WHO Drug Information Vol. 26, No. 1, 2012WHO Drug Information                                      ContentsRegulatory Focu...
WHO Drug Information Vol. 26, No. 1, 2012               Announcement       The 15th International Conference of    Drug Re...
WHO Drug Information Vol. 26, No. 1, 2012Regulatory FocusRegulation of medicines in China Over the past decade, China has ...
Regulatory Focus                                WHO Drug Information Vol. 26, No. 1, 2012Table 1. State Food and Drug Admi...
WHO Drug Information Vol. 26, No. 1, 2012                                 Regulatory Focusthrough the merger of medicines ...
Regulatory Focus                                                   WHO Drug Information Vol. 26, No. 1, 2012Table 2. Pharm...
WHO Drug Information Vol. 26, No. 1, 2012                                   Regulatory FocusRepublic of China. Based on th...
Regulatory Focus                               WHO Drug Information Vol. 26, No. 1, 2012from overseas applicants are handl...
WHO Drug Information Vol. 26, No. 1, 2012                                    Regulatory Focusand manufacturing processes. ...
Regulatory Focus                                 WHO Drug Information Vol. 26, No. 1, 2012non-prescription medicines was i...
WHO Drug Information Vol. 26, No. 1, 2012                                 Regulatory FocusSupervision of drug advertising ...
Regulatory Focus                                       WHO Drug Information Vol. 26, No. 1, 2012                          ...
WHO Drug Information Vol. 26, No. 1, 2012                                          Regulatory Focus3. National Bureau of S...
Regulatory Focus                                        WHO Drug Information Vol. 26, No. 1, 201223. Ministry of Health, N...
WHO Drug Information Vol. 26, No. 1, 2012Paediatric MedicinesBetter medicines for children:              The guideline aim...
Paediatric Medicines                                               WHO Drug Information Vol. 26, No. 1, 2012Table 1. Paedi...
WHO Drug Information Vol. 26, No. 1, 2012                                             Paediatric MedicinesTable 2. Paediat...
Paediatric Medicines                                            WHO Drug Information Vol. 26, No. 1, 2012sweetening agents...
WHO Drug Information Vol. 26, No. 1, 2012                                             Paediatric MedicinesTable 3. Route o...
Paediatric Medicines                                 WHO Drug Information Vol. 26, No. 1, 2012Q3A(R2) at http://www.ich.or...
WHO Drug Information Vol. 26, No. 1, 2012                                    Paediatric Medicines10. World Health Organiza...
Paediatric Medicines                             WHO Drug Information Vol. 26, No. 1, 2012Demand Forecast, a Procurement G...
WHO Drug Information Vol. 26, No. 1, 2012                                 Paediatric Medicines•	 Coordinating the developm...
WHO Drug Information Vol. 26, No. 1, 2012Safety and Efficacy IssuesBevacizumab: severe infectious                Ursodeoxy...
WHO Drug Information Vol. 26, No. 1, 2012                         Safety and Efficacy Issuessimvastatin be decreased from ...
Who Drug Information
Who Drug Information
Who Drug Information
Who Drug Information
Who Drug Information
Who Drug Information
Who Drug Information
Who Drug Information
Who Drug Information
Who Drug Information
Who Drug Information
Who Drug Information
Who Drug Information
Who Drug Information
Who Drug Information
Who Drug Information
Who Drug Information
Who Drug Information
Who Drug Information
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Who Drug Information

  1. 1. WHO Drug Information Vol. 26, No. 1, 2012WHO Drug Information ContentsRegulatory Focus Boceprevir: HIV protease inhibitorRegulation of medicines in China 3 interactions 33 Bortezomib: fatal if given intrathecally 33Paediatric MedicinesBetter medicines for children: Regulatory Action and News pharmaceutical formulations 15 Bevacizumab: suspension forBenznidazole: child-adapted dosage metastatic breast cancer 34 form approved 21 Drotrecogin alfa: withdrawal 34Use of drugs in paediatric health Dextropropoxyphene-containing conditions increasing 23 analgesics cancelled 34 Vemurafenib approved for meta-Safety and Efficacy Issues static or unresectable melanoma 35Bevacizumab: severe infectious Ecallantide: marketing authorization endophthalmitis and blindness 24 application withdrawal 35Ursodeoxycholic acid: serious Sitagliptin and pioglitazone: market- hepatic events 24 ing authorization applicationSimvastatin with amiodarone: withdrawal 35 dosage review 24 Voclosporin: marketing authorizationFenofibric acid: the ACCORD lipid application withdrawal 36 trial 25 Desloratadine: marketing authorizationBCG vaccine: lymphadenitis 25 application withdrawal 36Dabigatran etexilate mesylate: Electronic CTD implementation 36 bleeding events 26Dabigatran etexilate: caution in the ATC/DDD Classification elderly and renally impaired 26 ATC/DDD Classification (temporary) 37Dabigatran: risk of bleeding 26 ATC/DDD Classification (final) 40Pneumovax 23®: revaccination recommendations 27 Recent Publications,Somatropin-containing medicines: Information and Events positive benefit-risk balance 28 Pharmacovigilance Toolkit 42Pholcodine-containing cough Uppsala Monitoring Centre signals medicines 28 document: increased availability 42Antipsychotics in children and ado- Learning module: selective lescents: cardiometabolic reactions 29 serotonin reuptake inhibitors 42Citalopram hydrobromide: dose- Medicines access survey 43 dependent QT prolongation 30 ATC/DDD methodology course 43Brentuximab vedotin: new warning Access and Control Newsletter 43 and contraindication 31 Managing access to medicines and Quetiapine: information updated 31 health technologies 44Aliskiren: cardiovascular and renal events 32Natalizumab: progressive multifocal International Nonproprietary Names leukoencephalopathy 32 Recommended List No. 67 45 1
  2. 2. WHO Drug Information Vol. 26, No. 1, 2012 Announcement The 15th International Conference of Drug Regulatory Authorities (ICDRA) will be hosted by the State Agency for Medicines, Estonia, in collaboration with the World Health Organization The ICDRA will take place in Tallinn, Estonia, 23 – 26 October 2012 Information and registration at: http://www.icdra.ee http://www.who.int/medicines/icdra2
  3. 3. WHO Drug Information Vol. 26, No. 1, 2012Regulatory FocusRegulation of medicines in China Over the past decade, China has introduced significant changes to the regulation of medicines through modernizing its legislative framework in line with internatio- nal practice and by re-organizing the nation’s medicines administrative agency, the State Food and Drug Administration (SFDA). Medicines regulatory agencies (MRAs) have been established at national, provincial, city and county levels and, by the end of 2010, there were 2898 administrative organs and 1076 public institutions employing human resources of 45,393 and 24,939 respectively (1). The State Food and Drug Administration (SFDA) is the responsible agency for medicines adminis- tration nationwide. The medicines regulatory agencies at provincial level are res- ponsible for drug regulation in their administrative areas while the responsibilities of local level MRAs are legally defined or commissioned by upper level MRAs. Administratively, mainland China consists of 31 contiguous regions at provincial level, 333 at city level and 2856 at county level (2). As of November 2010, China registered an overall population of 1339,724,852 (3) and, in 2010, the country’s gross domestic product amounted to RMB 40120.2 billion (4). This article provides insight into changes taking place in the organizational structure, legislative framework and current situation of medicines regulation in China with a focus on medicines registration, manufacturing, distribution and use, advertising, and post-market safety monitoring as well as control of narcotics and psychotropic substances*. It also draws a picture of China’s pharmaceutical industry and offers a glimpse of the transformations taking place in the medicines regulatory scene set against a backdrop of international harmonization. * This article does not focus on traditional Chinese medicine, which would merit a separate article.Medicines regulatory situation of Human Resources and Social Security responsible for formulating theThe State Council of the People’s Repu- China National Formulary for Essentialblic of China is the executive arm of the Medicare and Industrial Injury Insu-Central People’s Government. It is the rance, the Ministry of Agriculture res-highest body of both state power and ponsible for supervision of raw materialstate administration (5). Departments for narcotic drugs and the Ministry ofunder the State Council are responsible Public Security which is responsible forfor related medicines regulatory adminis- monitoring the distribution of narcotictrative work as defined within the limits drugs and psychotropic substances.of their duties and include the NationalDevelopment and Reform Commission The State Food and Drug Administra-responsible for drug pricing, the Ministry tion (SFDA) was established in 1998Article by Xiaoqiong Zheng, Information Centre, State Food and Drug Administration, Beijing,China. 3
