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PDF hosted at the Radboud Repository of the Radboud University Nijmegen The following full text is a publisher's version. For additional information about this publication click this link. http://hdl.handle.net/2066/209436 Please be advised that this information was generated on 2021-09-26 and may be subject to change. Pharmaceutical Medicine (2019) 33:407–416 https://doi.org/10.1007/s40290-019-00302-2 ORIGINAL RESEARCH ARTICLE Ethnicity‑Specifc Drug Safety Data in European Medicines Agency Registration Dossiers, European Public Assessment Reports, and European and Singapore Drug Labels: Lost in Translation? Marc Maliepaard1,2 · Anne C. Taams1 · Cynthia Sung3,4 · Jalene Poh3 · Yang Yu1,2 Published online: 5 September 2019 © The Author(s) 2019 Abstract Background Information on drug safety in diferent ethnic populations reported in public documents such as the European Public Assessment Reports (EPARs), European Summary of Product Characteristics (SmPCs) or Singapore Package Inserts (SGPIs) generally appears limited. Objective This study aimed to clarify the extent of drug safety data in ethnic populations that is available in drug registration dossiers used for registration in the European Union (EU) and Singapore, and how much of this information is then included in the EPARs and SmPCs or SGPIs. Methods For this purpose, drug registration dossiers and these public documents for a selection of 25 drugs authorized both in the EU and Singapore were compared (note, the number of available full registration dossiers was only 24 due to a technical issue). Results Detailed safety data in ethnic groups were present in 23/24 (96%) of the drug registration dossiers, but was only present in 12/25 (48%) of the EPARs, 8/25 (32%) of the SmPCs, and 9/25 (36%) of the SGPIs. Furthermore, in many cases where ethnicity-specifc safety information was provided in the SmPC or SGPIs, details on the ethnic subpopulations was not provided. Conclusions Despite the fact that safety data analyzed with respect to ethnic populations are available in almost all screened registration dossiers, this information is often unknown to patients or prescribers as it was often not included in the EPARs, EU SmPCs or SGPIs. In order to increase the availability of such potentially important safety information, it is recommended to at least provide ethnic populations and group size in these public documents. In this way, trust in the registered drugs in diferent ethnic populations may be increased, and more robust treatment decisions may be obtained in clinical practice. 1 Introduction 1937 in the US and the thalidomide incident in the early 1960s in Europe [1, 2]. The safety review and monitoring One of the responsibilities of drug regulatory authorities systems established have enabled drug regulatory agencies is to govern the safe use of medicines. Both in the US and to manage safety events. For example, the thalidomide crisis many countries in Europe, the regulatory development of was prevented in the US due to the safety review process drug regulation and pharmacovigilance was fuelled by of the US FDA where the drug was not approved due to safety-related disasters, i.e. the sulfanilamide incident in insufcient data on the safety and efectiveness of the drug [3, 4]. Since their establishment, regulatory authorities such as the FDA and the European Medicines Agency (EMA) * Marc Maliepaard have strengthened their drug assessment processes to ensure [email protected] the efcacy, safety and quality of drugs available to their populations [5–8]. Predicting drug behavior in ethnic/racial 1 Medicines Evaluation Board, Utrecht, The Netherlands populations is gaining importance due to increased globali- 2 Department of Pharmacology and Toxicology, Radboud zation of both drug development and access to medicine. University Medical Centre, Nijmegen, The Netherlands Furthermore, pharmaceutical regulation is moving toward 3 Vigilance and Compliance Branch, Health Sciences global convergence, and many smaller national regulatory Authority, Singapore, Singapore authorities take reference from publicly available assessment 4 Duke-NUS Medical School, Singapore, Singapore Vol.:(0123456789) 408 M. Maliepaard et al. (SCAR) [18]. In this case, the allele variant HLA-B*5801 Key Points was related to the risk of SCAR, and, also in this case, the allele is more commonly found in East Asian subpopula- Ethnicity-specifc drug safety data were present in 96% tions [16, 19]. Another example of ethnicity diferences is of registration dossiers of new chemical entities exam- the lower dose of warfarin required in Singapore Chinese ined in this study, yet ethnicity-specifc safety informa- compared with Singapore Indians to achieve the optimal tion was