WHO Drug Information Vol 22, No. 1, 2008 World Health Organization WHO Drug Information Contents Challenges in Biotherapeutics Miglustat: withdrawal by manufacturer 21 Regulatory pathways for biosimilar Voluntary withdrawal of clobutinol cough products 3 syrup 22 Pharmacovigilance Focus Current Topics WHO Programme for International Drug Proposed harmonized requirements: Monitoring: annual meeting 6 licensing vaccines in the Americas 23 Sixteen types of counterfeit artesunate Safety and Efficacy Issues circulating in South-east Asia 24 Eastern Mediterranean Ministers tackle Recall of heparin products extended 10 high medicines prices 24 Contaminated heparin products recalled 10 DacartTM development terminated and LapdapTM recalled 11 ATC/DDD Classification Varenicline and suicide attempts 11 ATC/DDD Classification (temporary) 26 Norelgestromin-ethynil estradiol: infarction ATC/DDD Classification (final) 28 and thromboembolism 12 Emerging cardiovascular concerns with Consultation Document rosiglitazone 12 Disclosure of transdermal patches 13 International Pharmacopoeia Statement on safety of HPV vaccine 13 Cycloserine 30 IVIG: myocardial infarction, stroke and Cycloserine capsules 33 thrombosis 14 Erythropoietins: lower haemoglobin levels 15 Recent Publications, Erythropoietin-stimulating agents 15 Pregabalin: hypersensitivity reactions 16 Information and Events Cefepime: increased mortality? 16 Assessing the quality of herbal medicines: Mycophenolic acid: pregnancy loss and contaminants and residues 36 congenital malformation 17 Launch of procurement and supply Carbamazepine and skin reactions 17 management website 36 Canada Vigilance: a new name and data- Malaria research collection published 36 base 18 New pricing bulletin 37 Desmopressin and hyponatraemia 18 How to improve the use of medicines by consumers 37 Regulatory Action and News Model quality assurance system for procurement agencies 38 Influenza virus vaccines: northern Training courses in management and hemisphere winter 19 supply 38 Lumiracoxib-containing medicines: Pharmacists work to improve use of withdrawal 19 generics 39 Thalidomide approved for multiple myeloma 19 New genetic test for breast cancer 20 Recommended International Natalizumab for moderate-to-severe Nonproprietary Names: Crohn disease 20 41 First test to detect and identify 12 res- List 59 piratory viruses 21 1 WHO Drug Information Vol 22, No. 1, 2008 WHO Drug Information is also available online at http://www.who.int/druginformation NEW ! WHO Drug Information DIGITAL LIBRARY with search facility at http:// www.who.int/druginformation Subscribe to our e-mail service and receive the table of contents (PDF) of the latest WHO Drug Information To subscribe: send a message to [email protected] containing the text: subscribe druginformation 2 WHO Drug Information Vol 22, No. 1, 2008 Challenges in Biotherapeutics Regulatory pathways for challenges in evaluating the quality, safety and efficacy of these products. biosimilar products It was soon realized that marked differ- Innovative biotherapeutic products such ences exist in the definitions and regula- as insulin, human growth hormone and tory pathways for biosimilar products in erythropoietin offer promise for treating many countries. For example, in some many of the life threatening chronic Asian countries, a number of biosimilar diseases that present major challenges to products such as interleukins, interferons, public health programmes in both devel- erythropoetins, growth factors, hormones, oped and developing countries. enzymes and even monoclonal antibod- ies, are available on the market. How- Until now, the high cost of biotherapeutics ever, they are not defined as a class nor has often limited their use, particularly in are they approved within a distinct regula- low income countries. However, many of tory framework. In the European Union the current patents on these products are (EU), a few biosimilar products have been now expiring, offering an opportunity to approved so far through the European manufacturers to produce and market Medicines Agency (EMEA), which has the “generic” products. This will improve most well developed regulatory frame- availability and contribute to increased work for biosimilars so far and which is access at a more affordable price. De- supported by specific guidelines (1–3). pending on the jurisdiction, biotherapeutic products produced and marketed in this The existence of divergent approaches to way are referred to as ‘similar biological the regulatory oversight of biosimilars in medicinal products (bio-similars)’, ‘follow- different countries has revealed a need on protein products’, ‘subsequent-entry for defining globally acceptable regulatory products’ or ‘biogenerics’. expectations for these