Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Regulatory and economic conditions for clinical trials in children ***

Dr. Anja Tischlich (Abschlußjahr: 2002)

Despite the knowledge that children are subject to many of the same diseases as adults, and are, by necessity, often treated with the same medicinal and biological products, very few marketed products have had clinical trials performed in children or have labelling information for use in paediatrics. Early availability of adequate information to guide the appropriate use of medicinal products in children is a recognised need, unfortunately, not often met at present. The off-label and unlicensed use of medicines in the treatment of children is not best clinical practice. It is uncontrolled, and in such conditions there is no clear method of deciding which treatments are safe and effective, of informing other paediatricians of the safety and efficacy of medicines, or of capturing evidence on adverse events. It is in the interest of children that appropriate data be defined and generated to promote the safe and effective use of medicinal products in children.

This paper is concerned with the regulatory and economic conditions which have to be faced by a pharmaceutical manufacturer who plans to perform a clinical trial programme in children. Starting with an overview on diseases which occur and therefore need to be treated in children the required medicinal products are classified according to the relative frequency of occurrence in comparison with adults. Therapeutic areas where clinical data are missing are pointed out. An assessment of the difficulties involved in clinical trials in children is presented. The main obstacles are the difficulties of carrying out clinical trials in children, the difficulty of developing paediatric formulations and generally the cost of development for children in comparison with the limited return on invest a pharmaceutical manufacturer can expect.

A pharmaceutical manufacturer who plans to include children in his clinical trial programme has to meet formal legal and technical requirements for clinical trials in general (GCP aspects) as well as additional requirements for children. The formal requirements with special view on the additional requirements for children are presented.

Recent and current developments for the promotion of clinical trials in children in the European Union, the United States and Australia are described.
In the EU the European Network for Drug Investigation in Children (ENDIC) and the European Society for Clinical Pharmacy (ESCP) are acting to improve product development and availability and stress the need for European regulatory measures.
At the instigation of the French presidency in the European Council a draft memorandum on a future paediatric medicinal products directive was submitted to the Commission by July 2000. In this memorandum the current situation in Europe and abroad was analysed. Proposals were made to promote the development of medicinal products in Europe so that children may have the same guarantees of quality, effectiveness and safety as adults.
The "French memorandum" led to the "Paediatric Council Resolution" which was submitted to the Commission by December 2000. By this memorandum the Commission was called on to make proposals in the form of incentives, regulatory measures or other supporting measures in respect of clinical research and development, taking account of the ethical aspects of clinical trials on children, to ensure that new medicinal products for children and medicinal products already on the market are fully adapted to the specific needs of that population group.

Further to the December 2000 resolution new initiatives have come up. In 2001 the EFPIA Paediatric task force was created. They have worked out proposals for a programme of incentives and a proposal for a draft legislation. At the instigation of the CPMP an ad hoc Expert Group on Paediatrics was established. However even the Commission expected to finalise the whole initiative by the end of 2001 no draft legislation is available up today. This regulation would define the scope of the clinical trials on children, and overall create a set of regulatory, Intellectual Property and financial incentives to make both industry and public health structures develop effective and safe drugs adapted to the children. The text of a consultation paper now has been announced for beginning of February 2002. Once released, the industry will have between one and three months to give comments, and therefore the regulation project will be finalised by the Commission in September/October 2002.

In Germany, the Government has taken several measures and allocated funds to stimulate clinical research in children. A specific expert commission has been created, with the mission to define standards and give recommendations concerning medicines to be used and registered for children. At the instigation of the BMBF (German Federal Ministry for Education and Research) paediatric modules will be put in place in various Co-ordination Centers for Clinical Studies (KKS) which have been installed in 13 university hospitals in order to facilitate the recruitment of patients and to improve the infrastructure for clinical studies in children.

The FDA has implemented measures combining regulatory with economic incentives. The Paediatric Exclusivity Provision of FDAMA (1997) has been effective for obtaining paediatric studies for many medicinal products. An unprecedented number of paediatric studies have been or are projected to be conducted under this provision. Many of the studies have been conducted on medicinal products for important childhood diseases and on medicinal products that are used widely in children. The infrastructure for conducting paediatric trials also has been greatly strengthened, which should help to support continued progress.
The Agency's experience with the provision during the past years has also revealed that the provision has gaps: While a number of labels of medicinal products have been changed to incorporate findings from research conducted under the paediatric exclusivity provision, label changes typically occur long after FDA has granted the extension of market exclusivity. Important categories of medicinal products and age groups remain unstudied because of limitations on the availability of the incentive it offers. On January 4, 2002 the "Best Pharmaceuticals for Children Act" has been passed. It states that the Paediatric Exclusivity Provision included in the FDA Modernization Act of 1997 is maintained. Furthermore an FDA funding is planned for paediatric studies with off-patent drugs.

Finally the technical background of clinical development in children as provided by the respective ICH guideline (ICH-E11) is presented. This guideline represents a major step forward by providing a harmonised approach for the design and conduct of clinical trials in children allowing at the same time sufficient flexibility with respect to the ages of the population concerned, the characteristics of the pathology to be treated and especially concerning the timing of the trials. It will thereby help to facilitate the development of safe and effective use of medicinal products in children and eliminate the difficulties encountered by companies operating internationally.

Whereas in Europe there is up to now neither an obligation to submit clinical data from children nor definitive incentives for manufacturers who generate and submit such data the FDA has implemented measures combining regulatory with economic incentives. It is therefore to be hoped that in Europe regulations will be available soon requiring manufacturers to submit clinical data from children and at the same time providing incentives encouraging clinical development in children. These regulations should then foster an increase in the number of medicinal product investigations carried out in children, thereby improving their health care.
Only if medicinal products are investigated systematically in children reliable data can be obtained regarding efficacy, posology (including development of appropriate dosage forms), side-effects and contraindications and thereby dangers arising from off-label and unlicensed use can be avoided on a long-term basis.

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