Andy Martin

The EU Regulation on Paediatric Medicines,

  which came into force on 26 January 2007, aims to increase the availability of medicines specifically adapted and licensed for paediatric use. As such, it largely follows the example of the 'paediatric rule' in the US, which has helped to increase the number of paediatric medicines available there.

The regulation introduces some key changes to the marketing authorization (MA) that will be required for patented, orphan and off-patent products. It also provides for setting up a European database of paediatric clinical trials, a requirement to submit data from paediatric clinical trials to the regulatory authorities, and coordination of a European Paediatric Clinical Trials Network.  

There are some modest financial incentives on offer to induce manufacturers to develop new products or to continue marketing existing products for the paediatric population. This includes extending the patent protection for new medicines by 6 months, but only following completion of an agreed paediatric investigation plan (PIP) and submission of all the information to the regulatory authorities. In fact, the incentive will only apply if the product has an active Supplementary Protection Certificate (SPC), as the 6 months' patent protection will only be given as a 6-month extension of the SPC. Hence, there will be no incentive in cases where there is no SPC or where it has expired, and there is no mechanism to extend the duration of the period of the patent itself.  

Similarly, orphan medicinal products will receive an incentive in the form of an extra 2 years' market exclusivity in addition to the 10 years' market exclusivity that is granted on authorization. The financial incentives do not apply retrospectively, so should the contents of an agreed PIP be completed before entry into force of the regulation, the incentives will not be given. That is, unless the PIP contains "significant studies" completed after the regulation's entry into force. Presumably, the decision on significance will lie with the newly formed Paediatric Committee. The regulation also establishes a new type of MA, called the paediatric use marketing authorization (PUMA), intended to stimulate the development of off-patent products for paediatric use. Only medicines that are intended solely for use in children will be eligible for a PUMA. Even the EU/the European Medicines Agency (EMEA) joint statement describes the PUMA incentives as "relatively weak",

  so it remains to be seen whether they will actually encourage the development of new paediatric formulations for these older products.  

The PIP referred to above is a fundamental part of the new regulations. All MA applications for new medicines, including orphan medicines, must contain all the results of a previously agreed PIP. The plan will contain a full proposal of all the studies (and their timings) necessary to support the paediatric use of an individual product, and will cover all paediatric age groups and all necessary age-appropriate formulations.  

In some cases, it will be possible to defer the start of some or all of the studies regarding the development of the product in adults. In this case, the paediatric data will be provided after the initial MA has been granted. In other cases, the requirement may be waived for part or all of the paediatric population; for example, where there is no paediatric therapeutic need or where paediatric use of the product is inappropriate.  

However, unless a deferral or a waiver has been granted, paediatric data must be provided in all applications for the authorization of new medicinal products. This will apply from 26 July 2008. From 26 January 2009, this requirement will also apply to applications to add a new indication, pharmaceutical form or route of administration for medicines still covered by patent protection.  

The PIP is an R&D programme to ensure the necessary data are generated to determine the conditions in which a medicinal product may be authorized for paediatrics. The plan must specify the timing and the measures proposed to assess the quality, safety and efficacy of the medicinal product in all relevant subsets of the paediatric population, as defined in ICH E113. The PIP must be submitted to the Paediatric Committee no later than upon completion of the pharmacokinetic studies in adults.  

The committee can request further information or initial modifications to the plan. The regulation also allows for modifications of the plan at a later stage as the product development progresses. However, the Paediatric Committee must agree the plan, both to fulfil the requirements for a valid MA application and to satisfy qualification criteria for the financial incentives provided by the Regulation. If the committee refuses to agree a plan, the applicant can request it to re-examine its opinion. Following re-examination, a negative decision can be challenged in the European Courts of Justice.  

Another aspect of the regulation is that all products having an authorized paediatric indication will be required to display a new designated symbol on the package label. This applies irrespective of when the indication was granted. The meaning of this symbol must be explained in the patient information leaflet. Companies whose products were authorized for paediatric use before the publication of the symbol will have 2 years following publication to change their package labels to accommodate this symbol. 

If the EU experience matches that of the US, then the new regulation should help increase the development of paediatric medicines. In the US, between July 1998 and February 2004, new paediatric information was added to more than 60 labels of established medicines and in 41 cases, the new labels included important new information that impacted the safe and effective use of the medicine in children.

Of course, for the data to be generated, research is required, and a number of measures contained within the regulation aim to ensure that the research conducted in children is of high quality. Moreover, EMEA and its scientific committees will provide free advice to applicants on the design and conduct of the studies in a PIP, and on the design and conduct of paediatric pharmacovigilance and risk management systems. In support of the latter, the EMEA/Committee for Medicinal Products for Human Use (CHMP) have already finalized guidance on the conduct of pharmacovigilance in the paediatric population. Further guidance will be developed on the conduct of paediatric clinical trials in different therapeutic areas and in specific paediatric populations. In addition, the European Commission is developing a document on ethical considerations for clinical trials performed in children, which was released for a 4-month consultation period in October 2006.

