Pharmacovigilance Plan Research Articles

Le bénéfice des unes est-il celui des autres ? Le cas des usagères d’un progestatif de synthèse

This article focuses on the hierarchical structure of users of a synthetic progestin, Homodeor and its effects on the construction of a pharmacovigilance plan by a French health agency, at a time when an institutional desire is being expressed to work more closely with all patient associations. This case study is mainly on a qualitative survey led by interviewing agents, health professionals and user representatives, which aimed to explore the relationships and representations developed around this issue. Despite the diversity of progestin use, a hierarchy between the different user groups was gradually established. The pharmacovigilance measures were designed for a specific group of patients, presented as the ideal users of the drug. The case of Homodeor makes it possible to highlight the dynamics of competition between groups of patients, and more broadly, the challenges of taking minority groups into account in health policies in the light of their development context.

Spontaneous Adverse Event Reporting by COVID-19 Vaccinated Healthcare Professionals Through an Electronic Form Implemented by the Hospital Pharmacy.

Aim: Implementation of a web-form based pharmacovigilance plan for the spontaneous notification of adverse events to the Comirnaty® COVID-19 vaccine during its administration to hospital healthcare professionals. Methods: An electronic pharmacovigilance form was developed containing 8 pre-defined event options, an open answer option for the description of other events and/or symptoms, and a question about the overall intensity of symptoms. The adverse events reports were standardized according to physiological and pathological condition. Results: A total of 4119 adverse events notifications were obtained with a 45% rate of electronic notification. The most clinically relevant events reported were:tachycardia (n = 19), dyspnea (n = 7), chest pain (n = 6), facial/labial edema (n = 6), lipothymia (n = 5), bronchospasm (n = 2), herpetic infection (n = 2), vasculitis (n = 2), arrhythmia (n = 1), difficult to control arterial hypertension (n = 1), gastritis (n = 1), and spontaneous abortion (n = 1). Regarding the intensity of symptoms (n = 2928), 70.0% were reported as mild, 25.8% as moderate, and 4.27% as severe, with higher intensity in the second dose compared to first dose. The highest frequency of severe events were reported in the groups from 40 to 59 years in both vaccination periods. During the vaccination process, no hospitalizations and no deaths were notified and/or recorded. Conclusion: In this real world study, comparing with Comirnaty clinical trials program, it was observed a higher frequency of adenomegaly and gastrointestinal disorders. Noteworthy, the notification of a case of miscarriage. The use of hospital pharmacy pharmacovigilance electronic forms, seemed to be relevant to notification adherence and to obtain a greater and faster knowledge of COVID-19 vaccine safety profile.

Critical Overview of the Contents of Risk Management Plans for Medicines

The pharmacovigilance system plays one of the key roles in ensuring safety and efficacy of medicine use. The risk management process helps to ensure the most favourable benefit/risk ratio of a medicine or combination of medicines both for the target populations and the general public. Unavailability of a risk management process for medicines may adversely affect the health of the general population. One of the major documents in medicine risk management is the risk management plan (RMP).The aim of the study was to analyse compliance of RMPs submitted as part of registration dossiers with the requirements of the Eurasian Economic Union (EAEU), and to analyse problems arising during their preparation.Materials and methods: the authors analysed 200 RMPs submitted from January 1 until August 31, 2021.Results: it was determined that the most frequent mistakes made by pharmacovigilance officers are related to medicine summaries in RMPs covering several medicines, medicine safety specification parts of RMPs, description of risks in the pharmacovigilance plan and description of risk minimisation measures, and insufficient representation of the key elements of the medicine efficacy and safety overview in the RMP summary. For instance, RMPs often lack information on the epidemiology of indications for target populations in the EAEU, or RMPs may lack some of the major risks reflected in the patient information leaflets, or lack assessment of safety risk minimisation actions, etc.Conclusions: proper preparation of RMPs that would comply with the EAEU Good Pharmacovigilance Practice is inconceivable without further professional training of pharmacovigilance officers.

Development, evaluation and use of COVID-19 vaccines in older adults: Preliminary principles for the pandemic and beyond.

