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Guidance for Industry: Health Canada Addendum to ICH Guidance Document E11: Clinical Investigation of Medicinal Products in the Pediatric Population

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December 17, 2003

Notice

Our file number: 03-125003-605

Release and Adoption of Health Canada Addendum to the ICHFootnote 1 Guidance E11: Clinical Investigation of Medicinal Products in the Pediatric Population

The ICH guidance Clinical Investigation of Medicinal Products in the Pediatric Populations provides an outline of critical issues in pediatric drug development and approaches to the study of medicinal products in the pediatric population. The purpose of the guidance is to encourage and facilitate the conduct of studies that will permit appropriate labeling and use of medicinal products in the pediatric population, based on evidence from clinically and scientifically sound trials, thereby ensuring that this important patient group has access to the full benefits of therapies available to adults.

The ICH document states that it is "not intended to be comprehensive; other ICH guidances, as well as documents from regional regulatory authorities and pediatric societies, provide additional detail". This Health Canada addendum serves to complement the ICH guidance by clarifying the Canadian research and regulatory environment and is meant to more precisely define regulatory considerations for the timing and conduct of clinical studies in the pediatric population. The Health Canada Addendum also provides further guidance on ethical issues.

With the exception of the certain new ethical considerations as noted above, this addendum is based upon those portions of the 1997 draft Health Canada guidance Inclusion of Pediatric Subjects in Clinical Trials not specifically addressed by the more recent ICH guidance. With the adoption of the ICH guidance and this addendum, the 1997 draft guidance, in respect of which comments had previously been sought, is officially withdrawn.

This and other Guidance documents are available on the Therapeutic Products Directorate / Biologics and Genetic Therapies Directorate / Marketed Health Products Directorate Website (s). The availability of printed copies of guidance documents may be confirmed by consulting the Guidelines and Publications Order Forms (available on the TPD Website) or by contacting the Publications CoordinatorFootnote 2.

Should you have any questions regarding the content of the guidance, please contact:

For BGTD:
Submission Management Division
Centre for Policy and Regulatory Affairs
Biologics and Genetic Therapies Directorate
Fax: (613) 957-0364
SMD_Submissions@hc-sc.gc.ca
For TPD:
Senior Medical Advisor Bureau
Therapeutic Products Directorate
Fax: (613) 954-4474
smab_enquiries@hc-sc.gc.ca

Guidance For Industry

Health Canada Addendum to ICH Guidance Document E11: Clinical Investigation of Medicinal Products in the Pediatric Population

Published by authority of the Minister of Health

Date Adopted: 2003/12/17

Effective Date: 2003/12/17

Minister of Public Works and Government Services Canada 2003

Available in Canada through
Health Canada - Publications
Brooke Claxton Building, A.L. #0913A
Tunney's Pasture
Ottawa, Ontario
K1A 0K9

Tel: (613) 954-5995
Fax: (613) 941-5366

Catalogue No. H42-2/67-23-2003-1 E
ISBN 0-662-28952-8

Foreword

Guidance documents are meant to provide assistance to industry and health care professionals on how to comply with the policies and governing statutes and regulations. They also serve to provide review and compliance guidance to staff, thereby ensuring that mandates are implemented in a fair, consistent and effective manner.

Guidance documents are administrative instruments not having force of law and, as such, allow for flexibility in approach. Alternate approaches to the principles and practices described in this document may be acceptable provided they are supported by adequate scientific justification. Alternate approaches should be discussed in advance with the relevant program area to avoid the possible finding that applicable statutory or regulatory requirements have not been met.

As a corollary to the above, it is equally important to note that Health Canada reserves the right to request information or material, or define conditions not specifically described in this guidance, in order to allow the Department to adequately assess the safety, efficacy or quality of a therapeutic product. Health Canada is committed to ensuring that such requests are justifiable and that decisions are clearly documented.

This document should be read in conjunction with the accompanying notice, the ICH guidance document E11: Clinical Investigation of Medicinal Products in the Pediatric Population and the relevant sections of other applicable Health Canada guidance documents.

Table Of Contents

  1. Purpose
  2. Scope
  3. General Principles
  4. Background
  5. Timing Of Pediatric Studies
  6. Other Considerations
  7. Conclusion

1. Purpose

The ICH guidance document: Clinical Investigation of Medicinal Products in the Pediatric Population provides an outline of critical issues in pediatric drug development and approaches to the study of medicinal products in the pediatric population. The purpose of the guidance document is to encourage and facilitate the conduct of studies that will permit appropriate labelling and use of medicinal products in the pediatric population, based on evidence from clinically and scientifically sound trials, thereby ensuring that this important patient group has access to the full benefits of therapies available to adults.

The ICH document states that it is "not intended to be comprehensive; other ICH guidances, as well as documents from regional regulatory authorities and pediatric societies, provide additional detail". This Health Canada addendum serves to complement the ICH guidance by clarifying the Canadian research and regulatory environment and is meant to more precisely define regulatory considerations for the timing and conduct of clinical studies in the pediatric population. The Health Canada Addendum also provides further guidance on ethical issues.

