Transcript Basic Principles of GMP - World Health Organization

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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Dr Rägo
28 April – 2 May 2008
Pharmacovigilance and safety of medicines in
children
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: [email protected]
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Dr Rägo
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Pharmacovigilance and safety of medicines in
children
 Background
 What is a problem?
 What is WHO doing and planning to do?
 Ways forward
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Dr Rägo
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The Erice Manifesto: for global reform of the safety of
medicines in patient care
Drug Safety, 2007;30(3):187-90
 The science of pharmacovigilance--monitoring and evaluating drug
safety issues and communicating them effectively--is a vital activity
of worldwide significance in the safeguarding of patient welfare and
public health.
 Its clinical, public health and economic importance has been
demonstrated, but it needs to be better understood and appreciated
by politicians, the media and the public.
 Pharmacovigilance is evolving from being a largely reactive
discipline, concentrating on the discovery of harm caused by
marketed drugs, to a proactive study of their safety, effectiveness
and associated risk factors in normal medical practice and use by
patients.
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Dr Rägo
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Pharmacovigilance definition
 Pharmacovigilance is the science and activities relating to
the detection, assessment, understanding, and
prevention of adverse effects or any other possible
medicine-related problems (1)
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Dr Rägo
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Background
 Safety monitoring of medicine use in children is of paramount
importance since during the clinical development of medicines, only
limited data is generated through clinical trials.
 Use of medicines outside the specifications described in the license
(in terms of formulation, indications, contra-indications, age, etc.)
constitutes off-label and off-licence use and these are a major area
of concern.
 The use of unlicensed and off-label medicines for children has been
a common practice for decades, which does not offer the children
the same quality, safety and efficacy of medicines as is available for
adults
 Is the present situation against the UN Convention on the Rights of
the Child?
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Dr Rägo
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Safety of paediatric medicines: unrecognized
challenge?
 Relatively less or absent safety data as compared to
adult use
– Off-label use – no clinical trials, no safety information from trials
– Off-label use – reliance on spontaneous reporting, but …
– Difficulties of identifying ADRs in paediatric populations
 Specific safety issues due to
– Anatomy
– Physiology
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Dr Rägo
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Pharmaceutical development and safety:
suitability of dosage forms

Tablets not optimal below 3 yrs, even for 3-6 yrs
–

Development of formulations of strengths suitable for
administration to neonates, infants and young children should be
considered.