Development, evaluation and use of COVID-19 vaccines in older adults: Preliminary principles for the pandemic and beyond.

Post-Marketing Surveillance with a Biosimilar of Rituximab (Novex®) in Argentina

IntroductionNovex® is a biosimilar of Rituximab approved in Argentina having the same indications as the reference product (Mabthera®/Rituxan®). It is commercialized by Laboratorio Elea and since its commercial launch the first national pharmacovigilance plan for a Biosimilar mAb has been implemented.Material and MethodsIn order to detect deviations from expected frequencies of adverse events, a prospective treatment registry for NOVEX® was implemented since beginning of commercialization (November 26th, 2014). The Data Lock Point for this report is June 30th, 2017. Physicians registered the following information for each patient: age, gender, indication, dosing, dose frequency and date of treatment initiation and finalization. Treatment outcome and all Adverse Event detected were registered and coded using MedDRA dictionary.ResultsOne-hundred and eighty physicians have participated in this surveillance program. A total of 525 individual records, with at least 1 follow up point, were collected and included in analysis.The percentage of female patients was 52%. Age range was 10 - 90 years with a mean age of 63.3 years. The majority of patients have received NOVEX® due to a hematological disease (91.2% of cases) (table 1).Treatment duration ranged from 154 to 309 days (IQR), with mean of 239 days and median of 214 days. The number of cycles varied from 1 to 12 with a mean of 5.7.Twenty-four individual Case Safety Reports (ICSRs) were collected, with 29 Adverse Events, and the relative frequency of ICSR was 4.6%. Occurrence rates of adverse events were 1.2 per 100 administered cycles, and 0.022 per 100 treatment days. Fourteen serious adverse events (SAE) were collected and most of them were acute infusion related reactions.The most frequently reported AEs were:· Acute Infusion Related Reaction (14)· Arrhythmia (3)· Pneumonia (2)· Stroke (2)During the program, we detected 41 treatments with rituximab that were started before the launch of the product. Assuming these treatments had begun with Mabthera, this implies the occurrence of interchangeability in this subgroup.Because of the special interest of this condition, the frequency of ICSRs was analyzed. Two ICSRs were reported, with a relative frequency of 4.9 % (CI95%: 1.7 - 11.5%), which was similar to the whole frequency of the program. Therefore, it was considered that there were no significant differences in the level of reports in the group with interchangeability compared to the general group.ConclusionsThis post-marketing surveillance demonstrates a similar incidence of adverse events after the use of rituximab biosimilar when compared to the published data related to the reference product. Therefore, in terms of tolerability, this biosimilar product has a similar safety profile of that of the reference product. This data is consistent with the high similarity demonstrated during preclinical in vitro and in vivo characterization and the clinical efficacy and safety profile demonstrated in the comparative clinical trial. [Display omitted] DisclosuresPenna:Laboratorio ELEA: Employment. Fernández:Laboratorio ELEA: Employment. Spitzer:Laboratorio ELEA: Employment. Millan:mAbxience: Employment. Gomez:Laboratorio ELEA: Employment.

063 Flibanserin: Enhanced Pharmacovigilance Study to Assess and Analyze the Risks of Adverse Events of Special Interest

Flibanserin, a 5-HT1A agonist and 5-HT2A antagonist, is approved in the US and Canada for the treatment of acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. Flibanserin is subjected to an Enhanced Pharmacovigilance Plan (EPVP) in the USA only

Postmarketing Safety of Biosimilars: Current Status, Challenges, and Opportunities in the Spontaneous Reporting System.

