WHO Drug Information Vol. 24, No. 1, 2010 World Health Organization

WHO Drug Information

Contents Prequalification of Medicines Regulatory Action and News Programme Influenza vaccines: 2010Ð2011 northern WHO Prequalification of Medicines hemisphere 33 Programme: facts and figures European Medicines Agency: new for 2009 3 organizational structure and visual identity 33 Risk management systems for Regulatory Harmonization medicinal products 34 Updating medicines regulatory systems Orciprenaline sulphate: registration in sub-Saharan African countries 6 cancelled 35 Peramivir IV: emergency use International Nonproprietary authorization 35 Carisbamate: withdrawal of marketing Names authorization application 35 The glycosylation pattern of epoetins 21 Benfluorex withdrawal 35 Ethyl eicosapent: withdrawal of Safety and Efficacy Issues marketing authorization application 36 Didanosine: serious liver disorder 25 Olanzapine approved in adolescents 36 Bortezomib: updated safety information 25 Lisuride: withdrawal of marketing Deferasirox: renal events and gastro- authorization application 36 intestinal haemorrhage 25 Velaglucerase alfa approved for Sirolimus: drug monitoring assay Gaucher disease 37 comparison 26 Pneumococcal 13-valent conjugate Mycophenolate: pure red cell aplasia 26 vaccine approved 37 Fosamprenavir: myocardial infarction Monoclonal antibody products approved and dyslipidaemia 27 for chronic lymphocytic leukaemia 37 Exenatide: altered kidney function 27 Rosuvastatin: new indication approved 38 Drospirenone in oral contraceptives 28 Influenza A/H1N1: collection-to- Glucose test strips 28 detection assay 38 HIV drug combination: safety review of clinical trial data 28 Recent Publications, Sibutramine: ongoing safety review 29 Information and Events Becaplermin: contraindication in TSE tissue infectivity distribution patients with cancer 29 update 39 ACSOM — advisory committee Restricted availability of opioids for on safety of medicines 29 cancer patients 39 Transparency and the public pharma- Regulatory Scope ceutical sector 40 Tobacco product regulation 30 Recommended International Nonproprietary Names List 63 41

1 World Health Organization WHO Drug Information Vol. 24, No. 1, 2010

Announcement

The 14th International Conference of Drug Regulatory Authorities (ICDRA) will be hosted by the Health Sciences Authority, Singapore, in collaboration with the World Health Organization

The ICDRA will take place in Singapore from 30 November to 3 December 2010

Updated information is available at: http://www.icdra2010.sg http://www.who.int/medicines/icdra

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Prequalification of Medicines Programme

WHO Prequalification of Medicines Programme: facts and figures for 2009

The WHO Prequalification of Medicines Programme was launched in 2001 in part- nership with UNAIDS, UNICEF and the UN Population Fund, with support from the World Bank. Its focus is on tackling the quality problems commonly associated with medicines for treating HIV/AIDS, malaria and tuberculosis. In 2006, the Programme also laid the groundwork for prequalifying medicines and commodities for reproduc- tive health. This was in response to the fact that, in many developing countries, the need for family planning and reproductive health services remains urgent. Evaluation of medicines by the Programme includes assessment of data and infor- mation on safety, efficacy and quality. In addition, inspections are performed to as- certain compliance with good manufacturing practices. Inspection activities expanded in 2003 to include manufacturers of selected active pharmaceutical ingredients and, in 2004, to include clinical sites and contract research organizations. These are also inspected to verify compliance with good laboratory practices and good clinical prac- tices.

Prequalification of medicines issued for antimalarial medicines, anti- success in 2009 tuberculosis medicines, HIV/AIDS-related medicinal products, influenza-specific In 2009, a record 44 medicinal products antiviral medicines and medicinal prod- were prequalified of which 39 are generic. ucts and reproductive health products. By the end of 2009, the WHO list of The updated invitations incorporate prequalified medicines totalled 237 additional products and/or take into products manufactured in 16 countries. account revisions made to WHO treat- WHO prequalification “firsts” included ment guidelines. three reproductive health products as well as generic lopinavir/ritonavir, generic Assessment activities oseltamivir, generic tenofovir, cipro- The pace of dossier submission and floxacin infusion, generic ceftriaxone and assessment from previous years was generic abacavir oral solution. maintained. Eighty-four dossiers were submitted for evaluation and 53 dossiers Three medicines quality control laborato- were accepted for evaluation. Seven ries (QCLs) were also prequalified: one in dossier assessment sessions were held Kenya and two in Singapore. At the end in Copenhagen, during which 898 as- of 2009, a total of 11 QCLs had been sessment reports were produced: 528 for prequalified and a further 29 were work- HIV/AIDS-related products; 197 for ing towards becoming prequalified. antituberculosis medicines; 110 for Updated invitations for expressions of antimalarial medicines; 28 for influenza- interest to manufacturers to submit specific antiviral medicines and 35 for product dossiers for prequalification were reproductive health products. The Copen-

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hagen sessions include a training compo- with a report of corrective action they had nent for assessors from developing implemented following these inspections. countries and are enabling a growing The Prequalification of Medicines Pro- number of these to acquire stringent gramme is investigating the possibility of regulatory expertise. The Copenhagen conducting a “desk review” of these sessions also incorporate consultations documents and of any relevant quality between assessors and applicants so that review reports prepared by the manufac- the latter can discuss technical issues turers. Such review would be in lieu of an relating to their dossiers. The consulta- on-site inspection by WHO subject to tions benefit from the presence of a range specified conditions. The aim is to avoid of assessors with considerable experi- duplication of site inspections and to ence. Applicants pay their own costs to optimize use of inspection resources. In attend consultations and must be commit- the event, only two cases were found in ted to the prequalification process. which the inspection reports and correc- tive actions were considered to meet the Problems continue to be seen regarding requirements set by the inspection team antituberculosis products: the number of for allowing postponement of an on-site related dossiers continues to be low and inspection by WHO. An amendment to their quality is often poor. The Program- the WHO procedure for prequalification of me has therefore initiated a study to pharmaceutical products is now being review dossier deficiencies for these considered to make provision for this new products and determine which deficien- process. cies are most commonly observed at each evaluation stage. (Study results will Advice and assistance be published and guidance on how to WHO assessors continued to provide avoid deficiencies developed.) Addition- scientific advice to manufacturers during ally, members of the Programme team 2009. This included review of bioequiva- and the WHO China country office lence study protocols and responding on worked to secure funding from the Bill & a daily basis to specific questions relating Melinda Gates Foundation for a project to to quality, efficacy and safety. New provide technical support on quality guidance was issued on Submission of issues to manufacturers of fixed-dose Documentation for Prequalification of combination antituberculosis products. It Multisource (generic) Finished Pharma- is hoped that this will lead to increased ceutical Products approved by Stringent dossier submissions for these products. Regulatory Authorities, and an alternative procedure for accepting second-line TB Inspections product dossiers for assessment. Programme inspectors carried out 50 inspections in seven countries: 27 of The Programme organized ten technical finished pharmaceutical product manufac- missions to pharmaceutical manufactur- turing sites; seven of active pharmaceuti- ers and QCLs in seven different coun- cal ingredient (API) manufacturing sites; tries. Missions focused principally on ten of contract research organizations good manufacturing practice but also on (CROs) and six of pharmaceutical QCLs. dossier preparation and quality systems The majority of inspections were carried in QCLs. It also organized 12 training out in India, followed by China. workshops and co-organized or sup- ported a further five workshops for nearly A number of manufacturers were con- 800 participants. Workshops ranged from tacted in late 2009 and requested to introductory workshops on WHO Pre- submit their inspection reports from qualification and how to meet require- stringent regulatory authorities together ments, assessment of multisource inter-

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changeable medicines, and to the plan- medicines, six monographs for antituber- ning, implementation and assessment of culosis medicines and one monograph for stability studies. an influenza-specific antiviral medicine. The Committee also adopted: an update Testing of medicines quality of good practices for quality control The pilot phase of an activity to sample laboratories; a guideline for the prepara- and monitor the quality of paediatric and tion of a CRO master file; a guideline on second-line antiretrovirals and sulfa- requalification of prequalification dossiers; methoxazole-trimethoprim for treating various updates and revisions of good HIV/AIDS was completed. Nearly 400 manufacturing practice texts; and an medicines samples produced by 24 update of good distribution practices for manufacturers were collected, mostly pharmaceutical products. Each of these from treatment centres. Only three norms and standards is of direct rel- samples failed quality testing and none of evance to the Programme’s activities. the failures were life-threatening for patients. The results underscore that, Improving Prequalification of Medi- provided procurement and distribution cines Programme services practices are sound, medicines prequali- A business plan for the Prequalification of fied by the Programme can be viewed Medicines Programme was completed in with confidence by health workers and August 2009. It analyses the current patients alike. mandate and functions, maps perform- ance, estimates resources required for The quality of antimalarial medicines was coming years and makes recommenda- surveyed in six African countries for tions on how the Programme can improve artemisinin-based combination therapy organization and management. The plan and sulfadoxine-pyrimethamine oral projects an economic return on invest- dosage forms. Over 900 medicines ment of 170:1 for the Programme for the samples were collected from all levels of period 2009Ð2013. The projection is the distribution chain and informal market based on: projected availability of global and were screened using “minilabs” in funding for procuring medicines for cooperation with the relevant national treating HIV/AIDS, TB and malaria; medicines regulatory authority. Thereaf- projected prequalification of 105 addi- ter, 306 samples were fully tested in the tional medicines (around 90% of which laboratory: 74 samples were non-compli- will be generic medicines); and projected ant and demonstrated a range of quality estimated impact on additional volume of problems, including absence of the API in medicines that can be purchased as a two samples. A quality survey was also result of increased competition among initiated in Armenia, Azerbaijan, Belarus, generics. Kazakhstan, Ukraine and Uzbekistan. It focuses on antituberculosis medicines Survey of manufacturers containing rifampicin, isoniazid, kanamy- In late 2009, work started on develop- cin and ofloxacin. Testing is ongoing for ment of a first survey of manufacturers. the 291 samples collected. The aim is to obtain feedback on the services provided by the Programme and Norms and standards relevant to WHO to analyse where and how improvements prequalification activities to those services might be made. The 44th meeting of the WHO Expert Committee on Specifications for Pharma- Further information on the WHO Prequalifica- ceutical Preparations adopted seven tion of Medicines Programme, including the monographs for HIV and related condi- full list of medicines prequalified by WHO can tions, five monographs for antimalarial be found at: http://www.who.int/prequal

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Regulatory Harmonization

Updating medicines regulatory systems in sub-Saharan African countries

An effective medicines regulatory system ensures that all pharmaceutical products on the market are safe, effective and consistently meet approved quality standards (1). The World Health Organization (WHO) works with its Member States in assess- ing national regulatory systems to identify gaps, develop strategies for improvement and support countries in their commitment to build national regulatory capacity.

The WHO report, Assessment of medicines regulatory systems in sub-Saharan African countries (2), synthesizes the findings of rapid assessments performed over the last eight years of national medicines regulatory authorities (NMRAs) in 26 African countries: Angola, Benin, Botswana, Burkina Faso, Burundi, Cameroon, Chad, Democratic Republic of Congo, Cote d’Ivoire, Djibouti, Ethiopia, Gabon, Ghana, Kenya, Malawi, Mali, Mozambique, Niger, Nigeria, Rwanda, Senegal, South Africa, Sudan, United Republic of Tanzania, Uganda, Zambia. Although the emphasis of the missions was on capacity-building rather than a standardized comparison of indicators, the findings give a useful insight into the regulatory situation in Africa and potential areas for collaboration. The report sheds light on the urgent need for regu- latory capacity strenghtening in African countries and proposes action for sustain- able progress. A summary of the report is set out on the following pages.

