compared anti-PEG IgG and IgM to assess alternative mechanisms. METHODS: Selected anaphylaxis case-patients reported to U.S. Vaccine Adverse Event Reporting System December 14, 2020-March 25, 2021 were invited to provide a serum sample. mRNA COVID-19 vaccine study participants with residual serum and no allergic reaction post-vaccination ("controls") were frequency matched to cases 3:1 on vaccine and dose number, sex and 10-year age category. Anti-PEG IgE was measured using a dual cytometric bead assay (DCBA). Anti-PEG IgG and IgM were measured using two different assays: DCBA and a PEGylated-polystyrene bead assay. Laboratorians were blinded to case/control status. RESULTS: All 20 case-patients were women; 17 had anaphylaxis after dose 1, 3 after dose 2. Thirteen (65â¯%) were hospitalized and 7 (35â¯%) were intubated. Time from vaccination to serum collection was longer for case-patients vs controls (post-dose 1: median 105 vs 21â¯days). Among Moderna recipients, anti-PEG IgE was detected in 1 of 10 (10â¯%) case-patients vs 8 of 30 (27â¯%) controls (pâ¯=â¯0.40); among Pfizer-BioNTech recipients, it was detected in 0 of 10 case-patients (0â¯%) vs 1 of 30 (3â¯%) controls (pâ¯>nâ¯0.99). Anti-PEG IgE quantitative signals followed this same pattern. Neither anti-PEG IgG nor IgM was associated with case status with both assay formats. CONCLUSION: Our results support that anti-PEG IgE is not a predominant mechanism for anaphylaxis post-mRNA COVID-19 vaccination.
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Anafilaxia , Vacunas contra la COVID-19 , COVID-19 , Femenino , Humanos , Masculino , Anafilaxia/etiología , COVID-19/prevención & control , Vacunas contra la COVID-19/efectos adversos , Inmunoglobulina E , Inmunoglobulina G , Inmunoglobulina M , Inmunosupresores , Polietilenglicoles/efectos adversos , ARN Mensajero , Vacunación/efectos adversosRESUMEN
Continuous manufacturing (CM) sends materials directly and continuously to the next step of a process, eliminating hold times and reducing processing times. The potential benefits of CM include improved product quality, reduced waste, lower costs, and increased manufacturing flexibility and agility. Some pharmaceutical manufacturers have been hesitant to adopt CM owing to perceived regulatory risks such as increased time to regulatory approval and market entry, more difficulty submitting postapproval changes, and higher inspectional scrutiny. An FDA self-audit of regulatory submissions in the U.S. examined the outcomes, at approval and during the product lifecycle, of continuous manufacturing applications as compared to traditional batch applications. There were no substantial regulatory barriers identified for CM applications related to manufacturing process changes or pre-approval inspections. CM applicants had relatively shorter times to approval and market as compared to similar batch applications, based on the mean or median times to approval (8 or 3 months faster) and marketing (12 or 4 months faster) from submission, translating to an estimated $171-537 M in early revenue benefit.
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Tecnología Farmacéutica , Preparaciones FarmacéuticasRESUMEN
BACKGROUND: In January 2008, the Centers for Disease Control and Prevention began a nationwide investigation of severe adverse reactions that were first detected in a single hemodialysis facility. Preliminary findings suggested that heparin was a possible cause of the reactions. METHODS: Information on clinical manifestations and on exposure was collected for patients who had signs and symptoms that were consistent with an allergic-type reaction after November 1, 2007. Twenty-one dialysis facilities that reported reactions and 23 facilities that reported no reactions were included in a case-control study to identify facility-level risk factors. Unopened heparin vials from facilities that reported reactions were tested for contaminants. RESULTS: A total of 152 adverse reactions associated with heparin were identified in 113 patients from 13 states from November 19, 2007, through January 31, 2008. The use of heparin manufactured by Baxter Healthcare was the factor most strongly associated with reactions (present in 100.0% of case facilities vs. 4.3% of control facilities, P<0.001). Vials of heparin manufactured by Baxter from facilities that reported reactions contained a contaminant identified as oversulfated chondroitin sulfate (OSCS). Adverse reactions to the OSCS-contaminated heparin were often characterized by hypotension, nausea, and shortness of breath occurring within 30 minutes after administration. Of 130 reactions for which information on the heparin lot was available, 128 (98.5%) occurred in a facility that had OSCS-contaminated heparin on the premises. Of 54 reactions for which the lot number of administered heparin was known, 52 (96.3%) occurred after the administration of OSCS-contaminated heparin. CONCLUSIONS: Heparin contaminated with OSCS was epidemiologically linked to adverse reactions in this nationwide outbreak. The reported clinical features of many of the cases further support the conclusion that contamination of heparin with OSCS was the cause of the outbreak.
