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«ETHICAL CONSIDERATIONS FOR CLINICAL TRIALS PERFORMED IN CHILDREN Recommendations of the Ad hoc group for the development of implementing guidelines ...»

-- [ Page 1 ] --

06 October 2006

ETHICAL CONSIDERATIONS FOR CLINICAL TRIALS PERFORMED IN

CHILDREN

Recommendations of the Ad hoc group for the development of implementing

guidelines for Directive 2001/20/EC relating to good clinical practice in the

conduct of clinical trials on medicinal products for human use

12 September 2006

DRAFT AGREED BY AD HOC WORKING GROU

4 October 2006

RELEASE FOR CONSULTATION

31 January 2007

END OF CONSULTATION (DEADLINE FOR COMMEN

AGREED BY WORKING GROUP

Comments should be provided and sent to entr-pharmaceuticals@ec.europa.eu, or Fax +32-2-29 98046 Ethics, Clinical trials, Child, Neonate, Minor, Directive, Consent, Ethics

KEYWORDS

Committee, Assent

ETHICAL CONSIDERATIONS FOR CLINICAL TRIALS PERFORMED IN

CHILDREN

Recommendations of the Ad hoc group for the development of implementing guidelines for Directive 2001/20/EC relating to good clinical practice in the conduct of clinical trials on medicinal products for human use