Medicines regulation in Globalization of commerce and the developing countries merging of pharmaceutical companies has led to an increasing breakdown of Medicines are essential to health care national boundaries in medicines supply. and should be available to the inhabitants Substandard and counterfeit pharmaceu- of every country. Medicines regulation tical products are now reported from all aims to ensure that medicines circulating parts of the world (3). The problem is in national markets and international greatest in developing countries, which commerce are safe, effective and of good have insufficient funds for medicines quality, are accompanied by complete procurement, and even fewer resources and correct product information, and are to enforce quality standards and protect manufactured, stored, distributed and the medicines supply chain. used in accordance with good practices. Norms and standards for medicines Affordable products are now available quality are becoming more sophisticated with the potential to dramatically reduce and make the assessment of new chemi- morbidity and mortality in resource- cal entities especially challenging. WHO constrained countries. Although African continues to develop international norms countries import most of their pharmaceu- and standards to serve as guidance for ticals, the African Union has recently national regulatory systems. In practice started to promote local manufacture of however, medicine quality standards are medicines in Africa. subject primarily to the requirements in

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force in the country of destination (4). their technical judgement of the authors Regulating the increasingly complex together with the views expressed by channels of medicines supply requires relevant national regulatory officials. constant vigilance, adaptation and con- siderable organizational capacity and Country profiles resources. The 26 countries included in the report represented 88% of the population of Aim of the WHO report sub-Saharan Africa in 2007. Key eco- Assessments of medicines regulatory nomic and health-related data are also systems in sub-Saharan African countries summarized in the report (2). presents assessments of regulatory Pharmaceutical sector data contained in systems conducted in 26 sub-Saharan country reports indicated that African African countries over the past eight countries generally had: years. It identifies regulatory gaps and suggests priority activities to strengthen ¥ Limited pharmaceutical production regulatory capacity. capacity, while most depended mainly At the request of each country, national on imports. medicines regulatory authority (NMRA) ¥ Some pharmaceutical manufacturing assessments were carried out between activity catering mainly for domestic and 2002 and 2009 by teams composed of regional demand. However there were WHO experts, staff from NMRAs and/or some exporting countries. external consultants. Written terms of reference and an agenda for the visits ¥ A diverse distribution chain, with various were agreed beforehand with the regula- types of unauthorized outlets suggest- tory authority being assessed. The ing the presence of an informal market. duration of the visits varied depending on the complexity of the country’s regulatory In virtually all countries included in the functions, most visits took approximately report, limited public funds were available three to five working days. for law enforcement in general and for medicines regulation in particular. Addi- Data were collected by interviewing tionally, there were indications of the personnel, reviewing documents (manu- presence of parallel, unregulated medi- als, records, reports, files), analysing data cines markets, posing a serious risk to and/or observing activities. Findings were individual and public health. recorded on a comprehensive data collection tool developed by WHO (5) Nevertheless, differences did exist in the which has since been complemented by a efficiency of the measures implemented detailed guidance document (6). A draft among countries. This illustrates the report was submitted to the regulatory impact of political commitment and level authority after the visit together with a of resources allocated to medicines drafted proposal for a plan of action. The regulation. main aim of the visits, and the design of the tool itself, were geared towards Regulatory framework identifying priorities for strengthening regulatory capacity. They were not Legislation intended to provide comparable indicators Written laws, Acts or Statutes enacted by of regulatory capacity over time. Parliament give the NMRA the power to control medicines. Regulations prepared The strengths and weaknesses identified under the authority of an Act provide by the country reports are a reflection of directions on how regulatory functions are

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to be carried out. Guidelines are also All types of medicines should be regu- needed to interpret legislation and advise lated by the NMRA. At the same time, on how to comply with a regulation. The implementation of medicines regulation way in which these legal and explanatory should not be compromised by other, texts are drafted affects the efficiency of non-regulatory activities exerted by the medicines regulation. NMRA.

The legal framework should allow effec- Key findings tive implementation and provide ad- equate powers to the NMRA. Legislation ¥ Seventeen of 26 NMRAs (65%) had the should cover all products for which mandate to control veterinary medi- medicinal claims are made as well as cines. In four countries veterinary related manufacture and trade activities in medicines were controlled by another the public and private sectors. Countries Ministry, such as the Ministry of Agricul- should update their medicines legislation ture or Livestock. and regulations regularly to reflect na- tional realities and to address new phar- ¥ Eighteen of 26 NMRAs (69%) had some maceutical issues as they arise (1). policy or provisions to deal with tradi- tional or herbal medicines. While eleven Key findings of these registered traditional or herbal medicines, another two were about to ¥ In most countries, legislation had start doing so. evolved over many years. In only three countries had a medicines regulation ¥ NMRAs in eleven countries (42%) Act been adopted later than 2000. regulated a wide scope of products, ¥ Successive regulations and decrees which included foods, poisons, pesti- had created a complex legal framework cides, bottled water, cosmetics and/or with overlaps and grey areas. animal food supplements. ¥ Regulations for specific regulatory ¥ In seven countries, the NMRA was functions were missing in some coun- involved in designing and implementing tries, especially where the NMRA was national medicines strategies, imple- undergoing transformation. menting legislation or coordinating public sector medicines supply; in one Regulatory scope case a clearly distinguished unit was in In the last few decades, expansion of charge of policy issues. regulatory scope has been considered in many countries (7). A medicine has been Organizational forms defined as “Any substance or pharmaceu- One central authority should be account- tical product for human or veterinary use able for the overall effectiveness of that is intended to modify or explore medicines regulation. It should have physiological systems or pathological government backed legal power to states for the benefit of the recipient” (8). acquire and use resources, recruit and In addition to conventional medicines for dismiss staff, and make independent human use, this definition also includes decisions. The choice of a specific organi- biological medicines (including vaccines zational form will have an impact on the and blood products), veterinary medi- autonomy, visibility and accountability of cines, and traditional and herbal medi- an NMRA and would affect efficiency in cines, although the latter category is medicines control. challenging to define and to regulate (9).

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Key findings laboratories were part of the NMRA. In one of the remaining countries, there Historically, most NMRAs in Africa started was an NMRA laboratory which had life as departments under the Ministry of ceased to function. Health. Organizations of this type have little autonomy. They cannot recruit their ¥ Most countries had fragmented regula- own staff, nor can they offer adequate tory systems. Gaps and overlaps of salaries to attract and retain qualified responsibilities were common, espe- experts. With the maturation of regulatory cially in licensing (involving the Ministry systems, some countries are moving of Public Health or Ministry of Trade) away from this model and are establish- and inspection (involving pharmaceuti- ing their NMRAs as autonomous bodies cal councils, regional authorities or or as centralized parastatal agencies with public health inspectorates). their own management structures. ¥ Decentralization and cooperation ¥ Seventeen of 26 authorities (65%) were between authorities was problematic; departments of the Ministry of Health, 12 reports highlighted the lack of with very little or no autonomy to man- communication at operational level. age their own funds and human re- sources. ¥ In many cases, regulatory functions ¥ Seven NMRAs (27%) were in transition were not operational and in some cases or not formally constituted at the time of authorities were not legally delegated. the visit. Structure and management Regulatory functions NMRA responsibilities should cover all Funding medicines regulatory functions and Sustainable funding for NMRAs should be should be performed in a balanced derived from various sources: fashion. ¥ Fees, which contribute significantly to If functions are distributed between operational costs without being too high different authorities, either horizontally to discourage applications. (e.g., ministry of health, ministry of agriculture) or vertically (federal, state/ ¥ Public funding, to ensure a certain regional and local governments), a independence from the parties that central coordinating body should be MNRAs are mandated to regulate. accountable for all aspects of medicines regulation in the country (1). ¥ Donations to supplement limited public funds. Key findings NMRAs should have the autonomy to ¥ Four of the 26 NMRAs (15%) carried out retain and use the fees collected for functions of marketing authorization, services provided for their own purposes. licensing, inspection, quality control and pharmacovigilance together under one Key findings umbrella. ¥ Most NMRAs derived their funding from ¥ Seventeen NMRAs (65%) had access to more than one source, although the a functional national regulatory quality proportions varied from one country to control laboratory, while seven of these another.

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¥ Fees were commonly charged for initial ¥ Job descriptions for key personnel were marketing authorization, renewal and described as absent in five countries, retention. More rarely, fees were and as unclear or outdated in four. Four charged for importation of medicines, reports mentioned the absence of an inspection, analysis of samples and organigram. registering persons and premises. ¥ In some authorities, responsibilities ¥ Generally, the fees were lower than the were not assigned appropriately. One cost of services rendered, and were not NMRA director was at the same time retained or redistributed in full. the director of the national laboratory, resulting in an unmanageable workload. ¥ Nine NMRAs depend on government Three others were simultaneously in funding, with all fees paid directly to the charge of public sector medicines treasury and not redistributed. Four supply or tenders, creating a potential NMRAs also receive donor funding. conflict of interest. Funds allocated by the states were not always released on time. ¥ Four reports mentioned the absence of a legal adviser on the NMRA’s payroll. ¥ None of the NMRAs assessed had adequate and sustainable funding to Quality management systems cover operations. NMRAs perform critical and sensitive functions such as handling and assessing Human resource management marketing application dossiers containing Personnel engaged in medicines regula- confidential information, inspecting tion should be individuals of integrity and facilities and handling site master files. be appropriately trained and qualified. A quality management system (QMS) should ensure that the operations of an Human resource development pro- NMRA are carried out to defined, uniform grammes should be made available to standards, and that each step of the enable staff to keep up with develop- regulatory process is identified and ments in pharmaceutical science and documented. technology. Key findings Key findings ¥ Four NMRAs (15%) were in the process In general, human resource management of implementing a QMS and had ele- was virtually non-existent. This was the ments of the system in place, two others case especially where an NMRA was not were drafting a system. given importance by the Ministry of Health. As a result, lack of qualified staff ¥ None of the NMRAs had implemented a affected critical regulatory functions while comprehensive QMS. specific shortcomings included the following. Impartiality and transparency Medicines regulation is a public policy ¥ Only two of the 26 NMRAs (8%) had a that regulates private sector activities in human resource development plan, order to attain the promotion of public which was however not specific to the health. Conflicting interests therefore tasks of the NMRA. Specific training need to be recognized and managed needs and difficult access to sources of appropriately. current information were noted in most countries.

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To provide credible regulatory services, 2. Guidelines for applicants setting out NMRAs must have specific measures in the conditions, content and format of place to avoid conflict of interest in applications, and the detailed technical decision-making, to ensure confidentiality, requirements against which dossiers will to make their rules and decisions trans- be assessed, based on international parent, and to consult with stakeholders. guidelines (11Ð13).

Key findings 3. Standard operating procedures (SOPs) to assess submissions, and standard ¥ Nine of the 26 NMRAs had a dedicated formats to communicate and publish the web site. Five of these were in need of outcomes. updating, one was not functioning correctly at the time of the visit. As at 4. Involvement of an advisory committee November 2009, seven additional sites and expert assessors in adequate num- were identified (10). bers with specific, current expertise.

¥ Consultation with stakeholders took 5. Logistics for management, secure place in most countries, although it storage, retrieval and exchange of data tended to be limited to specific issues or with other regulatory departments, as well groups. as access to current scientific and techni- cal information. ¥ Current information was not always 6. Mechanisms to consider decisions publicly available: lists of approved from more stringent NMRAs. products or establishments were often missing and/or outdated. Little informa- Key findings tion was made public on decision- making. ¥ Some evaluation of technical docu- ments was performed in 19 of 26 ¥ Twenty-three of 26 NMRAs (88%) had countries (73%) to varying degrees of no written declaration of interest or stringency, at least for generic medi- confidentiality agreements in place, cines. although some had general rules of conduct such as a code for civil serv- ¥ The technical standard of evaluations ants. In the three countries which did was generally not in line with WHO have a specific written system, this did standards. For example, in at least four not apply to all technical staff involved. countries, guidelines did not exist. At least three NMRAs did not require the Medicines registration manufacturer to have GMP certification. A core regulatory function is the authori- At least six NMRAs did not assess zation of medicines based on a scientific summaries of product characteristics assessment of their safety, efficacy and (SPC). quality. ¥ The capacity to assess applications for To assess applications for marketing new innovator products was almost authorization, NMRAs need: non-existent. ¥ NMRAs in seven countries conducted 1. Legislation giving the NMRA the power only an administrative review of docu- to grant, renew, vary, suspend and ments, or no review at all at the time of withdraw marketing authorizations. the assessment.

