Biosimilars and haemophilia.

Biosimilars are drugs developed to be highly similar to their originator biologic (or ‘reference medicinal product’) with no clinically meaningful differences in purity, efficacy or safety. Production of biologics and biosimilars is highly complex and sensitive, with any change in manufacturing process having a potential impact on efficacy and safety. This review provides an overview of the manufacturing process for these drugs and considers the implications of any process changes. The scientific rationale underlying the regulatory comparability exercise for process-changed reference medicinal products and biosimilars is also discussed, as is the issue of ‘switchability’ from a reference medicinal product to its biosimilar. CT-P13 (Remsima®, Inflectra®), a biosimilar of infliximab, is used as a case study to discuss these issues.

Biological therapies are being used in many chronic conditions. Development of biosimilar medicines gives chances for wider access to biological treatment. The aim of the review was to present legal regulations of the marketing authorisation of biological medicines in the context of biosimilars medicines. The article focuses on the legislation of the European Union, which was established on the beginning of the XXI century and is very complex and strict. In the first part of the article were described basic terms in this field, such as biological medicine, biosimilar medicine, reference medicine and generic medicie. It also shows differnces between biosimilar and generic medicines. Main difference concerns the manufacturing process, because of which biosimilar will never be identical to the reference medicine. Next part concentrates on the proces of registration of new biological medicines, especially in the area of medicines’ indications to use and controversies related to them. The last part presents issues of the safety monitoring of biological medicines on european level. The purpose of european law in that field is to guarantee every registred biologic therapy is safe for the patients.

Abstract
 Biosimilars are non-innovative copy versions of biologic medicines which are proven to be clinically equivalent to, as effective and as safe as their reference biologics. Biosimilars creates opportunities for cost savings for payers, governments, and patients compared with the reference products. Pharmacist plays an essential role in developing biosimilar medicines from manufacturing to post-marketing pharmacovigilance monitoring. The aim of the current study was to explore the level of knowledge, behaviors and practices of a sample of Iraqi pharmacists towards biosimilar medicines. The current study was a cross sectional, carried out during May 2020. A total of 264 pharmacists )143 male, 121 female) were involved in this study. A web-based self-administered questionnaire was used for data collection . Regarding pharmacists’ knowledge of biosimilar medicines, the results showed that two questions received the highest percentages of adequate answers: biosimilar medicine requires preclinical and clinical studies (58.0%) and biosimilar medicines require more comprehensive data compared to generic drugs (56.1%). In contrast, marketing authorization of biosimilar medicines is granted on the sole investigation of pharmacokinetic bioequivalence received the lowest percentage of adequate answers (21.6%). In addition, the current study showed that more experience years and male gender associated with better knowledge. With respect to perceptions of pharmacists about biosimilar medicines, two statements received the highest percentage of pharmacist agreements: biosimilar medicines are tested in terms of efficacy and safety (64.4%) and biosimilar prescription allows for reducing costs (64.4%). At the same time, 40.2% of the participating pharmacists agreed with pharmacist replacing a reference biologic medicines with its biosimilar product. In conclusion, the majority of the surveyed pharmacists had insufficient knowledge towards biosimilar medicines. The study highlighted that Iraqi pharmacists needed more accurate comprehensive information concerning biosimilar medicines.

By definition, biosimilar medicinal products are biological medicinal products that are similar to other biological medicinal products that are already on the market-the reference medicinal products. Access to biosimilar medicines is a current reality. However, to achieve this goal, it is extremely important to consistently and scientifically substantiate the regulatory requirements necessary for biosimilar medicines when accessing the market. Based on an analysis of the raw materials and the type of methods used in the manufacturing processes of biological medicines, it is known that this tends to be more complex for the quality of the finished product than the manufacture of molecules obtained through a chemical process. It is then relevant to highlight the main differences between both products: biological medicines manufactured using biotechnology and the current generics containing active pharmaceutical ingredients (APIs) obtained from synthetic processes. Once arriving at the approval process of these medicinal products, it is imperative to analyse the guidance documents and the regulatory framework that create the rules that allow these biosimilar medicinal products to come to the market. The present review aimed at documenting comparatively the specific provisions of European legislation, through the European Medicines Agency (EMA), as well as the legislation of the United States of America, through the Food and Drug Administration (FDA). This was then translated into a critical appraisal of what concerns the specific criteria that determine the favourable evaluation of a biosimilar when an application for marketing authorisation is submitted to different regulatory agencies. The gathered evidence suggests that the key to the success of biosimilar medicines lies in a more rigorous and universal regulation as well as a greater knowledge, acceptance, and awareness of health professionals to enable more patients to be treated with biological strategies at an earlier stage of the disease and with more affordable medicines, ensuring always the safety and efficacy of those medicines.

