Peter Georgantopoulos

Regulatory and clinical considerations for biosimilar oncology drugs

Biological oncology products are integral to cancer treatment, but their high costs pose challenges to patients, families, providers, and insurers. The introduction of biosimilar agents-molecules that are similar in structure, function, activity, immunogenicity, and safety to the original biological drugs-provide opportunities both to improve health-care access and outcomes, and to reduce costs. Several international regulatory pathways have been developed to expedite entry of biosimilars into global marketplaces. The first wave of oncology biosimilar use was in Europe and India in 2007. Oncology biosimilars are now widely marketed in several countries in Europe, and in Australia, Japan, China, Russia, India, and South Korea. Their use is emerging worldwide, with the notable exception of the USA, where several regulatory and cost barriers to biosimilar approval exist. In this Review, we discuss oncology biosimilars and summarise their regulatory frameworks, clinical experiences, and safety concerns.

Generic oncology drugs: are they all safe?

Although the availability of generic oncology drugs allows access to contemporary care and reduces costs, there is international variability in the safety of this class of drugs. In this Series paper, we review clinical, policy, safety, and regulatory considerations for generic oncology drugs focusing on the USA, Canada, the European Union (EU), Japan, China, and India. Safety information about generic formulations is reviewed from one agent in each class, for heavy metal drugs (cisplatin), targeted agents (imatinib), and cytotoxic agents (docetaxel). We also review regulatory reports from Japan and the USA, countries with the largest pharmaceutical expenditures. Empirical studies did not identify safety concerns in the USA, Canada, the EU, and Japan, where regulations and enforcement are strong. Although manufacturing problems for generic pharmaceuticals exist in India, where 40% of all generic pharmaceuticals used in the USA are manufactured, increased inspections and communication by the US Food and Drug Administration are occurring, facilitating oversight and enforcement. No safety outbreaks among generic oncology drugs were reported in developed countries. For developing countries, oversight is less intensive, and concerns around drug safety still exist. Regulatory agencies should collaboratively develop procedures to monitor the production, shipment, storage, and post-marketing safety of generic oncology drugs. Regulatory agencies for each country should also aim towards identical definitions of bioequivalence, the cornerstone of regulatory approval.

Ticlopidine-associated ADAMTS13 activity deficient thrombotic thrombocytopenic purpura in 22 persons in Japan: a report from the Southern Network on Adverse Reactions (SONAR)