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Legal basis and regulations Timeframes for assessment of applica- tions ranged from three months to five ¥ Eighteen of 26 NMRAs (69%) operated years, depending on the complexity of within a legal basis which empowered assessments and available resources. them to assess applications for market- Fast-track mechanisms existed for certain ing authorization, with regulations that product types. Two reports mentioned the briefly outlined the requirements or short preparation and meeting times listed the components of dossiers to be available for committee members to make submitted for different types of products. their decisions, meaning that they may not be able to read all documents and ¥ Provisions for renewal of marketing carry out any real assessment. authorizations were in place, usually every five years. ¥ Although overall assessment time frames were long, little time was avail- ¥ Seven countries had provisions which able for an in-depth thorough assess- exempted wide ranges of products ment by experts due to scheduling (such as public sector imports or dona- difficulties and backlogs. tions) from registration or from specific requirements irrespective of quality risk. Expert assessors For example, in one country, all oral Most NMRAs had formal advisory com- solid-dose anti-infectives were exempt mittees. However, not all committees from in vivo bioequivalence studies. were operational, bringing assessment to a halt in two countries. Eleven countries Guidelines used external experts, two of them Some countries had guidelines which exclusively. Appointment of committee described the required content of submis- members and experts was not necessar- sions and gave brief instructions, but did ily based on specific regulatory expertise, not give sufficient guidance on technical and provisions for confidentiality and issues such as bioequivalence and declaration of interest were lacking in stability. Others described the administra- most countries. tive steps and others provided only checklists. A specific format for submis- ¥ Twenty-four of 26 country reports (92%) sions was not required in any of the mentioned the shortage of adequately countries. qualified assessors as an obstacle to ¥ Only three NMRAs (12%) provided timely dossier evaluation. detailed technical guidelines (but not in line with WHO Guidelines). Logistics ¥ Only four NMRAs (15%) had appropri- Procedures for assessment ate archiving space to store confidential Written SOPs for dossier assessment data securely. were either absent or they described only administrative steps such as checking the ¥ Only six of 26 countries (23%) had completeness of dossiers, payment of coherent, networked computerized fees or inclusion of samples, or were systems designed for medicines regis- checklists outlining elements of the tration. Nine (35%) had only manual assessment methodology. systems.

¥ Adequate SOPs for dossier assessment The latter shortcoming affected transpar- were in place in only three countries. ency and information-sharing with other

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departments. Lists of registered products The lack of mechanisms and procedures were not readily available, which made it that would enable NMRAs to benefit from difficult to verify the registration status of the scientific assessments and inspec- medicines circulating in the market and tions carried out by other well resourced those being imported. The countries and established regulators is a major which did publish a list did not include the cause of concern, as most of the authori- approved summary of product character- ties in the region have limited human istics (SPC) needed to verify package resources and scientific expertise. (See inserts, information for health profession- Figure 1.) als and advertising claims. Licensing of pharmaceutical Recognition of decisions establishments made by other NMRAs Health budgets in African countries are Certificates of pharmaceutical products low and a high percentage of health costs (CPPs) issued under the provisions of the are paid out of pocket. There are many WHO Certification Scheme on the Quality types of medicines outlets not managed of Pharmaceutical Products Moving in by a pharmacist. Concerns about the International Commerce (14) were parallel medicines market were voiced in commonly requested as part of applica- most country reports, such as this typical tions, but usually without considering the statement: “The illicit medicines market capacity of the issuing regulatory author- has become a real plague in the country. ity to certify that the data on the certifi- All therapeutic classes can be found, cates was correct. Conversely, one report including psychotropic medicines, and from an exporting country mentioned that there is no national strategy to combat the NMRA “issues CPP without ascertain- this situation.” ing that all prerequisites as specified by A mandatory system of licensing manu- WHO are fulfilled”. facturers, wholesalers/distributors and retailers is essential to ensure that ¥ Only two NMRAs (8%) explicitly relied medicines conform to acceptable stand- on other regulatory bodies/organizations ards of quality, safety and efficacy until which they considered stringent, includ- they reach the end user. Licensing must ing the WHO Prequalification Pro- be complemented by inspections and gramme (15). market surveillance. Figure 1. Resources for medicines registration

25

20

25

20 5

Number of NMRAs 0 Legal basis Guidelines SOPs for Assessors Secure IT system outline (tech. detail) assessment filing space

Adequate Existing but inadequate Not existing No information or not applicable

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NMRAs should ensure that all premises importation of pharmaceutical products and practices used to manufacture, store, on the basis of the product’s registration distribute and supply pharmaceutical status. products to patients comply with current guidelines on good manufacturing prac- Products for export should be subject to tice (GMP), good distribution practice the same standards as those for domestic (GDP) and good pharmacy practice consumption. (GPP). Key findings Key findings ¥ Control of imported products was weak. ¥ All countries except one had systems in In at least eight countries (31%) there place to license pharmaceutical estab- was no efficient system to verify the lishments. marketing authorization status and exemptions for imported products. ¥ Authorities other than the NMRA were involved in licensing in 16 countries ¥ Cooperation with police and customs (62%), resulting in overlaps, grey areas was consistently described as problem- and gaps in the control of pharmaceuti- atic. cal activities. ¥ Control of exports was not stringent. ¥ Decentralization of licensing, involving One report mentioned manufacturers’ regional authorities, was not organized illegal practice of issuing “free sale efficiently. Lack of coordination was certificates”, which leaves all control to commonly highlighted; lax control of the receiving country. licensing by local authorities was mentioned specifically in three country Inspections reports. Inspections conducted on pharmaceutical facilities should enable medicines regula- ¥ Licences or renewals were granted tory authorities to monitor whether phar- without inspection in some instances. maceutical activities are carried out in accordance with approved standards and ¥ In practice, good practices requirements guidelines. The efficiency of inspections were poorly enforced. In one country has a direct impact on the extent to which only one of many established manufac- medicines control is enforced. turers was licensed. A legal basis must be in place for inspec- Import and export control tions and enforcement. Planning of With the rapid introduction of high- routine inspections should be imple- technology medicines into import, export mented to regularly check compliance and distribution networks (including e- with relevant good practices in place. commerce), the safety, quality and efficacy of medicines on the market are A quality management system (16) matters of considerable concern. should ensure that inspections are planned, conducted, documented and Setting in place a registration system followed up in a consistent way, based on should not be considered as the only risk assessment. mechanism to guarantee the quality of products on the market. It should be Sufficient qualified inspectors and logistic complemented by other control measures resources must be available to cover the such as the authorization of each act of area to be regulated.

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Key findings ¥ Potential conflicts of interest were noted. Inspectors could be pharmacy ¥ A legal basis empowering the relevant technical directors or supervisors in at authority to perform inspections was in least three countries. Pharmacists from place in 17 countries. private retail and manufacturing facilities ¥ GMP was not required in at least nine were used as inspectors in another. countries. In at least two countries ¥ Inadequate logistic resources, espe- where GMP was required, none of the cially means of transport and communi- established manufacturers had GMP cation, were a major constraint. The certification. effectiveness of inspections suffered ¥ Only five of 26 countries (20%) had from these constraints. (See figure 2.) published GMP guidelines meeting WHO standards (two had national texts, Quality control and another three used the WHO text). Quality control (QC) aims to verify that Only one country had adequate GDP products comply with the specifications of guidelines. the marketing authorization. QC testing of pre-marketing samples can be useful to ¥ SOPs for inspection, if any, were mostly some extent, although applicants may in checklist format and were not com- take measures to ensure that their prehensive. registration samples will not fail. However, the same quality standards may not be ¥ No NMRA had a comprehensive quality met by each batch of product put on the management and planning system for market. QC testing of post-marketing inspections in place. samples thus acts as a deterrent against negligent or fraudulent manufacturing and ¥ Shortages of qualified inspectors were a trading practices. universal problem. The need for specific training of inspectors in current GMP NMRAs should have access to a quality was commonly highlighted. control laboratory with adequate capacity to undertake quality surveillance.

Figure 2. Resources for inspections

25

20

25

20

5

Number of NMRAs

0 Legal basis Published Standard Quality Inspectors Logistics GMP text Operating Management Procedures System

Adequate Existing but inadequate Not existing No information or not applicable

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QC facilities should have sufficient different sectors both at country level and qualified personnel and the necessary internationally (20). In both cases, the equipment and materials, and must deficient products pose a risk for indi- operate according to established stand- vidual and public health. ards. A quality management system, such as ISO 17025 (17), provides a framework A risk-based system of inspections and for QC laboratories to operate according sampling should be in place to monitor to defined procedures and standards. the quality of pharmaceutical products on WHO’s good practices for national phar- the market. Manufacturers should be maceutical control laboratories (18) and obliged to report complaints and quality guidance on good laboratory practice (19) problems to the NMRA. An effective recall provides detailed advice on organiza- procedure to remove defective products tional and technical issues. from the market should be in place.

If dossiers are assessed and samples The NMRA should coordinate an anti- tested, good collaboration between counterfeiting programme with all con- assessors and laboratory staff needs to cerned parties, including industry, cus- be in place. toms, police and any other stakeholders involved in trade or distribution of phar- Key findings maceuticals.

¥ A QMS was in place at five (29%) of the Key findings 17 functioning regulatory laboratories; three others had partial systems which ¥ Fourteen of 26 NMRAs (54%) lacked a were lacking essential elements and quality monitoring programme alto- were not fully operational. gether; seven had the capacity to test samples in case of complaints or in the ¥ Satisfactory staffing and equipment framework of specific programmes, and were in place in the majority of cases, only five (19%) had a systematic ap- but six laboratories were housed in proach. inadequate buildings. Ten reports mentioned QC testing for pre- ¥ Twenty of 26 NMRAs (77%) lacked a marketing applications. However, the written procedure to organize an effec- laboratories were not always given the tive recall; of the existing six procedures relevant dossiers, manufacturer’s refer- three needed clarification. Five reports ence materials and validated methods. noted the lack of batch traceability needed to recall products. This finding Market surveillance is consistent with the general absence of published GDP guidelines. Product quality monitoring Substandard pharmaceuticals may ¥ Anti-counterfeiting measures included circulate on the market if good practices inspections and surveillance in five in manufacturing, distribution and storage countries and awareness programmes are not adhered to. in three. No country had a specific, comprehensive programme in place at In addition, counterfeiting — the produc- the time of the visits. tion and distribution of medicines that are deliberately and fraudulently mislabelled Pharmacovigilance with respect to identity and/or source — Pre-marketing clinical trials are usually is becoming an increasing problem. It conducted on a small number of volun- requires a coordinated response from teers. Not all adverse reactions can be

16 WHO Drug Information Vol. 24, No. 1, 2010 Regulatory Harmonization

anticipated from these studies. NMRAs controlled pharmaceutical promotion to should implement a system to monitor varying extents. adverse events. For this to be effective, there must be a high probability for ¥ In 19 countries (73%) there was no adverse events to be identified and control of promotion and advertising in reported, reports must be reviewed and practice, meaning that even if the validated by experts, results must be fed regulations were in place, they were not back, and appropriate regulatory action implemented. must be taken. ¥ At least 13 NMRAs did not provide any Key findings independent medicines information to the public. ¥ Eight of 26 countries collected reports on adverse events, with three of the Oversight of clinical trials programmes being sufficiently estab- Clinical trials are an essential component lished to contribute a sizeable number of pharmaceutical research and develop- of results. Seven of the eight countries ment. They serve to establish the safety were members of the WHO Programme and efficacy of new medicines, and to for International Drug Monitoring (see develop new treatment uses of well http://www.who-umc.org/). known medicines. Clinical trials also include in vivo bioequivalence studies ¥ Where it existed, pharmacovigilance carried out with generic medicines to was generally not well integrated with establish their therapeutic interchange- other regulatory activities. Also, clinical ability with originator products. In all these surveillance measures implemented by types of studies the ethical rights and the specific national or NGO treatment safety of trial subjects must be protected, programmes were not organized or and the methodology must be designed envisaged. in such a way as to arrive at useful, scientifically valid results. Medicine promotion and advertising, provision of drug information NMRAs should control clinical trials jointly Information propagated through promo- with external bodies such as national or tion and advertising can significantly institutional ethics committees. Trials influence the way in which medicines are should conform with ethical principles for prescribed by health professionals and medical research involving human sub- used by consumers. Inaccurate and jects and the Declaration of Helsinki (21). misleading information therefore poses a Guidelines by the Council of International health risk. Organization of Medical Sciences (CIOMS) provide valuable additional NMRAs should control promotion and information on research ethics. advertising to ensure that any claims made correspond to the approved sum- WHO guidelines for GCP (22) and GLP mary of product characteristics (SPC). (19) should be followed. GMP of investi- They should also provide independent gational products should be verified. information on medicines to the public Other more specific guidelines on clinical and health professionals. research may apply.