  4. 4. Regulatory Focus WHO Drug Information Vol. 26, No. 1, 2012Table 1. State Food and Drug Administration functions• Formulate policies and programmes on the administration of drugs, medical de- vices, health foods and cosmetics, as well as food safety at the consumption level (restaurant, cafeteria, etc.) and supervise implementation. Take part in drafting relevant laws, regulations and normative documents.• Take charge of food hygiene licensing and food safety supervision at consumption level.• Formulate good practice for food safety at the consumption stage and supervise implementation; carry out investigation and monitoring work of food safety at consumption level, and release information related to supervision on food safety at consumption level.• Take charge of health foods, cosmetic hygiene licensing, hygiene supervision and relevant review and approval work.• Take charge of administrative and technical supervision of medicines and medical devices, take charge of formulating good practices for medicines, medical devices in aspects of research, production, distribution and use, and supervise implemen- tation.• Take charge of registration and supervision of medicines and medical devices; draw up relevant national standards for medicines and medical devices, and supervise implementation; carry out adverse drug reaction (ADR) monitoring and adverse event monitoring of medical devices; be responsible for drug and medical device re-evaluation and removal. Take part in formulating the national essential medicines list and adopting the national essential medicines system. Organize implementation of a classification system for prescription and non-prescription medicines.• Take charge in formulating regulations for traditional Chinese medicines (TCMs) and ethno-medicines, and supervise implementation, draw up quality standards for TCMs and ethno-medicines, formulating good agricultural practices for Chinese crude drugs and processing standards for prepared slices of Chinese crude drugs and supervising their implementation. Implement protection for certain TCMs.• Supervise the quality and safety of medicines and medical devices; regulate ra- diopharmaceuticals, narcotics, toxics and psychotropics, and release quality and safety information on medicines and medical devices.• Organize the investigation and take legal action against violation of laws and regu- lations concerning food safety at consumption level, and in research, production, distribution and use of medicines, medical devices, health food and cosmetics.• Direct relevant local work regarding food and drug administration, emergency response, inspection and information sharing.• Draw up and improve qualification systems for licensing pharmacists, direct and supervise the registration of licensed pharmacists.• Carry out international information exchange and cooperation related to food and medicines regulation.• Undertake other work assigned by the State Council and the Ministry of Health.4
  5. 5. WHO Drug Information Vol. 26, No. 1, 2012 Regulatory Focusthrough the merger of medicines regula- producing pharmaceutical preparations,tory functions of the State Pharmaceutical etc.Administration of China, the State Admi- • Product approval at clinical trial, pro-nistration of Traditional Chinese Medi- duction, and import levels.cine of the People’s Republic of China(SATCM) — also under the Ministry of • Authorization of medicines advertis-Health — and the Drug Administration ing and promotion of over-the-counterDepartment of the Ministry of Health, (OTC) and prescription-only medicines.namely the State Drug Administration(SDA) directly under the State Council. In • Implementation of quality assurance2003, with additional responsibilities for systems and compliance with goodfood regulation, the SDA became the cur- laboratory practice (GLP), good clinicalrent SFDA. In 2008, the SFDA reverted to practice (GCP), good manufacturingMinistry of Health responsibility. practice (GMP) and good distribution practice (GDP).The establishment of the SFDA to regu- • Post-marketing safety surveillancelate medicines was a milestone in the his- through a nationwide network encom-tory of medicines regulation in China and passing organization and electronican important achievement in healthcare management systems for adverse drugreform. From 1998 to 2011, the SFDA has reaction (ADR) reporting and monitor-been committed to public health through: ing.• Strengthening the science based ap- The SFDA makes decisions on marke- proach to medicines evaluation. ting authorizations and authorization of products for clinical trial and import.• Promoting quality assurance systems Decisions are based on reviews provided in enterprises involved in research, by the Centre for Drug Evaluation (CDE), production and distribution. an affiliated public organization providing• Facilitating the establishment of a na- technical support under SFDA administra- tional essential medicines system and tive supervision. Provincial MRAs assist the classification of prescription and the drug registration process through non-prescription medicines. preliminary work by verifying the original dossier application, format review and• Improving pharmacovigilance to safe- on-site inspection. Drug testing institutes guard public health. established or designated by drug regu- latory departments are responsible for• Ensuring the quality, safety, efficacy the drug testing which is required as part and accessibility of medicines. of drug review and approval and for drugIn addition to medicines regulation, quality control in accordance with the lawseveral other categories of health related (7).products are also regulated by the SFDA(6). (Table 1.) Pharmaceutical industry profile The Chinese pharmaceutical industry hasRegulatory responsibility and capacity made significant progress over the pastThe scope of medicines regulation in decade. According to a White Paper TheChina covers the whole life-cycle of medi- Status Quo of Drug Supervision in Chinacines, including: released by the Information Office of the State Council in 2008, China had the• Production, manufacturer licensing, capacity to produce 1500 types of drug provision of Internet-based pharmaceu- substance and over one billion doses tical information, Internet pharmaceuti- a year of 41 types of vaccine against cal trading, and medical institutions infection caused by 26 kinds of virus and 5
  6. 6. Regulatory Focus WHO Drug Information Vol. 26, No. 1, 2012Table 2. Pharmaceutical industry profile Indicator January–November 2010 January–June 2011 Gross industrial output 1123.9 714.6 (billion yuan) Among these: Among these: • APIs: 215.7 • APIs: 117.8 • FPPs: 318.56 • FPPs: 158.3 • Medical devices: 104.83 • Biological products: 59.1 • TCM preparations: 317.2 • TCM preparations: 119.2 International business 54.12 34.55 (billion US dollars) Among these: Among these: • Export: 35.80 • Export: 21.38 • Import: 18.32 • Import: 13.17 R&D percentage of gross 1.82% (figure for entire year) industrial output Fixed assets investment (billion yuan) 175.33 110.8 Profit (billion yuan) 111.4 62.9 Source: Department of Industry Coordination, National Development and Reform Commission at http://www.sdpc.gov.cn/ jjxsfx/t20110128_393383.htm National Development and Reform Commission at http://www.sdpc.gov.cn/zjgx/t20110323_400832.htm National Development and Reform Commission at http://www.ndrc.gov.cn/jjxsfx/t20110829_430931.htm National Bureau of Statistics of China. Ministry of Science and Technology of the People’s Republic of China. Ministry of Finance People’s Republic of China. Report on Investment in Scientific R&D, 2010, at http://www.sts.org.cn/tjbg/tjgb/ document/2011/20110928.htmpathogenic bacteria (8). By the end of world. This demands that the country’s2010, China counted more than 8000 regulatory activities are in line withpharmaceutical enterprises — including international standards. Current efforts toproducers of prepared Chinese crude reform health care inside China also pre-drugs, oxygen for medical use, diagnostic sent challenges for capacity building andagents, blood derived products and vac- regulation, while the quality and safety ofcines (9) — of which 4678 were produ- services and products provided within thecers of active pharmaceutical ingredients essential medicines programme need to(APIs) and finished pharmaceutical pre- be safeguarded.parations (FPPs) (1). In 2010, the grossindustrial output reached 1236.827 billion Legislative framework andyuan with annual total sales of medici- regulatory statusnal products at 682 billion yuan (10). Anoverview of the Chinese pharmaceutical China practises a unified, multilevel legis-industry profile is set out in Table 2. lative system (12). The National People’s Congress and its Standing CommitteeThe challenges of regulating the Chinese exercise the state’s power to make laws.pharmaceutical industry were highlighted The State Council formulates administra-in a speech given by the SFDA Deputy- tive regulations and, at provincial level,Commissioner Wu Zhen at the 2011 An- the People’s Congresses as well asnual Conference on National Medicines their standing committees establish localRegulation (11). Following international statutes. In the area of medicines regula-economic integration, China is now the tion, the main legislative instrument is thethird largest pharmaceutical market in the Drug Administration Law of the People’s6
