Industry consults on new regulations

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.

Consultation sought

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.¹ 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).

• The Paediatric Regulation.

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.

Andy Martin is pharmaceutical training centre manager at RSSL, UK.

Reference

1. Ethical Considerations for Clinical Trials Performed in Children http://ec.europa.eu