BackgroundIn January 2017, the European Commission approved Terrosa® (company code RGB-10) as one of the first biosimilar medicinal products of teriparatide for the same indications as for the reference medicinal product Forsteo® (Lilly France S.A.S.), which has been on the market in the European Union since 2003. The active pharmaceutical ingredient of the reference medicinal product is the biologically active 1-34 fragment of the endogenous human parathyroid hormone [PTH(1-34)]. It is one of the three bone anabolic agents used in the treatment of osteoporosis promoting bone formation and preventing fragility fractures.ObjectiveThe objective of this paper is to summarise the results of the comparative analysis of representative batches of both the RGB-10 drug product and the reference medicinal product performed by physicochemical and in vitro biological methods.MethodsA series of state-of-the-art analytical methods were applied in a comparative head-to-head manner for testing the similarity in respect to purity, content, structure and potency.ResultsBased on the results of the comprehensive physicochemical and biological characterisation, RGB-10 proved to be highly similar to the reference medicinal product with respect to the critical quality attributes investigated.ConclusionThe results of the quality comparability study demonstrated similarity of RGB-10 to the reference medicinal product, providing the scientific basis for conducting a specifically designed clinical programme, and supported registration of the Marketing Authorisation Application of RGB-10 in the EU.

Spanish Society of Hospital Pharmacy position paper on biosimilar medicines

In recent years, there has been a significant increase in the number of patients with malignancies treated with immune checkpoint inhibitors (ICIs), including the anti-programmed cell death protein 1 (anti–PD-1) agent pembrolizumab. One of the important aspects of conducting clinical trials with ICIs is the assessment of the risk of developing immune-related adverse events (irAEs).The aim of the study was to evaluate the safety of a pembrolizumab biosimilar (BCD-201, Pembroria) compared with a reference medicinal product using the results of a phase I clinical trial and the available medical literature.Materials and methods. A phase I double-blind, randomised, controlled clinical trial (BCD-201-1) has been conducted in patients with advanced melanoma and non-small-cell lung cancer (n=131). Patients were randomly allocated in a 1:1 ratio to receive either BCD-201 (Pembroria) or the reference medicinal product (Keytruda®), administered intravenously at a dose of 200 mg every 3 weeks for up to 24 weeks or until disease progression or unacceptable toxicity is observed. Since the trial results remain blinded at the time of this writing, treatment group data are masked.Results. The study demonstrated the equivalence of pharmacokinetics and comparable safety profiles of pembrolizumab biosimilar and reference medicinal products. Both medicinal products were well tolerated; the frequency of all-grade irAEs was comparable between treatment groups (21.2% in Group 1 vs 21.5% in Group 2). Most irAEs were mild to moderate, with the exception of a case of Grade 3 diarrhoea and immune-mediated enterocolitis in one study subject; there were no statistically significant differences in the median time to development of irAEs between treatment groups (Р=0.22, two-sided Wilcoxon test).Conclusions. The analysed period of the BCD-201-1 trial demonstrated comparable safety characteristics of Pembroria and Keytruda®, which is consistent with the published safety data on the latter. Information on the similarity of long-term safety profiles of the pembrolizumab biosimilar and the reference medicinal product will be obtained from ongoing clinical trials.

Searching for the role of primary prophylaxis in preventing inhibitor development in hemophilia A

