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
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Slide 1 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
E-Mail: ragol@who.int
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Slide 2 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?
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Slide 3 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
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Slide 4 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
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Slide 5 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"?
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Slide 6 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
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Slide 7 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
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Slide 8 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
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Slide 9 of 25
Dr Rägo
28 April – 2 May 2008
Children painted as small
adults
 Peter Paul Rubens (1577-1640) –
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
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Slide 10 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
–…
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Slide 11 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, 700
000 new cases had occurred over the 12 months
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Slide 12 of 25
Dr Rägo
28 April – 2 May 2008
Mortality and children: Global picture
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Slide 13 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
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Slide 14 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
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Slide 15 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
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Slide 16 of 25
Dr Rägo
28 April – 2 May 2008
Recent events
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Slide 17 of 25
Dr Rägo
28 April – 2 May 2008
Recent events
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Slide 18 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;
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Slide 19 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.
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Slide 20 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;
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Slide 21 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.
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Slide 22 of 25
Dr Rägo
28 April – 2 May 2008
Pharmaceutical Development
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
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Slide 23 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:
www.who.int/entity/medicines/publication
s/essentialmedicines/Promotion_safe_m
ed_childrens.pdf
 WHO Book Shop for orders:
http://www.who.int/bookorders/anglais/de
tart1.jsp?sesslan=1&codlan=1&codcol=1
5&codcch=705
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Slide 24 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
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Slide 25 of 25
Dr Rägo
28 April – 2 May 2008
Several further publications in journals
planned on medicines for children
Source: Clin Pharmacol Ther. 2007 Nov;82(5):503-5
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Slide 26 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 94-142)
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Slide 27 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 – 1st Model List for Essential
Medicine for Children
 Web site for information:
http://www.who.int/medicines/areas/rational_use/en/index.html
 Better medicines for children will be a topic for the upcoming 13th ICDRA in Bern
16 -19 September 2008 – two days pre-meeting planned during 14-15
September 2008
– Web site: http://www.who.int/medicines/icdra/en/
– Special web for 13th ICDRA will come up soon: http://www.icdra.ch
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Slide 28 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)
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Slide 29 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!
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Slide 30 of 25
Dr Rägo
28 April – 2 May 2008
Conclusion
 Only with the help of ALL stakeholders we can achieve
BETTER MEDICINES FOR CHILDREN
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Slide 31 of 25
Dr Rägo
28 April – 2 May 2008