Strategy and Tactics for European Clinical Trials

The European Union knows how important clinical trials are both to the health of patients and to the health of the pharmaceutical industry in Europe. So the last few weeks have seen intense European regulatory activity both at strategic and tactical levels in a bid to ensure that patients can continue to benefit from high-quality medicines from a competitive and innovative European industry.

Strategy
At the strategic level, senior European Union officials came out in early July with what is intended as an evolving document for the future of the industry. The document is grandly titled A stronger European-based pharmaceutical industry for the benefit of the patienta call for action.¹ This represents the outcome of two years of reflection on a dilemma that goes back much further. The question is how to promote private industry medicines innovation without bankrupting public social security agencies? Or from the other perspective, how to keep spending on medicines in Europe within reasonable limits without killing off European pharmaceutical research?

To say the EU has found a complete solution to the problem it perceives would be false. The underlying tensions in Europe, where each member state holds its own purse strings for spending on medicines, while the EU tries to establish an industrial policy, continue to baffle the brightest minds in Brussels (and beyond).

But to say that the EU has made no progress at all in its thinking would also be false. The document contains further evidence of a growing consensus within Europe on the merits of medicine research, and the need to prevent medicine research from relocating abroad. It firmly states In order to stop the process of erosion, Europe must act now if it is to retain its attractiveness as a location for industry in the years to come.

Clinical trials
Specifically on clinical trials, the document unequivocally recognizes, in a section headed Incentives for Research, that clinical trials are critical to pharmaceutical research. They are vital to public and health and represent a considerable investment for the pharmaceutical industry. It notes that the specially appointed expert group that has been carrying out these reflections for the last two years (known as the G10, because it consisted of ten key representatives of member states, the pharmaceutical industry, and the national health care agencies) has rightly stressed the need for better co-ordination between member states on clinical trials.

The paramount consideration in trial design must be the well-being of subjects, the document goes on. But there is scope for better European coordination, for simplification and harmonization of the administrative procedures governing trials, it accepts. The regulatory framework on clinical trials needs to be adapted, it states.Some of this adaptation is already under way, of course. The new EU clinical trials directive, as the document acknowledges, contains a provision setting up, for the first time, a European clinical trials database, to help communication between regulatory authorities to enable them to improve their oversight of trials and provide for enhanced protection of patients.

And much has already been achieved to ensure that the EU facilitates trials where the potential pool of clinical trial subjects is small, the document claimsciting work carried out or in progress in particular with orphan medicines and for pediatric indications. The incentives to produce orphan drugs (including 10-year marketing exclusivity, fee waivers, and provision of scientific advice) have generated 140 designations for new orphan medicines since the entry into force of this scheme in 2001.

Half a loaf
But the truth is that there are still almost insuperable limits to what the EU can do to improve the situation significantly. Because the fundamental problem is that most EU member states keep drug prices (or reimbursement levels) very low, industry is starved of funds for new drug development. And as long as the member states retain this competence (and they show no signs of readiness to cede it to the EU), the EU can do little more than offer pious expressions of hope that member states should take a more generous view of drug pricing and reimbursement. Member states have clear competence to take national measures in order to control healthcare expenditures, the document candidly admits.

On the basis that half a loaf is better than no bread, the affirmations of the value of clinical trials and of pharmaceutical research have been immediately welcomed by the European pharmaceutical industry. There has also been a more muted welcome for the expressions of good intention on areas more susceptible to EU interventionsuch as speeding up assessments of applications for marketing authorizations, promoting virtual institutes of health to stimulate and organize health and biotechnology research in Europe, and raising the concept of a European center for disease prevention and control.

Tactics
Another part of the half a loaf, as far as clinical trials are specifically concerned, is the range of EU activities, now underway, aimed at making tactical improvements to the conduct of clinical trialsfor the sake of the patient, and for the sake of the clinical trials sector itself. Unfortunately, not all these tactical exercises are necessarily seen as beneficial by the clinical trials sector.

Profiling GCP inspections
Take, for instance, the current efforts of the European Agency for the Evaluation of Medicinal Products to boost the profile of its inspections sector. This department is responsible for coordinating the verification of compliance with the principles of good clinical practice (GCP), good manufacturing practice (GMP), and good laboratory practice (GLP).

