| Slide 1 of 25 Dr Rägo 28 April – 2 May 2008 Pharmaceutical Development with Focus on Paediatric formulations WHO/FIP Training Workshop Hyatt Regency Hotel Sahar Airport Road Andheri East, Mumbai, India 28 April 2008 – 2 May 2008

| Slide 2 of 25 Dr Rägo 28 April – 2 May 2008 The need for paediatric medicines: WHO perspective Presented by: Lembit Rägo MD, PhD Contact details: Dr Lembit Rägo Coordinator, Quality Assurance and Safety: Medicines Medicines Policy and Standards World Health Organization Geneva Switzerland

| Slide 3 of 25 Dr Rägo 28 April – 2 May 2008 The need for paediatric medicines: WHO perspective Background What is a problem? Essential medicines and paediatric dosage forms What is WHO doing and planning to do?

| Slide 4 of 25 Dr Rägo 28 April – 2 May 2008 Health in the Millenium Development Goals (MDGs) MDG 4: Reduce child mortality Target 5 - Reduce by two-thirds, between 1990 and 2015, the under-five mortality rate Indicators: –13.Under-five mortality rate –14. Infant mortality rate –15. Proportion of one-year-old children immunized against measles

| Slide 5 of 25 Dr Rägo 28 April – 2 May 2008 Goal 4: Reduce child mortality. Where are we? Only 16 of 68 priority (form 97% of all such death) countries on track to reach MDG 4 on child survival In Sub-Saharan Africa 12 countries are experiencing worse rather than improved under-5 mortality rates Detailed country reports from Tanzania and South Africa Several poorly resourced countries such as Indonesia, Nepal, Laos, Bangladesh and Bolivia have shown that progress IS possible: they have reduced their under-5 mortality more than half since 1990 Source: Lancet Vol 371, No 9620, April 12-18, 2008

| Slide 6 of 25 Dr Rägo 28 April – 2 May 2008 Background Likely most of the medicines in paediatric practice used Globally –Do not have "paediatric indication" approved by regulators –Are used as "Off label" –Lack proper paediatric formulations XXI Century with all its technology achievements has given little to children –How long will children remain a "neglected population"?

| Slide 7 of 25 Dr Rägo 28 April – 2 May 2008 Background Why approved by regulators paediatric indications are important? –Mostly gives assurance that the indication is based on evidence i.e. based on clinical research in respective paediatric age group(s) –Makes it possible for generic manufacturers to refer to originators indication

| Slide 8 of 25 Dr Rägo 28 April – 2 May 2008 Background Why many medicines lack paediatric indications? –Research in paediatric populations more complicated and, perhaps, more costly –Paediatric population is not ONE, but several depending on the age group –May not necessarily be commercially attractive –Problem ignored as kids perceived as small adults (thus, no need for specific research and development) – History of art example

| Slide 9 of 25 Dr Rägo 28 April – 2 May 2008 Children painted as small adults PAOLO VENEZIANO Italian painter, Venetian school (b. before 1300, d. ca. 1360) Proportions as for adults

| Slide 10 of 25 Dr Rägo 28 April – 2 May 2008 Children painted as small adults Peter Paul Rubens ( ) – great Flemish master Boys are dressed as adults. At the time of the painting children were not thought of as different from adults or as human beings at another "stage" that required special attention, special clothes or social settings. Children were small adults who ate, dressed and socialized like adults

| Slide 11 of 25 Dr Rägo 28 April – 2 May 2008 Background Why different from adults? –Pharmacokinetics may be different –Pharmacodynamics may be different –Profile of toxicity and adverse reactions may differ –Need for different, suitable for children, pharmaceutical forms –…

| Slide 12 of 25 Dr Rägo 28 April – 2 May 2008 What is the problem? It is estimated that 10.6 million children under five die every year, many from treatable conditions Children suffer from the same illnesses as adults but they may be more seriously affected, particularily in developing world, by certain conditions –Respiratory tract infections –Malaria –Diarrhoeal diseases In 2005, 2.3 million children under 15 years were HIV positive, new cases had occurred over the 12 months

