Thijs J. Giezen

Safety-Related Regulatory Actions for Biologicals Approved in the United States and the European Union

CONTEXT Biologicals are a relatively new class of medicines that carry specific risks (eg, immunogenicity). However, limited information is available on the nature and timing of safety problems with their use that were identified after approval. OBJECTIVE To determine the nature, frequency, and timing of safety-related regulatory actions for biologicals following approval in the United States and/or the European Union. DESIGN AND SETTING Follow-up of a group of biologicals approved in the United States and/or European Union between January 1995 and June 2007. Vaccines, allergenic products, and products for further manufacture and transfusion purposes were excluded. MAIN OUTCOME MEASURES Nature, frequency, and timing of safety-related regulatory actions defined as (1) dear healthcare professional letters (United States) and direct healthcare professional communications (European Union), (2) black box warnings (United States), and (3) safety-related marketing withdrawals (United States and European Union) issued between January 1995 and June 2008. RESULTS A total of 174 biologicals were approved (136 in the United States and 105 in the European Union, of which 67 were approved in both regions). Eighty-two safety-related regulatory actions (46 dear healthcare professional letters, 17 direct healthcare professional communications, 19 black box warnings, and no withdrawals) were issued for 41 of the 174 different biologicals (23.6%). The probability of a first safety-related regulatory action, derived from Kaplan-Meier analyses, was 14% (95% confidence interval [CI], 9%-19%) 3 years after approval and 29% (95% CI, 20%-37%) 10 years after approval. Biologicals first in class to obtain approval had a higher risk for a first safety-related regulatory action compared with later approved products in that class (12.0/1000 vs 2.9/1000 months, respectively; hazard ratio, 3.7 [95% CI, 1.5-9.5]). Warnings mostly concerned the classes general disorders and administration site conditions, infections and infestations, immune system disorders and neoplasms benign, malignant, and unspecified. CONCLUSIONS The nature of safety problems identified after approval for biologicals is often related to the immunomodulatory effect (infections). Because the biologicals first to be approved in a class were more likely to be subjected to regulatory action, close monitoring is recommended.

Evaluation of post-authorization safety studies in the first cohort of EU Risk Management Plans at time of regulatory approval.

AbstractBackgound: Since November 2005, an EU Risk Management Plan (EU-RMP) has had to be submitted as part of a marketing application for all new chemical entities in the EU. In the EU-RMP, the safety profile of the medicine has to be described and pharmacovigilance activities should be proposed to study further safety concerns during use of the drug in the real-world setting. These activities include, for example, collection of spontaneously reported adverse events and post-authorization safety studies (PASS). Since the submission of an EU-RMP is a relatively new requirement, there is limited knowledge on the quality and completeness of the study protocols of PASS at the time of approval and there are no data on the influence of certain drug characteristics on the proposed pharmacovigilance activities. Objective: To examine the types of proposed pharmacovigilance activities in a sample of EU-RMPs, describe and evaluate the methodology of PASS, identify problems and propose remedies, and compare characteristics between biologicals and small molecules. Methods: Eighteen EU-RMPs (nine for biologicals, nine for small molecules) given a positive decision regarding the marketing application by the Committee for Medicinal Products for Human Use between November 2005 and May 2007 were included in this descriptive cohort study. The EU-RMPs were selected over time and different therapeutic areas. Classification of the safety concerns (‘important identified risks’, ‘important potential risks’, ‘important missing information’ within the EU-RMP was studied. For PASS, data source (registry, population-based database, sponsor-owned clinical trial database), source of study population to be included in PASS and comprehensiveness of study protocol (full protocol, limited protocol, study synopsis, short description, commitment without further information) were studied. Results: Compared to small molecules, safety concerns for biologicals were less frequently classified as important identified risks (relative risk [RR] 0.6; 95% CI 0.3, 1.0) and more frequently as important missing information (RR 1.6; 95% CI 1.0, 2.7).Forty-seven PASS were proposed; 31 for biologicals and 16 for small molecules. Compared with studies proposed in population-based databases (4 for biologicals, 8 for small molecules), studies in registries (18 for biologicals, 4 for small molecules) were more frequently proposed for biologicals than for small molecules (RR 2.5; 95% CI 1.1, 5.7). About 60% of the proposed PASS will include EU inhabitants. No full study protocols were submitted; 26% involved a limited study protocol, 33% a study synopsis, 37% a short description and 4% a commitment without further information. Conclusion: Approximately 40% of the study proposals for PASS were classified as a short description or a commitment to perform a study without further information, precluding an adequate scientific assessment. Study ing non-EU populations may give rise to difficulties with generalizability of the results to the EU due to differences in patient characteristics, differences in the indication for the medicine and different healthcare systems. This study emphasizes the need for more complete study proposals to be submitted earlier on in the evaluation period and for the inclusion of EU inhabitants in PASS. In addition, differences in the characteristics between biologicals and small molecules, e.g. in the data source proposed, support the need for individualized tailored PASS depending on the type of drug.