present in only 48% of the European Public therapeutic range for balancing bleeding risk with risk of Assessment Reports (EPARs), 32% of the European a recurrent thromboembolic event; the diference in doses Union Summaries of Product Characteristics (SmPCs) between these ethnic groups is explained in large part by the and 36% of the Singapore Package Inserts (SGPIs). diferent distributions of the VKORC1 and CYP2C9 geno- National regulatory authorities in non-European regions types in the two ethnic populations [20]. that reference European Medicines Agency (EMA) These examples illustrate that diferent ethnic populations public documents may therefore be unaware of safety may react diferently to drugs and that the prevalence of data for specifc groups that may be pertinent to ethnic diferent adverse events (AEs) in diferent ethnic popula- populations in their countries. tions can be a clue to a potential genetic association. In this light, it is understandable that pharmaceutical companies Ethnicity-specifc safety information for a drug often would generally analyse and compare AEs in diferent ethnic remains unknown to prescribers because translation from populations included in clinical trials in support of registra- dossiers towards EPARs and SmPCs/SGPIs is incom- tion of a medicinal product [21]. Such safety information plete. in ethnic groups is included in the beneft–risk evaluation It is recommended that public documents from EMA before drug marketing authorization (MA) can be granted. assessments include specifc information on ethnic In the EU, as a matter of transparency, relevant outcomes populations and group sizes in clinical trials to increase of such evaluations are summarized in public documents transparency of the totality of evidence available on such as the European Public Assessment Report (EPAR) and authorized drugs. in the Summary of Product Characteristics (SmPC), both of which can be accessed on the EMA website by patients and health care professionals [22]. Likewise, in Singapore, the approved package inserts (SGPIs) can also be accessed reports from well-regarded medicine registration authorities by patients and health care professionals on the website of to facilitate the approval process and expedite access to inno- the Health Sciences Authority (HSA), the Singapore drug vative medicines in their countries [9]. Of note, in this paper regulatory agency. the term ‘ethnicity’ will be used in order to classify diferent Since the EU population mainly consists of Caucasians, origins, a term that is considered broader and considered to historically, patients with Caucasian background often form encompass the term ‘race’. the majority of the patients included in the clinical trials sup- Over the last decade, it has become increasingly clear porting drug registration in the EU. However, increased glo- that safety can be variable in diferent ethnic populations. balization has led to the situation that more non-Caucasian For example, in the case of carbamazepine, which is indi- people live in Europe and that more value needs to be given cated for the treatment of epilepsy, bipolar disorder and in the EU to safety information in other ethnic populations. trigeminal neuralgia, very rare but severe skin reactions In Singapore, the Singapore population mainly consists of such as Stevens–Johnson syndrome (SJS) and toxic epider- three non-Caucasian ethnicities (≈ 75% Chinese, ≈ 14% mal necrolysis (TEN) have a higher incidence in South-East Malay and ≈ 9% Indian). The HSA takes reference from the Asian populations compared with Caucasian/White popula- ICH E5 Guideline (Ethnic Factors in the Acceptability of tions (in fact pointing at the same population, with the term Foreign Clinical Data) and accepts the use of foreign clini- Caucasian generally more often used in the European Union cal data in regulatory submissions supporting drug regis- [EU] region and the term Whites more often used in the US tration. Hence, the clinical dossier submitted to the HSA region) [10–14]. Patients carrying the HLA-B*1502 allele is mostly the same as that submitted to major regulatory have a signifcantly higher risk of developing SJS/TEN, and agencies, such as the EMA and FDA, and the foreign clinical this allele is more prevalent in certain Asian subpopulations, data are assessed if it can be extrapolated to the Singapore such as Han Chinese (1.9–12.4%), Thai (≈ 7.5%), Malay population [23]. In this light, it is considered very valuable (≈ 8%) and Indian (2–6%), partially accounting for the to include the detailed breakdown of the ethnic background increased incidence of carbamazepine-induced SJS/TEN in and group size of the patients in the clinical studies (i.e. these ethnic populations [15–17]. Likewise, allopurinol was breakdown of the various