Recombinant drug products successfully treat many life-threatening and chronic diseases. The high cost of these drugs makes them inaccessible to the patients particularly in developing countries. Patent expiration of innovator recombinant drug products has led to the development of biosimilars or similar biologics by several manufacturers. Unlike generics, these are not identical to their innovator products because of the differences in the manufacturing process; however, they are similar in quality characteristics, biological activity, safety, and efficacy. The regulatory procedures used for generic drugs cannot be applied for biosimilars as they are large complex structures produced from living cells and can produce potential risk of immune-based adverse reactions. Out of several safety issues related to biosimilars, two main safety concerns are variable potency and immunogenicity, for which a robust long-term pharmacovigilance system is needed. Various guidelines have been issued for the regulatory approval and pharmacovigilance of biosimilars by USFDA, EU, and pharma-emerging countries like China and India. The article includes the pharmacovigilance plan of biosimilars in these countries, discusses the challenges and opportunities in pharmacovigilance through spontaneous reporting systems, and suggests amendments in the existing suspected adverse event reporting form of the Pharmacovigilance Programme of India.

Pharmacovigilance capacity strengthening for WHO prequalification: The case of the trivalent influenza vaccine manufactured by Instituto Butantan

Instituto Butantan is a biomedical research center and vaccine manufacturer affiliated with the São Paulo State Secretary of Health in Brazil. In 2013, Instituto Butantan successfully licensed its trivalent influenza vaccine, in order to support the Brazilian National Immunization Program's influenza vaccination strategy, which was introduced in 1999. In order to respond to the increasing influenza vaccine demand worldwide, Instituto Butantan is undergoing prequalification of its trivalent influenza vaccine by the World Health Organization (WHO). A key requirement of the prequalification review was the submission of a pharmacovigilance plan, including an active surveillance evaluation, for the trivalent influenza vaccine, and proof of a functional pharmacovigilance system at Instituto Butantan. The aim of this paper is to describe the capacity strengthening process of the pharmacovigilance system at Instituto Butantan for the WHO prequalification of the trivalent influenza vaccine. This process was supported by PATH and the U.S. Federal Government Biomedical Advanced Research and Development Authority (BARDA). The key strategic axes for this capacity strengthening process included the improvement of organizational structure, human resources training, internal processes and procedures, appropriate documentation, and acquisition of an E2B compliant pharmacovigilance database. The project led to the establishment of a functional pharmacovigilance system compliant with international regulatory requirements.

Postmarketing Safety of Biosimilars: Current Status, Challenges, and Opportunities in the Spontaneous Reporting System.

Recombinant drug products successfully treat many life-threatening and chronic diseases. The high cost of these drugs makes them inaccessible to the patients particularly in developing countries. Patent expiration of innovator recombinant drug products has led to the development of biosimilars or similar biologics by several manufacturers. Unlike generics, these are not identical to their innovator products because of the differences in the manufacturing process; however, they are similar in quality characteristics, biological activity, safety, and efficacy. The regulatory procedures used for generic drugs cannot be applied for biosimilars as they are large complex structures produced from living cells and can produce potential risk of immune-based adverse reactions. Out of several safety issues related to biosimilars, two main safety concerns are variable potency and immunogenicity, for which a robust long-term pharmacovigilance system is needed. Various guidelines have been issued for the regulatory approval and pharmacovigilance of biosimilars by USFDA, EU, and pharma-emerging countries like China and India. The article includes the pharmacovigilance plan of biosimilars in these countries, discusses the challenges and opportunities in pharmacovigilance through spontaneous reporting systems, and suggests amendments in the existing suspected adverse event reporting form of the Pharmacovigilance Programme of India.

The use of validated and nonvalidated surrogate endpoints in two European Medicines Agency expedited approval pathways: A cross-sectional study of products authorised 2011-2018.