Pharmacovigilance of Biopharmaceuticals Challenges Remain

Biopharmaceuticals are important treatment options for a variety of chronic and sometimes life-threatening diseases. Compared with the traditional small molecule drugs, biopharmaceuticals have specific characteristics, which might also influence their safety profile. They have, for example, a complex production process, limited predictability of preclinical to clinical data, a high potential for immunogenicity, and adverse events can often be related to an exaggerated pharmacology. The limited predictability of preclinical to clinical data and the known limitations of randomized controlled trials results in limited knowledge of the safety profile of biopharmaceuticals at the point of their approval, underlining the need for pharmacovigilance. Due to their specific characteristics, pharmacovigilance activities required for biopharmaceuticals might differ from those required for small molecules. This review discusses characteristics and potential challenges with the pharmacovigilance and risk management of biopharmaceuticals as compared with small molecules, and proposes remedies for some of the emerging problems.Spontaneous reporting of adverse drug reactions (ADRs) is important in the detection of new, rare and/or serious ADRs. However, causality assessment remains complicated because of concomitant diseases or drugs. This is particularly the case with biopharmaceuticals, as they are often indicated to treat severe and/or life-threatening diseases in patients who often have other diseases and are treated with concomitant medication.Proactive risk management has been implemented in the EU by the obligatory submission of an EU risk management plan (EU-RMP). In this, the (potential) risks should be described and pharmacovigilance activities proposed. Pharmacovigilance activities can be either routine or additional (post-authorization safety studies [PASS]) activities. During safety assessment, stakeholders are encouraged to use knowledge obtained with biopharmaceuticals with a comparable pharmacology. PASS of biopharmaceuticals with a comparable pharmacology may therefore be used to complement each other.Since biopharmaceuticals are often used in a specialized hospital setting, it is expected that large population-based databases will contain limited information on biopharmaceuticals. Registries have therefore been shown to be an important tool to obtain pharmacovigilance data.Since small changes in the production and purification process might alter the safety profile, activities to improve traceability of the specific biopharmaceutical responsible for the ADR should be taken into account.Key messages in safety management of biopharmaceuticals remain: be prepared for the unexpected, be aware of confounding by disease (severity) and maintain exposure ascertainment/traceability throughout the logistical chain.

Mapping the Safety Profile of Biologicals A Disproportionality Analysis Using the WHO Adverse Drug Reaction Database, VigiBase