  7. 7. WHO Drug Information Vol. 26, No. 1, 2012 Regulatory FocusRepublic of China. Based on this, the cines regulation, it reflects the internallegal framework of medicines regulation and external driving forces modelling me-is established and regularly improved. dicines regulation in China, for example: • First released in1985 following enact-Drug Administration Law ment of the Drug Administration Law.The Drug Administration Law was issuedby the National People’s Congress. It was • Revised to reflect establishment of theenacted in 1985, and amended in 2001. SDA in 1998.The 2001 revision has achieved betterharmonization with regard to international • Revised in response to China’s mem-practice and provides a modern base bership to the World Trade Organiza-for control over the tion in 2001.quality, safety and • Revised to reflect theefficacy of medicines Drugs/medicines refer to articles 2001 revision of thein China. The Law which are used in the prevention, Drug Administrationapplies to all parties treatment and diagnosis of human Law.engaged in research diseases and intended for the re-and development, pro- gulation of the physiological func- • Updated followingduction, distribution, tions of human beings, for which adoption of the Admi-use, and administra- indications, usage and dosage nistrative Licensingtion. In 2002, the State are established. These include Law of the People’sCouncil also adopted Chinese crude drugs, prepared Republic of China inRegulations for Imple- slices of Chinese crude drugs, tra- 2004.mentation of the Drug ditional Chinese medicine prepa-Administration Law of rations, chemical drug substances Under the Provisions,the People’s Republic and their preparations, antibiotics, a series of measuresof China. biochemical drugs, radiopharma- relating to procedures ceuticals, sera, vaccines, blood and products haveThe Drug Administra- products and diagnostic agents. been issued, includingtion Law 2001 com- (Article102 of the Drug Administra- Supplementary provi-prises 106 articles in tion Law) sions for TCM registra-ten chapters, inclu- tion (2008), Provisionsding: General Provi- New drugs refer to medicines for on-site inspectionsions, Control of Drug which have not been marketed in drug registrationManufacturers, Control within the territory of the People’s (2008), Provisions forof Drug Distributors, Republic of China. (Article 83 of special review andControl of Pharmaceu- the Regulation). approval for new drugticals in Medical Insti- registration (2009)tutions, Control of Drugs, Control of Drug and Provisions for technology transfer ofPackaging, Control of Drug Pricing and drugs (2009). Provisions for drug stan-Advertising, Inspection of Drugs, Legal dards is currently under developmentLiabilities, and Supplementary Provisions. (14).Based on the framework of the Drug Ad- Applications are classified into newministration Law, a comprehensive legal medicines, generic medicines, importsystem including regulations, provisions, medicines and their supplementary appli-and guidelines has been established. cations, as well as re-registration. (Article 11.12.)Medicines registrationProvisions for drug registration 2007 (13) The first two classifications – new medi-is in its fifth edition and fourth update. As cines and generic medicines – apply tothe most frequently revised rule in medi- domestic applicants, whereas requests 7
  8. 8. Regulatory Focus WHO Drug Information Vol. 26, No. 1, 2012from overseas applicants are handled • New drugs offering significant clinicalaccording to those for imported medi- advantage for the treatment of diseasescines. Any application for changing a such as AIDS, malignant tumours anddosage form or route of administration, rare disorders, etc.or claiming a new indication for marketed • New drugs for the treatment of dis-medicines, is submitted through the new eases for which effective therapeuticdrug application (NDA) process which methods are not available.covers applications for registration ofmedicines not previously marketed inChina. (Article 12.12.) Quality assurance In China, good manufacturing practicesThe SFDA has additionally formulated (GMP) is a set of principles and proce-Requirements for application dossiers in dures which should be followed in orderCTD format for pharmaceutical products to provide assurance that each medicinalbased on the common technical docu- product is safe and of the required quality.ment (CTD) of the International Confe- This comprises requirements relating torence on Harmonization of Technical premises, equipment, personnel, docu-Requirements for Registration of Pharma- mentation and quality control. Theseceutical for Human Use (ICH) taking into requirements are enforced through sys-consideration the actual situation of drug tems of factory inspection and mandatoryresearch and development in China. The licensing of factories which manufactureRequirements were issued in September medicines.2010 (15). Since its first promulgation in 1988 (16),An application for generic medicines will China’s Good Manufacturing Practiceapply to production of medicines having for Drugs was revised in 1992 and 1998.an existing national medicines standard The latest version of GMP (2010 Revi-for marketing approval by the SFDA. sion) released by the Ministry of HealthThe application process for a biological has been effective since 1 March 2011product is the same as that for an NDA. (17). It consists of 14 chapters and 313(Article 12.12.) articles based on the concepts of qualityAn application for an imported drug refers risk management and whole processto the registration application for medi- control of drug manufacturing. It attachescines manufactured abroad to be marke- greater importance on the scientific na-ted in China. (Article 12.12.) ture, instructions, functions and manoeu- verability consistent with WHO GMP.Special review procedures to encourageinnovation also exist. Speciality products Overseas manufacturers of medicinesare given priority in review and approval. supplied to China must provide evidenceA specific fast track procedure applies to that goods are manufactured to a stan-the following products (Article 4.12): dard of GMP equivalent to that expected of Chinese manufacturers of the same• Active ingredients extracted from goods. plants, animals and minerals, etc. and their preparations not yet marketed National drug standards in China. Newly discovered Chinese National drug standards in China include crude drugs and their preparations. the Pharmacopoeia of the People’s Repu-• Chemical drug substances and their blic of China, drug registration specifi- preparations and biological products cations, etc., published by the Ministry not yet approved for marketing in China of Health/SFDA, including technical or abroad. requirements such as testing methods8
  9. 9. WHO Drug Information Vol. 26, No. 1, 2012 Regulatory Focusand manufacturing processes. (Article overview of SFDA’s work in the area of136.12.) The 2010 edition of The Phar- medicines registration including produc-macopoeia of the People’s Republic of tion, clinical trials, and other key areas.China is available in three volumes andcontains 4567 monographs (18). Provisions for medicines usePre-approval requirements for Medicines use is covered by the nationalclinical trial applicants essential medicines system and list. This includes classification of medicines into• Safety evaluation in pre-clinical studies prescription and non-prescription catego- should comply with GLP (19). ries.• Clinical trials (including bioequivalence studies) should be conducted in compli- Essential Medicines ance with GCP. (Article 30.12.) Over the past three decades, the concept of essential medicines has evolved in• Drugs used for clinical trials should be China from a list to an integrated strategy manufactured in facilities in compliance based on a national medicines policy and with GMP. (Article 35.12.) is a key objective of healthcare reform• A drug can be used for a clinical trial (21). only after being tested and qualified. Vaccines, blood products and other China released its first National Essen- biological products specified by the tial Medicines List in 1982 following the SFDA should be tested by drug test- launch of the WHO Model List of Essen- ing institutes designated by the SFDA. tial Drugs in 1975. In 2009, the National (Article 36.12.) Essential Medicines Committee was established (22). The Provision for aAll clinical trials (including bioequivalence National Essential Medicines List (interim)studies) need prior SFDA approval. (23) and a Position paper on implemen- tation of the National Essential Medicines• The approved clinical trial should be System (24) were published in 2009. The conducted in a certified research institu- Position Paper defines essential medi- tion that operates in compliance with cines as those which satisfy the health Chinese GCP. care needs and are available to the public• For overseas applicants intending to at all times in adequate amounts and in conduct an international multicentre appropriate dosage forms, affordable clinical trial in China, drugs used for the price and equitable access to the public. clinical trial should already be approved or in phase II or III clinical trial over- The National Essential Medicines List has seas. While approving the conduct of been regularly updated and the current an international multicentre clinical trial, 2009 edition is the Seventh edition. Cove- the SFDA may require the applicant to rage of products has expanded from a first conduct a phase I clinical trial in focus on chemical pharmaceuticals in the China. (Article 44.12.) first edition to TCM in the second edition, and was again extended to include prepa-• Any preventive vaccine trial not having red slices of Chinese crude drugs in the first been registered overseas is prohib- current 2009 edition. ited in China. (Article 44.12.) Classification of prescription andSFDA publishes an Annual report on the non-prescription medicinesevaluation and approval of drug regis- At the National Health Conference intrations (20). The report provides an 1996, classification of prescription and 9