TABLE OF CONTENTS

EXECUTIVE SUMMARY

1. INTRODUCTION - RATIONALE FOR THE DEVELOPMENT OF

RECOMMENDATIONS

2. SCOPE

3. ETHICAL PRINCIPLES

4. LEGAL CONTEXT

4.1 LEGAL CONTEXT

4.2 RELEVANT GUIDELINES

5. DEFINITIONS/ GLOSSARY

5.1 ETHICS COMMITTEE

5.2 LEGAL REPRESENTATIVE OF THE MINOR

5.3 MINOR

5.4 INFORMED CONSENT

5.5 ASSENT

5.6 AGE GROUPS

6. INFORMED CONSENT

6.1 INFORMED CONSENT FROM THE LEGAL REPRESENTATIVE

6.2 REQUIREMENTS FOR INFORMED CONSENT OF THE LEGAL REPRESENTATIVE IN THE VARIOUS

MEMBER STATES

6.3 INFORMED CONSENT (AND ASSENT FOR CHILDREN) OF FAMILIES WITH DIFFERENT CULTURAL

BACKGROUND

6.4 CONSENT (AND ASSENT) AT THE BEGINNING OF A TRIAL AND CONTINUED CONSENT AND

ASSENT DURING TRIAL

6.5 WITHDRAWAL OF THE INFORMED CONSENT

6.6 INFORMED CONSENT IN EMERGENCY TRIALS

7. ASSENT FROM CHILDREN

7.1 ASSENT ACCORDING TO AGE GROUPS

7.1.1 Neonates (preterm and term),infants and pre-school children

7.1.2 Children of school age (from about 6 years old)

7.1.3 Consent and assent in adolescents

7.2 ASSENT IN EMERGENCY TRIALS

7.3 DIFFERENCE OF OPINION BETWEEN THE CHILD AND THE LEGAL REPRESENTATIVE.............. 12

8. ETHICS COMMITTEE’S COMPOSITION IN RESPECT OF PAEDIATRIC TRIALS.. 12

8.1.1 Examples of Paediatric expertise

8.1.2 Opinion on the protocol

9. PAEDIATRIC CLINICAL TRIAL DESIGNS

Page 2/34

9.1 DESIGN AND ANALYSIS

9.2 PAEDIATRIC CONTROL GROUPS

9.2.1 Use of placebo

9.2.2 Superiority versus non inferiority trials

9.2.3 Controlled trials using reference medicinal products devoid of marketing authorisation in children

9.2.4 Clinical trials using medicinal products containing radio-isotopes

10. PAIN, DISTRESS, AND FEAR MINIMISATION

11. ASSESSMENT OF THE LEVEL OF RISK AND ITS MONITORING

11.1 ASSESSEMENT OF RISK

11.2 MONITOR THE LEVEL OF RISKS

12. MEASURES OF BENEFIT

12.1 DIRECT BENEFIT

12.2 DIRECT BENEFIT FOR THE GROUP

13. ASSAYS IN RELATION TO AGE/BODYWEIGHT - BLOOD SAMPLING.................. 18 13.1 TYPE OF ASSAYS

13.2 VOLUME OF BLOOD

14. STUDIES IN NEONATES (TERM AND PRE-TERM)

15. HEALTHY CHILDREN/ ‘VOLUNTEERS’ STUDIES

16. VACCINES

17. PAEDIATRIC FORMULATIONS TO BE USED IN PAEDIATRIC TRIALS............... 19

18. INDIVIDUAL DATA PROTECTION

19. UNNECESSARY REPLICATION OF TRIALS

19.1 PUBLICATION OF TRIALS AND OF RESULTS

19.2 INTERNATIONAL DATABASE AND AVAILABILITY TO THE PUBLIC

20. ADVERSE REACTIONS AND REPORTING

21. INDUCEMENTS VERSUS COMPENSATION FOR CHILDREN

22. INSURANCE ISSUES

23. TRIALS IN CHILDREN IN NON-EU COUNTRIES

24. ETHICAL VIOLATIONS, AND NON COMPLIANCE WITH GCP

25. ANNEX 1 (RESPONSES TO QUESTIONNAIRE)

26. ANNEX 2

27. REFERENCES (SCIENTIFIC AND / OR LEGAL)

27.1 GENERAL GUIDANCE

27.2 NORTH AMERICA GUIDANCE

27.3 NATIONAL GUIDANCE ON ETHICS OF CTS IN CHILDREN

27.4 RELEVANT PUBLICATIONS ON RESEARCH AND CTS IN CHILDREN

27.5 CONSENT AND ASSENT – PARENTAL DECISIONS

27.6 NEONATE

–  –  –

This document has been developed by the ad hoc group for the development of implementing guidelines for Directive 2001/20/EC1 relating to good clinical practice in the conduct of clinical trials on medicinal products for human use, chaired by the European Commission. The document provides recommendations on various ethical aspects of clinical trials performed in children from 0 up to 18 years. This will contribute to the protection of children who are the subject of clinical trials in the EU.





As the approval of clinical trials, including ethical approval, is primarily a competence of the Member States, any recommendations on ethical aspects of clinical trials in children will also facilitate a harmonised approach to clinical trials across the EU, thereby facilitating the conduct of clinical trials in the EU. The protection against the risks of research in such a vulnerable population is paramount whilst this should not lead to denying them the benefits of research. Children are not small adults and there is a need to carry out specific trials that cannot be performed in adults. In general, children (minors) are unable to consent but their assent should be obtained using age appropriate information.

Ethics Committees need paediatric expertise to balance the benefits and risks of research in children.

The lack of consent has implications on the design, analysis and the choice of comparators used in the trials, which should only be performed by trained investigators with paediatric experience. Pain, fear, distress and parental separation should be prevented and minimised when unavoidable. The neonate represents the most vulnerable of all paediatric age groups and requires even more careful review.

Finally, various other aspects relating to the performance of trials in children are discussed.

1. INTRODUCTION - RATIONALE FOR THE DEVELOPMENT OFRECOMMENDATIONS

This document has been developed by the ad hoc group for the development of implementing guidelines for Directive 2001/20/EC relating to good clinical practice in the conduct of clinical trials on medicinal products for human use, chaired by the European Commission. The document provides recommendations on various ethical aspects of clinical trials performed in children from 0 up to 18 years. This will contribute to the protection of children who are the subject of clinical trials in the EU.

As the approval of clinical trials, including ethical approval, is primarily a competence of the Member States, any recommendations on ethical aspects of clinical trials in children will also facilitate a harmonised approach to clinical trials across the EU, thereby facilitating the conduct of clinical trials in the EU.

Trials are necessary and should aim at progressing the well-being and treatment, prevention and diagnosis of ill health (WHO definition) including in children. The same ethical principles apply across age ranges, from children to the elderly. However, the third recital of Directive 2001/20/EC (hereinafter the Clinical Trials Directive) in particular recognises the need for investigation of medicinal products in the vulnerable population of children (i.e., minors in the meaning of the Clinical Trials Directive) whilst ensuring their protection: “However, there is a need for clinical trials involving children to improve the treatment available to them. Children represent a vulnerable population with developmental, physiological and psychological differences from adults, which make age- and development- related research important for their benefit. Medicinal products, including vaccines, for children need to be tested scientifically before widespread use. This can only be achieved by ensuring that medicinal products which are likely to be of significant clinical value for children are fully studied. The clinical trials required for this purpose should be carried out under conditions affording the best possible protection for the subjects. Criteria for the protection of children in clinical trials therefore need to be laid down.” Specific protection should be defined for research performed in children, at all stages and ages.

DIRECTIVE 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use.

Page 5/34 The reasons why medicinal products need to be studied in children have been detailed in various publications. To sum up, children are not small adults. Differences in pharmacokinetics and dynamics, and in adverse reactions are common in children compared to adults. Growth and maturation processes, as well as specific diseases are not found in adults. Specific consequences of medical interventions may be seen in children and may appear long after exposure. This has been unfortunately demonstrated by previous catastrophes with the use of untested medicinal products, and most often occurred in children.

Because of the special protection they deserve, children should not be the subject of clinical trials when the research can be done in less vulnerable subjects (i.e. adults). If research in children proves necessary, the least vulnerable among them should usually be included (i.e., older children). This document proposes the application of ethical principles as they are understood currently. With time, the need for revision of this document may emerge.

2. SCOPE

This document is intended to provide guidance on various ethical aspects of the performance of interventional clinical trials falling under the provisions of Directive 2001/20/EC and its implementing texts. Medicinal products may be used with a view to treating, preventing or diagnosing a disease or condition.

The document is intended for sponsors of clinical trials, ethics committees and investigators of clinical trials performed in children of all ages (minors). This document is without prejudice to the obligations created by Directive 2001/20/EC and the need to follow EMEA guidelines (Article 4 of the same Directive).

It focuses on the specificities of paediatric clinical trials and should therefore be read in conjunction with appropriate legal texts and guidelines.

The recommendations in the document aim to contribute to the protection of the rights of children (minors) who are vulnerable and unable to give informed consent. The clinical trials performed in children should be carried out under conditions providing the best possible protection for this vulnerable population whilst recognising children have the right to benefit from research.

3. ETHICAL PRINCIPLES

Ethical principles referred to in this document are those expressed for example in the Declaration of Helsinki, the United Nations Convention on the Rights of the Child, and in the Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine: Convention on Human Rights and Biomedicine. These principles are also expressed and developed in the ICH E6 guideline on Good Clinical Practice.



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