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Four children under 36 months died by choking on albendazole tablets
during a deworming campaign in Ethiopia in 2007. Forcing very small
children to swallow large tablets may cause choking and asphyxiation. For
younger than 36 months tablets are discouraged. The formulation should be
a safe single dose formulation (e.g. granules, liquid for oral use etc.) to
replace the tablets currently in use.
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Administration of adult formulations requires dilution or administration of
miniscule volumes to be administered over a period of time. This leads to
administration errors (intra-venous drips running fast, errors in dosage
calculation and dilution), especially in circumstances that require urgent
actions (as in emergency units, premature units and paediatric and
neonatal intensive care units).
Dr Rägo
28 April – 2 May 2008
Pharmaceutical development and safety:
suitability of excipients
 Benzyl alcohol is commonly used as preservative in multidose injectable
pharmaceutical preparations. For this purpose, concentrations in the range of
0,5 – 2% are used and the whole amount of benzyl alcohol injected is generally
very well tolerated. Concentrations of 0,9% are used in Bacteriostatic Sodium
Chlorine (USP) and Bacteriostatic Water for intravenous use (USP).
 Toxic effects of benzyl alcohol including respiratory vasodilatation, hypertension,
convulsions and paralysis have been known for years. However, little is known
about the toxic effects or levels of benzyl alcohol and the metabolic acidosis
caused by accumulation of the metabolite benzoic acid in neonates, especially in
sick premature infants. Deaths in neonates were associated with administration
of 99 to 234 mg/kg/day in large volume parenteral solutions or endotracheal
solutions.
 FDA has recommended that neither intra-muscular flushing solutions containing
benzyl alcohol nor dilutions with this preservative should be used in newborn
infants.
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Dr Rägo
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Excipients related to safety concerns (a)
Ernest et al., 2008
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Dr Rägo
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Excipients related to safety concerns (b)
Ernest et al., 2008
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Are regulations addressing the problem?
 Legislative initiatives to stimulate paediatric research:
push (legal obligations) and pull (positive incentives)
– US has been ahead of Europe
– Recently European Commission took a legislative initiative:
Regulation 1901/2006 which entered into force on 26 January
2007 is not ideal but hopefully boosts paediatric research
 Specific guidelines such as ICH guidelines
 Not enough activities in well resourced settings (ICH
countries – EU, Japan and US) and practically no
activities in non-ICH countries
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Dr Rägo
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US legislative actions: more clinical data in children
 US provision in the 1997 Food and Drug Administration (FDA) Modernisation Act.
The American "pediatric exclusivity" provision provides a 6 month patent
extension for companies willing to perform paediatric clinical investigations at the
request of the FDA.
 In 2001 it was said to have resulted in studies being undertaken on over 70
diseases and conditions specific to children, with 32% of these studies covering
neonates and infants. According to the FDA, "the pediatric exclusivity provision
has done more to generate clinical studies and useful prescribing information for
the pediatric population than any other regulatory or legislative process to date"
 The USA has since enacted two further pieces of legislation: the 2002 Best
Pharmaceuticals for Children Act (BPCA) and the 2003 Pediatric Research
Equity Act (PREA). The former extended the paediatric exclusivity provision and
provided incentives for off-patent products, while the latter granted the FDA the
authority to demand that companies provide paediatric studies in specific cases,
changing what had been a voluntary scheme.
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Dr Rägo
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EU initiatives
 Legislation came into force in January 2007 (Regulation (EC) (15)
1902/2006 of the European Parliament and of the Council,
amending Regulation (EC) (16) 1901/2006 on medicinal products
for paediatric use).
 Aims to enhance the safety of medicines for children by increasing
research, development and authorisation of medicines based on
specific paediatric experience, without subjecting the paediatric
population to unnecessary clinical trials.
 It creates requirements for the pharmaceutical industry regarding
the development of medicines for paediatric use, as well as
providing incentives to industry for such developments. A
framework to manage the operation of the legislation, including
creation of a scientific paediatric committee is also addressed.
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ICH E11: Clinical Investigation of Medicinal
Products in the Paediatric Population
 Addresses the clinical investigation of medicinal products in the
paediatric population but it does not address the problem of offlabel use.
 Children undergo various stages of physiological development.
Moreover, they represent a wide spectrum of physiological and
developmental stages from the newborns through adolescents,
before they become adults.
 Each of these stages may have a different need and response to
any drug. Studies performed in adults do not always reflect what
happens in children. Extrapolating information from studies that
have been carried out in adults can only be done to a limited extent
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Dr Rägo
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Adverse drug reactions in clinical trials
Sammons et al, 2008
Only 13 (2%!) had Safety Monitoring Committees (SMC). Six trials
were terminated early due to significant drug toxicity and all had
SMCs. Conclusion: ALL paediatric trials should have SMCs
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Dr Rägo
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ICH E2E: Pharmacovigilance Planning
 The ICH E2E addresses the issue of paediatrics as an important
subpopulation to be taken into account in developing a risk
management plan.
 The safety specification addresses the populations potentially at-risk
(where the product is likely to be used) such as children, and
outstanding safety questions which warrant further investigation to
refine understanding of the benefit-risk profile during the postapproval period.
 The pharmacovigilance plan provides details of planned
pharmacoepidemiological studies to be performed (more details in
the EMEA guideline on Conduct of Pharmacovigilance for Medicines
used by the Paediatric Population, 28 June 2006).
 However, this all concerns ONLY new medicines
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Dr Rägo
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Obstacles related to ADR reporting in paediatric
patients in resource poor settings
 Lack of medically qualified staff
 Lack of incentives, experience and skills in reporting ADRs and
ADEs
 High proportion of off-label and unlicenced use
 Virtually all medicines OTC
 High level of poorly evaluated phytotherapeutic, ayurvedic,
anthroposophic, traditional and homeopathic medications, which
are considered as “soft” and less toxic medicines among parents,
caretakers and even health professionals
 Irrational use of medicines, including overuse of antibiotics etc.
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Dr Rägo
28 April – 2 May 2008
WHO and medicines safety in children
 2nd meeting of the Advisory Committee on Safety of
Medicinal Products (ACSoMP), 27-29 October 2004,
WHO, Geneva
– Recommended that the issue of safety of medicines in
children is an important issue that needs to be addressed
– Several actions were also recommended …including
promoting safety of medicines in children
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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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Dr Rägo
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Content (2)
1. Introduction
2. Current situation
2.1 Present status of medicine treatment in children and adolescents around the
world
2.2 Consequences of present status
2.3 General risk factors that predispose children to develop an ADR
2.4 Differences between the paediatric subpopulations and adults
2.5 The need for additional, independent paediatric medicines development studies
2.6 Legal and regulatory framework
2.7 Consequences of the lack of medicine development studies in children and
authorization of paediatric medicines
3. The essential role of safety monitoring in the life cycle of a medicine
3.1 Pre-marketing medicine safety assessment
3.2 Post-marketing medicine safety monitoring for all medicines available in the market
including those used “off-label”
3.3 Risk to benefit considerations in children
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Content (2)
4. Medication errors
5. Primary responsibility of stakeholders
6. Guidance: Measures to be taken
6.1 Improvement of awareness among stakeholders
6.2 Methods, approaches, and structural changes for an effective medicine safety monitoring
system at the national level
6.3 Installation of methods and structural changes for an effective medicine safety
monitoring system at the national level
6.4 Impact measurement and audit
7. Measures to be taken by WHO
Annex I
Pharmacovigilance methods
Annex 2
Recent information on ADRs to marketed medicines in children
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Conclusions
 Safety of medicines in paediatric populations remains
challenging for both well resourced and resource poor
settings
 All stake holders have a role and obligation to improve
safety of medicines in children
 Developing proper paediatric formulations can contribute
to the safety of medicines in children, reduce suffering
and save lives
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Dr Rägo
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References
1. The Importance of Pharmacovigilance; Safety Monitoring
of Medicinal Products, WHO Geneva, 2002
2. Ernest TB et al.(2007), Developing paediatric medicines:
identifying the needs and recognizing the challenegs.
Journal of Pharmacy and Pharmacology, 59:1043-1055
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Dr Rägo
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