Key findings Trials should be monitored for compliance with all applicable guidelines. Investiga- ¥ Most countries had some legal provi- tors should be required to report on the sions for the control of medicines outcomes promptly, including any serious promotion. Seven of 26 countries (27%) adverse events encountered.

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Key findings As a result of these drawbacks, medi- cines regulation was not being carried out ¥ In 18 of 26 countries (69%) clinical trials to the fullest extent. The findings confirm were controlled to some extent, mostly the results of a 2004 questionnaire survey with regard to ethical review. conducted by WHO in 38 African Member States, which found that 90% of countries ¥ Where ethics committees were involved, were in a situation which did not allow NMRAs retained little or no control due them to adequately carry out regulatory to lack of capacity, unclear assignment functions (23). of responsibilities or non-representation in the relevant committees. Despite the universally scarce resources ¥ Adherence to GLP and GCP was not a and the health workforce crisis experi- requirement in 22 countries (85%); enced throughout sub-Saharan Africa, detailed GCP guidelines were found in marked differences were noted in the only two countries (8%). relative efficiency of medicines control among countries, showing that political ¥ Eight reports mentioned the absence of commitment at national level can make a import controls and GMP requirements difference. for investigational products. ¥ Only four country reports mentioned that On the positive side, many countries were greatly committed to improving their inspections of clinical trials were being conducted. medicines regulatory capacity: reviews of systems were invited and regulatory restructuring is being adapted. However, Conclusions in many cases, the transformation proc- The countries included in this report had ess has created new administrative legal provisions for the most essential hurdles for effective decision-making, needs of medicines control. However, management and release of funding. their regulatory systems presented some weaknesses. Generally, the legal frame- The follow-up assessments conducted in work had evolved over time, resulting in a four countries showed progress in spe- fragmentation of responsibilities with gaps cific areas. However, for a sound, well- and grey areas and a multitude of provi- resourced national medicines regulatory sions which were difficult to implement. system to operate within the difficult conditions imposed by African markets, Many NMRAs were allowed little power commitment must be long term. and autonomy, and were unable to oversee the full range of regulatory The way forward should be towards functions, with few having systems for effective implementation of medicines accountability or managerial commitment. control in practice. Political will and Lack of sustainable funding restricted substantial human and financial re- operations to a great extent. Virtually all sources will be needed for this purpose. NMRAs suffered from staff shortages. For Countries will need to take concerted the most part, assessors and inspectors action if they are to expand access to were unable to satisfactorily attain the medicines of assured quality and safety level of scientific and technical expertise for their populations. It was felt that the needed to fully implement regulatory following approaches would be the most tasks. Many regulatory requirements and useful in building regulatory capacity in processes were not in line with recom- Africa. mended WHO standards.

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WHO should: 3. Caudron JM, Ford N, Henkens M et al. Substandard Medicines in resource-poor ¥ Encourage African countries to provide settings: a problem that can no longer be NMRAs with adequate organizational ignored. Trop Med Int Health. 2008;13(8): structure, sufficient autonomy and 1062Ð72. http://www.msf.org.za/docs/ ScientificDocsTMIH2008_Vol13_ sub- sustainable resources to enable them to standards.pdf carry out operations. 4. US Pharmacopeia Drug Quality and ¥ Encourage and assist African countries Information Program. Matrix of Drug Quality to regularly assess their own regulatory Reports in USAID-assisted Countries. July systems in a standardized way. The 1st, 2008. Available at www.uspdqi.org WHO assessment tool and the accom- panying guidance have been developed 5. World Health Organization. Data collection for this purpose. tool for assessment of regulatory authorities. http://www.who.int/medicines/areas/ quality_safety/regulation_legislation/assess- Countries should: ment/en/index.html

¥ Consider mechanisms to share the 6. World Health Organization. Practical outcomes of regulatory assessments Guidance for Conducting a Review (based on among NMRAs. the WHO Data Collection Tool for the Review of Drug Regulatory Systems). Regulatory ¥ Work towards effective implementation Support Series, No.12. 2007. http://www.who. of all essential regulatory functions int/medicines/ under the umbrella of an NMRA net- work. 7. World Health Organization. Ratanawijitrasin S, Wondemagegnehu E. Effective drug regulation: A multicountry study. Geneva: ¥ Continuously harmonize, adapt and 2002. http://www.who.int/medicines update the legal framework for medi- cines regulation based on internationally 8. World Health Organization. Guidelines for recognized norms, standards and best registration of fixed-dose combination medici- practices. nal products. Annex 5. In: Technical Report Series, No. 929, 2005. http://whqlibdoc.who. ¥ Provide specific, relevant training for int/trs/WHO_TRS_ 929_eng.pdf assessors, inspectors and other techni- cal staff, in line with current technical 9. World Health Organization. National policy on traditional medicine and regulation of requirements and good practices. herbal medicines. Report of a WHO global survey. 2005. http://apps.who.int/ References medicinedocs/collect/medicinedocs/pdf/ 1. World Health Organization. Effective medicines regulation: ensuring safety, efficacy 10. World Health Organization. List of Globally and quality. WHO Policy Perspective on identified Websites of Medicines Regulatory Medicines No. 7. Geneva: WHO, 2003. http:// Authorities (2009). http://www.who. int/entity/ apps.who.int/medicinedocs/pdf/s4921e/ medicines/areas/quality_safety/regulation_ s4921e.pdf legislation/ListMRAWebsites.pdf

2. World Health Organization. Assessment of 11. World Health Organization. Marketing medicines regulatory systems in sub-Saharan authorization of pharmaceutical products with African countries (under preparation) http:// special reference to multisource (generic) www.who.int/medicines products: A manual for drug regulatory

19 Regulatory Harmonization WHO Drug Information Vol. 24, No. 1, 2010

authorities. Regulatory Support Series, No. 5. 18. UNDP/World Bank/WHO Special Pro- WHO/DMP/RGS/98.5 (1999) http://www. gramme for Research and Training in Tropical who.int/prequal/info_general/documents/ Diseases (TDR). Handbook. Good laboratory practice (GLP). Quality practices for regulated 12. World Health Organization. Multisource non-clinical research and development (2001) (generic) pharmaceutical products: guidelines at http://www.who.int/tdr/svc/publications/ on registration requirements to establish interchangeability. Annex 7. In: Technical 19.World Health Organization. Good practices Report Series, No. 937, 2006. http:// for national pharmaceutical control laborato- whqlibdoc.who.int/trs/WHO_TRS_ 937_ ries. Annex 3. In: Technical Report Series, No. eng.pdf 902, 2002. http://apps.who.int/prequal/ info_general/documents/TRS902/ 13. World Health Organization. Guidelines for WHO_TRS_902-Annex 3.pdf organizations performing in vivo bioequiva- lence studies. Annex 9. In: Technical Report 20. World Health Organization. Fact sheet on Series, No. 937, 2006. http://whqlibdoc. counterfeiting. Key facts. July 2009. http:// who.int/trs/WHO_TRS_937_ eng.pdf www.who.int/medicines/services/counterfeit/ CfeitsFactSheetJuly09.pdf 14. World Health Organization. Guidelines for implementation of the WHO certification 21. World Medical Association. Declaration scheme on the quality of pharmaceutical Of Helsinki — Ethical Principles for Medical products moving in international commerce. Research Involving Human Subjects, Annex 10. In: Technical Report Series, No. (amended by the 59th WMA General Assem- 863, 1996. Current version of the guideline bly, Seoul, October 2008). http://www.wma. available at http://www.who.int/medicines/ net/en/30publications/10policies/b3/index.html areas/quality_safety/regulation_legislation/ certification/en/ 22. World Health Organization. Guidelines for good clinical practice (GCP) for trials on 15. World Health Organization. Procedure for pharmaceutical products. Annex 3. In: Techni- prequalification of pharmaceutical products. cal Report Series, No. 850, 1995. http:// Annex 3. In: Technical Report Series, No. 953, www.who.int/medicinedocs/collect/ 2009. http://www.who.int/medicines/publica- medicinedocs/pdf/whozip13e/whozip13e.pdf tions/pharmprep/pdf_trs953.pdf#page=164 23. Organisation mondiale de la Santé, 16. World Health Organization. Quality Comité Régional de l’Afrique. Cinquante- systems requirements for national good sixième session, Addis-Abéba, Ethiopie, 28 manufacturing practice inspectorates. Annex août–1er septembre 2006. Autorités de 8. In: Technical Report Series, No. 902, 2002. réglementation pharmaceutique: situation http://apps.who.int/prequal/info_general/ actuelle et perspectives. Rapport du Directeur documents/TRS902/WHO_TRS_902-Annex régional. http://www.afro.who.int/rc56/docu- 8.pdf ments/french/afr_rc56_11_ autorites_ reglement_ pharmaceutique.pdf 17. International Organization for Standardiza- tion. General requirements for the compe- tence of testing and calibration laboratories. ISO/IEC 17025:2005. 2005.

20 WHO Drug Information Vol. 24, No. 1, 2010 International Nonproprietary Names

The glycosylation pattern well characterized, clinically tested, approved and distributed under the brand of epoetins name Dynepo¨ in the European Union. The human gene for erythropoietin was Almost at the same time as Dynepo¨ cloned in the early 1980s and recom- appeared on the market, the first biosimi- binant production processes were set up lar epoetin products were introduced: a by several companies shortly thereafter. product developed by Sandoz was Commencing in 1989, these processes marketed under three brands (Binocrit¨; have led to the introduction of two thera- Epoetin alfa¨; Abseamed¨) and a prod- peutic compounds onto the market, uct developed by Stada/Hospira mar- epoetin alfa and epoetin beta. Both of keted under two brands (Silapo¨; these recombinant versions of human Retacrit¨). Common to all biosimilar erythropoietin are manufactured in epoetins so far is the claim of similarity to engineered Chinese Hamster Ovary epoetin alfa and production in CHO cells. (CHO) cells. The INN they use is rather epoetin alfa (Sandoz products) or epoetin zeta (Stada/ In parallel with epoetin alfa and epoetin Hospira products). A further epoetin beta development, two other versions of produced in CHO cells has recently been epoetins have been developed. One was approved in the European Union as a de produced in Baby Hamster Kidney (BHK) novo development: epoetin theta from cells and another in C127 (mouse epithe- Ratiopharm (Biopoin¨; Ratioepo¨; lial) cells. The BHK product received the Eporatio¨).* International Nonproprietary Name (INN) In conclusion, the majority of products on epoetin omega and the C127 product the market in the European Union, North epoetin gamma. Neither of these two America and parts of Asia are derived products reached the market in the from CHO cells, while BHK derived European Union, North America or Japan products are available widely in develop- for intellectual property reasons. Epoetin ing countries. However, the C127 product omega, developed by Elanex, has been never reached the market, and the only manufactured in several developing product based on a human cell system countries and used in Latin America, India (Dynepo¨) has been withdrawn from the and other countries for many years under European Union market. different trade names (Epomax¨; Hemo- max¨, etc.). Glycosylation Further development involved the use of Glycosylation is an inherent feature of the a human fibroblast cell line (HT1082) particular cell line used for manufacturing producing erythropoietin by activating the erythropoietin and will depend on the endogenous erythropoietin gene. This enzymatic machinery of the cell and the product, under the INN epoetin delta, was growth conditions used for cultivating the cells. CHO cells in general show glyco- Prepared by Dr Anton Haselbeck, Head of New Technologies, Roche Pharma Research, * Development of modified versions of erythro- Germany. (This article does not necessarily poietin, such as darbepoetin or mircera, will represent the views of WHO) not be covered in this summary.