| Slide 13 of 25 Dr Rägo 28 April – 2 May 2008 Mortality and children: Global picture

| Slide 14 of 25 Dr Rägo 28 April – 2 May 2008 What is the problem? Lack of paediatric indications –Not all essential medicines have paediatric indications –Some antiretrovirals do not have paediatric indications or have only for some age groups – difficulties in dosing combination therapies Lack of paediatric formulations –Dosing difficulties –Paediatric FDCs needed for HIV/AIDS and malaria, also TB –Can have dramatic consequences Example: International public health treatment program used for children big chewable tablet which caused in some cases chocking – more than 10 children died from asphyxia as no qualified help was available in the field. Death was avoidable if proper pharmaceutical form had been used …but cost and easiness of use considerations may take over

| Slide 15 of 25 Dr Rägo 28 April – 2 May 2008 What is the problem? Paediatric formulations, even if existing –May not be optimal –May have problems from supply management point of view Large volumes if liquids/syrups Stability problems with syrups Paediatric formulations usually of much higher price –In average three times more expensive –Higher price limits accessability, and stimulates use of adult formulations

| Slide 16 of 25 Dr Rägo 28 April – 2 May 2008 What WHO is doing? Recently (2006) paediatric medicines was made one of the priorities of the WHO medicines work –Create a "WHO Paediatric Model List of Essential Medicines" and "WHO Paediatric Model Formulary" –Form a sub-committee of the respective WHO Expert Committee to facilitate work on paediatric medicines –Update WHO treatment guidelines to incorporate latest paediatric evidence and dosing information – Promote appropriate development of paediatric formulations and upon need develop pharmaceutical quality control specifications –Intensify work on pharmacovigilance of paediatric medicines –Give paediatric medicines priority in Prequalification Programme –Consider giving additional regulatory advise and training in order to facilitate development and regulatory approval of paediatric medicines

| Slide 17 of 25 Dr Rägo 28 April – 2 May 2008 Recent events

| Slide 18 of 25 Dr Rägo 28 April – 2 May 2008 Recent events

| Slide 19 of 25 Dr Rägo 28 April – 2 May 2008 World Health Assembly Resolution WHA60.20 (May 2007) – (1) Member States are urged: –(1) to take steps to identify appropriate dosage forms and strengths of medicines for children, and to encourage their manufacture and licensing –(2) to investigate whether currently available medicines could be formulated to make them suitable for use in children; –(3) to conduct surveillance of antimicrobial resistance of locally available and commonly prescribed medicines for children; –(4) to encourage research and development of appropriate medicines for diseases that affect children, and to ensure that high-quality clinical trials for these medicines are conducted in an ethical manner; –(5) to facilitate timely licensing of appropriate, high-quality and affordable medicines for children and innovative methods for monitoring the safety of such medicines, and to encourage the marketing of adequate paediatric formulations together with newly developed medicines;

| Slide 20 of 25 Dr Rägo 28 April – 2 May 2008 World Health Assembly Resolution WHA60.20 (May 2007) – (2) Member states are urged (cont.) –(6) to promote access to essential medicines for children through inclusion, as appropriate, of those medicines in national medicine lists, and procurement and reimbursement schemes, and to devise measures to monitor prices; –(7) to collaborate in order to facilitate innovative research and development on, formulation of, regulatory approval of, provision of adequate prompt information on, and rational use of, paediatric medicines and medicines authorized for adults but not approved for use in children; –(8) to use all necessary administrative and legislative means including, where appropriate, the provisions contained in international agreements, including the agreement on Trade-Related Aspects of Intellectual Property Rights, in order to promote access to essential medicines for children.