Biosimilars, the journey has begun

BackgroundPharmacists being the drug experts need to be well aware of the applied handling of biosimilar medicines (BSMs). They are an integral educator, trailblazer, and advocate of biosimilar integration across all clinical settings. Therefore, the current study was conducted to assess the pharmacists’ knowledge, attitude, and practices of integrating BSMs into clinical practice.MethodsThe cross-sectional study was conducted from August 2019 to November 2019. The community pharmacies, clinical and academic settings in Karachi were approached for gathering the responses of pharmacists towards BSMs and interchangeable products using a 30-item survey form. Pearson correlation and independent sample t-test were used to identify the relationship among independent variables and the responses, considering p values <0.05 as statistically significant.ResultsOverall, there were 305 survey forms used with a response rate of 87.14%. More than 80% of the respondents have good knowledge about the definition, characteristics, safety and efficacy, compatibility, cost issues, and utilization of BSMs. Around half of the respondents (48.9%, [95% CI 46.6–51.2]) were confident in using BSMs in clinical practice. However, they were concerned about the BSM’s safety profile (45.2%, [95% CI 42.1–48.3]), quality (30.2%, [95% CI 28.3–32.1]), and efficacy issues (32.3%, [95% CI 31.2–37.5]).ConclusionThe findings revealed that pharmacists were well informed about the BSMs. However, some of the responses to the attitude demonstrated a lack of understanding of the application of that knowledge. The respondents persuaded that advanced patterns of diseases, product marketing stipulations, and need for better patient care drives higher demand for developing BSMs and were enthusiastic about gaining more insight to integrate BSMs into routine clinical practice.

The traditional drug manufacturing process involves numerous qualitative attributes that directly impact product quality. The Process Analytical Technology approach considers that to enhance process control, identifying critical process parameters and critical quality attributes that affect the manufacturing process is very much necessary. The Ayurvedic drug manufacturing process is more driven by fuzzy qualitative attributes. The present study was executed to identify the Critical Process Parameters and Critical Quality Attributes in the manufacturing process of a herbo-mineral formulation, viz. Arogyavardhini Rasa. Fuzzy set Qualitative Comparative Analysis (fsQCA) methodology was adopted to observe and identify the critical parameters. The study was executed in three steps, viz. Data collection, Data arrangement, and Analysis. The raw data collected was arranged and analyzed in the software R studio using the package QCA in four steps, viz. Calibration, Analysis of Necessity and Sufficiency, Truth Table construction, and Minimization. The results obtained show that Size reduction, Mardana, and Drying are the identified Critical Process Parameters that, in combination, lead to the outcome, i.e., good product quality. Thus, this study proves that Fuzzy Set Qualitative Comparative Analysis can be used as an efficient tool for the identification and measurement of the Critical Process Parameters that affect the Critical Quality Attributes and, thereby, the product quality in the manufacturing of Arogyavardhini Rasa.