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sylation capabilities similar to human cells from BHK cells, another rodent cell line with some slight differences. The amino used, basically shows the same structural acid sequence encoded in the gene and elements as CHO, whereas other cell inserted into the production cell line lines, like the human line HT1081, may dictates the position (the exact amino show certain differences. acid) where a carbohydrate chain can be attached. The location within the se- Nevertheless, all cells will produce a quence and, more importantly, within the great variety of glycoprotein molecules three-dimensional structure of the protein with different carbohydrate structures influences the nature of the final carbo- which in the course of manufacturing will hydrate structure. be further refined by selecting a subset of these molecules as the therapeutic entity. In general there are two ways carbo- This process will further influence the hydrates can be attached to proteins, actual carbohydrate heterogeneity of a either N-glycosidically on asparagine glycoprotein drug. Thus, the process will (Asn) residues or O-glycosidically on finally define the end product. serine (Ser) or threonine (Thr) residues. Erythropoietin contains three asparagine Carbohydrate structures residues in a sequence motif sufficient for N-glycosylation and one serine used for of epoetins O-glycosylation. The four sites are glyco- CHO-derived products (epoetin alfa, sylated in human erythropoietin as well beta, theta, zeta) as in all recombinant epoetin products on Three N-linked carbohydrate structures the market. This leads to approximately are predominantly of the tetra-antennary 15 major carbohydrate structures (glyco- complex type. Characteristic for CHO forms) present in all epoetins in some- glycosylation is a high degree of complex what different quantitative distribution. structures with LacNAc repeats (GlcNAc- Gal); there is a tendency to have smaller For secretory proteins like erythropoietin, complex type structures (e.g., bi-anten- the glycosylation process starts with an nary and tri-antennary on Asn 24, where- initial attachment of a precursor carbohy- as Asn38 and Asn83 almost exclusively drate structure to the growing polypeptide carry tetra-antennary structures with chain. This carbohydrate structure will be variable numbers of LacNAc repeats. further modified during the secretion process of the glycoprotein from the Minor structures, like high-mannose-types endoplasmic reticulum through the Golgi with phosphate groups can also be found apparatus and finally through secretory if sophisticated analytical tools are vesicles to the outside of the cell. This applied, as well as hybrid-type structures. process of modifying the carbohydrate chains involving numerous enzymes from Sialic acids (mainly NeuAc) are bound the host cell during secretion is the main exclusively α2Ð3 to galactose as CHO reason for the heterogeneity obtained in cells lack the enzyme for the formation of the final carbohydrate structures. α2Ð6 linkages found on human glycopro- teins. A small percentage (approximately All CHO production cells, albeit devel- 1%) of the sialic acid appears as N- oped independently, generally produce glycolyl-neuraminic acid (NeuGc). glycosylation patterns which consist of a number of CHO-typical structures with There are quantitative differences in the quantitative differences in the distribution glycosylation patterns of epoetin alfa, of the individual structures. The glyco- beta and zeta reflecting the actual CHO sylation pattern of erythropoietin obtained production clone and unique production

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process used. The glycosylation profile of very similar profile with respect to epoetin theta has not been released yet. antennarity and sialylation was revealed. The O-linked carbohydrate is smaller and However, the amount of glycoforms consists of 2 to 4 sugars bound to Serine- without an O-glycan chain was slightly 126. (See Figures 1 and 2 below). higher for epoetin zeta as compared to epoetin alfa. On the other hand, the As an example, statements from the amounts of undesired variants of sialic European Public Assessment Reports acid, N-glycolyl neuraminic acid and O- (EPAR) of two biosimilar epoetins devel- acetyl neuraminic acid were higher oped using epoetin alfa (Eprex¨) as the in the reference product as compared to reference product describing carbohy- epoetin zeta”. drate similarities and differences highlight the issue of using glycosylation patterns BHK derived product (epoetin omega) as a discriminator for different epoetins: Nimtz et al (1) reported a significant amount (2 to 4 %) of phosphorylated Binocrit¨ (epoetin alfa) high-mannose type structures on the Asn- “Differences were observed at the glyco- 24 glycosylation site, otherwise a very sylation level. Phosphorylated high similar carbohydrate pattern, as seen in mannose type structures in HX575 were erythropoietin from CHO cells, was detected at higher levels than in Eprex/ observed. Since phosphorylated high- Erypo®”. mannose structures are also found in Silapo¨ (epoetin zeta) erythropoietins from CHO cells (although “With respect to the glycan moieties, the in somewhat lower amounts) this feature overall range of structures was found to does not qualitatively differentiate BHK- be comparable. Even upon sub- derived erythropoietin from CHO-derived fractionation of glycans of both products a erythropoietin. Figure 1. Main N-linked carbohydrate structures of erythropoietin (terminal sialic acids omitted)

Figure 2. Main O-linked carbohydrate Codes structures of erythropoietin Mannose(Man) N-acetylglucosamine (GlcNAc) Galactose (Gal) Fucose(Fuc) N-acteylneuraminic acid (NeuAc)

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HT1081 derived product (epoetin delta) lished production process with all analy- Llop et al (2) report on the carbohydrate tical and clinical data available to the pattern of epoetin delta and conclude that manufacturer. the pattern is similar to CHO-derived epoetins with slightly less bi- and tri- Even greater differences in the glycoform antennary structures. Neu5Gc cannot be pattern have been observed among found in epoetin delta as humans cells various epoetin products marketed cannot synthesize this sialic acid variant. outside the European Union, USA, and But since it is only a minor component in Japan which were developed independ- CHO-derived products it is not suitable as ently without adequate proof of similarity a general analytical feature to distinguish to a reference product. These are, never- CHO-derived from human-cell derived theless, often marketed using the INN products. epoetin alfa (3Ð5).

Conclusion Since both the cell line and the produc- All epoetins (regardless of INN) exhibit a tion processes define the glycosylation glycosylation pattern which is quantita- pattern, a unique INN for each independ- tively different from each other and mainly ently manufactured epoetin is fully justi- reflects the individual production cell fied. clone and the unique production process. Even small differences in the glycosyla- References tion pattern may or may not have an 1. FEBS Letters 1995; 365:203Ð208 impact on clinically relevant parameters like in vivo elimination time and safety. 2. Analytical Biochemistry 2008; 383:243Ð254 The complexity of the glycosylation 3. Schellekens, H. European Journal of pattern does not allow a prediction based Hospital Pharmacy 2004; 3:43Ð47; solely on analytical data if the comparison can only be carried out at final product 4. Park, S.S. et al. Journal of Pharmaceutical level. The situation is different if small Sciences 2009; 98:1688Ð1699 changes in the glycosylation pattern can 5. Reichel, C. et al. Drug Test Analysis 2009; be followed over time within an estab- 1:43Ð50.

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Safety and Efficacy Issues

Didanosine: serious A lower starting dose is recommended in liver disorder patients with moderate or severe hepatic impairment, and those patients should be United States of America — The Food monitored closely. Contraindications and Drug Administration (FDA) is alerting include hypersensitivity to bortezomib, healthcare professionals to the risk of boron, or mannitol. Velcade¨ should be non-cirrhotic portal hypertension in administered under the supervision of a patients using didanosine (Videx¨ or physician experienced in the use of Videx EC¨). Didanosine is used to treat antineoplastic therapy. Complete blood human immunodeficiency virus (HIV) counts should be monitored frequently infection. during treatment.

The FDA became aware of cases of non- There have been reports of peripheral cirrhotic portal hypertension through neuropathy, hypotension congestive heart adverse event reports. The FDA believes failure and new onset of decreased left the clinical benefits of didanosine for ventricular ejection fraction, acute diffuse certain patients with HIV continue to infiltrative pulmonary disease of unknown outweigh its potential risks. The decision etiology, reversible posterior leuko- to use this drug, however, must be made encephalopathy syndrome, nausea, on an individual basis between the diarrhoea, constipation, and vomiting, treating physician and the patient. Dida- thrombocytopenia and neutropenia, nosine already has a boxed warning for gastrointestinal and intracerebral haemor- lactic acidosis and hepatomegaly with rhage, tumour lysis syndrome, cases of steatosis. Didanosine in combination with acute liver failure. other antiretroviral agents as well as Reference: Communication from the Takeda hydroxyurea or ribavirin has been associ- Oncology Company at http://www.fda.gov ated with the development of liver toxicity. Reference: MedWatch Alert, 29 January 2010 Deferasirox: renal events and at http://www.fda.gov gastrointestinal haemorrhage Bortezomib: updated Canada — Deferasirox (Exjade®) is indicated in the management of chronic safety information iron overload in patients with transfusion- United States of America — The new dependent anaemias aged six years or label for bortezomib (Velcade¨) contains older. The product is also indicated in the important updates to the full prescribing management of chronic iron overload in information including dose adjustments patients with transfusion-dependent for patients with moderate to severe anaemias aged two to five who cannot be hepatic impairment. Bortezomib is indi- adequately treated with desferoxamine. cated for the treatment of patients with multiple myeloma or mantle cell lym- Therapy with deferasirox should be phoma who have received at least one initiated and maintained by physicians prior therapy. experienced in the treatment of chronic iron overload due to blood transfusions.

25 Safety and Efficacy Issues WHO Drug Information Vol. 24, No. 1, 2010

Review of adverse events for patients that are not interchangeable. Healthcare treated with deferasirox suggests a professionals should be aware that the greater risk of kidney failure, gastrointesti- methods used to measure sirolimus nal haemorrhage (potentially fatal) and whole blood concentration have a direct deaths in patients with myelodysplastic impact on the values obtained. Improper syndrome (MDS) and in elderly patients adjustment to the dose of sirolimus based compared to younger patients with other on the use of differing assay methods can chronic anaemias such as α-thalassae- lead to allograft rejection (if the patient is mia and sickle cell disease. Many of the underdosed) or toxicity (if the patient is adverse events reported are common to overdosed). elderly patients and patients with MDS, making it difficult to draw conclusions. Therapeutic drug monitoring is recom- mended for patients taking Rapamune¨. Risk factors for kidney failure include pre- Adjustments to the targeted range should existing compromised renal function, and be made according to the assay being it is therefore recommended that creati- used to determine the sirolimus trough nine clearance (and/or serum creatinine) concentration. Several immuno-assays be assessed twice before initiating have been developed that allow for rapid therapy. Weekly monitoring of creatinine turnaround of results. Most immuno- clearance (and/or serum creatinine) is assays have a positive bias of approxi- recommended in the first month after mately 15Ð20% relative to the reference initiation or modification of therapy, and HPLC assay with detection by tandem monthly thereafter. mass spectrometry due to antibody cross- reactivity with sirolimus metabolites. Gastrointestinal haemorrhage is a known However, it has recently come to the adverse reaction of deferasirox. There attention of the manufacturer that one of have been rare reports of fatal gastroin- the more commonly used immunoassay testinal haemorrhage, especially in platforms, IMx¨, generally yields results elderly patients who had advanced with a negative bias of approximately haematologic malignancies and/or low 10% relative to HPLC/MS/MS. platelet counts. In the review of death cases in the MDS Reference: Communication from Wyeth patient population, it was apparent that (Pfizer) dated 26 November 2009 at http:// www.hc-sc.gc.ca and 20 January 2010 at approximately two-thirds of deaths were http://www.hsa.gov.sg/publish/hsaportal/en/ in patients who had received less than six health_ products_regulation/safety_ informa- months of therapy, indicating that patients tion/DHCPL.html with advanced disease and a correspond- ing poor prognosis have been treated. Mycophenolate: pure These patients are unlikely to derive benefit from treatment with deferasirox. red cell aplasia Reference: Communication from Novartis Canada — The manufacturer of myco- Pharmaceuticals Canada Inc. dated 30 phenolate sodium (Myfortic¨) has in- November 2009 at http://www.hc-sc.gc.ca formed healthcare professionals of reports of pure red cell aplasia (PRCA) in Sirolimus: drug monitoring patients when treated in combination with assay comparison other immunosuppressive agents. Canada — Different laboratory assays Mycophenolate sodium, an immuno- used to measure sirolimus (Rapamune¨) suppressive agent, is currently indicated trough concentrations generate results for the prophylaxis of organ rejection in

26 WHO Drug Information Vol. 24, No. 1, 2010 Safety and Efficacy Issues

patients receiving allogeneic renal trans- a potential association between fosam- plants, administered in combination with prenavir calcium and myocardial infarc- cyclosporine, and corticosteroids. tion in HIV-infected adults.