AbstractBackground: Biologicals have specific characteristics, as compared with the small molecule drugs, and carry specific risks. Safety problems, for example infliximab and the risk for tuberculosis, have been identified via spontaneous reports of suspected adverse drug reactions (ADRs). However, in general there is limited data on the nature of spontaneously reported suspected ADRs for biologicals. Objective: To map the safety profile of biologicals as compared with all other drugs. In addition, mechanistic classes of biologicals will be compared. Methods: Data was obtained from the ADR database (VigiBase) maintained by the WHO Collaborating Centre for International Drug Monitoring. A disproportionality analysis was performed in which case reports for biologicals and all other drugs (the reference group), reported between January 1995 and December 2008, were selected. Vaccines were not included in the analysis. Suspected ADRs were classified according to Medical Dictionary for Regulatory Activities (MedDRA®) version 12.0 at the System Organ Class (SOC) level. Biologicals were classified into mechanistic classes: antibodies, cytokines, enzymes, growth factors, hormones (reference group), interferons, receptors and others/various. The safety profile of the biologicals versus all other drugs in the database and of the various mechanistic classes of biologicals was compared using the proportional reporting ratio (PRR). Results: 19 1004 case reports containing 546474 suspected ADRs were reported for 62 different biologicals, and 2 556 209 case reports containing 8 761 522 suspected ADRs were reported for all other drugs (the reference group). It was found that two-thirds of all suspected ADRs reported for biologicals were reported for five active substances: etanercept (20.3%), interferon-β-1a (15.6%), infliximab (11.6%), teriparatide (10.7%) and adalimumab (9.0%).Comparison of the safety profile of biologicals and the reference group showed that suspected ADRs for biologicals were more frequently reported in the SOCs ‘Infections and infestations’ (PRR 4.5), ‘Surgical and medical procedures’ (PRR 2.4) and ‘Neoplasms benign, malignant and unspecified’ (PRR 2.1), and less frequently reported in the SOCs ‘Psychiatric disorders’ (PRR 0.4), ‘Vascular disorders’ (PRR 0.4) and ‘Pregnancy, puerperium and perinatal conditions’ (PRR 0.4).Regarding the differences in safety profile between various mechanistic classes of biologicals, compared with hormones (reference group), ‘Infections and infestations’ were more frequently reported for receptors and antibodies. ‘Neoplasms benign, malignant and unspecified’ were more frequently reported for antibodies, cytokines, interferons and receptors, and less frequently for enzymes as compared with the reference group. Conclusions: In VigiBase, five biologicals comprise two-thirds of the suspected ADRs reported for biologicals, which might distort the relation found between a specific biological and a specific adverse event in case of quantitative signal detection. Therefore the choice of reference group to be used in case of quantitative signal detection should be considered very carefully.This study confirmed that biologicals have a different safety profile compared with all other drugs in the database and, within the group of biologicals, differences exist between mechanistic classes. Infections are, for example, frequently reported for receptors and antibodies, which often have an immune compromising effect. Such predictable safety issues should be specifically studied by preregistration clinical trials and/or targeted pharmacovigilance. In addition, since not all adverse reactions can be predicted or detected during development, spontaneous reporting remains an important tool for the early detection of signals.

Safety-related regulatory actions for orphan drugs in the US and EU: a cohort study.

Background: Drugs for rare diseases, so-called orphan drugs, are often intended for serious or chronically debilitating diseases. Safety information is more limited at the time of approval for orphan drugs as a result of various factors, such as the limited number of patients in clinical trials, quality of the clinical trials and special approval procedures. Several studies have been conducted on safety-related regulatory actions for drugs, but none of these have specifically focused on orphan drugs.Objective: To determine the frequency and nature of safety-related regulatory actions for orphan drugs in the US and EU.Methods: This cohort study examined publicly available data from the websites of US and EU regulatory authorities on orphan drugs approved in the US and/or the EU between January 2000 and December 2007. The main outcome measures were the nature, frequency and timing of safety-related regulatory actions, defined as (i) safety withdrawals; (ii) ‘black-box’ warnings; and (iii) written communications to healthcare professionals issued by the US FDA or the European Medicines Agency between January 2000 and June 2008.Results: Ninety-five orphan drugs were approved during the study period (75 in the US, 44 in the EU, and 24 in both regions). Ten products (10.5%) received a safety-related regulatory action. No safety withdrawals, four black-box warnings and 12 written communications were identified. The probability of a first safety-related regulatory action for orphan drugs was 20.3% after 8 years of follow-up. Orphan drugs approved by accelerated approval (relative risk [RR] 3.32; 95% CI 1.06, 10.42), oncological products (RR 7.83; 95% CI 0.96, 63.82) and products for gastrointestinal and metabolism indications (RR 10.44; 95% CI 1.25, 87.27) may have a higher risk for a safety-related regulatory action.Conclusions: The probability of a first safety-related regulatory action for an orphan drug was slightly lower than that reported in the literature for biologicals in one study and new molecular entities in another study. However, detection of safety issues may be complicated by the limited experience with orphan drugs in practical use due to the low prevalences of the diseases they are used for. Doctors and pharmacists should therefore be vigilant with regard to the occurrence of a safety-related issue for orphan drugs.