General pediatricians are usually not familiar with the treatment and management of patients with bleeding disorders. Hemophilia is the most common severe coagulation factor deficiency. Early recognition of this condition and adequate understanding of its management are of extreme importance to prevent treatment- and condition-specific complications that lead to the development of chronic disabilities in children. Pediatricians must be aware of the role that comprehensive hemophilia treatment centers play for these patients and the need to establish a multidisciplinary model as the gold standard for hemophilia management.After completing this article, readers should be able to: Hemophilia A and B are inherited bleeding disorders characterized by the partial or complete deficiency of circulating coagulation factors VIII (FVIII) or IX (FIX), respectively. The hallmark of severe hemophilia is the presence of recurrent, spontaneous, prolonged, and abnormal bleeding episodes primarily involving soft tissues and synovial joints.Hemophilia A, or classical hemophilia, has been described since ancient times. The earliest documentation is found in the Talmud, a collection of Jewish law writings, from the fourth century. These manuscripts state that infant boys were exempt from the covenant of circumcision if 2 previous sons from the same mother had died due to severe bleeding associated with the procedure. (1) In 1803, John Conrad Otto was the first physician to report a hemorrhagic disorder, characterized by joint and muscle bleeds, that exclusively affected males in the same family. It was not until 1828 that Friedrich Hopff, a student at the University of Zurich, and his professor, Dr Schonlein, used the term haemorrhaphilia for patients presenting with this constellation of symptoms. (1)Hemophilia has often been called "the royal disease" because several members of the European royal family were affected by the condition. Queen Victoria of England, the most famous hemophilia carrier, passed the condition to several of her own children, spreading the disorder to other European royal families. The most renowned case is Tsarevich Alexei, son of the Russian Czar Nicholas II. Today, we know that this royal disease was in fact hemophilia B. Hemophilia B is also known as Christmas disease after Stephen Christmas, the first person described with the condition in 1952. (1)Hemophilia A is 4 times more common than hemophilia B, comprising 80% of all hemophilia cases. The estimated prevalence of hemophilia A is approximately 1 in 5,000 male live births (2)(3) and of hemophilia B is 1 in 30,000 male live births. Hemophilia affects all ethnic and racial groups. A recent meta-analysis estimated that there are approximately 1,125,00 males living with hemophilia worldwide, of whom approximately 418,000 have severe hemophilia. (4)(5)(6) It has also been reported that in the United States the prevalence of severe disease is approximately 50% for patients with hemophilia A compared with approximately 30% for patients with hemophilia B. (7)(8)(9)Abnormal bleeding can occur when specific components of the hemostatic system are missing or dysfunctional. Hemostasis is the sequential and self-regulated physiologic process beginning as soon as a tissue or blood vessel injury occurs. Normal hemostasis produces formation of a stable platelet-fibrin clot that stops bleeding while maintaining normal blood flow. Vasoconstriction at the site of vessel injury is the initial step. This is followed by "primary hemostasis," when an initial, but unstable, platelet clot gets formed through the adhesion, activation, and aggregation of platelets on the damaged vascular endothelium. Primary hemostasis relies on an adequate quantity of functionally normal von Willebrand factor (VWF). Stabilization of the platelet plug through the formation of a covalently cross-linked fibrin-platelet clot occurs during "secondary hemostasis." Secondary hemostasis consists of the activation of all coagulation factors in the coagulation cascade (Fig 1). Within the cascade, FVIII and FIX form an enzymatic complex with coagulation factor X (FX), producing activated FX, which ultimately induces a "thrombin burst," facilitating the formation of the fibrin-platelet clot.Regulation of the hemostatic process occurs through fibrinolysis. Fibrinolysis consists of dissolving the formed clot after the wound-healing process is completed, thereby preventing the formation of a thrombus in otherwise normal blood vessels. Components of the fibrinolytic system include antithrombin, tissue factor pathway inhibitor (TFPI), protein C, and protein S. (10)In hemophilia, a partial or complete deficiency of either FVIII or FIX will result in decreased formation of fibrin, causing a bleeding diathesis characterized by recurrent and prolonged bleeding episodes. (11) FVIII or FIX levels are expressed either as a percentage of normal activity or as international units per deciliter. The reference range for both factors fluctuates between 50% and 150% (0.50–1.50 IU/dL).Hemophilia is inherited in an X-linked recessive pattern. Males are predominantly affected because they have only a single X chromosome, which expresses the defective gene. Affected males can transmit the disease-causing gene only to their female offspring, designated "obligate carriers." Hemophilia carriers have one normal and one abnormal FVIII or FIX gene and have a 50% chance of transmitting the gene to any child; males inheriting the hemophilia gene express the disease, and females become hemophilia carriers (Fig 2).Carrier females might or might not manifest low factor levels and symptoms. Mild hemophilia can be present in up to 25% of heterozygous female carriers. (2) Infrequently, females can manifest a severe bleeding phenotype. This occurs in the context of a compound heterozygous female born from a father with hemophilia and a hemophilia carrier mother. A female carrier can also have hemophilia because of extreme lyonization of the normal X chromosome.Since the FVIII gene was first described in 1983, different mutation variants in the FVIII and FIX genes have been identified. (7) The most frequent variants in patients with hemophilia A are the intron 22 and intron 1 inversions. The former is identified in close to 52% of patients with severe hemophilia A, whereas the latter is encountered in 1% to 5% of all patients with hemophilia A. The most common genetic