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening generalized disorder. The classic TTP ‘pentad’ is thrombocytopenia, microangiopathic hemolytic anemia (MAHA), renal impairment, neurological symptoms, and fever (Amorosi & Ultmann, 1966). Laboratory studies identified deficiency of plasma ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type 1 motifs 13) activity (ADAMTS13:AC) among some TTP patients (Furlan et al, 1998; Tsai & Lian, 1998). ADAMTS13 cleaves the peptide bond between Thy1605 and Met1606 in the A2 domain of von Willebrand factor (VWF) subunit. VWF is released into the plasma as unusually large VWF multimers (UL-VWFMs), which are degraded into smaller size VWF multimers by ADAMTS13. In the late 1990s, studies in the United States identified 117 cases of TTP that developed after initiation of the thienopyridine, ticlopidine; although at that time, ADAMTS13 activity levels were not widely available (Bennett et al, 1999; Steinhubl et al, 1999). A study of seven patients in the United States with ticlopidine-associated TTP found that all seven had severe deficiency of ADAMTS13 activity and five had detectable antibodies to ADAMTS13 activity (Tsai et al, 2000). We now report on 22 individuals from Japan with ticlopidine-induced TTP and compare these findings to those from the United States. Ticlopidine was the primary anti-platelet agent in Japan from 1989 to 2006. Since 1998, our laboratory at Nara Medical University has been a nationwide referral centre in Japan for thrombotic microangiopathies (TMAs), including TTP (Fujimura & Matsumoto, 2010). The study protocol was approved by the Ethics Committee of Nara Medical University Hospital. TTP diagnostic criteria were: microangiopathic haemolytic anaemia (haemoglobin ≤ 120 g/l), Coombs test negative, undetectable serum haptoglobin (<1 μmol/l), more than 2 fragmented red cells (schistocytes) in a microscopic field with 9100 magnification, increased serum lactate dehydrogenase (LDH) above institutional baseline, thrombocytopenia (platelet count ≤ 100 × 109/l), absence of evidence for disseminated intravascular coagulation and no other identifiable cause of TTP. Additional information on fever ≥37°C; and central nervous system and renal function data were abstracted. Patients were included if, in addition to criteria for idiopathic TTP, the patient had received ticlopidine prior to TTP onset. Before therapeutic plasma exchange or plasma infusion was initiated, whole blood samples (five ml) were withdrawn from each patient and placed into plastic tubes containing 1/10 volume of 3.2% sodium citrate. Plasma was separated by centrifugation at 3000 g for 15 min at 4°C, kept in aliquots at −80°C until testing, and sent to our laboratory with clinical information. Until March 2005, ADAMTS13:AC was determined by classic VWF multimer (VWFM) assay with a detection limit of 3% of the normal control (Furlan et al, 1996; Kinoshita et al, 2001). Thereafter, a chromogenic ADAMTS13-act-enzyme-linked immunosorbent assay (ELISA) with a detection limit of 0-5% of the normal control was developed, and replaced the VWFM assay. Plasma ADAMTS13 inhibitor (ADAMTS13:INH) titres were analysed either by classic VWFM assay or chromogenic ADAMTS13-act-ELISA using heat-inactivated plasmas at 56°C for 30 min. A total of 22 ticlopidine-associated TTP patients fulfilled the inclusion criteria (Table I). Age at diagnosis ranged from 41 to 89 years, with the median age of onset of 69 years. Females accounted for 45.5% of the cohort. Ticlopidine had been administered for a median of 27-5 d (range, 14–35 d) but was discontinued after a clinical diagnosis of TTP was made. Median values for hemoglobin were 83 (60–146) g/l, platelets 9–5 (3.57) × 109/l, and serum creatinine 132.6 (35–380) μmol/l. Abnormal neurological findings were noted in 63.6%. All of the patients had 4 BU/ml. Both ticlopidine-associated TTP deaths did not receive therapeutic plasma exchange. Table I Characteristics of ticlopidine-associated thrombotic thrombocytopenic purpura in Japan and United States. To our knowledge, this is the first study to report detailed characteristics of ticlopidine-associated TTP among patients outside of the United States. Our findings, from a cohort of ticlopidine-associated TTP patients in Japan, identified severe ADAMTS13 deficiency and antibodies to ADAMTS13 in 100% of these 22 individuals. A decade earlier, severe ADAMTS13 deficiency was reported in 100% of seven patients with ticlopidine-associated TTP in the United States and antibodies to ADAMTS13 in five of these patients (Bennett et al, 1999; Tsai et al, 2000). While ticlopidine-induced TTP is undoubtedly a rare disease, it is reassuring that the original observations reported from the United States have been independently replicated in Japan (Bennett et al, 1999; Steinhubl et al, 1999). Limitations of our study should be identified. Follow-up ended at the time of hospital discharge, which prevented us from reporting on relapse rates. Ticlopidine is rarely used today, having been replaced by clopidogrel in 1999 because of safety concerns. Our research has shown that clopidogrel, unlike ticlopidine, does not lead to ADAMTS13 antibody formation and deficiency of ADAMTS13 activity and the rare cases of clopidogrel-associated TTP are not responsive to therapeutic plasma exchange. Also, very little is known about TTP associated with prasugrel (the newest thienopyridine), despite 14 cases of prasugrel-associated TTP having been reported to the Food and Drug Administration in 2009 and 2010 (Jacob et al, 2012). Careful pharmacovigilance to identify severe adverse drug reactions developing among small numbers of persons can serve as important warning signals for potentially serious adverse drug events internationally.

Consensus on the Existence of Functional Erythropoietin Receptors on Cancer Cells

Consensus on the Existence of Functional Erythropoietin Receptors on Cancer Cells Even when the US Food and Drug Administration approved erythropoietin to treat chemotherapy-induced anemia in 1993, concern was raised that administration of erythropoietin may lead to tumor growth. This possibility was derived from concern that erythropoietin receptors or homologous receptors reside on cancer cells and respond to exogenous erythropoietin, inducing activation of the cell signaling pathway and cellular functional changes. There has been widespread disagreement on this topic. Before 2008, a review found that scientists without funding from manufacturers of erythropoiesis-stimulating agents (ESAs) were more likely than scientists with such funding or scientists employed by manufacturers of ESAs to report erythropoietin receptors on solid tumor cells, erythropoietin-induced signaling changes, or cellular function changes.1 Three studies have been published by scientists employed by manufacturers of ESAs, which was too small a number to allow for direct comparisons between findings of academic scientists and scientists employed by manufacturers of ESAs.1 In 2007, the National Cancer Institute convened a workshop seeking to facilitate consensus on this topic. Thirteen of 14 academic scientists without funding from manufacturers of ESAs reported that erythropoietin receptors were involved in cancer progression while all 6 scientists employed by manufacturers of ESAs reported the opposite (A. Mufson, PhD, written communication, August 2015) (Table). Review of subsequent studies provides opportunities to evaluate whether consensus was achieved after the workshop. Our hypothesis is that differences in findings regarding erythropoietin receptors between academic scientists and scientists employed by manufacturers of ESAs would persist after the workshop.