BackgroundIn situations of unmet medical need or in the interests of public health, expedited approval pathways, including conditional marketing authorisation (CMA) and accelerated assessment (AA), speed up European Medicines Agency (EMA) marketing authorisation recommendations for medicinal products. CMAs are based on incomplete benefit-risk assessment data and authorisation remains conditional until regulator-imposed confirmatory postmarketing measures are fulfilled. For products undergoing AA, complete safety and efficacy data should be available, and postauthorisation measures may include only standard requirements of risk management and pharmacovigilance plans. In the pivotal trials supporting products assessed by expedited pathways, surrogate endpoints reduce drug development time compared with waiting for the intended clinical outcomes. Whether surrogate endpoints supporting products authorised through CMA and AA pathways reliably predict clinical benefits of therapy has not been studied systematically. Our objectives were to determine the extent to which surrogate endpoints are used and to assess whether their validity had been confirmed according to published hierarchies.Methods and findingsWe used European Public Assessment Reports (EPARs) to identify the primary endpoints in the pivotal trials supporting products authorised through CMA or AA pathways during January 1, 2011 to December 31, 2018. We excluded products that were vaccines, topical, reversal, or bleeding prophylactic agents or withdrawn within the study time frame. Where pivotal trials reported surrogate endpoints, we conducted PubMed searches for evidence of validity for predicting clinical outcomes. We used 2 published hierarchies to assess validity level. Surrogates with randomised controlled trials supporting the surrogate-clinical outcome relationship were rated as ‘validated’. Fifty-one products met the inclusion criteria; 26 underwent CMAs, and 25 underwent AAs. Overall, 26 products were for oncology indications, 10 for infections, 8 for genetic disorders, and 7 for other systems disorders. Five products (10%), all AAs, were authorised based on pivotal trials reporting clinical outcomes, and 46 (90%) were authorised based on surrogate endpoints. No studies were identified that validated the surrogate endpoints. Among a total of 49 products with surrogate endpoints reported, most were rated according to the published hierarchies as being ‘reasonably likely’ (n = 30; 61%) or of having ‘biological plausibility’ (n = 46; 94%) to predict clinical outcomes. EPARs did not consistently explain the nature of the pivotal trial endpoints supporting authorisations, whether surrogate endpoints were validated or not, or describe the endpoints to be reported in the confirmatory postmarketing studies. Our study has limitations: we may have overlooked relevant validation studies; the findings apply to 2 expedited pathways and may not be generalisable to products authorised through the standard assessment pathway.ConclusionsThe pivotal trial evidence supporting marketing authorisations for products granted CMA or AA was based dominantly on nonvalidated surrogate endpoints. EPARs and summary product characteristic documents, including patient information leaflets, need to state consistently the nature and limitations of endpoints in pivotal trials supporting expedited authorisations so that prescribers and patients appreciate shortcomings in the evidence about actual clinical benefit. For products supported by nonvalidated surrogate endpoints, postauthorisation measures to confirm clinical benefit need to be imposed by the regulator on the marketing authorisation holders.

Practical Issues Concerning the Approval and Use of Biosimilar Drugs for the Treatment of Multiple Sclerosis in Latin America.

The use of biosimilar drugs for multiple sclerosis (MS) has become widespread in Latin America, with the goal of reducing costs of treatments, promoting the sustainability of healthcare systems, and improving patient access to these therapies. There is currently a need to define and comply with requirements to guarantee the efficacy, safety, and quality of these drugs. Thus, the objective of the present study was to compile up-to-date information from each Latin American country assessed on (a) approval of biosimilar drugs by regulatory agencies; (b) use of biosimilar drugs, pharmacovigilance plans, risk management; and (c) update in the knowledge on different molecules. To do so, a group of experts from Argentina, Bolivia, Brazil, Chile, Colombia, Costa Rica, Ecuador, Mexico, Panama, Peru, Uruguay, and Venezuela met to discuss the current situation regarding good practices and risks associated with the use of biosimilar drugs in their respective countries. Regulation, risk management plans, and pharmacovigilance in the whole continent must guide the strategies on the commercialization and access of biosimilar drugs and copies of complex molecules. Current regulations must be implemented for the registration of biosimilar drug products and complex molecules. It is paramount to ensure that new products follow the best quality standards at all stages beyond being safe and efficient. Uncontrolled interchangeability between original biological and biosimilar should be avoided. Latin America requires the implementation and full use of strong pharmacovigilance programs. National and multinational clinical studies are required to demonstrate the similarity in safety, efficacy, and immunogenicity profiles of complex molecules, as well as biological and biosimilar products.Plain Language SummaryPlain language summary available for this article.