variants identified in hemophilia B are missense mutations, which account for approximately 47% of all cases. (12) The "My Life, Our Future" project was established in 2012 with the goal of creating a repository of genetic information from people with hemophilia in the United States. FVIII of FIX gene sequence analysis was offered at no cost to patients with hemophilia and suspected carriers. In 2018, an interim analysis identified 700 previously unreported genetic variants and reclassified as nondeleterious several variants previously reported as causative hemophilia mutations. (13)Hemophilia is classified as mild, moderate, and severe based on the measurable factor activity level (Table 1). There is a direct correlation between FVIII or FIX levels and the severity and relative frequency of patient signs and symptoms. Patients with severe and moderate deficiencies tend to present symptoms in the first months after birth. (2)(14)(15) It has been suggested that patients with hemophilia B seem to have less severe bleeding signs and symptoms and better long-term outcomes than patients with hemophilia A. (16)Because neither FVIII nor FIX crosses the placenta, bleeding signs and symptoms in persons with hemophilia, especially those with severe forms, can present soon after birth; in some instances, bleeding can even occur in utero. In infants, intracranial hemorrhage (ICH) occurring either during birth or shortly thereafter is a significant concern. The use of forceps during delivery and vacuum extraction are considered high-risk factors for the development of ICH. The overall incidence of ICH at birth in newborns with hemophilia is estimated to be 4% to 5%, although cases of spontaneous ICH have also been reported. (17) ICH also needs to be considered in cases of head trauma, such as an infant falling from a crib or bed. When suspecting an ICH in a child with hemophilia, immediate infusion of factor concentrate before a head computed tomographic scan is indicated and should not be delayed.The hallmark of hemophilia bleeding is the occurrence of spontaneous acute hemarthrosis. Acute hemarthrosis is defined as the sudden onset of bleeding into the joint space, accompanied by joint swelling, pain, and reduced range of motion of the affected joint. Ankles, knees, and elbows are the most frequently affected joints. The clinical manifestations of joint bleeding vary depending on the patient's age and are sometimes challenging to recognize by medical providers. Infants can present with irritability and unwillingness to use the affected limb. Older children and adults can present with prodromal symptoms characterized by a warm or tingling sensation or feeling of fullness and stiffness of the affected joint before onset of the more characteristic swelling and reduced range of motion. Point-of-care musculoskeletal ultrasonography (POC-MSKUS) is becoming a preferred imaging modality for both the acute assessment and management of joint bleeds (Fig 3) and for monitoring of the development and progression of subclinical joint disease. As opposed to other imaging modalities such as magnetic resonance imaging, POC-MSKUS is less invasive, does not require sedation, is less time-consuming, and has been found to be exceptionally sensitive in detecting very low amounts of intra-articular blood. (18)(19) At the moment, multiple hemophilia-specific POC-MSKUS scoring systems have been developed and are in different stages of validation. (19)When more than 4 bleeding episodes occur in the same joint in a 6-month period, the patient is considered to have developed a "target joint." Repetitive bleeding in the joint space causes a chronic inflammatory reaction, characterized by a cytokine-mediated oxidative process and iron deposition, resulting in vascular proliferation, synovial hypertrophy, and chronic synovitis. Chronic synovitis will trigger an irreversible and destructive process known as hemophilic arthropathy.Muscle bleeding with subsequent hematoma formation is also common in persons with hemophilia. Large muscles, such as the iliopsoas or quadriceps, are most commonly affected. Patients with muscular bleeding can present with mild and nonspecific signs and symptoms: an iliopsoas bleed can manifest as vague groin pain and an inability to extend the hip. If the provider is suspicious for a psoas bleed, imaging confirmation with magnetic resonance imaging or POC-MSKUS is indicated.Extensive muscle bleeding might result in a compartment syndrome, affecting neurovascular structures. Large amounts of blood loss in muscle can lead to pseudotumor formation. Hemophilic pseudotumor is a rare complication, occurring in 1% to 2% of patients with severe hemophilia. (1) A pseudotumor is a chronic, slowly expanding, encapsulated cystic mass that evolves after recurrent hemorrhages in extra-articular musculoskeletal structures.Another bleeding site is the gastrointestinal tract. Patients with bowel hematomas can have signs and symptoms mimicking an acute abdomen. (20) Hematuria, secondary to bleeding arising from the kidneys or the bladder, is a frequent manifestation in persons with hemophilia, especially those with severe deficiencies. (21) Bleeding related to tooth eruption is rare. Dental care is extremely important in persons with hemophilia. Medical providers should promote early consistent dental hygiene practices to reduce the risk of development of periodontal disease. Preventive dental care (dental cleanings) should occur regularly. Dental extractions can require referral to an inpatient setting.Carriers or women with mild hemophilia are also at risk for abnormal reproductive uterine bleeding associated with their menstrual period and childbirth. They can also face bleeding challenges during surgery or dental extractions. (22)A complete family history exploring possible manifestations of bleeding in other family members is essential for the evaluation of a patient suspected of having hemophilia. Given the known genetic etiology of the disorder, questions about extended family members can prove enlightening. Depending on the studied population, 30% to 50% of patients with hemophilia will be found to have a sporadic de novo mutation. These patients are born to a noncarrier mother with a negative family history. For this reason, pediatricians should always consider the possible diagnosis of hemophilia in any male newborn with severe and unusual bleeding and an isolated prolonged