  10. 10. Regulatory Focus WHO Drug Information Vol. 26, No. 1, 2012non-prescription medicines was identi- for narcotic medicines production (Articlefied as a key feature of the reform and 5.25). MRAs above provincial leveldevelopment of China’s healthcare have established information monitoringsystem (25). In June 1999, the Provision networks and share information related tofor classification of prescription drugs products (research, production, distribu-and non-prescription drugs (interim) and tion, use, storage and transportation) withthe first list of non-prescription medicines the public security agency at the same(OTC) was released. In 2001, control level. (Article 58.25.)over prescription and OTC classificationmanagement became a legal require- Clinical trialsment under the Drug Administration Law. Clinical trials of narcotics listed as a(Article 37.7.) category 1 psychotropic should not be conducted in healthy subjects. (ArticleIn 2004, the SFDA took a dynamic ma- 13.25.)nagement approach to the control of ProductionOTC medicines (26). Henceforth, OTC The SFDA and MoA draw up an annualmedicines could be switched to prescrip- cultivation plan based on production, clini-tion-only status as a result of any safety cal needs and national storage capacity.related issues. To further standardize Cultivation enterprises are designated byinformation and labelling of non-prescrip- the SFDA and MoA. (Article 14.25.)tion medicines, the SFDA revised themodel insert for non-prescription drugs in Distributors and distribution2007 (27). By the end of 2011, the SFDA National wholesalers who distributehad issued 5697 package inserts for non- narcotic drugs and category 1 psycho-prescription drugs, including 1170 chemi- tropic substances among the provincescal drugs and 4527 TCMs (28). are licensed by the SFDA. (Article 24.25.) Narcotic drugs and category I psychotro-Control of narcotics and pic drugs are not permitted in retailing.psychotropic substances (Article 30.25.)The Regulation for control of narcoticsand psychotropics was adopted by the Information sharingState Council on 26 July 2005. It con- Reports on product-related informationsolidates and amends the former two are provided quarterly by city-level MRAsseparate regulations for narcotic drugs to upper level MRAs. (Article 59.25.)and psychotropic substances releasedin 1987 and 1988. The more stringent Electronic distribution oversightprovisions are in line with the respec- Real-time dynamic monitoring of produc-tive International Conventions under the tion, purchase, sales, inventory and flowprinciple of balancing control measures of narcotic drugs and category 1 psycho-and access (29). The main points include, tropic substances is realized through theamong others: Electronic Medicines Supervision and Regulation Network (30).Coordinated supervisionDepartments under the State Council Control of drug promotion and advertisinginvolved in narcotic and psychotropic Control of OTC and prescription-onlycontrol include the SFDA, Ministry of medicine advertising ensures accurateAgriculture (MoA) and Ministry of Public content, compliance with the law andSecurity (MPS). The MoA and SFDA avoidance of misleading information. Thehold joint responsibility for narcotics and legal basis for drug advertising is vestedthe MPS is responsible for oversight of in the SFDA approved package insert/distribution and the medicinal plans used labelling information. (Article 6.27.)10
  11. 11. WHO Drug Information Vol. 26, No. 1, 2012 Regulatory FocusSupervision of drug advertising is the Drug safety monitoringresponsibility of the SFDA and the State Establishing a reporting system onAdministration for Industry and Com- adverse drug reactions (ADRs) is requi-merce (SAIC). The current legislative fra- red under Article 71 of the Drug Admi-mework for medicines advertising Provi- nistration Law 2001. It is a legal obliga-sions for drug advertisement examination tion for manufacturers, distributors and(SFDA Order 27) and Drug advertisement medical institutes to report serious ADRs.examination and release standards (SAIC Improving the ADR evaluation system isOrder 27) (31) was issued jointly by the also highlighted in the 2010 State Counciltwo departments and became effective in schedule. Among the five Priorities in theMay 2007. reform of the medicine and healthcare system, an ADR evaluation system isAdvertising is prohibited (Article 3.27) for: a necessary part of the essential medi-• Narcotics, psychotropic substances, cines policy (33). The Provisions for ADR toxic medicines and radiopharmaceuti- reporting and monitoring released in 2011 cals. by the Ministry of Health clearly define the appropriate procedure, timeframe, and• Pharmaceutical preparations produced responsibilities of stakeholders (34). by medical institutions.• Products specifically for military use. China’s ADR monitoring work was initia- ted in 1989 through establishment of the• Preparations under trial production. ADR Monitoring Centre within the Ministry• Products that have been prohibited by of Health. Over the past two decades, the SFDA for production, sale or use. in addition to development of the appro- priate legislative framework, key progressThe SFDA implements a risk based made includes formal membership ofregulatory approach in terms of content of China’s ADR Centre to the WHO Inter-advertisements and category of product national Drug Monitoring Programme in(e.g., OTC or prescription-only medi- 1998. The first National annual report oncines). The key points are: ADR monitoring was released in 2009. The ADR network is expected to be• Only OTC products can be advertised expanded to 400 sub-centres nationwide directly to the consumer and all ad- with an on-line information reporting sys- vertising materials should state that tem functioning as of 2010 (35). In 2011, purchase and use should be made in China signed an agreement with the accordance with a pharmacist’s instruc- WHO Collaborating Centre for Interna- tions or guidance. (Article 8.27.) tional Drug Monitoring (Uppsala Monito-• Prescription medicines can only be ring Centre) with the aim of enhancing advertised in medical or pharmaceu- data exchange from China’s Adverse tical journals assigned by the Ministry of Drug Reaction Monitoring database and Health and SFDA. The advertisement VigiBase — the WHO global database should state that it is specifically di- containing over 6 million ADR reports. rected to medical professionals. (Article The project agreement will also improve 8.27.) the Drug Dictionary of China, and signal detection and patient safety data mining• The prescription/trade name cannot techniques (36). be used within the advertising slogan. (Article 5.27.) According to the Guideline on streng-• By the end of June 2011, 544 publi- thening the establishment of an ADR cations had been designated by the monitoring system released by the SFDA Ministry of Health/SFDA (32). in 2011, the future China ADR monito- 11
  12. 12. Regulatory Focus WHO Drug Information Vol. 26, No. 1, 2012 Roadmap for Drug Safety National drug safety plan 2011—2015 The Roadmap for Drug Safety adopted on 7 December 2011 sets out the overall objectives and priorities for pharmaceutical products, which should be produced under conditions satis- fying good manufacturing practices (GMP). Priorities include: Standards improvement. Standards for chemical medicines and biological products will comply with international requirements. China should take the lead in developing internatio- nal standards for traditional Chinese medicine (TCM) Quality control capacity building. A focus will be made on strengthening improvement of quality control institutions at national level, upgrading conditions at provincial level and strengthening mobile testing capacity of institutions at county level. Whole process oversight. Systems will be launched for quality assurance of medicines and medical devices. All marketed products will be subject to bar coding and all medicines controlled under electronic track and trace systems. Postmarketing system. A special focus will be made on the monitoring and assessment of new drugs, TCM injectables and high risk products. Essential medicines. The essential medicines system will be improved through ensuring safety and accessibility. The withdrawal and recall of medicines. This will be improved and a credit rating system established for enterprises. Efforts to combat substandard and counterfeit products willl continue. Medicines approval. An in-depth reform of the medicines administrative approval system will be carried out following strict criteria and standardized procedures. The revision and establishment of drug-related laws and regulations will be accelerated.ring and reporting system will be based • Regulation and authorization of infor-on international standards supported by mation provision, whether commercialinformation technology with an early war- or non-commercial.ning capability, combined with four-level • Regulation and licensing of Internet-SFDA and stakeholder participation (37). based medicines transactions, including third party e-commerce platform provid-Internet-related pharmaceutical ers, business-to-business (B2B) anddistribution and information business-to-consumers (B2C).Internet based activities related to medi-cines need to be licensed by the MRAs. ReferencesUnder the two legal documents released 1. State Food and Drug Administration (2011).by the SFDA, Requirement for Internet- SFDA annual statistics report 2010. At http://based service provision of pharmaceuti- www.sfda.gov.cn/WS01/CL0108/66530.htmlcal information 2004 and Requirementsfor review and licensing of Internet-based 2. Ministry of Civil Affairs of the People’spharmaceutical transactions 2005, regu- Republic of China (2011). Statistical reportlation involves two spheres: on social service development in China 2010. At http://www.mca.gov.cn/article/zwgk/ mzyw/201106/20110600161364.shtml12