Systematic Approach to Pharmacovigilance beyond the Limits: The SouthernNetwork on Adverse Reactions (SONAR) Projects

As of 2013, the Southern Network on Adverse Reactions (SONAR) team described 50 significant adverse drug reactions (sADRs) associated with FDA approved drugs. The team also investigates policy issues surrounding pharmacovigilance. Herein we describe the systematic approach to pharmacovigilance taken by the Southern Network on Adverse Reactions and discuss major findings from the group. By 2015, the team hopes to have identified 20 additional sADRs focusing on biologics, biosimilars, and biobetters. The ultimate goal of SONAR is to decrease the timescale between ADR detection and the dissemination of information regarding the sADR

Progressive multi-focal leucoencephalopathy among ibrutinib-treated persons with chronic lymphocytic leukaemia.

Wang: No relevant conflicts of interest. Morrissette: No relevant conflicts of interest. Lieberman: No relevant conflicts of interest. Timlin: No relevant conflicts of interest. Schuster: Nordic Nanovector: Membership on an entity’s Board of Directors or advisory committees; Janssen: Research Funding; Novartis: Research Funding; Genentech: Consultancy; Gilead: Research Funding; Hoffman-LaRoche: Research Funding; Celgene: Consultancy, Research Funding; Phamacyclics: Consultancy, Research Funding. Mato: Gilead: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pronai Pharmaceuticals: Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy; Celgene Corporation: Consultancy, TG Therapeutics: Research Funding; Acerta: Research Funding. Jie Wang Jennifer Morrissette David B. Lieberman Colleen Timlin Stephen J. Schuster Anthony R. Mato Center for CLL, and Center for Personalized Diagnostics, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA E-mail: anthony.mato@uphs.upenn.edu

Melanoma complicating treatment with natalizumab for multiple sclerosis: A report from the Southern Network on Adverse Reactions (SONAR)

A 43‐year‐old female with multiple sclerosis developed urethral melanoma. The only potential risk factor was treatment with natalizumab, a humanized monoclonal antibody against α4 integrins. To investigate the risk‐exposure relationship, we reviewed this case, all other published cases, and cases of natalizumab‐associated melanoma reported to regulatory agencies. Data sources included the Food and Drug Administrations (FDA) Adverse Event Reporting System (FAERS) (2004–2014), a FDA Advisory Committee Meeting Report, and peer‐reviewed publications. In the United States, the manufacturer maintains an FDA‐mandated Tysabri Safety Surveillance Program (part of the Tysabri Outcomes Unified Commitment to Health (TOUCH)) of natalizumab‐treated patients. We statistically compared reporting completeness for natalizumab‐associated melanoma cases in FAERs for which information was obtained entirely from the TOUCH program versus cases where FAERS information was supplemented by TOUCH program information. FAERS included 137 natalizumab‐associated melanoma reports in patients with multiple sclerosis. Median age at melanoma diagnosis was 45 years (range: 21–74 years). Changes in preexisting nevi occurred in 16%, history of cutaneous nevi occurred in 22%, diagnosis within 2 years of beginning natalizumab occurred in 34%, and 74% had primary surgical treatment. Among seven natalizumab‐treated MS patients who developed biopsy‐confirmed melanoma on treatment and reported in the literature, median age at diagnosis was 41 years (range: 38–48 years); and the melanoma diagnosis occurred following a median of 12 natalizumab doses (range: 1–77 doses). A history of mole or nevi was noted in four patients and a history of prior melanoma was noted in one patient. Completeness scores for reports were significantly lower for FAERS cases reported from the TOUCH program versus FAERS cases supplemented by TOUCH information (median score of 2 vs. 4 items out of 8‐possible items, P < 0.0007). Clinicians should monitor existing nevi and maintain suspicion for melanoma developing in natalizumab‐treated patients. The TOUCH Safety Surveillance Program, currently focused on progressive multifocal leukoencephalopathy, should be expanded to include information on other serious complications including malignancies, particularly if they are immunologic in nature.

PS01.79: Epidemiology and Characteristics of US Veterans with NSCLC Using US Veterans Affairs (VA) Database: Topic: Medical Oncology

withHRof 0.55, 0.56, 0.43, 0.16 for age groups<45, 75-79, 80-84, and >85, respectively(P < 1x10). LC survivors with carcinoma, NOS or carcinoid had significantly reduced risks versus adenocarcinoma(HR1⁄40.55, 0.27, P1⁄41.0x10, 4x4-10 respectively). The stratification by quintiles of the estimated risk shows that the observed proportion of SPLC cases was significantly higher in the 5 quintile group(6.53%) versus the 1st quintile group(1.69%)(P<10). The decision curve analysis yielded a range of risk thresholds(1%-11.5%) atwhich the clinical net benefit of the risk model-based strategy was larger than those under hypothetical “all-screening” or “no-screening” scenarios. Conclusion: The risk-stratification approach for SPLC can be potentially useful in identifying LC survivors to be screened by CT. More comprehensive environmental and genetic data would help enhance the predictability and stratification of the risk model for SPLC.