products. It was Worldwide, varying degrees of regulatory agreed that WHO should develop a global preparedness exist for the approval of regulatory guideline for biosimilar prod- biosimilars. In order to consolidate ucts to help WHO Member States meet thinking on the current situation, a WHO the challenge of establishing appropriate informal consultation was organized in national oversight (4). April 2007 by the Quality, Safety and Standards Team of the WHO Department Consequently, a drafting group has been of Immunization, Vaccines and Biologi- organized and is developing a WHO cals. The consultation was attended by guideline on Biosimilar/Follow-on protein/ national regulatory authorities from Subsequent-entry products. A number of developing and developed countries, key issues for future discussion were also innovator and generic biopharmaceutical highlighted during the meeting. industries, and academia. The objectives of the meeting were to discuss the current Terminology status of so-called “similar” biological Terminology currently used is not consist- medicinal products — biosimilars — and ent between the various countries and to review regulatory pathways and jurisdictions. In the EU, the term ‘similar 3 Challenges in Biotherapeutics WHO Drug Information Vol 22, No. 1, 2008 biological medicinal products’, commonly requires a thorough comparability exer- referred to as ‘biosimilars, is defined in cise to generate evidence substantiating the legislation. EU terminology and the the similar nature, in terms of quality, EMEA regulatory guidelines for bio- safety and efficacy, of the new biosimilar similars have been adopted in Australia product and the chosen reference or also. In the USA, biosimilars are termed comparator product. ‘follow-on protein products’, and in Japan ‘follow-on biologicals’. In Canada they are The second scenario considers that a referred to as ‘subsequent entry bio- thorough comparability exercise may not logics’. In India and Iran, they are usually be required but rather reliance on publicly referred to as biogenerics. WHO aims to available information coupled with addi- establish globally acceptable terminology. tional non-clinical and clinical studies to This issue is the starting point for defining demonstrate similarity could be used. In the ‘scope’ of the international guideline, the second approach, reliance on the therefore, it will hopefully be resolved reference product may not be as essen- during the development of the draft. For tial and a new biosimilar product ap- convenience, the term ‘biosimilars’ is proved with this approach would not be used in this document. granted all the indications of the refer- ence product. At the current time, it is Concept of biosimilars considered that further clarity and real The term ‘generic medicines’ refers to examples are needed to assist in devel- chemically-derived products which are opment of this second scenario as a therapeutically equivalent to the agreed regulatory pathway. reference or originator product. For such generics, demonstration of bioequiva- Proof of similarity lence with the originator product is usually In general, a biosimilar product may be appropriate to infer therapeutic equiva- approved following an abbreviated lence. However, it is unlikely that regulatory process based on the claim biotherapeutics can generally follow this that it is similar to an existing licensed standard approach for generics because product. The key issue to agree is how of their relatively large and complex much data are required to demonstrate molecular structures, which are more similarity. There was consensus in the difficult to adequately characterize in the WHO meeting that a comparability laboratory. programme should involve all aspects of development, with full analytical compara- Based on current analytical techniques, bility of quality, and abridged studies for two biologicals produced by different the non-clinical and clinical components manufacturing processes cannot be of a licence application. shown to be identical, but similar at best. For these reasons, the standard generic But there were clear differences between approach is scientifically not applicable to countries in the approach to non-clinical development of biosimilar products and and clinical studies for biosimilars. Al- additional non-clinical and clinical data though there was a strong view that are usually required. comparative studies remain central to an abbreviated regulatory process, in some Principally, two different strategies for countries non-clinical studies might be developing biosimilar products can be reduced to non-comparative studies for envisaged. The first scenario can be toxicity (single and/or repeat-dose), termed a ‘full comparability approach’