| Slide 1 of 25 April 2007 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 2 of 25 April 2007 Pharmaceutical Development Introduction to the course Presenter: Dr Lembit Rägo Coordinator, Quality Assurance and Safety: Medicines (QSM) Medicines Policy and Standards (PSM) World Health Organization Geneva, Switzerland

| Slide 3 of 25 April 2007 The need for paediatric medicines: WHO perspectiv e Background What is a problem? Essential medicines and paediatric dosage forms What is WHO planning to do?

| Slide 4 of 25 April 2007 Health in the Millenium Development Goals Goal 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 April 2007 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 6 of 25 April 2007 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 7 of 25 April 2007 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 8 of 25 April 2007 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 9 of 25 April 2007 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, particularly 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 10 of 25 April 2007 Mortality and children: Global picture

| Slide 11 of 25 April 2007 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 12 of 25 April 2007 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 accessibility, and stimulates use of adult formulations

| Slide 13 of 25 April 2007 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" –For 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 14 of 25 April 2007 Recent events

| Slide 15 of 25 April 2007 Recent events

| Slide 16 of 25 April 2007 What will happen next? Many of the mentioned activities already developing, some completed Better medicines for children will be a topic for the upcoming World Health Assembly in May 2007 Web site for information: ml

| Slide 17 of 25 April 2007 Instead of conclusions Many thanks to –FIP (Industrial Section) –All respected individuals who contributed with their time, knowledge, enthusiasm and energy to make this training course to happen

| Slide 18 of 25 April 2007 Instead conclusions Need to replicate the course already clear now Feedback and suggestions from the resource persons and audience welcome to improve the course Help us to improve the course!

| Slide 19 of 25 April 2007 Conclusion Only with the help of ALL stakeholders we can achieve BETTER MEDICINES FOR CHILDREN