| slide 1 of 25 dr rägo 28 april – 2 may 2008 pharmaceutical development with focus on paediatric...

| Slide 1 of 25 Dr Rägo 28 April – 2 May 2008

Pharmaceutical Development with Focus on Paediatric formulations

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


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]




Background

What is a problem?

What is WHO doing and planning to do?

Ways forward


The Erice Manifesto: for global reform of the safety of medicines in patient care

Drug Safety, 2007;30(3):187-90

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.


Pharmacovigilance definitionPharmacovigilance 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)


BackgroundBackground

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?


Safety of paediatric medicines: unrecognized challenge?

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


Pharmaceutical development and safety:suitability of dosage forms

Pharmaceutical development and safety:suitability of dosage forms

Tablets not optimal below 3 yrs, even for 3-6 yrs– 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.

Development of formulations of strengths suitable for administration to neonates, infants and young children should be considered. 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).


Pharmaceutical development and safety:suitability of excipients

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.


Excipients related to safety concerns (a)Ernest et al., 2008

Excipients related to safety concerns (a)Ernest et al., 2008


Excipients related to safety concerns (b) Ernest et al., 2008

Excipients related to safety concerns (b) Ernest et al., 2008


Are regulations addressing the problem?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


US legislative actions: more clinical data in children 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.


EU initiativesEU 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.


ICH E11: Clinical Investigation of Medicinal Products in the Paediatric Population

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 off-label 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


Adverse drug reactions in clinical trialsSammons et al, 2008

Adverse drug reactions in clinical trialsSammons 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


ICH E2E: Pharmacovigilance Planning 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 post-approval 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


Obstacles related to ADR reporting in paediatric patients in resource poor settings

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.


WHO and medicines safety in childrenWHO 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


Promoting Safety of Medicines for ChildrenWHO, 2007 (pp 1- 60)

Promoting Safety of Medicines for ChildrenWHO, 2007 (pp 1- 60)

Text on the web as follows: www.who.int/entity/medicines/publications/essentialmedicines/Promotion_safe_med_childrens.pdf

WHO Book Shop for orders: http://www.who.int/bookorders/anglais/detart1.jsp?sesslan=1&codlan=1&codcol=15&codcch=705


Content (2) 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


Content (2)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


ConclusionsConclusions

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


ReferencesReferences

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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