  13. 13. WHO Drug Information Vol. 26, No. 1, 2012 Regulatory Focus3. National Bureau of Statistics of China 14. State Food and Drug Administration.(2011). Bulletin of key figures for the 6th Natio- Zhang Wei (2010). Latest progress in develop-nal Population Survey 2010. At http://www. ment of the Chinese pharmaceutical industrystats.gov.cn/tjfx/jdfx/t20110428_402722253. and administration of drug registration. 2010 China–Japan Symposium on Global Clinical4. National Bureau of Statistics of China Trials and Ethnic Factors, China. At http://(2011). Preliminary verification bulletin on www.pmda.go.jp/english/past/2010_sympo/2010 annual gross domestic product (GDP). file/201005_03.pdfAt http://www.stats.gov.cn/tjdt/zygg/sjxdtzgg/t20110907_402752625.htm 15. State Food and Drug Administration. SFDA issues Requirements for application5. Constitution of the People’s Republic of dossiers in CTD format for a pharmaceuticalChina (Full text after amendment on 14 March product. News Release. 11 October 2010. At2004). At: http://www.npc.gov.cn/englishnpc/ http://eng.sfda.gov.cn/WS03/CL0757/62297.Constitution/node_2825.htm html6. State Food and Drug Administration. Mainresponsibilities of SFDA. At http://eng.sfda. 16. State Food and Drug Administrationgov.cn/WS03/CL0756/ (2011).Good manufacturing practice for drugs (2010 Revision) issued. News Release. At7. Order of the President of the Peoples Repu- http://eng.sfda.gov.cn/WS03/CL0757/62350.blic of China (No. 45). Article 6 of the Drug htmlAdministration Law of the People’s Republicof China. At http://eng.sfda.gov.cn/WS03/ 17. State Food and Drug Administration. GoodCL0766/61638.html manufacturing practice for drugs, (2010 Revi- sion). ( MOH Decree No. 79.) At http://eng.8. Information Office of the State Council sfda.gov.cn/WS03/CL0768/65113.htmlof the People’s Republic of China (2008).Status quo of drug supervision in China. 18. State Food and Drug AdministrationAt http://www.gov.cn/english/2008-07/18/ (2010). The Third General Assembly of thecontent_1049011.htm Ninth Chinese Pharmacopoeia Commission and the Summing-up Conference on Compi-9. State Food and Drug Administration (2011). lation of The 2010 Chinese Pharmacopoeia.Database of Pharmaceutical manufacturers. Beijing. News Release. At http://eng.sfda.gov.Official website of SFDA at http://app1.sfda. cn/WS03/CL0757/62334.htmlgov.cn/datasearch 19. State Food and Drug Administration.10. Southern Medicine Economic Research Notice for facilitating the implementation ofInstitute of SFDA (2011). Medicinal Economic GLP. Guo shi yao jian an(2006)587. At http://Newspaper. Capital-driven time is coming. www.sda.gov.cn/WS01/CL0055/10619.htmlAt http://www.yyjjb.com/html/2011-07/13/content_146414.htm 21. State Food and Drug Administration (2010). 2009 Report on the evaluation and11. State Food and Drug Administration. Wu approval of drug registrations. At http://www.Zhen (2011). National Conference on Medi- sda.gov.cn/WS01/CL0236/54135.htmlcines Regulation. News Release. At http://app1.sfda.gov.cn/WS01/CL0287/68457.html 21. Xinhua News Agency (2009). Deepening reform in healthcare system and establishing12. National People’s Congress. At http:// the county’s essential medicines system. Atwww.npc.gov.cn/pc/11_4/2007–11/20/ http://news.xinhuanet.com/politics/2009-11/15/content_1617713.htm content_12462632.htm13. State Food and Drug Administration 22. Ministry of Health (2009). National Essen-(2007). Provisions for drug registration. At tial Medicines Committee established. Athttp://www.sda.gov.cn/WS01/CL0053/24529. http://www.moh.gov.cn/publicfiles/business/html htmlfiles/wsb/pwsyw/200905/40493.htm 13
  14. 14. Regulatory Focus WHO Drug Information Vol. 26, No. 1, 201223. Ministry of Health, National Development 29. The State Council (2005). Regulation forand Reform Commission, Ministry of Industry control of narcotics and psychotropics. Atand Information Technology, Ministry of Super- http://www.sfda.gov.cn/WS01/CL0784/23500.vision, Ministry of Finance, Ministry of Human htmlResources and Social Security, Ministry ofCommerce, State Food and Drug Adminis- 30. State Food and Drug Administrationtration, State Administration of Traditional (2007). Notice on the establishment of aChinese Medicine (2009). Provision for Natio- monitoring network for narcotics and psy-nal Essential Medicines List (Interim). At http:// chotropics. Guo shi yao jian ban(2007)482,www.moh.gov.cn/publicfiles/business/htmlfiles/ 3 August,2007. At http://former.sfda.gov.cn/mohbgt/s7692/200908/42512.htm cmsweb/webportal/W945325/A64022736.html24. Ministry of Health, National Development 31. State Food and Drug Administration. Stateand Reform Commission, Ministry of Industry Administration for Industry and Commerceand Information Technology, Ministry of Super- (2007). Drug advertisement examination andvision, Ministry of Finance, Ministry of Human release standards. At http://www.sfda.gov.cn/Resources and Social Security, Ministry of WS01/CL0053/24526.htmlCommerce, State Food and Drug Adminis-tration, State Administration of Traditional 32. State Food and Drug AdministrationChinese Medicine (2009). Position Paper (2011). Online database of SFDA web siteson implementation of the National Essential at http://app1.sfda.gov.cn/datasearch/face3/Medicines System. At http://www.moh.gov. dir.htmlcn/publicfiles/business/htmlfiles/mohywzc/s3581/200908/42498. 33. General Office of the State Council of the People’s Republic of China (2010). Guo25. State Drug Administration. Guo yao jian ban han (2010)67. At http://www.gov.cn/an(1999)460. Facilitating China’s classifi- zwgk/2010-04/19/content_1586732.htmcation of prescription and non-prescriptionmedicines. At http://www.sda.gov.cn/WS01/ 34. Ministry of Health (2011). Provisions forCL0055/9684.html ADR reporting and monitoring. At http://www. sfda.gov.cn/WS01/CL0053/62621.html26. State Food and Drug Administration(2004). Guo shi yao jian an(2004)101, 35. State Food and Drug Administration.Conducting the switch of prescription and Yan min. Development of ADR reporting andOTC. At http://www.sda.gov.cn/WS01/ monitoring in China. 14th ICDRA, Singapore,CL0055/10268.html at http://www.who.int/medicines/areas/qua- lity_safety/regulation_legislation/icdra27. State Food and Drug Administration(2004). Guo shi yao jian zhu(2007)54. Noti- 36. The UPPSALA Monitoring Center (2011).fication of release of the insert sheet model SFDA in China and the UMC – Collaborationfor over-the-counter medicines. At http:// in sharing global patient safety information.former.sfda.gov.cn/cmsweb/webportal/W472/ At http://www.umc-products.com/DynPage.A64019346.html aspx?id=75618&news=1009628. State Food and Drug Administration 37. State Food and Drug Administration(2011). Database of model insert for over-the- (2011). Guideline on strengthening the esta-counter medicine. Official website of SFDA at blishment of an ADR monitoring system. Athttp://app1.sfda.gov.cn/datasearch/face3/dir. http://www.sfda.gov.cn/WS01/CL0844/6693614
  15. 15. WHO Drug Information Vol. 26, No. 1, 2012Paediatric MedicinesBetter medicines for children: The guideline aims to:pharmaceutical formulations • Inform regulatory authorities and manu- facturers of issues that require specialSafe and effective pharmacotherapy in attention in the development of paedi-paediatric patients requires the timely atric medicines taking into accountingdevelopment of medicines to suit the age, new trends and developments as wellphysiological condition and body size of as efforts undertaken by regulatorythe child. However, use of unlicensed and authorities.off-label medicines in children is wide-spread. Formulations developed specific- • Focus on conditions and special needsally for children are urgently needed. in developing countries. The guideline indicates sources of detailed instruc-In 2007, the World Health Organization tions for the development of paediatric(WHO) launched the “Make Medicines medicine formulations. (A list of guide-Child Size” project. The WHO Quality lines and literature appearing in theAssurance Programme has contributed guideline are reproduced on page 19.)to the project by developing norms and The guideline covers paediatric dosagestandards for global application. The forms, dosage forms to be consideredWHO Expert Committee on Specifications in particular, oral administration, rectalfor Pharmaceutical Preparations have administration, parenteral administration,recently endorsed a first guideline and dermal and transdermal administration,several monographs related to paediatric inhalations and packaging and labelling.medicines. Extemporaneous preparations and com-Guideline development pounding are not within the scope of theA preliminary draft document “ Develop- document. However, a separate sup-ment of paediatric medicines: points to plementary guidance document entitledconsider” was discussed at the Expert “Provision by healthcare specialists ofCommittee’s Forty-second meeting in patient-specific preparations that are not2007. A further text was prepared based available as authorized products: pointson the above draft and on “Formulations to consider” is under preparation.of choice for the paediatric population”published by the European Medicines Paediatric dosage form selectionEvaluation Agency in 2006. Preparatory The guiding principles in selecting pae-work involved coordination with ongoing diatric dosage forms should be, as foractivities both within and outside WHO, adults, the balance of risk/benefit takingin particular with the European Medicines into account the specific needs of theAgency (EMA), UNICEF, and the WHO 0–18 year-old population.Essential Medicines Programme. Afterwide circulation for comment, “Develop- Convenient, reliable administration.ment of paediatric medicines: points to The administered dose should be ad-consider in pharmaceutical formulation” justed to the age and needs of the patientwas adopted at the Forty-sixth Expert and manipulation of the dose should beCommittee meeting in October 2011. kept to a minimum. Paediatric medicines 15