Overall, the regulation is to be welcomed. EU figures claim that more than 50% of the medicines used to treat the children of Europe have not been tested and are not authorized for use in children.

  In effect, doctors are prescribing medicines without knowing that they are effective, what dose is appropriate and what adverse reactions the child may suffer. That is not a happy statistic, and the new regulation should go some way to improving the situation in Europe.  

is pharmaceutical training centre manager at RSSL (UK).

1. Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004 (Official Journal L378,27/12/2006 p 1–19) . 

3. Note for guidance on clinical investigation of medicinal products in the paediatric population (CPMP/ICH/2711/99). 

www.emea.eu.int/pdfs/human/ich/271199en.pdf

4. Summary of regulation on medicines for paediatric use. 

Articles

New regulation of children's medicines

The International Conference on Harmonization (ICH) expects to publish its tripartite guideline describing modern quality systems for consultation this spring. This will bring nearer to the end a process that began in 2003 to: "Develop a harmonized pharmaceutical quality system applicable across the life cycle of the product emphasizing an integrated approach to quality risk management and science."  

The expectation at this stage is that the guideline will augment existing good manufacturing practices (GMPs) with modern quality system elements for pharmaceutical manufacturing.  

It could be argued that the pharmaceutical industry is already awash with documents that define quality systems including several ISO (e.g., ISO 9000: Quality Management Systems), ICH, FDA and Eudralex documents. Indeed, the ICH proposes using many of these documents as its starting point, but then intends that the proposed ICH quality guideline would bridge different regional regulations. 

Currently, definitions and interpretations of quality system terms, principles, application and expectations vary between the regions, industry and regulatory agencies. The potential for inconsistencies is exacerbated through using various aspects of quality systems and concepts, particularly when implementing quality by design, continual improvement and quality risk management. Such divergence challenges an efficient and effective industry, and regulatory processes.  

By creating an internationally harmonized pharmaceutical quality systems guideline that manufacturers can use to assess their process, products and systems, the ICH hopes to avoid detrimental impacts of variability such as delays in medicine availability and the launch of new products, and different approaches to compliance inspections. 

It is also anticipated by ICH and industry this proposed ICH guideline will focus on quality systems that facilitate ICH Q8 "Pharmaceutical Development" and ICH Q9 "Quality Risk Management" implementation, thereby maximizing the benefits of these two guidelines' concepts.  

However, harmonizing anything is complex and the consultation process will probably highlight areas of dispute. Most observers though, will be in favour of anything that both improves quality across the board, and assists the industry to develop and demonstrate a process of continual improvement. 

The Directorate General for Enterprise and Industry has released a draft document, 

Ethical Considerations for Clinical Trials Performed in Children

, which provides recommendations on various ethical aspects of clinical trials performed on children.

  It aims to contribute to their protection as the subject of clinical trials, as well as facilitate a harmonized approach to clinical trials across the EU Member States. Because the approval (including ethical approval) of clinical trials is primarily a national competence, this harmonization is aimed at facilitating the conduct of clinical trials in the EU.  

The third recital of Directive 2001/20/EC (the Clinical Trials Directive) recognized the need to investigate medicinal products in the vulnerable population of children (or 'minors' according to the Clinical Trials Directive) while ensuring their protection. Specific reference was made to the "need for clinical trials involving children to improve the treatment available to them". It went on to observe that: "Criteria for the protection of children in clinical trials therefore need to be laid down." 

In addition to the Directive, the proposed guidelines will also have to be read in the context of other directives including: 					

Directive 2001/83/EC (relating to medicinal products for human use).

Directive 2005/28/EC (laying down principles and detailed guidelines for good clinical practice as regards investigational medicinal products for human use).

National legislation also comes to bear on the guidelines because different nationalities within the EU have widely differing legislation defining key concepts such as a 'minor' and the 'legal representative of a minor.' In clinical trials involving children, issues of consent and assent are complicated, and despite the International Convention on Human Rights and the Helsinki Declaration, there is scope for national differences concerning what is actually required to gain the consent of a legal representative.  

For older children, confidentiality issues must be addressed, and potential conflicts of interest concerning information disclosure to a parent or legal guardian. Again, there are national differences in data protection legislation. 

It is these issues, and many others outlined in the recommendations, that highlight the need to develop specific guidelines for clinical trials in children to be followed across all EU nations.  

It is also important to recognize that children are not small adults. Differences in pharmacokinetics and dynamics, and in adverse reactions are common in children compared with adults. Growth and maturation processes, as well as particular diseases, are not found in adults. Specific consequences of medical interventions may be seen in children and may appear long after exposure. This has, unfortunately, been demonstrated by catastrophes with the use of untested medicinal products, which most often occurred in children. 

Because of the special protection children deserve, these recommendations (Ethical Considerations for Clinical Trials Performed in Children) argue that they 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).  

Consultation on this document is scheduled to end on 31 January.  

is pharmaceutical training centre manager at RSSL, UK. 

Ethical Considerations for Clinical Trials Performed in Children 

The ICH hopes to avoid detrimental impacts of variability such as delays in medicine availability and the launch of new products, and different approaches to compliance inspections.