2. Scope

This addendum is directed towards new indications for approved medicinal products, new active substances, new formulations or combinations of approved medicinal products, including drugs, biological therapies and interventions, that are intended to be used in the pediatric population.

3. General Principles

Medicinal products should be studied in subjects with demographic and disease characteristics that are representative of the range of patients likely to receive the product once it is marketed. Drugs may behave in a qualitatively different manner in demographic (gender, age, race) and other (concomitant illness, concomitant drugs) subsets of the population; there may also be quantitative differences including dose-response relationships, pharmacokinetic parameters, magnitude of effect, risk of an adverse event and other variables which need to be defined in these specific groups.

4. Background

Various physiological, clinical, legal, ethical and technical issues unique to the pediatric population should be considered when proposing to enroll pediatric patients in clinical trials. In the past, the pediatric population has frequently been either excluded from clinical trials (due to real or perceived legal and ethical considerations) or restricted to research addressing diseases specific to the pediatric population. It is now recognized that the pediatric population should be included in the clinical development of medicinal products. The potential beneficial or detrimental effects of therapeutic interventions should be determined, age-appropriate dosing regimens should be developed, the impact of physiological and maturational changes on drug pharmacokinetics should be assessed and potential drug interactions, which may occur with drug regimens specific to the pediatric population should be explored.

5. Timing Of Pediatric Studies

Considerations identified in the ICH guidance regarding the decision to proceed with a pediatric development program do not preclude the need to alter timing and toxicologic evaluation based on the possibility of other specific requirements related to the nature of the medicinal product and/or the targeted patient population.

Special consideration is warranted when clinical trials are conducted in the absence of adult information for medicinal products intended for use only in the pediatric population (for example, for the treatment of specific newborn or congenital metabolic disorders) or, when clinical trials are conducted in the early stages of development of a product in adult subjects. The expected potential benefit to pediatric patients may justify, in these cases, the appropriateness of studies being undertaken.

It is also recognized that extrapolation of conclusions based on the effects observed in adults is not always useful (or feasible), since the responses in pediatric patients and particularly in some subgroups, may be quite different from those reported for adults.

5.1 Medicinal Products for Diseases Predominantly or Exclusively Affecting Pediatric Patients ( ICH E11 guidance, section 2.3.1)

For medicinal products developed specifically for use in the pediatric population, enrollment of pediatric patients may proceed following initial safety and tolerability data, which will usually be obtained in adults. The adult human data should be supplemented by preclinical in vitro and animal data which document the structural, physico-chemical, biologic, pharmacologic, immunogenic, and mutagenic properties of the specific product. This is particularly so for products with a known potential for effects on growth, maturation and differentiation of cell lines. By this stage, it is expected that all preclinical toxicologic studies would be completed. In addition, the toxicologic potential of the product on adult, juvenile and neonatal animals, with particular emphasis on growth and development, and possible later effects on fertility should be characterized. Carcinogenicity studies should be conducted for any product for which there may be a carcinogenic potential based on the characteristics of the product itself, or its relationship to a class of drugs or structurally similar products having such potential. Carcinogenicity studies should be completed for products intended for long term use, unless specific circumstances prevent the conduct of such studies or make them irrelevant.

5.2 Medicinal Products Intended to Treat Serious or Life-Threatening Diseases, Occurring in Both Adults and Pediatric Patients, for Which There are Currently No or Limited Therapeutic Options (ICH E11 guidance, section 2.3.2)

In general, requirements prior to enrolling pediatric patients in clinical trials would include data on the site and mode of action of the product, data on the physico-chemical, biologic, pharmacologic and toxicologic properties of either the specific medicinal product or the therapeutic class. Where available, this would include all adult human safety and efficacy data.

5.3 Medicinal Products Intended to Treat Other Diseases and Conditions (ICH E11 guidance, section 2.3.3)

These are medicinal products under active development for diseases where therapeutic options already exist. For such products, the enrollment of pediatric patients may proceed following the documentation of sufficient evidence of safety and efficacy in adult patients. By this stage it is expected that all preclinical toxicologic studies have been completed. The need for special preclinical toxicologic studies in juvenile or neonatal animals would be dependent on the nature of the product, the safety profile in adults and/or on the toxicologic profile demonstrated in preclinical studies.

5.4 Medicinal Products currently marketed for adults

For marketed medicinal products where pediatric labelling is being proposed or where new indications/formulations are being developed, enrollment of the pediatric population in clinical trials may proceed if there is evidence of safety and efficacy in the adult population and where the structural, physico-chemical and biologic properties of the specific product or class of drug/biologic are well documented in animals and in adult human studies and the product/class has been shown to be essentially free of serious toxicities.

Additional neonatal/juvenile animal studies should be conducted for those marketed medicinal products predicted or shown to have a potential for serious toxicities (product or class specific) in animal or human studies. Animal mutagenicity and carcinogenicity studies should be completed prior to enrollment of pediatric patients in clinical trials, unless otherwise indicated.