activated partial thromboplastin time (aPTT) despite a negative family history of hemophilia. (23)When hemophilia is suspected, the initial laboratory evaluation should include a complete blood cell count, prothrombin time, aPTT, mixing studies in case of prolonged aPTT, a fibrinogen level, and a VWF antigen and activity level.Children with hemophilia present with an isolated prolonged aPTT and a normal platelet count and prothrombin time/international normalized ratio. Patients with severe hemophilia usually have an aPTT 2 or 3 times higher than the upper limit of normal. Unless the patient has an active inhibitor to FVIII or FIX, the aPTT mixing study will correct with the addition of normal plasma. Some cases of mild hemophilia can present with a normal aPTT due to poor sensitivity of the assay in the setting of mildly reduced FVIII or FIX levels. It is not possible to determine the severity of a hemophilia solely on the degree of prolongation of the aPTT. A specific assay to quantify the activity levels for FVIII or FIX will not only confirm the diagnosis but will help to differentiate other inherited bleeding disorders, such as deficiencies of coagulation factors XI or XII, which are also associated with an isolated prolonged aPTT. (24) Genetic testing is an important part of the hemophilia diagnostic evaluation. In addition to allowing accurate genetic counseling, some recognized mutations are associated with the potential risk of inhibitor development, the most common and severe complication of hemophilia treatment today.Newborn males born to a known hemophilia carrier should have their factor level quantified at the time of delivery using a cord blood sample. Cord blood testing is preferred over venipuncture because the collection of cord blood minimizes the risk of traumatic bleeding. Invasive procedures, such as circumcision, should be delayed until the diagnosis of hemophilia is confirmed or eliminated. In babies confirmed to have hemophilia whose parents request a circumcision; the procedure should be electively performed by an experienced surgeon in collaboration with the hemophilia treatment center (HTC).Patients with mild hemophilia might not be diagnosed until adolescence or early adulthood in the setting of surgical or dental procedures. Abnormal and excessive bleeding will lead to the diagnosis.Ascertaining a hemophilia carrier's baseline factor activity is important for management, but if normal, it does not rule out the carrier's status. Genetic testing is more reliable than measurement of factor levels, especially in a woman with normal or borderline normal factor activity. Accurate identification of hemophilia carriers is important for managing current bleeding symptoms and troubleshooting potential bleeding complications associated with pregnancy and delivery. Knowledge of carrier status allows appropriate recommendations for testing offspring. (2) Women with suspected hemophilia should also be tested for von Willebrand disease (VWD), as VWD variants or severe type 3 VWD can have a bleeding phenotype similar to that of hemophilia.Traditionally, clotting factor replacement has been the standard of care for hemophilia. (25)(26) However, hemostatic adjuvant therapies are also helpful in controlling acute bleeding episodes.Treatment of hemophilia has evolved significantly (Fig 4). In the 1950s and 1960s, bleeding events were treated with whole blood, fresh frozen plasma, or cryoprecipitate. Individuals with severe hemophilia experienced prolonged hospitalizations with bleeding events and developed significant joint morbidity. The 1970s brought the development of plasma-derived factor concentrates. In the 1980s through the early 1990s, contamination of these products with human immunodeficiency virus as well as hepatitis B and C devastated the hemophilia community. During that era, in the United States most individuals with hemophilia would treat bleeding events only on demand due to difficulties with an adequate supply of factor concentrates and concerns about factor concentrate safety. (27) In response to the human immunodeficiency virus and hepatitis epidemics, factor concentrate purity and safety became the therapeutic focus. Purification strategies for plasma-derived concentrates incorporated the development of enhanced blood donor screening and the development of techniques for viral removal and inactivation: pasteurization, solvent or detergent treatment, dry heating, immunoaffinity chromatography, and, more recently, nanofiltration. These techniques have into no of viral in patients using plasma-derived factor concentrates since the Today, factor concentrates are of the human FVIII or FIX gene in cell the and human of concentrates based on either the or of human or plasma-derived are concentrates are commonly used in the United States. These concentrates neither human nor plasma-derived in their cell the development of the treatment in hemophilia to from bleeding episodes to the use of of factor concentrate to prevent bleeding is defined as or (Table early in has been to compared with Early has been to result in a more than in joint bleeding and significant in joint disease, hemophilic and on standard concentrates FVIII at to per 2 to 3 for patients with hemophilia A and FIX at to for patients with hemophilia B. to prevent bleeding episodes is to the needs of the can be used for bleeding factor levels of 80% to or for management of bleeds, and iliopsoas It is that factor levels than 50% to are depending on the specific procedure (Table hemostasis should be by an coagulation in with the patient's for acute bleeding episodes is by the patient's by the percentage of FVIII this is by of in patients with hemophilia A. For patients with hemophilia B, the will the patient's by the percentage of FIX level, by 1 of should be to children with hemophilia at The of Hemophilia these than should be to the site of for at after and should be to the site for at It is not to factor concentrate before the of For circumcision, it is to the circulating factor VIII or IX levels to 80% to before the procedure. The also the use of as an management of hemophilia has become some patients have to adequate treatment due to with and time This has to the development of extended factor concentrates on treatment through the of for There have been recent extended FVIII concentrates developed with different protein and and that a prolongation of