PRCA is a type of anaemia that develops Elevations in triglyceride levels are secondary to failure of erythropoiesis. already described in the prescribing PRCA describes a condition in which information which has now also been RBC precursors in bone marrow are modified to highlight that increases in nearly absent, while megakaryocytes and cholesterol have occurred with treatment. white blood cell precursors are usually This statement includes a recommenda- present at normal levels. PRCA may be tion that triglyceride and cholesterol idiopathic or occur as a manifestation of testing should be performed prior to an underlying condition. Approximately initiating therapy with fosamprenavir 5% of all cases of PRCA are drug in- calcium tablets and oral suspension and duced. Patients with PRCA may present at periodic intervals during therapy. with fatigue, lethargy, and/or abnormal paleness of the skin (pallor). Anaemia is References the primary clinical concern in PRCA. The degree of anaemia can range from 1. Communication from GlaxoSmithKline subclinical to severe. Anaemia in acute dated November 2009 at www.fda.gov/ self-limited PRCA is barely noticeable; medwatch however, profound anaemia can occur in 2. Lang S, Mary-Krause M, Cotte L et al. chronic acquired PRCA and in congenital Impact of Specific NRTI and PI Exposure on PRCA. Patients with severe anaemia the Risk of Myocardial Infarction: A Case- have symptoms and signs of uncompen- Control Study Nested within FHDH ANRS sated anaemia and present with weak- CO4. 16th Conference on Retro-viruses and ness, tachycardia, and dyspnoea. Opportunistic Infections (CROI 2009) Febru- ary 8 Ð11, 2009, Montreal, Canada. As of 31 October 2009, between five and ten cases of PRCA out of an esti- 3. DAD Study Group. Class of antiretroviral mated cumulative worldwide exposure of drugs and the risk of myocardial infarction. N Engl J Med. 2007;356(17): 1723-35. 208 978 patient-years have been re- ported in patients receiving Myfortic¨ in combination with other immunosuppres- Exenatide: altered sive agents (such as tacrolimus, cy- kidney function closporine, corticosteroids). No cases are from Canada. United States of America — The Food and Drug Administration (FDA) has Reference: Communication from Novartis approved revisions to the drug label for Pharmaceuticals Canada Inc. dated 21 exenatide (Byetta¨) to include informa- December 2009 at http://www.hc-sc.gc.ca tion on post-marketing reports of altered kidney function, including acute renal Fosamprenavir: myocardial failure and insufficiency. infarction and dyslipidaemia Exenatide, an incretin-mimetic, is ap- United States of America — Fosam- proved as an adjunct to diet and exercise prenavir calcium is indicated in combina- to improve glycaemic control in adults tion with other antiretroviral agents for the with type 2 diabetes mellitus. treatment of HIV infection. The manufac- turer of fosamprenavir calcium (Lexiva¨) From April 2005 through October 2008, has informed healthcare professionals of the FDA has received 78 cases of altered

27 Safety and Efficacy Issues WHO Drug Information Vol. 24, No. 1, 2010

kidney function. Some cases occurred in The use of oral contraceptives is associ- patients with pre-existing kidney disease ated with increased risk of several serious or in patients with one or more risk factors conditions including venous and arterial for developing kidney problems. thrombotic and thromboembolic events. The risk of morbidity and mortality in- Revisions to the drug label include: creases significantly in the presence of other underlying risk factors such as ¥ Byetta¨ should not be used in patients hypertension, hyperlipidaemias, obesity with severe renal impairment (creatinine and diabetes. clearance <30 ml/min) or end-stage renal disease. Reference: Press Release, Saudi Food and Drug Authority, 1 March 2010 at http:// ¥ Caution should be applied when initiat- www.sfda.gov.sa/En/Drug/News/697 ing or increasing doses of Byetta¨ from 5 mcg to 10 mcg in patients with moder- Glucose test strips ate renal impairment (creatinine clear- ance 30 to 50 ml/min). Saudi Arabia — The Saudi Food and Drug Authority’s (SFDA) National Center ¥ Patients should be monitored carefully for Medical Devices Reporting has found for the development of kidney dysfunc- that test strips to measure blood glucose tion and evaluate continued need if by the glucose dehydrogenase pyrrolo- kidney dysfunction is suspected while quinoline quinone (GDH-PQQ) method using the product. cannot distinguish between glucose and other non-glucose sugars, including Reference: MedWatch Alert, 2 November 2009 at http://www.fda.gov maltose, xylose, and galactose found in certain drug and biological formulations or resulting from the metabolism of a drug or Drospirenone in oral therapeutic product. This leads to inaccu- contraceptives rate readings and possibly inappropriate medical intervention. Saudi Arabia — Recently, the Saudi Food and Drug Authority’s (SFDA) Na- Therefore SFDA has advised healthcare tional Drug and Poison Information providers to refer to device labelling to Center (NDPIC) has received questions confirm the used blood sugar measuring from patients and healthcare profession- methodology. SFDA advice to the public als about the safety of two combined oral is to stop using these strips since there contraceptive drugs Yasmin¨ and Yaz¨. are other glucose test strip methodologies not affected by the presence of non- Yasmin¨ is different from other birth- glucose sugars. control pills because it contains the progestin drospirenone. Drospirenone Reference: Press Release, Saudi Food and may increase potassium. Therefore, Drug Authority, 22 December 2009 at http:// patients with kidney, liver or adrenal www.sfda.gov.sa/En/Drug/News/697 disease should not take Yasmin¨. Other drugs may also increase potassium and HIV drug combination: safety patients who are currently on daily, long- review of clinical trial data term treatment for a chronic condition should consult their healthcare provider United States of America — The Food about whether Yasmin¨ is safe for use and Drug Administration (FDA) is review- and, during the first month of use, a blood ing clinical trial data about a potentially test to check potassium levels should be serious effect on the heart from the use of performed. the antiretroviral medications saquinavir

28 WHO Drug Information Vol. 24, No. 1, 2010 Safety and Efficacy Issues

(Invirase¨) in combination with ritonavir 2. MedWatch Alert. Follow-Up to the Novem- (Norvir¨). The data suggest that together ber 2009 Early Communication about an the two drugs may affect the electrical Ongoing Safety Review of Sibutramine, activity of the heart. Marketed as Meridia¨, dated 21 January 2010 at http://www.fda.gov Saquinavir and ritonavir should not be used in patients already taking medica- Becaplermin: contraindication tions known to cause QT interval prolon- in patients with cancer gation or in patients with a history of QT interval prolongation. European Union — Following a review of the available data on a possible risk of Reference: FDA Safety Announcement, 23 cancer in patients using becaplermin February 2010 at http://www.fda.gov/Drugs/ (Regranex¨), the European Medicines DrugSafety/PostmarketDrug SafetyInformation Agency (EMEA) has concluded that the forPatientsandProviders/ucm201221.htm medicine must not be used in patients who have any form of cancer. A similar Sibutramine: ongoing restriction previously applied, but only for safety review patients who had a skin cancer close to the area where the gel was to be applied. United States of America — The Food and Drug Administration (FDA) has Regranex¨ is a gel that is used together notified healthcare professionals of a with other wound care measures to treat review of additional data indicating an long-term skin ulcers in people with increased risk of heart attack and stroke diabetes. in patients with a history of cardiovascular disease using sibutramine. Based on the Reference: Press Release, http://www. serious nature of the review findings, a emea.europa.eu and http://www.ema. new contraindication has been added to europa.eu/ humandocs/PDFs/EPAR/ the sibutramine drug label stating that Regranex/31245209en.pdf sibutramine is not to be used in patients with a history of cardiovascular disease, ACSOM — advisory committee including: on safety of medicines

¥ History of coronary artery disease; Australia — A new expert advisory stroke or transient ischemic attack; committee on medicines safety, called the heart arrhythmias; congestive heart Advisory Committee on the Safety of failure; or peripheral arterial disease. Medicines (ACSOM), has replaced the Adverse Drug Reactions Advisory Com- ¥ Uncontrolled hypertension. mittee (ADRAC). This new committee exists as a statutory committee in its own Patients currently using sibutramine right and has broader and enhanced should talk with their healthcare profes- terms of reference compared to ADRAC. sional to determine if continued use of A key role of ACSOM will be the provision sibutramine is appropriate and discuss of expert advice to the Therapeutic any questions they may have about their Goods Administration (TGA) about the treatment. appropriateness of risk management References plans and risk minimization strategies for new high-risk medicines. 1. MedWatch Alert. Meridia¨ (sibutramine hydrochloride): Follow-Up to an Early Commu- Reference: Therapeutic Goods Administra- nication about an Ongoing Safety Review, tion, Medicines Safety Update, No.1, 2010 at dated 21 January 2010 at http://www.fda.gov http://www.tga.gov.au

29 WHO Drug Information Vol. 24, No. 1, 2010

Regulatory Scope

Tobacco product regulation

Regulation of tobacco products is endorsed by the WHO Framework Convention on Tobacco Control. Regulation serves public health goals by providing an understand- ing of tobacco products and meaningful surveillance of their manufacture, packag- ing, labelling and distribution. Tobacco product regulation includes regulation of the contents and emissions of tobacco products by testing, measuring and mandating disclosure of the results and regulating their packaging and labelling.

Chemical consumer products are usually regulated after a review of the scientific evidence on the hazards presented by the product, the exposure likely to occur, the patterns of use and the marketing messages of the manufacturer. Many jurisdictions require manufacturers to classify and label products according to their hazardous properties, to control the hazardous contents or to limit the advertising, promotion and sponsorship of such products. Electronic nicotine delivery systems deliver nico- tine and other substances but do not contain tobacco, and smokeless tobacco is produced in ‘cottage’ industries or can be modified significantly by the end user. Both therefore pose a significant challenge to regulation, as they may fall outside the scope of domestic regulatory regimes for tobacco products. Nevertheless, their popu- larity and the fact that they are marketed as alternatives to cigarette smoking indi- cate the need to characterize them, regulate them and ensure that the public is properly informed of the potential health hazards of these products.

Electronic nicotine delivery menthol. The meeting followed a WHO press release in 2008, which asserted systems that WHO does not consider electronic The WHO Study Group on Tobacco cigarettes to be a legitimate tobacco Product Regulation (TobReg) reviews the cessation therapy. scientific evidence on topics related to tobacco product regulation and identifies The TobReg recommendations address the research needed to fill regulatory electronic nicotine delivery systems gaps in tobacco control. The Study Group (ENDS) designed for nicotine delivery to is composed of national and international the respiratory system. This designation scientific experts on product regulation, encompasses products that contain treatment of tobacco dependence and tobacco-derived substances but in which laboratory analysis of tobacco ingredients tobacco is not necessary for their opera- and emissions. tion. ENDS are marketed under a variety of brand names and descriptors, including At its fifth meeting, the Study Group ‘electronic cigarettes’, ‘ecigarro’, ‘electro- addressed regulation of electronic ciga- smoke’, ‘green cig’ and ‘smartsmoker’. rettes, smokeless tobacco toxicants, ‘roll- ENDS pose significant public health your-own’ products, products marketed issues and raise questions for tobacco as cessation aids, particles in smoke and control policy and regulation because:

30 WHO Drug Information Vol. 24, No. 1, 2010 Regulatory Scope

Figure 1. Prototype e-cigarette devices

Rechargeable battery Vaporizing chamber

Indicator light Replaceable ingredients cartridge tip

Electronic circuit Cartridge

Battery Atomizer Inhaler

¥ Manufacturers have not fully disclosed and avoiding the controls levied on the chemicals used in ENDS; tobacco products. An important regulatory consideration is the validity of the market- ¥ There are few data on emissions or ing claims made for the products, which actual human exposure; include statements that ENDS are smok- ing cessation aids and that they deliver ¥ The health effects have not been stud- safer nicotine but at variable levels ied; compared to those in cigarettes.