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Anticoagulantes/efectos adversos , Sulfatos de Condroitina/efectos adversos , Brotes de Enfermedades , Contaminación de Medicamentos , Heparina/efectos adversos , Anticoagulantes/química , Estudios de Casos y Controles , Edema/inducido químicamente , Edema/epidemiología , Heparina/química , Humanos , Hipotensión/inducido químicamente , Hipotensión/epidemiología , Náusea/inducido químicamente , Náusea/epidemiología , Diálisis Renal , Taquicardia/inducido químicamente , Taquicardia/epidemiología , Estados Unidos/epidemiología , Urticaria/inducido químicamente , Urticaria/epidemiologíaRESUMEN
Hereditary Angioedema (HAE) is a rare genetic disease generally caused by deficiency or mutations in the C1-inhibitor gene, SERPING1, a member of the Serpin family. HAE results in acute attacks of edema, vasodilation, GI pain and hypotension. C1INH is a key inhibitor of enzymes controlling complement activation, fibrinolysis and the contact system. In HAE patients, contact system activation leads to uncontrolled production of bradykinin, the vasodilator responsible for the characteristic symptoms of HAE. In this study, we present the first physiological in vivo model to mimic acute HAE attacks. We evaluate hypotension, one of the many hallmark symptoms of acute HAE attacks using Serping1 deficient mice (serping1-/-) and implanted telemetry. Attacks were induced by IV injection of a silica nanoparticle (SiNP) suspension. Blood pressure was measured in real time, in conscious and untethered mice using implanted telemetry. SiNP injection induced a rapid, reversible decrease in blood pressure, in the presence of angiotensin converting enzyme (ACE) inhibition. We also demonstrate that an HAE therapeutic, ecallantide, can prevent HAE attacks in this model. The in vivo murine model described here can facilitate the understanding of acute HAE attacks, support drug development and ultimately contribute to improved patient care.
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Angioedemas Hereditarios/fisiopatología , Proteína Inhibidora del Complemento C1/genética , Modelos Animales de Enfermedad , Animales , Bradiquinina/genética , Activación de Complemento/genética , Activación de Complemento/inmunología , Proteína Inhibidora del Complemento C1/metabolismo , Edema/tratamiento farmacológico , Femenino , Fibrinólisis/genética , Hipotensión/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Péptidos , Serpinas/genéticaRESUMEN
PURPOSE: To characterize the nature of a heparin contaminant's clinical effects in cases reported to the Adverse Event Reporting System (AERS). The FDA received reports of heparin-associated adverse events (AEs) starting in late 2007-early 2008 during a national investigation of allergic-type events. The investigation identified Baxter Healthcare-brand heparin product due to its strongest association with the events. Later, oversulfated chondroitin sulfate (OSCS), a heparin-like contaminant, was discovered. METHODS: This study was a case series of heparin reports in AERS received 1 January 2008 to 31 March 2008. Variables considered were frequency of treatment settings, AEs, mortality; as well as heparin dose and OSCS contamination. RESULTS: Five hundred seventy-four AERS cases (unduplicated reports) were identified and included. Of 94 cases with a fatal outcome, 68 reported at least one AE term from the list used to identify an allergic-type event. Nearly 75% of AEs in cases of IV administration (n = 170/233) reportedly occurred within 10 minutes, whereas over half of subcutaneous administration cases (n = 13/23) resulted in times-to-event of greater than 24 hours. Although cases with a time-to-event of less than 10 minutes appeared to correlate with higher levels of OSCS contamination, no clear differences were noted between high- and low-to-absent OSCS concentration lots with respect to AEs observed. CONCLUSIONS: Intravenous administration and a higher OSCS concentration appeared to correlate with a more rapid onset of event. The FDA continues to monitor AEs associated with heparin use and has taken appropriate regulatory action to ensure a safe heparin drug supply.
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Anticoagulantes/efectos adversos , Sulfatos de Condroitina/efectos adversos , Hipersensibilidad a las Drogas/etiología , Heparina/efectos adversos , Adolescente , Adulto , Sistemas de Registro de Reacción Adversa a Medicamentos , Anciano , Anciano de 80 o más Años , Anticoagulantes/química , Anticoagulantes/normas , Niño , Preescolar , Sulfatos de Condroitina/química , Sulfatos de Condroitina/normas , Contaminación de Medicamentos , Femenino , Heparina/química , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Tiempo , Estados Unidos , United States Food and Drug Administration , Adulto JovenRESUMEN
The scientific and regulatory issues that are associated with the possible introduction of 'follow-on' versions of protein drug products are the topic of considerable debate at present. Because of the differences between protein drug products and small-molecule drugs, the development of follow-on versions of protein products presents more complex scientific challenges than those presented by the development of generic versions of small-molecule drugs. Here, with a view to illustrating the Food and Drug Administration's (FDA's) scientific reasoning and experience in this area, we discuss past examples of the FDA's actions involving the evaluation of various types of follow-on and second-generation protein products and within-product manufacturing changes. The FDA believes its evaluation of the safety and effectiveness of follow-on protein products will evolve as scientific and technological advances in product characterization and manufacturing continue to reduce some of the complexity and uncertainty that are inherent in the manufacturing of protein products.
