Children and medicinal products
Children are not small adults. They represent a particularly vulnerable group of patients since they react to medicinal products in a different way. Infants usually metabolise medicinal products less rapidly and also excrete them more slowly. Some medicinal products can moreover affect growth and development.
These and other specific aspects must be taken into consideration when prescribing and dispensing medicinal products for children. In addition, medicinal products that were developed for adults are in many cases not appropriate for children. Small children are usually unable to swallow tablets, and refuse to take a syrups unless it has a pleasant taste.
2. Current situation
The use of a product for children is only officially approved if clinical trials have been carried out with the corresponding age group. In many cases, new medicinal products are however initially – or even only – developed for adults. This problem exists worldwide.
It is frequently the case that clinical trials on efficacy and safety for younger age groups are not even conducted with medicinal products that have been on the market for some time; this particularly applies for newborns and infants. Often, age-appropriate dosage strengths for children, infants and babies do not exist, and / or there are no appropriate dosage forms such as suppositories, drops, syrup, etc.
The reasons for fewer investments being made in research and development for diseases affecting children include, on the one hand, the fact that this is a smaller market, and on the other that trials on children are more difficult to conduct. The population concerned is moreover not a uniform one (a newborn is, for example, not comparable with a 15-year old adolescent).
The product information should be used in order to see whether a medicinal product can be used by children and adolescents. If the corresponding clinical trials have been conducted, the product information for healthcare professionals will – for medicinal products that have been authorised in recent years – contain information in this respect for these professionals (doctors and pharmacists). For older medicinal products, however, this information was not included in the information and precise details regarding the dosage for children and adolescents were frequently missing.
This problem was addressed during the years 2003-2009, and today nearly all medicinal product information should contain appropriate information concerning paediatric use, and specify the age group as of which paediatric use is authorised. It should be noted that stating a dosage in milligrams per kilogram of body weight (mg/kg) is not an indication that it can be used for children and adolescents, and nor does it mean that the medicinal product concerned is authorised for paediatric use.
In many cases, paediatricians must rely on their personal, practical experience when prescribing, since no medicinal products for paediatric use have been developed for the treatment of certain diseases, and only a product that has been authorised for adults can be used. This type of prescribing (so-called off-label use) is permitted under the Therapeutic Products Act as long as the acknowledged rules relating to medical and pharmaceutical sciences are taken into consideration.
It is precisely in such cases, however, that suspected adverse reactions are reported in the interests of safety. Such reports are made using the form available on the Swissmedic website, for the intention of the regional pharmacovigilance centres (whose addresses can be found on the reporting form).
The reception point for SUSAR reports is SUSAR@swissmedic.ch or Swissmedic, Clinical Trials Division.
The CIOMS form should be used, and preferably as an electronic version (pdf), always together with the accompanying SUSAR form.
In order to foster the conducting of clinical trials with children, Swissmedic offers the pharmaceutical industry – on request – an extension to the protection period for their medicinal product if it is a new development in connection with use for children.
The Ordinance on Fees levied by Swissmedic, valid as of 1 January 2013 (HgebV), foresees a fee reduction of 90% for the authorisation of, and major variations to, medicinal products with exclusively paediatric indications. Major variations include, for example, an additional indication, dosage recommendation or dosage strength. This measure is intended to foster developments in the area of paediatric medication.
For all paediatric studies carried out in the USA or the EU that have led to extending use to children (new indication, new pharmaceutical form, new dosage recommendation, etc.), Swissmedic has urged pharmaceutical companies to also submit a corresponding application to Swissmedic. Although it cannot be made mandatory under Swiss legislation on therapeutic products for authorisation holders / pharmaceutical companies to do so, they are encouraged to submit such applications voluntarily, in the spirit of assuming responsibility and in the interests of the safety of medicines when treating children and adolescents.
When evaluating an authorisation application, Swissmedic moreover checks whether the international recommendations to conduct clinical trials on paediatric populations have been taken into consideration. For that reason, Swissmedic's Instructions for New APIS ("Instructions, authorisation of human medicines with new active pharmaceutical ingredients and major variations") has been updated accordingly.
When developing dosage forms appropriate to patient age, the EU Guideline "Pharmaceutical Development of Medicines for Paediatric Use" should be taken into consideration.
3. The way forward
In the Guideline E11 of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), a description is provided of when, and in what situation, paediatric data should be submitted.
Switzerland has recognised this Guideline. Initiatives on the part of authorities have been launched worldwide with the objective of providing support for the development and the placing on the market of medicinal products for children. In the USA, for example, new legal principles have been created in order to foster the conducting of clinical trials with children. To date, this initiative has been highly successful, and clinical trials with children have been carried out not only with newer but also on older medicinal products.
In the EU, a law was enacted on 26 January 2007 that aims to improve the situation regarding medicinal products for paediatric use ("Regulation of the European Parliament and of the Council on medicinal products for paediatric use and amending regulation”). Swissmedic is committed to ensuring that the relevant documents regarding the use of medicinal products in the paediatric population are also available to pharmaceutical companies in our country.
Within the framework of the revision of the Therapeutic Products Act, and among other changes, legal measures relating to paediatric medicinal products are foreseen.
Work on the revision of the Therapeutic Products Act had taken nearly five years when the Federal Council transferred the proposed draft (E-HMG) and the dispatch to the Federal Parliament on 7 November 2012. The Federal Office of Public Health, which is leading the revision of the Act, expects that the revised version will come into force on 1 January 2016. This relatively late entry into force is related to the fact that following the final approval in Parliament, the necessary implementing provisions regulations must first be drawn up.
The draft is presently being handled by the Parliamentary Committee for Social Security and Health (SGK-N). After the last meeting of this committee for the 2013, the parliamentary services (on behalf of the SGK-N; see Art. 45 of the Parliament Act (ParlA) [SR 171.10]) provided information on the deliberations. The press release states that the Committee voted in favour (by 10 votes to 8, with 5 abstentions) of the proposal by Parliament for the introduction of a paediatric investigation plan that is intended to improve pharmacotherapy within paediatric medicine.
For that reason, before clinical trials with a view to the authorisation of medicinal products are conducted, it will in future be necessary to draw up a paediatric investigation plan that establishes the requirements relating to the development of the medicinal product with regard to paediatrics.
4. Definition of off-label use / unlicensed use
Off-label use is particularly frequent within paediatrics, because no tested, authorised medicinal products are available for this age group. In addition, the pharmaceutical forms (such as tablets) are often inappropriate for this age group, and special dosage strengths for capsules must be manufactured.
In Swissmedic's experience, the term "off-label" use is often used as a synonym for "unlicensed use". For clarification, these terms are defined below:
Off-label use: Use for indications, age groups or labels other than those stated in the information for healthcare professionals.
Off-label use falls under the responsibility of the doctor concerned (preservation of therapeutic freedom)
Unlicensed Use: Use of medicinal products that are not authorised
Treatment with medicinal products that are not authorised is not permitted except for those cases specified in the provisions of the Therapeutic Products Act (HMG; SR 812.21).
The use of medicinal products that are not subject to mandatory authorisation in accordance with Article 9, para. 2 of the Therapeutic Products Act is not unlicensed use.
Situation at the beginning of 2014.