FVIII The approximately allows as opposed to 3 times per or other This is due in part to the of factor VIII with its carrier protein in the There might soon be a of FVIII concentrates that extend the FVIII to or even less frequent to extended FIX concentrates have been more in using or These have to or current hemophilia treatment has on the specific clotting factor to promote normal are therapies to either the of the factor or the of coagulation the is a developed to activated FIX and on the mimicking the FVIII (Fig is has a of 4 to and is for in individuals with hemophilia A with and to its of has the potential to severe events such as and These events have been reported in individuals with hemophilia A and are and activated prothrombin complex concentrate for bleeding episodes. Acute or surgical bleeding in hemophilia A must be with of FVIII concentrate because is only for first for hemophilia A is a in patient for that the aPTT and FVIII activity will not be accurate in the patient because the require activation of Accurate FVIII activity the use of a factor VIII assay should a patient require of FVIII therapies in development are based on the that some individuals with hemophilia and such as deficiency or factor have a bleeding phenotype. is an for of gene in thereby the of This of a potential risk for development of analysis from a 1 clinical reported a patient associated with involving the development of after FVIII concentrate The clinical and reported long-term and safety for the 2 is a inhibitor that excessive by the tissue factor with activated coagulation factor and activated in the coagulation is an that the physiologic of in patients with hemophilia and This is clinical These studies were due to a of but clinical have since less developed of activated protein C or protein are a was to the of activated protein C while its other hemostasis in hemophilia potential of activated protein C is A has also been developed in hemophilia to of protein which can These therapies can be for for hemophilia has been the of patients with hemophilia. Hemophilia B the first in the early with gene followed a by hemophilia A. The genetic for the FVIII or FIX gene is into a and is The viral with genetic is to that become and the clotting gene FVIII and FIX have been in patients with severe hemophilia to levels consistent with those found in mild hemophilia, or even normal hemostatic levels. A mild in levels occurring with gene is Patients are usually treated with a of long-term safety potential into the although this occurs significantly less than with other for gene include long-term of and the appropriate therapeutic a of the levels of FVIII and and it can be used to bleeding in patients with mild hemophilia A have a response to this is defined as a to baseline FVIII levels, with a to after is not in patients with severe hemophilia A and is not indicated in patients with hemophilia B. response with and it is usually in children than 2 due to its potential risk of and such as and are helpful in controlling bleeding in with fibrinolytic such as the and They can be used in with factor replacement to prevent bleeding associated with surgical procedures. These have also to be in controlling in women with mild long-term complications of hemophilia are chronic with hemophilic and the development of to coagulation factor concentrates people with hemophilia are living persons with hemophilia are as have a incidence of disease, and chronic disease. (21) The bleeding risk in hemophilia and the of for managing these a higher risk of medical development of is the most severe complication of hemophilia treatment It a and important clinical for the medical are specific FVIII or FIX that the activity of the are reported to occur in approximately of patients with severe hemophilia A and 5% of patients with severe hemophilia B. tend to the first although most will the first to a age of 1 to 2 at Patients with moderate and mild hemophilia can but as adults or risk factors associated with an risk of inhibitor development have been identified. specific genetic mutations, and a family history of and and are known to be and risk factors for inhibitor risk factors for inhibitor development include early age at first treatment type of concentrate used in treatment, and the use of the study was the first and the in risk of inhibitor development between plasma-derived and factor concentrates in previously children with hemophilia A. suggested that patients concentrates are more to than those plasma-derived However, the study was the United and study had an of mutations associated with higher risk of inhibitor These a about the appropriate to in diagnosed children with hemophilia. It is also important to that not all concentrates were in the the of these be to all FVIII standard and extended therapeutic goal for patients with is complete of the the most for inhibitor It using and frequent of factor concentrates to the patient's system to the factor and the of the for are and on both the patient's clinical and has become for patients with hemophilia A and studies have in preventing bleeding episodes when patients with hemophilia A with are on of on although these patients will require a or of FVIII concentrates to treat acute bleeding episodes. It is for the medical provider to know the patient's inhibitor status and to acute bleeding episodes in the use of such as activated concentrate and activated prothrombin complex concentrates or the need for higher of FVIII with hemophilia or FIX with hemophilia for the management of hemophilia state that a multidisciplinary comprehensive care model should be established when for individuals with hemophilia. have been established the This treatment that persons with hemophilia have to a range of clinical and appropriate laboratory for the adequate management of their condition and associated In the Hemophilia a to establish the of a of hemophilia diagnostic and treatment centers in the United States. there are more than the The of this comprehensive during the has the of not only for persons with hemophilia but also for all people with bleeding disorders, allowing to live more and A study of persons with hemophilia that individuals treated at an were less to of a complication compared with those not care at an persons with hemophilia used a treatment center were less to be for bleeding Dr A. at the University of Hemophilia for her to the