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Aprobación de Drogas , Proteínas/normas , Proteínas Recombinantes/normas , Albúminas/normas , Alérgenos , Calcitonina/normas , Epoetina alfa , Eritropoyetina/normas , Vacunas contra Hepatitis B/normas , Hialuronoglucosaminidasa/normas , Estados Unidos , United States Food and Drug AdministrationRESUMEN
Warfarin was selected as a case study to examine confounding when comparing a product across different manufacturers because it is a narrow therapeutic index drug with prevalent beliefs for brand-name superiority. Medicare beneficiaries aged ≥65 years with atrial fibrillation and an incident outpatient warfarin prescription from July 2006 through July 2015 were included in the study population (N = 746,098). Substantial imbalances were observed between brand-name warfarin and generics for (i) clinical comorbidity, (ii) socioeconomic status, (iii) prescriber specialty, (iv) recent ambulatory and emergent care, (v) drug adherence, (vi) pharmacy setting (e.g., retail, mail-order), and (vii) risk scores for bleeding and thrombosis. Patients receiving brand-name warfarin were healthier than patients receiving generic manufactured warfarin. Utilization of generic warfarin products also differed by geographic region and pharmacy setting. Manufacturer-level comparative-safety studies for causal inference should carefully consider the presence of these imbalances and their potential for introducing healthy user bias.
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Sustitución de Medicamentos/normas , Medicamentos Genéricos/normas , Warfarina/normas , Anciano , Anciano de 80 o más Años , Fibrilación Atrial/tratamiento farmacológico , Comorbilidad , Medicamentos Genéricos/uso terapéutico , Femenino , Humanos , Revisión de Utilización de Seguros , Masculino , Medicare , Cumplimiento de la Medicación/estadística & datos numéricos , Aceptación de la Atención de Salud/estadística & datos numéricos , Farmacia/clasificación , Características de la Residencia , Factores de Riesgo , Sesgo de Selección , Factores Socioeconómicos , Especialización/estadística & datos numéricos , Estados Unidos , Warfarina/uso terapéuticoRESUMEN
This cross-sectional study uses Traditional Medicare and Medicare Advantage claims data to evaluate uptake of biosimilars relative to their reference products.
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Biosimilares Farmacéuticos , Medicare Part C , Estados Unidos , Transporte BiológicoRESUMEN
Despite a slow beginning, monoclonal antibodies have had many successes over the past decade. It is important that these successes continue, bringing more products for more indications to market. Although manufacturing is not the most common cause of product failure, product quality issues can delay antibody development. Manufacturing has depended on the triad of process validation, process control and product testing. Applying product knowledge proactively to manufacturing (quality by design) may allow greater flexibility and maintain or improve product quality. An integrated approach to biological characterization is an important aspect of product knowledge. Greater product knowledge also facilitates development in other disciplines. Independent of manufacturing strategy, there are a number of regulatory hurdles in initial and ongoing antibody development. These are described to help prevent unnecessary delays.
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Anticuerpos Monoclonales , Industria Farmacéutica/tendencias , Animales , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/farmacología , Composición de Medicamentos , Diseño de Fármacos , Humanos , Control de CalidadRESUMEN
Failures surrounding pharmaceutical quality, particularly with respect to product manufacturing issues and facility remediation, account for the majority of drug shortages and product recalls in the United States. Major scientific advancements pressure established regulatory paradigms, especially in the areas of biosimilars, precision medicine, combination products, emerging manufacturing technologies, and the use of real-world data. Pharmaceutical manufacturing is increasingly globalized, prompting the need for more efficient surveillance systems for monitoring product quality. Furthermore, increasing scrutiny and accelerated approval pathways provide a driving force to be even more efficient with limited regulatory resources. To address these regulatory challenges, the Office of Pharmaceutical Quality (OPQ) in the Center for Drug Evaluation and Research (CDER) at the U.S. Food and Drug Administration (FDA) harbors a rigorous science and research program in core areas that support drug quality review, inspection, surveillance, standards, and policy development. Science and research is the foundation of risk-based quality assessment of new drugs, generic drugs, over-the-counter drugs, and biotechnology products including biosimilars. This is an overview of the science and research activities in OPQ that support the mission of ensuring that safe, effective, and high-quality drugs are available to the American public.