Inicial request agreement with researchers of ANMAT, (Argentinean FDA), to present clinical trials to obtain approval and registers of complex manipulated cellular therapy products and products to be used in tissue engineering

Background & Aim Introduction In 2011 the Argentinean National Administration for Medicines, Food and Technology (ANMAT) stablished the Register of Products for Advanced Therapies. In 2016, under the INAME umbrella (National Institute of Medicines) generated the division of Biologicals. In 2018 they published the new Rules for GMP Medicine productions, where chapters 8 and 9 were dedicated to cellular and genetic engineered products respectively. Methods, Results & Conclusion Methods The main obstacle for clinical trial regulators was the lack of information of how to homologate the knowledge of Drug Characterization, Pharmacokinetics, Pharmacodynamics and Safety the analogic study for cellular products. To approach this problem Center for Research on Tissue Engineering and Cellular Therapy (CIITT) presented a full documentation for a clinical trial. It was written following FDA recommendations and theoretical concepts, presented during the Global Regulatory Perspective (GRP) annual conferences. Then, a careful discussion with the regulators was sustained, satisfying all the concerns that they had it. Results The University Ethical Committee (Equivalent to the US IRB) took almost a year to provisionally approved this package of documents, because its definitive approval was pending under ANMAT approval. Then, with the provisional approval the papers were presented to ANMAT. The parallel explanation on characterization, pharmacokinetic, pharmacodynamics and safety of a DRUG with a Cellular Product was accepted. On this common ground, they asked for specific preclinical experiments for the data on the specific cellular products presented. Briefly, ANMAT asked for the Specific Identity, Purity, Potency and Safety. The Safety also included CMC process, animal oncogenicity, induction of autoimmunity, and organ toxicity (Anatomo-pathology organ analysis and serologic toxicity detection. The studied were done in disease animal models, using same route, doses and schedule of administration, as well as using an alternative route of administration. After approval of the experimental data they pass the protocol and the companion documentation to the clinical commission and to the ethical review committee of ANMAT. They processed the protocol with similar rules than a Drug Clinical Trials. A pharmacovigilance plan for each patient should also be presented and reinforced. Conclusion Even when this methodology is not referred to an actual official guideline, it allowed as to present to ANMAT therapeutic products.

Challenges and Prospective Solutions in Non-classical Herbal Formulations: A Review

Non-classical herbal formulations have gained momentum in the recent past. These formulations, however, have not been well integrated with the modern system of medicine in most of the countries in the world. This is due to the lack of enough scientific evidence pertaining to its long-term safety and efficacy. Besides, the paucity of authentic monographs on the impurity profiling, standardization protocols, lack of guideline on the fixed-dose combinations and absence of programmed pharmacovigilance plan for herbal drugs are among the major caveats. In recent years, few issues pertaining to the classical herbal formulations are being addressed to some extent. However, the issues on non-classical modern formulations remain the same. Hence, the objective of this mini-review is to shed light on the major flaws and challenges of these formulations and provide some expert opinion to counter these issues.

Revisión de dosieres de heparina y enoxaparina: Incumplimiento de la normativa de Costa Rica para el registro sanitario de biosimilares farmacéuticos

Objetivo: Determinar los aspectos esenciales de la reglamentación de Costa Rica referente al registro sanitario de biosimilares y compararlos con la información brindada en los dosieres de laboratorios fabricantes de heparina y enoxaparina. Materiales y métodos: Se examinó el Reglamento de Inscripción y Control de Medicamentos Biológicos: RTCR 440:2010. Luego, se solicitaron los dosieres enviados por los laboratorios fabricantes y se comparó su información con respecto a los datos solicitados por el reglamento anterior. Finalmente, se evaluó la importancia de la información solicitada. Resultados: El RTCR 440:2010 solicita información química, farmacéutica y biológica del producto farmacéutico terminado, resultados sobre seguridad y eficacia, datos administrativos y documentación legal. Para los biosimilares, se debe presentar el ejercicio de biosimilitud y un plan de farmacovigilancia. Esta información no está presente en su totalidad en los dosieres revisados. Conclusiones: Los productos revisados no cumplen con los requisitos solicitados por el reglamento costarricense en lo que respecta al ejercicio de biosimilitud. Por ende, no fueron presentados para el trámite de sus registros sanitarios ante el Ministerio de Salud de Costa Rica.