  16. 16. Paediatric Medicines WHO Drug Information Vol. 26, No. 1, 2012Table 1. Paediatric dosage form indicators Dosage form Advantage Consideration Reference Flexible solid Priority dosage form. Not suitable for dosage forms, e.g., Suitable for both medicines requiring a orodispersible developed and precise dose titration tablets developing countries May be used for Compatibility of API various APIs and breast milk Potentially for use in children > 6 months Oral medicines for Suitable for precise dose Platform technology for WHO: precise dose titration measurement or titration multiparticulate solids QAS/11.399/Rev.1* Parenteral For severe diseases Requires a trained formulations and conditions caregiver Rectal preparations Severely ill children or Cultural barriers to use children unable to swallow *Zhao N et al (2010). Tablet splitting: product quality assessment of metoprolol succinate extended release tablets. Working document. WHO/QAS/11.399/Rev.1should preferably be ready-to-use formu- End-user needs. Paediatric medicineslations. Alternatively, the dosage form should be easy to use and affordable withshould be designed to subdivide into regard to:smaller, uniform doses of appropriate sizefor accurate dosing. • Supply (e.g., ease of transportation, storage requirements).Acceptability and palatability. The • Access to clean water.dosage form should be palatable, easyto administer and acceptable to the • Adequate product information (e.g.,patient. It should also be developed to how to administer; compatibility andavoid any potential interactions with food incompatibility with food ingredients).and medicine or effects on bioavailability.If administration with common food or Dosage formsliquids is acceptable, information sup- Although the most appropriate dosageported by evidence-based compatibility form should be based on a case-by-studies should be provided in the patient case evaluation, in general, flexible solidinformation leafet. dosage forms are likely to prove most suitable for global use and should be prio-Dosing frequency. A minimum dosing ritized (Table 1).frequency should be preferred to facilitatecompliance with the dosing schedule for Formulation designolder children or caregivers. Instructions Many items need to be considered in theon the dosing frequency should be based design of formulations for paediatric use.on the pharmacokinetic and pharmaco- Those mentioned in the Development ofdynamic properties of the active phar- paediatric medicines document includemaceutical ingredient (API) but may be quality, the Biopharmaceutics Classifi-influenced by the design of the dosage cation System (BCS), excipients, colou-form. ring agents, antimicrobial preservatives,16
  17. 17. WHO Drug Information Vol. 26, No. 1, 2012 Paediatric MedicinesTable 2. Paediatric formulation design indicators Item Consideration (key) Selected references 1. Quality Acceptable level of impurities in APIs WHO: QAS/10.376 Degradation products in FPPs ICH :Q3A(R2);Q3B;Q3C Safety margins on APIs and FPPs EMA: CPMP/SWP/5199/02 Safety studies in juvenile animals EMEA/CHMP/SWP/431994/2007 FPP compliance CPMP/SWP/QWP/4446/00 Dissolution testing to address The International Pharmacopoeia gastric pH of the child FIP/AAPS guidelines 2. BCS BCS-based API classification WHO. Technical Report Series, Transporter function and metabolic No.937, Annex 8. enzymes (typically CYP3A4) Excipients affecting transit time (efflux) 3. Excipients Safety profile of paediatric excipient Breitkreutz J,Boos J (2007). Paedi- in the target age groups atric and geriatric drug delivery. Route of administration Shehab N et al (2009), Exposure Single and daily dose of excipient to the pharmaceutical excipients Duration of treatment benzyl alcohol and propylene Acceptability for intended age group glycol among critically iII Potential alternatives neonates. American Academy Regulatory status in intended market of Pediatrics. “Inactive” ingredients in pharma- ceutical products. WHO. Technical Report Series. Evaluation of certain food additives. 4. Colouring Use is generally discouraged Pollock I, Young E, Stoneham M agents Use may be justified in certain cases, (1989). Survey of colorings e.g. to avoid accidental dosing errors and preservatives in drugs. (several strengths) Pefferi G, Restani P (2003). Acceptable number for use is limited The safety of pharmaceutical Azo-dyes should be avoided excipients. Risk of allergic reactions associated with natural colourants 5. Antimicrobial Potential to cause adverse reactions in Public statement on antimicrobial preservatives infants and neonates preservatives in ophthalmic Avoid use whenever possible preparations for human use Keep to minimum concentration level (EMEA/622721/2009). Solid dosage forms do not need free-mercury-containing preservatives in ophthalmic preparations 6. Sweetening Safety in specific conditions (diabetes, agents fructose intolerance, phenylketonurea) Laxative effect 7. Taste Cultural differences in taste and acceptability Ernest TB et al (2007). Developing masking develop taste for maximum acceptability paediatric medicines: identifying Non-cariogenic sweeteners and flavours the needs and recognizing preferred the challenges. 8. Solubility Higher risks for parenteral preparations enhancers vs. oral preparations Children vulnerable to the effects of ethanol Toxicity on brain maturation highly probable Chronic exposure linked to dependence in adults and adolescents 17
  18. 18. Paediatric Medicines WHO Drug Information Vol. 26, No. 1, 2012sweetening agents, taste making and tration route are highlighted and relevantsolubility enhancers. references are listed. (See Table 2.)Route of administration Next stepsThe common route of administration Although development of paediatric medi-discussed in the document covers oral, cines is still subject to limited knowledgerectal, parenteral, dermal and transder- in some areas, progress is rapidly beingmal administration and inhalation. Special made.issues for consideration of each adminis-Table 3. Route of administration and formulations Administration Special considerations References Oral liquid preparations • preferred route for paediatric patients Strickly RG et al (2007). • drops • stabilizing agents are a major drawback Paediatric Drugs. A (microbial and chemical) • stability of multidose preparations review of commer- • powders and granules • risks of incorrect dosing cially available oral for reconstitution • dose-measuring device critical (drops) formulations. • suspensions • stability parameters of oral suspensions Siewert M et al (2003). FIP/AAPS guidelines Administration through for dissolution/ nasogastric tubes • no effects from saliva and gastric juice: in vitro release may afffect bioavailability testing of novel/ • potential absorption of API into special dosage tube material forms. Thomson SA et al Solid dosage forms (2009). Mini-tablets: • powders and multiparticulate • Improved stability, good dosage uni- new modality to preparations formity, options for different doses deliver medicines • immediate-release tablets • crushing tablets may affect bioavailability to preschool-age • capsules (only if allowed by manufacturer) children. • chewable tablets • chewable tablets may be chewed or Seager H (1998). swallowed whole (dissolution test Drug–delivery conditions same as for tablets) products and • effervescent dosage forms • control moisture and humidity in the zydis fast- manufacture, packaging dissolving and storage of effervescents dosage form. • effervescents: caution in renal insufficiency • dispersible and soluble tablets • dispersible and soluble tablets: flexibility ICH E11 for water-soluble APIs EMEA/622721/2009 • sustained-release formulations • labelling instructions for sustained-release formulations (including coated tablets and matrix tablets): not to be broken or chewed • orodispersible dosage forms • orodispersibles may be moisture-sensitive Rectal suppositories • important route of administration for children severely ill or unable to swallow rectal liquids • concordance and compliance of rectal preparation may be lower • cultural and regional acceptance barriers18
  19. 19. WHO Drug Information Vol. 26, No. 1, 2012 Paediatric MedicinesTable 3. Route of administration and formulations (continued) Administration Special considerations References Parenteral • preferred route of administration for seriously WHO. Multisource ill children and clinically unstable term and (generic) pharma- preterm neonates (developed world setting). ceutical products: • limited experience of needle-free injection guidelines on device use in children. registration require- • increased blood perfusion in sustained- ments to establish release preparations. interchangeability • safety profile of each excipient and suitability (2006). for intended use. Dermal and transdermal Transdermal patches • hydration of the skin and thickness of stratum corneum in children different from adults. • unintended systemic absortion through dermis a potential risk for many APIs. • safety profile of excipients. • test for local tolerance and acceptability. Inhalations Liquids for nebulization • total lung deposition important for Krause J, Breitkreuts J clinical efficacy of preparation. (2008). Improving drug Metered dose inhalers (MDIs) • small airway diameter in children, deposition delivery in paediatric by impact in upper and central airways may medicine. Dry powder inhalers (DPIs) be significantly higher in children. Dolovich M (2000). Influence of inspira- tory flow rate, particle size and airway caliber in aerosolized drug delivery to the lung. Schüepp K, Jauernig J, Janssens H (2005). In vitro determination of the optimal particle size for nebulized aerosol delivery to infants.Bibliography cifications for Pharmaceutical Preparations.1. European Medicines Agency. Clinical Inves- Technical Report Series, No. 929, Annex 5.tigation of Medicinal Products in the Paediatric Guidelines for registration of fixed-dose com-Population, ICH Topic E11. January 2001 bination medicinal products (2005) at http://CPMP/ICH/2711/99 at http://www.ema.europa. www.who.int/medicineseu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002926. 4. World Health Organization. Pharmaceu- tical development for multisource (generic)2. World Health Organization. Guideline on pharmaceutical products. Working documentquality risk management (working document QAS/08.251/Rev.1 at http://www.who.int/QAS/10.376) at http://www.who.int/medicines medicines3. World Health Organization. Thirty-ninth 5. International Conference on Harmonization.report of the WHO Expert Committee on Spe- Impurities in new drug substances. ICH Topic 19
