EU to Put the IT into Clinical Trials

The timetable for European Union plans to bring clinical trials more fully into the world of information technology has emerged. At the end of July, an outline was agreed upon by an obscure but influential group of experts on what should happen next for clinical trials in the esoteric world of telematics and pharmaceuticals.

The priorities the group sets out for clinical trials in medicines for human use are to provide information technology (IT) support for the implementation of the EU rules on clinical trials (Directive 2001/20/EC), to develop a database of reports of Suspected Unexpected Serious Adverse Reactions occurring during clinical trials (SUSARs), and to develop a database of information on clinical trials.

The first deadline is the end of this year. A first iteration of the SUSARs database is now scheduled for December 2003. This will be followed—according to the timetable set by the telematics experts—by production implementation of the SUSARs database by April 2004. Later in 2004, a first version of the database of information on clinical trials (known as EudraCT, and foreseen in the clinical trials directive) is scheduled for development, and by 2005 it should be extended, upgraded, and modified as necessary. The European Agency for the Evaluation of Medicinal Products is envisaged as the responsible body for carrying out the program, and the money for it is foreseen to come from the EMEA budget.

The Telematic Steering Committee—as the expert group is known—specified implementation priorities, objectives, timetables, and budgets for half-a-dozen key pharmaceutical regulatory activities: notably the Euro PHARM Database, the projected European pharmaceutical database of harmonized information for all authorized medicines, in all EU official languages, with different levels of entry and inquiry for general public, physicians, and regulators. But it also covers EudraNet, EudraVigilance (a system to optimize monitoring of the safety of medicines on the market throughout the EU, permitting safe and fast exchange of information, from industry, between regulators), E-Submissions and EudraTrack, as well as clinical trials. It urges the creation of specific mechanisms and audit procedures for monitoring the relative progress of each project, and specific financial road maps for budgetary control.

Behind these projects is a strategy the EU has been working on for more than a year “to provide guidance for the development and operation of the structure of the pharmaceutical IT systems.” The main objectives of European pharmaceutical policy and legislation remain the same—a high level of protection of public health, a single market for pharmaceuticals, competitive capacity for the European pharmaceutical industry, and preparations for EU enlargement in 2004. But putting policies and legislation into effect is increasingly dependent on effective IT solutions.

The strategy has been agreed between member states, the European Agency for the Evaluation of Medicinal Products and the European Commission. The Telematic Steering Committee is in charge of its monitoring and development. Among the broad objectives are to:

• bring more efficiency into the operation of the EU regulatory procedures on medicines marketing and surveillance.
• allow safe exchange of information within the system.
• involve pharmaceutical companies so as to promote e-submission and e-reporting.

It claims to ground its initiatives “in the real and, if possible, validated needs of users.”

Linking GMP and GCP

Before the summer break, the European Commission released updated guidance for good manufacturing practice (GMP) for investigational medicinal products. This is another of the detailed measures implementing the EU’s clinical trials directive, but it also takes account of the requirements of the experience of industry and regulators. (The updated guidance takes the form of an updated Annex 13 to the EC Guide to Good Manufacturing Practice, providing supplementary guidance on the application of the principles and guidelines of GMP to investigational medicinal products.)

The underlying principle is that investigational medicinal products should be produced in accordance with the principles and the detailed guidelines of Good Manufacturing Practice for Medicinal Products (The Rules Governing Medicinal Products in The European Community, Volume IV). But, it says, in clinical trials “there may be added risk to participating subjects compared to patients treated with marketed products,” and applying GMP to the manufacture of investigational medicinal products is intended to ensure that trial subjects are not placed at risk and that the results of clinical trials are unaffected by inadequate safety, quality, or efficacy arising from unsatisfactory manufacture. Equally, it is intended to ensure that there is consistency between batches of the same investigational medicinal product used in the same or different clinical trials, and that changes during the development of an investigational medicinal product are adequately documented and justified.

The guideline recognizes that there are additional complexities in the production of investigational medicinal products in comparison to marketed products:

• The lack of fixed routines.
• The variety of clinical trial designs, consequent packaging designs.
• The need for randomization and blinding.
• The increased risk of product cross-contamination and mix up.

There may also be incomplete knowledge of the potency and toxicity of the product and a lack of full process validation. Marketed products may be used which have been repackaged or modified in some way.

So what’s needed, the guideline insists, is personnel with a thorough understanding of, and training in, the application of GMP to investigational medicinal products. Cooperation is required with trial sponsors who undertake the ultimate responsibility for all aspects of the clinical trial, including the quality of investigational medicinal products. And the increased complexity in manufacturing operations requires a highly effective quality system.

Another push for pediatrics

The vague EU plans for action to promote the development of pediatric medicines (see this column, ACT June 2003) are not evolving fast enough for some EU member states. Belgium has raised the matter at the EU Council of Ministers, and urged faster action.

Belgium pointed out that as far back as December 2000, the EU Council of Ministers for Health asked for proposals to be made “as soon as possible” for agreement at European level on incentives, regulatory measures or other supporting measures in respect of clinical research, and development targeted at pediatric medicinal products. The aim then—and now—is to ensure that new medicines and products already on the market are adapted to the specific needs of children. At the same time, the ethical aspects of clinical trials involving children and the internationally acknowledged standards for the protection of minors with regard to medical scientific research “should also be taken into account.”

It is now more than a year (February 2002, in fact) since work started on a draft regulation to promote medicines intended for children, Belgium remarked, but despite the preparations by the European Commission (the EU institution whose job it is to make formal legislative proposals), “the Council and the Parliament have received no formal proposal to date.” Belgium went on its statement to emphasize “the precariousness” of the present situation. The pharmaceutical industry, said Belgium, is waiting, “indefinitely postponing submission of registration dossiers for pediatric medicinal products in the expectation of the probable incentives in the new regulations to come.”

So Belgium urged the Council and the Commission “to take stock of the issue with a view to satisfying the needs of the European pediatric population without delay.” The Council formally took note of the Belgian intervention—which is a polite way of saying none of the other member states disagreed violently, but there was no rush to join Belgium on the barricades, either. For its part, the Commission again told the Council what was already well-known, in a well-rehearsed formulation: that “after the consultation process launched in February 2002, it expects to be in a position to present a proposal on child-specific medicines possibly at the end of this year or during the first quarter of 2004.” Meanwhile, as ACT has already reported, an extended assessment of ways and means is planned by the Commission for later this year—but has still not started.