| Slide 21 of 25 Dr Rägo 28 April – 2 May 2008 World Health Assembly Resolution WHA60.20 (May 2007) – (3) WHA60.20 requested WHO Director-General: –(1) to promote the development, harmonization and use of standards for clinical trials of medicines for children; to revise and regularly update the Model List of Essential Medicines in order to include missing essential medicines for children, using evidence-based clinical guidelines; and to promote application of such guidelines by Member States and international financing bodies, with initial focus on treatments for HIV/AIDS, tuberculosis, malaria and chronic diseases; –(2) to ensure that all relevant WHO programmes, including but not limited to that on essential medicines, contribute to making safe and effective medicines as widely available for children as for adults; –(3) to promote the development of international norms and standards for quality and safety of formulations for children, and of the regulatory capacity to apply them;

| Slide 22 of 25 Dr Rägo 28 April – 2 May 2008 World Health Assembly Resolution WHA60.20 (May 2007) – (4) WHA60.20 requested WHO Director-General (cont.): –(4) to make available evidence-based treatment guidelines and independent information on dosage and safety aspects of essential medicines for children, progressively to cover all medicines for children, and to work with Member States in order to implement such guidelines; –(5) to collaborate with governments, other organizations of the United Nations system, including World Trade Organization (WTO) and World Intellectual Property Organization (WIPO), donor agencies, nongovernmental organizations and the pharmaceutical industry in order to encourage fair trade in safe and effective medicines for children and adequate financing for securing better access to medicines for children; –(6) to report to the Sixty-second World Health Assembly, and subsequently as appropriate, through the Executive Board, on progress achieved, problems encountered and specific actions needed to further promote better access to medicines for children.

| Slide 23 of 25 Dr Rägo 28 April – 2 May 2008 Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Protea Hotel Victoria Junction, Waterfront Cape Town, South Africa Date: 16 to 20 April 2007 Pharmaceutical Development

| Slide 24 of 25 Dr Rägo 28 April – 2 May 2008 Promoting Safety of Medicines for Children WHO, 2007 (pp 1- 60) Text on the web as follows: s/essentialmedicines/Promotion_safe_m ed_childrens.pdf WHO Book Shop for orders: etart1.jsp?sesslan=1&codlan=1&codcol= 15&codcch=705

| Slide 25 of 25 Dr Rägo 28 April – 2 May 2008 Several further publications in journals planned on medicines for children Source: Bulletin of World Health Organization, v 85, no 9, September 2007

| Slide 26 of 25 Dr Rägo 28 April – 2 May 2008 Several further publications in journals planned on medicines for children Source: Clin Pharmacol Ther Nov;82(5):503-5

| Slide 27 of 25 Dr Rägo 28 April – 2 May 2008 New guidance to be developed Draft points to consider document about developing paediatric formulations under development Additional guidance on paediatric fixed dose combinations considered –WHO has specific guidelines for fixed dose combination drugs that have been adopted by the Expert Committee on Specifications for Pharmaceutical Preparations –Guidelines for registration of fixed-dose combination medicinal products, WHO Technical Report Series No 929, Annex 5, Geneva 2005 (pp )

| Slide 28 of 25 Dr Rägo 28 April – 2 May 2008 What will happen next? Many of the mentioned activities now developing, some completed The Expert Committee on Selection and Use of Essential Medicines will discuss and approve the paediatric subcommittee work – 1 st Model List for Essential Medicine for Children Web site for information: Better medicines for children will be a topic for the upcoming 13 th ICDRA in Bern September 2008 – two days pre-meeting planned during September 2008 –Web site: –Special web for 13 th ICDRA will come up soon:

| Slide 29 of 25 Dr Rägo 28 April – 2 May 2008 Instead of conclusions Many thanks to those who helped us to make this course happen –All respected individuals who contributed with their time, knowledge, enthusiasm and energy to make this training course to happen –FIP (Industrial Section)

| Slide 30 of 25 Dr Rägo 28 April – 2 May 2008 Instead conclusions Need to replicate the course exists Feedback and suggestions from the resource persons and audience welcome to improve the course Help us to improve the course!

| Slide 31 of 25 Dr Rägo 28 April – 2 May 2008 Conclusion Only with the help of ALL stakeholders we can achieve BETTER MEDICINES FOR CHILDREN