Traceability of biologicals: present challenges in pharmacovigilance

Introduction: Traceability is important in the postmarketing surveillance of biologicals, since changes in the manufacturing process may give rise to product- or batch-specific risks. With the expected expansion of the biosimilar market, there have been concerns about the ability to trace individual products within pharmacovigilance databases. Areas covered: The authors discuss the present challenges in the traceability of biologicals in relation to pharmacovigilance, by exploring the processes involved in ensuring traceability. They explore both the existing systems that are in place for the recording of exposure information in clinical practice, as well as the critical steps involved in the transfer of exposure data to various pharmacovigilance databases. Expert opinion: The existing systems ensure the traceability of biologicals down to the manufacturer within pharmacy records, but do not support the routine recording of batch information. Expected changes in supply chain standards provide opportunities to systematically record detailed exposure information. Spontaneous reporting systems are the most vulnerable link in ensuring traceability, due to the manual nature of data transfer. Efforts to improve the traceability should, in the short term, be focused toward encouraging health professionals and patients to systematically record and report detailed exposure information. Long-term solutions lie in expanding the accessibility to, and increasing the electronic exchange of exposure data.

Rituximab-induced thrombocytopenia: A cohort study

The combined information of drug exposure and laboratory test results on an individual patient level obtained in daily clinical practice can add important information about the safety of a drug. Thrombocytopenia is a known adverse drug reaction of rituximab, which has already been identified during the preregistration trials, but knowledge on incidence and risk factors in clinical practice is limited. We, therefore, aimed to estimate the incidence and explore the risk factors for the development of rituximab‐induced thrombocytopenia (a platelet count, <100 × 109 platelets/L) in clinical practice. Ninety patients were eligible for inclusion of which 27 developed thrombocytopenia (cumulative incidence, 30%) within 30 days after administration of rituximab and 18 patients developed grade 3/4 thrombocytopenia (cumulative incidence, 20%). Patients with and without thrombocytopenia were compared to explore risk factors. Patients with a relatively low platelet count (217 vs. 324 × 109/L, P = 0.011) before administration of rituximab had a higher risk for the development of thrombocytopenia, and although not statistically significant, patients treated with rituximab within the oncology setting (OR, 4.7; 95% CI, 1.0–23.3), independent of concomitant use of cytostatics, as compared to the autoimmune diseases and patients with a high platelet distribution width (PDW) (16.1 vs. 15.8, P = 0.051). In conclusion, the incidence of rituximab‐induced thrombocytopenia was higher than that identified during the clinical trials. Healthcare professionals should consider thrombocytopenia as a relevant reaction during treatment with rituximab. More frequent monitoring of the platelet count is especially advised in patients treated in the oncology indication and/or with a low platelet count and high PDW.

Pharmacovigilance of biosimilars from a regulatory point of view: Is there a need for a specific approach?

The introduction of recombinant DNA and hybridoma techniques more than 25 years ago enabled the large-scale production of biopharmaceuticals, which resulted in important new treatments for a variety of chronic and sometimes life-threatening diseases [4,18]. The recent expiration of patents of some biopharmaceuticals, like growth hormones, granulocyte colony-stimulating factors, and erythropoietin, makes it possible for pharmaceutical companies to produce so-called “biosimilars”, which are also called “biogenerics” or “follow-on biologics” [13]. Biosimilars are defined by the European Medicines Agency (EMEA) as biopharmaceuticals claimed to be similar to a reference medicinal product based on the demonstration of the similar nature of the two products, in terms of quality, safety and efficacy. Biosimilars are approved on the basis of an abbreviated dossier, in which comparability between the reference product and the biosimilar has been shown both for efficacy and safety. In addition, it is possible to extrapolate therapeutic comparability shown for one indication to other indications of the reference medicinal product [2,3] as was done for the recombinant derived growth hormone Valtropin. For Valtropin it was agreed that data obtained in a comparative double-blind phase III study, where the reference product Humatrope was compared with Valtopin, for the indication ‘Children with growth hormone deficiency’ could be extrapolated to all indications for which the reference product Humatrope had already been approved [8]. Requirements for the dossier of the marketing application for different active substance is laid down in product specific guidelines [2,3]. Compared to small molecules biopharmaceuticals in general, have different characteristics and therefore may carry specific risks. Small molecules are synthesized chemically, whereas biopharmaceuticals are large-complicated molecules which are manufactured in living cells [4,18]. Biopharmaceuticals have a very complex production and purification process involving multiple steps. This carries the risk of influencing the characteristics of the end product, and possibly the safety profile of the end product, at