The introduction of biologic therapies has revolutionized the treatment of inflammatory bowel disease (IBD) and has significantly improved the disease course and outcomes for many patients. Biologics are the main drivers of cost in many IBD units and biosimilars, although are not better than originators, are usually cheaper and thus can increase the availability of this type of therapy. Biosimilar are highly similar to innovator but, due to the complex structures of innovators and the variability inherent in the manufacturing process, they are no identical. This fact cause concerns with respect to the efficacy and safety in medical community, especially in the medical indications in which no specific clinical trials with biosimilars have been performed as IBD. Nowadays, two biosimilars to infliximab, CT-P13 and SB2, has been approved by European Medicines Agency in all the indications of the reference product. To date, the available evidence suggests that switch from reference medicinal product (infliximab) to the biosimilar (CT-P13 or SB2) is feasible since published studies have not observed significantly difference in terms of efficacy, immunogenicity and safety. However, the experts agreed that by now there is not sufficient evidence to consider infliximab biosimilars interchangeable with the originator compound. In this manuscript, we will review the processes involved in the manufacturing and regulatory approval of biosimilars and examine the evidence presently available on approved biosimilars in Europe for IBD.

PSY112 - Economic Impact of The End of The Market Exclusivity for Orphan Drugs

Recombinant human follicle-stimulating hormone (r-hFSH) is widely used in fertility treatment. Although biosimilar versions of r-hFSH (follitropin alfa) are currently on the market, given their structural complexity and manufacturing process, it is important to thoroughly evaluate them in comparison with the reference product. This evaluation should focus on how they differ (e.g., active component molecular characteristics, impurities and potency), as this could be associated with clinical outcome. This study compared the site-specific glycosylation profile and batch-to-batch variability of the in-vivo bioactivity of Bemfola, a biosimilar follitropin alfa, with its reference medicinal product GONAL-f. The focus of this analysis was the site-specific glycosylation at asparagine (Asn) 52 of the α-subunit of FSH, owing to the pivotal role of Asn52 glycosylation in FSH receptor (FSHR) activation/signalling. Overall, Bemfola had bulkier glycan structures and greater sialylation than GONAL-f. The nominal specific activity for both Bemfola and GONAL-f is 13,636 IU/mg. Taking into account both the determined potency and the nominal amount the average specific activity of Bemfola was 14,522 IU/mg (105.6% of the nominal value), which was greater than the average specific activity observed for GONAL-f (13,159 IU/mg; 97.3% of the nominal value; p = 0.0048), although this was within the range stated in the product label. A higher batch-to-batch variability was also observed for Bemfola versus GONAL-f (coefficient of variation: 8.3% vs 5.8%). A different glycan profile was observed at Asn52 in Bemfola compared with GONAL-f (a lower proportion of bi-antennary structures [~53% vs ~77%], and a higher proportion of tri-antennary [~41% vs ~23%] and tetra-antennary structures [~5% vs <1%]). These differences in the Asn52 glycan profile might potentially lead to differences in FSHR activation. This, together with the greater bioactivity and higher batch-to-batch variability of Bemfola, could partly explain the reported differences in clinical outcomes. The clinical relevance of the differences observed between GONAL-f and Bemfola should be further investigated.