5.5 Biologic and Biotechnology Products and Therapies and Vaccines:

Studies of biological therapeutic products and of vaccines should evaluate the potential for the following effects:

  • immunogenicity with antibody production and/or the stimulation or suppression of other naturally produced substances that could affect drug efficacy and safety;
  • serious immunotoxicity or other long-lasting unwanted immunomodulation;
  • any other unwanted long-term effects on major effector systems (i.e., coagulation, inflammation), on normal physiologic functions, maturation or growth;
  • potential deleterious effects in trials involving vaccines in healthy pediatric subjects; and,
  • adverse effects on cycling (young) versus quiescent (adult) cell populations in cell transplantation therapies.

Special preclinical and adult human studies may be necessary to evaluate these effects prior to the enrollment of the pediatric population in clinical trials of these products. The response in pediatric patients with an immature immune system and other distinctive developmental features may be different from the responses reported in adults.

Clinical trials for somatic cell or gene therapy in pediatric patients will be considered on a caseby- case basis.

6. Other Considerations

There are cases where safety and/or ethical considerations or administration problems exclude all or certain segments of the pediatric population from participating in clinical trials during the developmental phases of a medicinal product. In such cases, Health Canada will give consideration to post-marketing surveillance or special post-marketing studies in order to obtain pertinent safety and efficacy information which can be utilized to develop appropriate labelling recommendations for the pediatric age group.

6.1 Ethical Issues

Ethical considerations are important in all aspects of clinical research; the interests of patients should always prevail over those of science and society. Ethical considerations are most poignant when research is conducted in the pediatric population. While ethical considerations may have precluded and, on occasion still stand in the way of pediatric research, it is now increasingly accepted that research involving pediatric patients is not only permissible, but even necessary, under certain conditions. This conclusion rests on considerations of possible harm to the pediatric population in the absence of pediatric research, injustice to pediatric patients if they are deprived of possible benefits available to adults as a group; respect for parents or guardians and pediatric patients who are invited to participate in research; and professional obligation to ensure the best possible health care for the pediatric population.

Research in the pediatric population should be based on scientifically and ethically valid considerations. These considerations will include implicitly the legitimacy of trials conducted in healthy pediatric subjects when vaccines and other preventative products are being developed. Studies should only be undertaken if some direct benefit for the group of patients is obtained from the clinical trial and only where such research is essential to validate data obtained in clinical trials on persons able to give informed consent, or by other research methods. In addition, such research should either relate directly to a clinical condition occurring in the pediatric population or be of such a nature that it can only be carried out on this group of patients.

Any ethical decision in respect of pediatric trials should ensure that provincial and territorial requirements governing consent, assent, guardianship and surrogate consent issues are appropriately fulfilled. Additional references available either federally or provincially should be consulted.

6.2 Disclosure and Consent

Health Canada recognizes that the final decision concerning enrollment of a pediatric subject into a clinical trial remains with the investigator, the patient's representative (parent or legal guardian) and the pediatric subject when he or she is capable of giving assent or consent, depending on the applicable provincial statute. In the case of clinical trials involving the development of medicinal products, the responsibility for providing accurate and adequate information to the patients and their representatives, about the medicinal product and the trial is shared by the investigator(s) with the research institution, the appropriately constituted Research Ethics Board, and the sponsor of the clinical trial.

In all cases, the Informed Consent document and the Investigator's Brochure should include all available information regarding the potential risk(s) and harms associated with the trial, including information about known product- or class-specific animal and human toxicity together with full disclosure of any evidence of possible short or long-term hazard(s) if any, to the pediatric subject.

If sufficient data are not available, as is frequently the case when a new medicinal product is used for a catastrophic illness, the Informed Consent should explicitly note the lack of information and the potential for risk.

7. Conclusion

The ICH guidance document Clinical Investigation of Medicinal Products in the Pediatric Population and this addendum provide guidance allowing the safe, efficient, and ethical conduct of studies in the pediatric population.

As an extension of these guidance documents and when appropriate, it is expected that subset analysis of clinical trial data to document the presence or absence of significant differences in the pediatric population will be presented in the marketing applications for medicinal products. This may include an analysis of the effects of developmental changes on pharmacokinetics and dosing regimens, potential effects of the medicinal product on growth and development, frequency and type of adverse reactions, alteration of the therapeutic index, drug interactions, and any specific or unique characteristic of the use of the product in the pediatric population. Product Monographs should reflect in the appropriate sections, the level and extent of data available on the use of the medicinal product in the pediatric population. The inclusion of a statement under 'Pediatric Use' to indicate the lack of experience in pediatric subjects and the absence of evidence of safety and efficacy in this group is not helpful to pediatric prescribers. Sponsors should make all possible efforts to obtain the required information.

Useful Reference Document

Next link will take you to another Web site Best Practices for Health Research Involving Children and Adolescents

Footnotes

Footnote 1

International Conference on Harmonisation of Technical Requirements for the Registration of Pharmaceuticals for Human Use

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Footnote 2

Tel: (613) 954-6466; E-mail: publications_coordinator@hc-sc-gc.ca

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