Research on Insufficient Information for Pharmaceutical Products

Several issues concerning medicines remain unclear, including the availability of known, but not easily recognizable information. This review evaluates the mechanisms of side effects and the various risk indications included in package inserts. The results can be summarized as follows. 1) Short-term exposure to gatifloxacin significantly induced insulin secretion and increased the cytosolic Ca2+ concentration of islet cells by augmenting extracellular Ca2+ influx and its release from the endoplasmic reticulum. Alternatively, there was a decline in the cellular insulin level and reactivity to sulfonylurea after prolonged exposure. The insulin depletion was greater than that produced by other fluoroquinolones. 2) The elution of di(2-ethylhexyl)phthalate (DEHP) from the infusion set could be associated with the solubilizers in the injection medicines. The package inserts of several products containing polysorbate or ethanol had no warning about DEHP. Although there was a slight correlation between polysorbate content and descriptions on package inserts, the use of DEHP-containing devices was prohibited for some products, even with limited amounts of polysorbate. Therefore, the package insert statements should be reviewed to reflect appropriately the extent of DEHP elution. 3) Risk management plan consists of strategies to minimize the potential risks of medicines. One approach could be to introduce reminders on package inserts; however, of 268 potential risks associated with 81 products, 56 were not mentioned in package inserts. Because most postmarketing pharmacovigilance plans depend on spontaneous reporting by healthcare personnel, the descriptions on package inserts should be reexamined.

Results on exposure during pregnancy from a pregnancy registry for AS04-HPV-16/18 vaccine.

To assess pregnancy outcomes after exposure to AS04-HPV-16/18 vaccine (Cervarix, GSK, Belgium) prior to, or during pregnancy, as reported to a pregnancy registry. A pregnancy exposure registry was established to collect data in the United Kingdom and the United States. Exposure was defined as vaccination with AS04-HPV-16/18 within 60days before the estimated conception date and delivery. Reporting was voluntary. Between September 2007 and November 2015, 306 pregnancy exposure reports were received of which 181 were prospective, evaluable reports. From these 181 reports, 154 (85.1%) pregnancies resulted in a live birth, 14 (7.7%) in spontaneous abortion, one (0.5%) in stillbirth, and 12 (6.6%) were electively terminated. There was no clustering of outcomes with respect to the timing of exposure. There were 18 infants born with a congenital anomaly of which nine were minor structural defects, seven were major structural defects, one was a hereditary disorder and one was likely the result of a congenital infection. In three cases of structural defect (two minor and one major), there was a temporal association to vaccination during the critical developmental period of gestation. There was no cluster or constellation of congenital anomalies suggestive of possible teratogenesis. The pharmacovigilance plan to investigate the effects of inadvertent exposure to AS04-HPV-16/18 vaccine during pregnancy included assessment of pregnancy outcomes among women enrolled in clinical trials, evaluation of pregnancy exposure reports from all countries as part of routine passive safety surveillance, a large, well conducted post-authorization observational study, and the pregnancy registry. These registry data complement other data from clinical trials and post-marketing surveillance showing no evidence that vaccination with AS04-HPV-16/18 during the defined exposure period (within 60days before conception until delivery) increases the risk of teratogenicity.