¥ Marketing and use could undermine ENDS are a category of consumer public smoking bans, which are impor- products designed to deliver nicotine to tant tobacco control interventions; the lungs after one end of a plastic or metal cylinder is placed in the mouth, like ¥ Products could also undermine smoking a cigarette or cigar, and inhaled to draw a cessation efforts by proposing unproven mixture of air and vapours from the devices for smoking cessation in the device into the respiratory system (see place of products of proven efficacy. figure 1). They contain electronic vapori- zation systems, a rechargeable battery ¥ ENDS might also undermine the pre- and charger, electronic controls and vention of tobacco use because of their replaceable cartridges that may contain appearance and marketing as safe nicotine and other chemicals. Some alternatives to tobacco products for non- brands are claimed to deliver a range of tobacco users, including children. nicotine concentrations or no nicotine at all, and some are claimed to provide ENDS fall into a regulatory gap in most sensory experiences similar to those countries, escaping regulation as drugs obtained with major cigarette brands. The

31 Regulatory Scope WHO Drug Information Vol. 24, No. 1, 2010

chemicals used to produce the odours cigarette substitutes. An added concern is and flavours that simulate those of the safety of the chemical combinations in cigarettes have not all been identified, various ENDS cartridges, which have not although some products claim to include been evaluated for either short-term or ‘menthol’. Some devices have light- long-term safety. It is possible that at emitting diodes, to reproduce the appear- some time in the future ENDS might be ance of a burning cigarette tip. The developed as smoking cessation aids. premise stated by some marketers of the However, currently, the evidence is products is that ENDS provide nicotine insufficient to conclude that any of the that would otherwise be obtained by ENDS products is an effective smoking tobacco use. cessation aid.

The United States Food and Drug Admin- In summary, claims for the effectiveness istration recently analysed the chemicals of ENDS for smoking cessation and other in 18 varieties of ENDS cartridges mar- health effects must be substantiated by keted with two different brands and found rigorous studies of pharmacokinetics, significant variation in contents and trials of safety and efficacy and review deliveries. Several contained “detectable and approval by major drug regulatory levels of nitrosamines, tobacco-specific authorities. The types of data and studies compounds known to cause cancer”. The that would be required include: Administration’s testing also revealed that the nicotine levels were inconsistent with ¥ Complete listing of the chemicals used the information on the cartridge labels in ENDS products. and that some cartridges that were stated not to contain nicotine actually did. ¥ Listing and reporting of the concentra- tions of chemicals delivered to the Delivery of nicotine to the lung raises consumer. concern about safety and addiction that ¥ Comparisons of the effect of ENDS on go beyond that related to currently smoking cessation with that of approved approved nicotine replacement therapy. nicotine replacement therapies and Concern about the safety of ENDS is placebo. associated with the probable exposure of the lung to repeated dosing, perhaps ¥ Adverse effects of these products. hundreds of times a day for many months, if these products are used as a Reference: World Health Organization. WHO smoking cessation aid, or for years, for Study Group on Tobacco Poduct Regulation. smokers who use them as long-term Technical Report Series, No. 955 (2009).

32 WHO Drug Information Vol. 24, No. 1, 2010

Regulatory Action and News

Influenza vaccines: 2010-2011 each country. National public health northern hemisphere authorities are responsible for making recommendations regarding the use World Health Organization — Pandemic of the vaccine. influenza A(H1N1) viruses emerged in March 2009 and remain globally predomi- Reference: Recommended viruses for nant, while seasonal influenza A(H1N1), influenza vaccines for use in the 2010Ð2011 A(H3N2) and B viruses circulated at very northern hemisphere influenza season. low levels in many countries during the Weekly Epidemiological Record, 85:10 (2010). period September 2009 to January 2010. European Medicines Agency: Pandemic A(H1N1) 2009 viruses were new organizational structure antigenically and genetically similar to and visual identity A/California/7/2009. Vaccines containing A/California/7/2009 antigen stimulated European Union — The European anti-HA antibodies of similar titres against Medicines Agency officially unveiled a the vaccine virus and recent pandemic package of changes on 8 December A(H1N1) 2009 viruses. 2009 with the launch of a new organiza- tional structure and new visual identity. Very few seasonal influenza A(H1N1) viruses were reported. Of these, the Among the highlights of the new organi- majority were antigenically and geneti- zational structure is the integration of cally similar to the (previous northern human pre- and post-authorization hemisphere) vaccine virus A/Brisbane/59/ activities into one unit, to guarantee 2007. seamless lifecycle-management of medicines. The creation of a new unit for It is recommended that the following patient health protection further strength- viruses be used for influenza vaccines in ens the Agency’s focus on safety-monitor- the 2010Ð2011 influenza season (north- ing of medicines. In addition, a dedicated ern hemisphere): group for the management of product data and documentation will improve the ¥ an A/California/7/2009 (H1N1)-like efficiency of data management processes virus; throughout the Agency.

¥ an A/Perth/16/2009 (H3N2)-like virus A new public web site for the Agency is (A/Wisconsin/15/2009 is an A/Perth/16/ nearing the end of development and will 2009 (H3N2)-like virus and is a 2010 be launched in the coming months. With southern hemisphere vaccine virus); the current website being visited more than 700 000 times each month, the new ¥ a B/Brisbane/60/2008-like virus. site is being designed with the needs of the public in mind, offering improved As in previous years, national or regional navigation and search functionality, control authorities approve the composi- providing better access to information on tion and formulation of vaccines used in public-health issues.

33 Regulatory Action and News WHO Drug Information Vol. 24, No. 1, 2010

Reference: Press Release, EMA/704918/ ness by health technology assessment 2009, 8 December 2009 at http://www.ema. bodies in the EU Member States. europa.eu/ Relative effectiveness assessments are Risk management systems increasingly used in the European Mem- for medicinal products ber States to help policy makers to identify the most valuable medicines. Australia — In April 2009 the Therapeu- tic Goods Administration (TGA) formally Reference: CHMP assessment templates and adopted the European Guideline on Risk guidance at http://www.ema.europa. eu/htms/ Management Systems for Medicinal human/chmptemplates/artemplates.htm Products for Human Use (EMEA/CHMP/ 96268/2005). NIH and FDA: fast-track Applications for the registration of certain innovations higher risk prescription medicines (new United States of America — The Food chemical entities, applications for paediat- and Drug Administration (FDA) and the ric use, new dosage forms, new routes of National Institutes of Health (NIH) have administration and significant extensions unveiled an initiative designed to acceler- of indication) are now required to include ate the process from scientific break- a Risk Management Plan as part of the through to the availability of new, innova- application. tive medical therapies for patients. The Risk Management Plan is meant to document not only what is known about The initiative involves two interrelated the safety of the medicine at that particu- scientific disciplines: lar point in time (termed the Safety ¥ Translational science, the shaping of Specifications), but also potential risks basic scientific discoveries into treat- that require further elucidation and how ments. the sponsor intends to investigate those risks. ¥ Regulatory science, the development and use of new tools, standards and Reference: Therapeutic Goods Administra- approaches to more efficiently develop tion, Medicines Safety Update, No.1, 2010 at products and to more effectively evalu- http://www.tga.gov.au ate product safety, efficacy and quality.

Relative effectiveness Both disciplines are needed to turn bio- assessments: joint action medical discoveries into products that benefit people. European Union — The European Medicines Agency and representatives As part of the effort, the agencies will from the European network for Health establish a Joint NIH-FDA Leadership Technology Assessment (EUnetHTA) Council to spearhead collaborative work Joint Action met in London on 11 Febru- on important public health issues. The ary 2010 for the first of a series of work- Joint Leadership Council will work to shops. This initiates a new collaboration, ensure that regulatory considerations in which the European Medicines Agency form an integral component of biomedical and EUnetHTA will be considering how research planning, and that the latest the European Public Assessment Report science is integrated into the regulatory (EPAR) could make a better contribution review process. to the assessment of relative effective-

34 WHO Drug Information Vol. 24, No. 1, 2010 Regulatory Action and News

In addition, the NIH and the FDA will requirements are in place for this unap- jointly issue a Request for Applications, proved drug. making US$ 6.75 million available over three years for work in regulatory science. Reference: FDA News, 23 October 2009 http://www.fda.gov Reference: FDA Ð NIH News Release, 24 February 2010 at http://www.fda.gov and Carisbamate: withdrawal of http://.www.nih.gov4. marketing authorization Orciprenaline sulphate: application registration cancelled European Union — The manufacturer of carisbamate (Comfyde¨) has notified the Saudi Arabia — The Saudi Food and European Medicines Agency () of its Drug Administration (SFDA) has an- decision to withdraw its application for a nounced the cancellation of orciprenaline centralized marketing authorization for sulphate (Alupent¨) registration due to its the medicine Comfyde¨. hazards to the heart and the availability of more safe alternative drugs. This medicine was intended to be used Accordingly, the Drug Products and for adjunctive treatment of partial onset Manufacturers’ Registration Committee seizures with or without secondary decided to cancel registration of this generalization in patients aged 16 years product and recall it from the market. or older. SFDA also asked the manufacturer to recall any available stocks from the local The decision to withdraw the application market to protect the health of the public. was based on feedback from the Commit- SFDA requests all concerned to use other tee on Human Medicinal products alternative drugs. (CHMP) indicating that the Committee is unlikely to reach a favourable opinion Reference: Communication dated 15 Febru- without additional efficacy data, which at ary 2010 at www.sfda.gov.sa/ar/drug this time cannot be provided. Reference: Press Release, EMA/32401/2010, Peramivir IV: emergency 20 January 2010. http://www.ema.europa. eu/ use authorization United States of America — The Food Benfluorex withdrawal and Drug Administration (FDA) has European Union — The European notified healthcare professionals that, in Medicines Agency has recommended the response to a request from the Centers withdrawal of all medicines containing for Disease Control and Prevention, it has benfluorex in the European Union be- issued an emergency use authorization cause their risks, particularly the risk of (EUA) for the investigational antiviral drug heart valve disease, are greater than their peramivir in certain adult and paediatric benefits. patients with confirmed or suspected 2009 H1N1 influenza infection who are Doctors should stop prescribing ben- admitted to a hospital. IV peramivir is fluorex-containing medicines and con- authorized only for hospitalized adult and sider alternative treatments. Because paediatric patients for whom therapy with heart valve disease can develop some an IV drug is clinically appropriate. years after treatment, patients who have Given that limited safety data are avail- taken benfluorex in the past should tell able on peramivir, mandatory reporting their doctor so that they can be checked

35 Regulatory Action and News WHO Drug Information Vol. 24, No. 1, 2010

for the signs and symptoms of heart valve treatment of bipolar I disorder. When disease. deciding among the alternative treat- ments available for adolescents, clini- Benfluorex is approved for use in over- cians should consider the increased weight patients with diabetes, combined potential for weight gain and hyperlipidae- with an appropriate diet. mia.