  20. 20. Paediatric Medicines WHO Drug Information Vol. 26, No. 1, 2012Q3A(R2) at http://www.ich.org/fileadmin/Pu- EMEA/566810/2008. at http://www.ema.blic_Web_Site/ICH_Products/Guidelines/Qua- europa.eu/docs/en_GB/document_library/lity/Q3A_R2/Step4/Q3A_R2__Guideline.pdf Scientific_guideline/2009/09/WC500003754. pdf6. European Medicines Agency. Impurities innew drug products, ICH Topic Q3B. CPMP/ 14. World Health Organization. Fortieth reportICH/2738/99 at http://www.ema.europa.eu/ of the WHO Expert Committee on Specifi-docs/en_GB/document_library/Scientific_gui- cations for Pharmaceutical Preparations.deline/2009/09/WC500002676.pdf Technical Report Series, No. 937, Annex 7: Multisource (generic) pharmaceutical pro-7. European Medicines Agency. Impurities: ducts: guidelines on registration requirementsguideline for residual solvents, ICH Topic to establish interchangeability (2006) at http://Q3C. February 2009. CPMP/ICH/283/95 at www.who.int/medicineshttp://www.ema.europa.eu/docs/en_GB/docu-ment_library/Scientific_guideline/2009/09/ ReferencesWC500002674.pdf 1. Kearns GL et al. Developmental phar-8. European Medicines Agency. Guide- macology – drug disposition, action andline on the limits of genotoxic impurities therapy in infants and children. N Eng J Med(CPMP/SWP/5199/02). EMEA/CHMP/ 2003;349(12):1157–1167.QWP/251344/2006 at http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_ 2. European Medicines Agency. Reflectionguideline/2009/09/WC500002903.pdf paper: formulations of choice for the paediatric population. (EMEA/CHMP/PEG/196810/2005)9. European Medicines Agency. Q&A on the at http://www.nppg.scot.nhs.uk/misc/choicepa-CHMP Guideline on the limits of genotoxic per0605.pdfimpurities. EMEA/CHMP/SWP/431994/2007at http://www.ema.europa.eu/docs/en_GB/do- 3. Ernest TB et al. Developing paediatriccument_library/Scientific_guideline/2009/09/ medicines: identifying the needs and reco-WC500002903.pdf gnizing the challenges. J Pharm Pharmacol 2007;59:1043–1055.10. European Medicines Agency. Note forguidance on specification limits of residues of 4. Krause J, Breitkreutz J. Improving drugmetal catalysts (CPMP/SWP/QWP/4446/00). delivery in paediatric medicine. Pharma-17 December 2002. http://www.ema.europa. ceutical Medicine 2008;22:41–50.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003588.pdf 5. Allen LV. Dosage form design and develop- ment. Clin Ther 2008;30(11):2102–2111.11. World Health Organization. Fortieth reportof the WHO Expert Committee on Specifica- 6. Siewert M et al. FIP/AAPS guidelines fortions for Pharmaceutical Preparations. Techni- dissolution/in vitro release testing of novel/cal Report Series, No. 937, Annex 8, Proposal special dosage forms. Dissolution Technolo-to waive in vivo bioequivalence requirements gies 2003; February Issue, page 15.for WHO Model List of Essential Medicinesimmediate-release, solid dosage forms (2006) 7. Breitkreutz J, Boos J. Paediatric andat http://www.who.int/medicines geriatric drug delivery. Expert Opin Drug Deliv 2007;4(1):37–45.12. European Medicines Agency. Publicstatement on antimicrobial preservatives in 8. Shehab N et al. Exposure to the phar-ophthalmic preparations for human use. 8 maceutical excipients benzyl alcohol andDecember 2009. EMEA/622721/2009 at http:// propylene glycol among critically ill neo-www.techtran.co.jp/techtr_j/globepharm/ nates. Pediatric Critical Care Medicineemea091208.pdf 2009;10(2):256-259.13. European Medicines Agency. Guide- 9. “Inactive” Ingredients in Pharmaceuticalline on the investigation of medicinal pro- Products: Update: http:/www.pediatrics.org/ducts in the term and preterm neonate. cgi/content/full/99/2/26820
  21. 21. WHO Drug Information Vol. 26, No. 1, 2012 Paediatric Medicines10. World Health Organization. Technical 15. Thomson SA et al. Mini-tablets: new mo-Report Series, Evaluation of certain food addi- dality to deliver medicines to preschool-agedtives. List of publications: http://www.who.int/ children. Paediatrics 2009;123(2):e235–e238.ipcs/publications/jecfa/reports/en/index.html. 16. Seager H. Drug-delivery products and the11. Pollock I, Young E, Stoneham M. Survey Zydis fast-dissolving dosage form. J Pharmof colourings and preservatives in drugs. Brit. Pharmacol1998;50:375–382.Med J 1989;299:649–651. 17. Dolovich M. Influence of inspiratory flow12. Pefferi G, Restani P. The safety of rate, particle size and airway caliber in aero-pharmaceutical excipients. Il Farmaco 2003; solized drug delivery to the lung. Respiratory58:541–550. Care 2000;45:597–608.13. Mennella JA, Beauchamp GK. Optimi-zing oral medications for children. Clin Ther 18. Schüepp K, Jauernig J, Janssens H. In2008;30(11):2120–2132. vitro determination of the optimal particle size for nebulized aerosol delivery to infants. J14. Strickly RG et al. Paediatric drugs – Aerosol Med 2005;18(2):225–235.A review of commercially available oral formu-lations. J Pharm Sci 2007;97(5):1731–1774.Benznidazole: child-adapted America, and kills some 12,000 peopledosage form approved each year, making it the leading para- sitic killer in the Americas. The ChagasBrazil’s National Health Surveillance parasite is primarily transmitted via theAgency (ANVISA) has granted registra- bite of the blood-sucking triatome bug.tion of a new paediatric dosage form of In addition to blood transfusion, organbenznidazole, developed through a par- transplant, or ingesting infected food, thetnership between the Pernambuco State parasite is also transmitted during preg-Pharmaceutical Laboratory (LAFEPE) nancy from mother to child.of Brazil and the Drugs for NeglectedDiseases initiative (DNDi). Registration This new dosage form for children repre-of this formulation of benznidazole was sents real progress for several reasons.made on 12 December 2011. Children are at especially high risk ofThis new tablet is easier-to-administer infection, with a majority of them bornand a safer treatment of Chagas disease from infected mothers. It is known thatin infants and young children under the early treatment using benznidazole in theage of two, as they will receive accu- first year of life can eliminate the parasiterate dosage. Until now, benznidazole in more than 90% of infected newborns.was available only as a 100 mg tablet Thus, babies infected with Chagasfor adults. Treatment for young children disease will benefit the most from thisrequired cutting adult pills into tiny slivers new paediatric tablet.— up to 12 pieces depending on thechild’s weight — and crushing and mixing The new 12.5 mg tablet is easily disper-them with water or juice, to be administe- sible and adapted for babies and child-red twice a day for 60 days. This difficult ren up to two years of age (20 kg bodyand inefficient method often results in weight). Treatment is designed to useimproper dosing, risks of increased side- one, two, or three tablets, depending oneffects, ineffective treatment, or treatment weight (recommended dosage, 5–10 mg/stoppages. kg body weight/day).Chagas disease affects an estimated Tools to facilitate implementation of andeight to ten million people, mostly in Latin access to the new treatment include a 21
  22. 22. Paediatric Medicines WHO Drug Information Vol. 26, No. 1, 2012Demand Forecast, a Procurement Guide, dosage form. The new tablet will beand a Tool Box providing training and produced by LAFEPE, a public pharma-educational materials for doctors, other ceutical manufacturer run by the State ofhealth professionals, mothers, and care- Pernambuco in Brazil and the sole globalgivers regarding appropriate use of the producer of benznidazole.treatment. Reference: DNDi Drugs for NeglectedIn 2008, DNDi and LAFEPE entered a Diseases initiative at http://www.dndi.orgjoint development agreement for thisUse of drugs in paediatric health pharmaceutical company representatives.conditions increasing In the absence of experimental studies in paediatric populations, informationIn the past, treatment decisions involving provided by these sources may be basedthe use of drugs in infants, children and more on expert opinion or local practiceyouth were often derived from the data and experience (5).in drug studies involving adults (1, 2).However, the safety and efficacy of medi- Drug investigations in paediatric popu-cations may be significantly different in lations can be faced with multiple chal-paediatric patients than in adult patients lenges. Some examples include:owing to differences in developmentalphysiology, disease pathophysiology, • Defining appropriate ethical adaptationsand developmental pharmacokinetics of clinical trials for studies involvingand pharmacodynamics (2). This unders- infants, children and youth (1).tanding has led to the use of the phrase«children are not just small adults,» a • Ensuring adequate sample sizes (1, 2).statement that emphasizes the urgent • Choosing objective, clinically relevantneed for evidence from high-quality trials endpoints that can be measured in ainvolving paediatric patients (2). valid and reliable manner (1, 2).The use of drugs to treat paediatric • Overcoming technical difficulties, suchhealth conditions in Canada is increasing as the need for frequent blood sampling(3). Infants, children and youth repre- (1).sent nearly one-quarter of Canada’s • Improving pharmacoepidemiologic andpopulation and, on average, receive four pharmacovigilance practices aimed toprescriptions a year from a range of more coordinate the development of reliablethan 1200 different drugs (3, 4). None- information about drug benefits andtheless, data on the efficacy and safety of harms to reduce uncertainties about themost medications prescribed for pediatric use of drugs in paediatric populations.patients are limited (2, 3, 5). • Expanding the availability of age-appro-When prescribing a medication for an priate product formulations (e.g., liquid«off-label» indication in infants, child- formulations).ren or youth, health professionals mayconsult available sources of information, Health Canada, like other regulatorysuch as peer-reviewed medical literature, authorities around the world, recognizespaediatric dosing manuals and textbooks, the need to strengthen information relateddrug formularies at children’s hospitals, to paediatric health. In pursuit of this ob-community pharmacists and the relevant jective, some of its key activities include:22
  23. 23. WHO Drug Information Vol. 26, No. 1, 2012 Paediatric Medicines• Coordinating the development of paedi- References atric information through the regulatory 1. Matsui D, Kwan C, Steer E, et al. The trials system and other means. and tribulations of doing drug research in• Coordinating how this information is children. CMAJ 2003;169(10):1033–4. made available and accessible. 2. Klassen TP, Hartling L, Craig JC, et al.• Raising awareness of child health Children are not just small adults: the urgent needs and safety issues related to the need for high-quality trial evidence in children. development and use of health prod- PLoS Medicine 2008;5(8):1180–2. ucts and food. 3. Abi Khaled L, Ahmad F, Brogan T, et al.• Promoting conditions that enable in- Prescription medicine use by one million formed decisions about the health and Canadian children. Paediatr Child Health nutrition of infants, children and youth. 2003;8(A):6A–56A.To help improve safety data about health 4. Junker A. Canadian pediatric clinical trialsproducts for the paediatric population, it activity 2005-2009. Maternal Infant Childis important for healthcare providers to Youth Res Network 2010;Aug:1–19.continue to report adverse reactions inboth paediatric and adult populations. 5. Matsui D, Jardine M, Steer V, et al. Where physicians look for information on drugExtracted from Canadian Adverse Reaction prescribing for children. Paediatr Child HealthNewsletter, Volume 22, Issue 1, January 2012 2003;8(4):219–21. 23
  24. 24. WHO Drug Information Vol. 26, No. 1, 2012Safety and Efficacy IssuesBevacizumab: severe infectious Ursodeoxycholic acid: seriousendophthalmitis and blindness hepatic eventsCanada — Health Canada has informed Canada ­ Ursodeoxycholic acid (Urso- —healthcare professionals of new safety diol®) is indicated for the managementinformation regarding unauthorized use of cholestatic liver diseases. Canadianof bevacizumab (Avastin®) when repac- Product Monographs for ursodiol®kaged for intra-vitreal injection. products have been updated in October, 2011 to reflect data from a long-termThree clusters of serious ocular compli- clinical trial in primary sclerosing cholan-cations, including acute ocular inflam- gitis (PSC) finding an increase in seriousmation, endophthalmitis, and infectious liver adverse events in patients takingendoph-thalmitis resulting in blindness, an unapproved ursodiol dose (twice thehave been recently reported in California, recommended dose).Florida and Tennessee. Although theseclusters continue to be investigated, it is • The recommended ursodiol dose ispossible that the events of blindness from 13–15 mg/kg/day for adults with choles-streptococcal endophthalmitis in Florida tatic disease.were due to repackaging of bevacizumab • In a clinical trial in patients with PSC,without proper aseptic technique. long-term use of twice the recommend- ed dose of ursodiol® was associatedBevacizumab is a recombinant huma- with improvement in serum liver testsnized monoclonal antibody that is direc- but did not improve survival, and wasted against vascular endothelial growth associated with higher rates of seriousfactor (VEGF). It is authorized for intra- adverse events (including death or livervenous administration in the following transplantation) compared to placebo.indications: • Improved serum liver tests do not• First-line treatment of patients with always correlate with improved liver metastatic carcinoma of the colon or disease status. rectum in combination with fluoro- pyrimidine-based chemotherapy. Reference: Communication from Aptalis Phar- ma Canada dated 1 December 2011 at http://• Treatment of patients with unresectable www.hc-sc.gc.ca/dhp-mps/medeff/advisories- advanced, metastatic or recurrent non- avis/prof/_2011/avastin_8_hpc-cps-eng.php squamous non-small cell lung cancer in combination with carboplatin/paclitaxel Simvastatin with amiodarone: chemotherapy regimen. dosage review• Treatment of patients with glioblastoma United States of America — The Food after relapse or disease progression, and Drug Administration (FDA) has following prior therapy. advised of a dose limitation for simvas-Reference: Communication from Hoffmann- tatin from 10 mg to 20 mg when co-ad-La Roche dated 2 December 2011 at http:// ministered with the cardiac drug amioda-www.hc-sc.gc.ca/dhp-mps/medeff/advisories- rone. In June 2011, the FDA previouslyavis/prof/_2011/avastin_8_hpc-cps-eng.php recommended that the dose limitation for24
  25. 25. WHO Drug Information Vol. 26, No. 1, 2012 Safety and Efficacy Issuessimvastatin be decreased from 20 mg to Reference: FDA Drug Safety Communica-10 mg, and has now reconsidered that tion, 9 November 2011 at http://www.fda.gov/recommendation. Unlike other interacting Drugs/DrugSafety/ucm278837.htmdrugs, there were no pharmacokinetic orclinical trial data to support the simvasta- BCG vaccine: lymphadenitis tin dose reduction approved with ami-odarone. Therefore FDA has determined Singapore — The Health Sciencesthat the simvastatin dose limitation, when Authority (HSA) has updated healthcaretaken with amiodarone, should be res- professionals on suspected reports oftored to 20 mg.   lymphadenitis following the administration of the Bacillus Calmette-Guérin (BCG)In patients who are taking both simvasta- Vaccine Staten Serum Institute (SSI)®.tin and amiodarone, the dose of simvas- This observation arose from the activetatin should not exceed 20 mg per day. surveillance and monitoring of vaccineThe simvastatin drug labels (Zocor® and adverse events (VAEs) at the sentinel sitegenerics, Vytorin®) have been updated to at KK Women’s and Children’s Hospitalreflect this correction. (KKH).Reference: FDA Drug Safety Communication, In 2009, HSA collaborated with KKH to15 December 2011 at http://www.fda.gov/ initiate active surveillance for VAEs rela-Drugs/DrugSafety/ucm283137.htm ted to H1N1 vaccines in pregnant women and children. This was subsequentlyFenofibric acid: the ACCORD expanded to include all VAEs followinglipid trial childhood immunization.United States of America — The Food In Singapore, BCG vaccine is routinelyand Drug Administration (FDA) has given to newborns as part of the Nationaladvised that the cholesterol-lowering Childhood Immunization Schedule. Sincemedicine fenofibric acid (Trilipix®) may June 2003, the BCG vaccine manufactu-not lower a patient’s risk of having a heart red by SSI is the sole BCG vaccine regis-attack or stroke. This is based on data tered in Singapore. BCG Vaccine SSI®from the Action to Control Cardiovascular contains an attenuated strain of Mycobac-Risk in Diabetes (ACCORD) Lipid trial, terium bovis (BCG), Danish strain 1331.which evaluated the efficacy and safety offenofibrate plus simvastatin combination In 2009, there were 26 reports of BCG-therapy versus simvastatin alone in pa- associated lymphadenitis of which 23tients with type 2 diabetes mellitus. FDA cases (88%) presented as suppurativereviewed this trial as part of its ongoing lymphadenitis. Of these, 22 cases requir-investigation of the safety and efficacy of ed surgical intervention such as excisionTrilipix®.  or incision and drainage. In 2010, there were 25 reports of lymphadenitis. SixteenIn the ACCORD Lipid trial, there was no cases (64%) presented as suppurativesignificant difference in the risk of expe- lymphadenitis which required surgicalriencing a major adverse cardiac event intervention. From January 2011 tobetween the group treated with fenofi- October 2011, the reports of lymphaden-brate plus simvastatin compared with itis increased to 53.simvastatin alone. In addition, a subgroupanalysis showed that relative to treatment An increase in the number of suspectedin men, there was an increase in the reports of BCG-associated suppurativerisk for major adverse cardiac events in lymphadenitis has also been identifiedwomen receiving the combination therapy in some countries such as Ireland andversus simvastatin alone. Latvia in recent years. However, the 25

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