Evaluation of Pharmacovigilance Practice in Pharmaceutical Companies in Nigeria

Nigeria provides strong commercial opportunities for both domestic and multinational pharmaceutical companies. Both local and international regulations require marketing authorization holders to monitor the safety of their pharmaceutical products; however, the extent to which these regulations are being followed is not clear. The objective of this study was to evaluate pharmacovigilance practices in pharmaceutical companies in Nigeria. In this descriptive study, a pretested questionnaire was distributed to 67 pharmaceutical companies based in Lagos, Nigeria. The questionnaire focused on nine basic pharmacovigilance requirements to assess pharmacovigilance practices at each company. A total of 31 companies (46 %) returned the study questionnaire; the majority were domestic companies marketing imported pharmaceutical products. Eight companies (26 %) had a pharmacovigilance unit as an integral part of either the regulatory or the medical unit. There were no standalone pharmacovigilance units. Fewer than ten companies had standard operating procedures for processing individual case safety reports, periodic safety update reports, conducting clinical trials, and training of staff on pharmacovigilance and risk-management plans. We found very little implementation of quality pharmacovigilance systems in the pharmaceutical companies surveyed. Improvements are needed to ensure effective safety monitoring by pharmaceutical companies in Nigeria. Regular inspections, audits, and enforcement of pharmacovigilance guidelines by health authorities would improve and strengthen pharmacovigilance systems in Nigeria.

Introducing New Biosimilars Into Current Treatment Algorithms

Three biosimilar products are now licensed for the treatment of rheumatic diseases in Europe. The European Medicines Agency (EMA) requires that similarity between a biosimilar and its reference product is demonstrated using a rigorous, stepwise process that includes extensive physicochemical and biological analytical testing, non-clinical pharmacology, clinical evaluations, and pharmacovigilance plans. Each step is highly sensitive to any differences between products and progressively reduces any uncertainty over similarity; all steps must be satisfied to demonstrate biosimilarity. The US Food and Drug Administration (FDA) requires a similar stringent biosimilar development process. The etanercept biosimilar SB4 (Benepali®), recently approved for the treatment of rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis (ankylosing spondylitis, non-radiographic axial spondyloarthritis), and plaque psoriasis, is herein used to demonstrate the detailed analytical characterisation and clinical testing that are required by the EMA before biosimilars are approved for use. A comprehensive characterisation study involving >55 physiochemical and >25 biological assays demonstrated that SB4 has highly similar structural, physicochemical, and biological quality attributes to reference etanercept. A Phase I study demonstrated pharmacokinetic equivalence between SB4 and reference etanercept in healthy male subjects. Furthermore, a Phase III, randomised, controlled trial performed in patients with moderate-to-severe rheumatoid arthritis despite treatment with methotrexate (MTX) showed that SB4 was equivalent to etanercept in terms of efficacy, safety, and immunogenicity. In conclusion, the biosimilar development process performed according to EMA or FDA guidelines is highly rigorous and comprehensive. Biosimilars such as SB4 are now available in clinical practice and are likely to improve access, reduce costs, and ultimately, improve health outcomes.

Design and methods for a Scandinavian pharmacovigilance study of osteonecrosis of the jaw and serious infections among cancer patients treated with antiresorptive agents for the prevention of skeletal-related events.

ObjectiveOsteonecrosis of the jaw (ONJ) is a recognized complication of potent antiresorptive therapies, especially at the doses indicated to prevent skeletal complications for cancer patients with bone metastases. This paper describes the rationale and methods for a prospective, post-authorization safety study of cancer patients treated with antiresorptive therapies.MethodsAs part of a comprehensive pharmacovigilance plan, developed with regulators’ input, the study will estimate incidence of ONJ and of serious infections among adult cancer patients with bone metastases treated with denosumab (120 mg subcutaneously) or zoledronic acid (4 mg intravenously, adjusted for renal function). Patients will be identified using routinely collected data combined with medical chart review in Denmark, Sweden, and Norway. Followup will extend from the first administration of antiresorptive treatment to the earliest of death, loss-to-follow-up, or 5 years after therapy initiation. Results will be reported for three treatment cohorts: denosumab-naïve patients, zoledronic acid-naïve patients, and patients who switch from bisphosphonate treatment to denosumab. ONJ cases will be identified in three newly established national ONJ databases and adjudicated by the committee that functioned during the XGEVA® clinical trials program.ConclusionThis study will provide a real world counterpart to the clinical trial-estimated risks for ONJ and serious infections for cancer patients initiating denosumab or zoledronic acid. The establishment of ONJ databases in the three Scandinavian countries will have potential benefits outside this study for the elucidation of ONJ risk factors and the evaluation of ONJ treatment strategies.

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