Reference: Press release,EMA/CHMP/ It is recommended that medication thera- 815033/2009, 18 December 2009 at http:// py for paediatric schizophrenia and www.ema.europa.eu/ bipolar I disorder be initiated only after a thorough diagnostic evaluation has been Ethyl eicosapent: withdrawal performed and careful consideration of marketing authorization given to the risks associated with medica- application tion treatment. Medication treatment for both paediatric schizophrenia and bipolar European Union — The manufacturer of I disorder should be part of a total treat- ethyl eicosapent (Ethyl Eicosapent¨), ment programme that includes psycho- 500 mg soft gelatine capsules has noti- logical, educational and social interven- fied the European Medicines Agency of tions. its decision to withdraw its application for a centralized marketing authorization. The types of adverse events observed in adolescents were similar to those seen in Ethyl eicosapent was expected to be adult patients. However, the magnitude used for the long-term stabilization of and frequency of some events were symptoms in patients with Huntington greater in adolescents than in adults. disease, a hereditary neurological disor- Compared to patients from adult clinical der of the central nervous system that trials, adolescents were likely to gain causes progressive degeneration of cells more weight and have greater increases in the brain. in total cholesterol, triglycerides, LDL Withdrawal of the application was based cholesterol, prolactin and hepatic on preliminary comments which indicate transaminase levels, and sedation. that the CHMP is unlikely to conclude a Reference: FDA News, 24 October 2009 favourable opinion without additional http://www.fda.gov efficacy information. Reference: Press Release, EMA/796337/ Lisuride: withdrawal of 2009, 8 December 2009 at http:// marketing authorization www.ema.europa.eu/ application Olanzapine approved in European Union — The manufacturer of adolescents lisuride (Nenad¨) has notified the Euro- pean Medicines Agency of its decision to United States of America — The Food withdraw its application for a centralized and Drug Administration (FDA) has marketing authorization for the Nenad¨, approved of the use of oral olanzapine 2.5 and 5.0 microgram/h transdermal (Zyprexa¨) in adolescents (ages 13Ð17). patch. Nenad¨ was expected to be used in adults with moderate-to-severe idi- Olanzapine is indicated for the treatment opathic restless legs syndrome. of schizophrenia and acute treatment of manic or mixed episodes associated with Withdrawal of the application was based bipolar I disorder and maintenance on the CHMP’s view that the data pro-

36 WHO Drug Information Vol. 24, No. 1, 2010 Regulatory Action and News

vided do not allow the Committee to coccal disease (IPD) and otitis media. conclude on a positive benefit-risk bal- The new vaccine extends the protection ance in the claimed indication. to six additional types of the disease causing bacteria. Reference: Press Release, Doc. Ref. EMEA/ 781919/2009. 3 December 2009 at http:// www.ema.europa. eu/ Prevnar 13¨ is approved for the preven- tion of invasive disease caused by 13 different serotypes of the bacterium Velaglucerase alfa approved Streptococcus pneumoniae. It also is for Gaucher disease approved for the prevention of otitis media caused by the seven serotypes United States of America — The Food shared with Prevnar¨. The bacterium can and Drug Administration (FDA) has ap- cause infections of the blood, middle ear, proved velaglucerase alfa for injection and the covering of the brain and spinal (VPRIV) to treat children and adults with cord, as well as pneumonia. a form of the rare genetic disorder, Gaucher disease. Common adverse reactions reported after administration of Prevnar 13¨ were pain, VPRIV provides long-term enzyme re- redness and swelling at the injection site, placement therapy for Type 1 Gaucher irritability, decreased appetite and fever. disease, the most common form of the genetic disorder. It is an alternative to Reference: FDA News Release, 24 February imiglucerase (Cerezyme¨), another 2010 at http://www.fda.gov enzyme replacement therapy.

The most common adverse reactions to Monoclonal antibody products VPRIV are allergic reactions. Other approved for chronic lympho- observed adverse reactions with VPRIV cytic leukaemia are headache, dizziness, abdominal pain, back pain, joint pain, nausea, fatigue/ United States of America — The Food weakness, fever, and prolongation of and Drug Administration (FDA) has activated partial thromboplastin time, a approved the monoclonal antibody measure of clotting time. rituximab (Rituxan¨) to treat certain patients with chronic lymphocytic leukae- Reference: FDA News Release, 26 February mia (CLL), a slowly progressing blood 2010 at http://www.fda.gov and http:// and bone marrow cancer. www.ninds.nih.gov/disorders/gauchers/ gauchers.htm 2 Rituximab, an anti-cancer drug, is in- tended for patients with CLL who are Pneumococcal 13-valent beginning chemotherapy for the first time conjugate vaccine approved and for those who have not responded to other cancer drugs for CLL. Rituximab is United States of America — The Food administered with two other chemo- and Drug Administration (FDA) has therapy drugs, fludarabine and cyclo- approved Prevnar 13¨, a pneumococcal phosphamide. 13-valent conjugate vaccine for infants and young children ages 6 weeks through FDA approved ofatumumab (Arzerra¨) in 5 years. Prevnar 13¨ will be the succes- October 2009 for patients whose cancer sor to Prevnar¨, the pneumococcal 7- is no longer being controlled by other valent conjugate vaccine licensed by the forms of chemotherapy and benda- FDA in 2000 to prevent invasive pneumo- mustine (Treanda¨) in March 2008 for

37 Regulatory Action and News WHO Drug Information Vol. 24, No. 1, 2010

patients with CLL who had not received amount of a substance known as high prior treatment. sensitivity C-reactive protein in their blood and at least one additional traditional Rituxan¨ carries a boxed warning for cardiovascular risk factor such as smok- infusion reactions. A decrease in normal ing, high blood pressure, a family history white blood cells was also commonly of premature heart disease, or low observed in patients enrolled in the amounts of high-density lipoprotein or clinical trials. Other boxed warnings for HDL cholesterol. Rituxan¨ include rashes and sores in the skin and mouth; progressive multifocal Reference: FDA News Release, 9 February leukoencephalopathy (PML); and tumour 2010 at http://www.fda.gov lysis syndrome. Influenza A/H1N1: collection- Reference: FDA News Release, 2 February 2010 at http://www.fda.gov to-detection assay United States of America — The manu- Rosuvastatin: new indication facturer of Longhorn Influenza A/H1N1-09 approved Prime RRT-PCR Assay¨ has been granted Emergency Use Authorization United States of America — The Food (EUA) from the Food and Drug Adminis- and Drug Administration (FDA) has tration (FDA) for a ready-use assay that approved the cholesterol-lowering medi- requires no mixing prior to use. cation rosuvastatin (Crestor¨) for some patients who are at increased risk of heart The device includes PrimeStore¨, a disease but have not been diagnosed. clinical collection and transport solution that preserves the released nucleic acids, The new indication is for reducing the including labile RNA for testing and likelihood of a heart attack or stroke or contains an internal positive control, the need for a procedure to treat blocked providing the first specimen collection or narrowed arteries in patients who have solution to contain an internal RNA never been told they have heart disease control capable of tracking the degrada- but are nevertheless at increased risk of a tion of the sample from the point of cardiac event. collection.

Specifically, this includes men 50 years of Reference: Longhorn Vaccines & Diagnostics, age and older and women 60 years of New Release, 22 February 2010 at http:// age and older who have an elevated www.lhnvd.com

38 WHO Drug Information Vol. 24, No. 1, 2010 Recent Publications, Information and Events

TSE tissue infectivity faeces) in which infectivity had not been distribution update detected, have since been found to contain infectivity or PrPTSE and there- The data reported in the World Health fore have been moved from the category Organization (WHO) Tables on Tissue of ‘‘tissues with no detectable infectivity’’ ’’ Infectivity Distribution in Transmissible to the category of ‘‘lower-infectivity Spongiform Encephalopathies were tissues.’’ originally assembled by an expert group appointed during a WHO Consultation The inclusion of infectivity data in CWD in held in 2003 and subsequently updated these Tables was considered important during a later Consultation held in 2005. for three reasons: As new information became available, the tables were updated and now reflect ¥ CWD is continuing its spread to new the current status of knowledge about regions of North America. infectivity in body tissues, secretions, and ¥ Infectivity has been convincingly dem- excretions of humans with sporadic or onstrated in several bodily secretions variant Creutzfeldt-Jakob disease (CJD); and excretions of infected deer. cattle with typical or atypical bovine spongiform encephalopathy (BSE); sheep ¥ CWD is the only form of animal trans- with scrapie and, (for the first time), deer missible spongiform encephalopathy or elk with chronic wasting disease (TSE) that exists in the wild and, al- (CWD). though not presently considered to be an important concern for humans, could It is not the purpose of the document to pose serious problems of control in the revise the current WHO Guidelines on future, especially as a potential source Tissue Infectivity Distribution in Trans- of infection in other animal species. missible Spongiform Encephalopathies published in 2006, which remain valid, Reference: World Health Organization. Tables but new information on tissue infectivity on Tissue Infectivity Distribution in Transmissi- distribution is important in the context of ble Spongiform Encephalopathies. WHO/ potential transmission of variant CJD EMP/QSM/2010.1 at http://www.who.int/ medicines through human blood and blood products, as well as through medicinal products Restricted availability of prepared with bovine-derived materials, and may have implications for future opioids for cancer patients recommendations. A report regarding the regulations and restrictions preventing cancer patient Since the publication in 2006 of Major access to medication to relieve strong Categories of Infectivity, Annex 1 in the cancer pain has been released by the WHO Guidelines on Tissue Infectivity European Society for Medical Oncology Distribution in Transmissible Spongiform (ESMO) and the European Association Encephalopathies, some tissues (ovary, for Palliative Care (EAPC). uterus, mammary glands/udder, skin, adipose tissue, and heart/pericardium) The study, published online in Annals of and body fluids (saliva, milk, urine, and Oncology, collected data from twenty-one

39 Recent Publications, Information and Events WHO Drug Information Vol. 24, No. 1, 2010

eastern European countries and twenty in late 2004. The goal of the GGM western European countries to evaluate programme is to contribute to health the availability of official lists of allowed systems strengthening and prevent opioid drugs (formulary) for the manage- corruption by promoting good governance ment of strong pain, the cost of opioid in the pharmaceutical sector. medication to patients and the regulatory barriers that can make it more difficult, if The purpose of the national assessment not impossible, for cancer patients and is to provide countries with a comprehen- their doctors to get access to these sive picture of the level of transparency medications in a timely manner. and potential vulnerability to corruption of the following eight functions of the phar- The study found that in many European maceutical sector: countries (particularly in eastern Europe) the balance between enabling cancer ¥ Registration of medicines. patients to receive the pain relief that they need, while, at the same time, preventing ¥ Control of medicines promotion. prescription drugs being diverted for ¥ Inspection of establishments. substance abuse in illicit drug markets, is weighted too much in favour of the latter. ¥ Control of clinical trials.

References ¥ Licensing of establishments. ¥ Selection of essential medicines. 1. Annals of Oncology, at http://www.oxford journals.org/our_journals/annonc/press_ ¥ Procurement of medicines. releases/freepdf/mdp581.pdf ¥ Distribution of medicines. 2. European Society for Medical Oncology, at http://www.esmo.org The methodology probes the perception 3. Formulary availability and regulatory of pharmaceutical policy makers and barriers to accessibility of opioids for cancer other stakeholders about transparency pain in Europe: a report from the ESMO/EAPC and provides both qualitative and quanti- Opioid Policy Initiative. Annals of Oncology, tative information on the level of transpar- 21: pp 615-626, 2010 DOI: 10.1093/annonc/ ency present in the eight areas. mdp581 4. Access to therapeutic opioid medications in The assessment should be viewed as a Europe by 2011? Fifty years on from the starting point for investigating weak- Single Convention on Narcotic Drugs. Pallia- nesses and strengths in the national tive Medicine, 24: pp109-110 DOI: 10.1177/ medicine regulatory and supply manage- 0269216309360103 ment systems. It represents the beginning of a process aimed at bringing long- Transparency and the public lasting changes through efforts to pharmaceutical sector strengthen the national health systems. Twenty-six countries have adopted the The Assessment Tool for Measuring GGM and conducted the assessment. Transparency in the Public Pharmaceuti- cal Sector represents the first step of a Reference: Assessment Tool for Measuring three-phase approach within The World Transparency in the Public Pharmaceutical Health Organization’s Good Governance Sector. http://www.who.int/medicines/areas/ for Medicines (GGM) Programme started policy/goodgovernance/

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