The sectors tasks include coordinating any GMP, GCP, or GLP inspections requested by the Committee on Proprietary Medicinal Productsthe EMEAs senior scientific bodyin connection with the assessment of marketing authorization applications or related assessment procedures. In a new presentation of its inspectorate function, the EMEA explains that inspections may be necessary to verify specific aspects of the clinical or laboratory testing, the manufacture and control of the product, or ensuring compliance with GMP, GCP, GLP, and quality assurance systems.

A widely held view within the clinical trials community is that better EU coordination of inspections could improve the way trials are inspected, by standardizing the approach in the most professional wayand thus eliminating some of the national variability that can plague an internationally conducted trial. But the optimism is balanced by an equally widely held fear that the exercise contains a risk of compounding rather than clarifying the approach of inspectors.

So the clinical trials community is watching closely to see what the out-turn is as the EMEA sector organizes and chairs regular meetings of European Union GCP and GMP inspectors. The sector is involved in coordinating GCP inspections for the EUs centralized procedure for obtaining marketing authorizations. And through the work of the GCP inspections services group, which focuses on harmonization and co-ordination of GCP related activities at EU level, the sector helps prepare new and revised guidance on GCP topics, coordinates advice on the interpretation of EU GCP requirements and related technical issues, and helps develop EU-wide procedures relating to GCP inspections. The GCP inspections services groupwhich the EMEAs inspection sector chairsmeets four times a year, with representatives of the GCP inspectorates of Switzerland, Iceland, and Norway; observers from the central and eastern European countries (eight of which will become full EU member states next May); and representatives of Collaboration Agreement of Drug Regulatory Authorities in European Union Associated Countries. As to the effectiveness of these efforts, the jury is still out.

Paying for GCP inspections
Again in a bid to make life both easier for the industry andin the longer termsafer for patients, the EMEA has also just set out in some detail the way it charges for its services in assessing marketing authorization applications, including conducting inspections of good clinical practice. The guidance is limited to applications through the centralized procedure that the EMEA operates. It does not cover routine GCP inspections of clinical trial sites initiated by the competent authorities of the member states themselves, who make their own arrangements for reimbursement with the company concerned.

The EU rules specify a flat-rate fee for each inspection, plus travel expenses incurred by the inspectors for inspections conducted outside the EU.² But it is possible that more than one inspection is requested by the authorities in the context of assessing a single application, and the applicant is then liable for more than one inspection fee. The EMEA clarification, in particular, concerns how to determine what constitutes a single, distinct inspection, and thus how the total of inspection fees is calculated.

A single inspection, says EMEA, is one that covers a particular clinical trial activity relating to a product for which an application has been made, carried out at a specific clinical trial-related site, and conducted on a specific occasion. Any other inspection concerning any additional clinical trialrelated activity and/or site is considered to be a further, distinct inspection, even if it relates to the same application.

To make it absolutely clear, EMEA also points out that a single responsibility or set of directly related responsibilities involved in the conduct of clinical trials constitutes a single clinical trial activity. A physical location that contains one or more clinical trial facilities (in a separate building) at the same address constitutes a single clinical trial site.

Although no one wants to pay for inspections, they are a necessary evil. At the very least, knowledge of where some of the costs are to be incurred should help in planning the financing of clinical studies.

Still grappling with the directive
The European Forum for Good Clinical Practice (EFGCP) is continuing to make sense of another important tactical exercise now under way: the European Commissions guidance documents in support of the EU Clinical Trials Directive (2001/20/EC), which have recently been finalized (see this column, ACT June 2003).

EFGCP has been exploring partnerships for implementing the directive, at a meeting in Brussels in June, in collaboration with the European Cancer Managers Research Forum, the European Commission, and the European Organisation for Research and Treatment of Cancer. The EFGCPs aim is to get all parties involved in European clinical research to establish a shared platform for the implementation of GCP, both at European level, and in the 15 current (and ten future) member stateswhich are supposed to have introduced the directives provisions into their national legislation by May this year, so the directive can be brought into force in May 2004. EFGCP wants to make sure the new rules create a competitive and quality based European clinical research framework that guarantees the best in medicinal development for public health and Europes citizens.

As EFGCP points out, particular focus needs to be placed on clinical trials and translational research, connecting European academic excellence with innovative research-based industry. This first EFGCP step in building partnerships of this type was intended to focus on the coordination of the implementation of GCP in cancer research, across European research centers, and across sectors.

But one of the central questions raisedand still not answeredis how efficient clinical trial authorization processes that protect potential research participants while ensuring the efficient development of medicines can be implemented in Europe. The entire sector remains anxious that the way the EU member states put the rules into effect will not make it easier to conduct international trialsand could still make them harder. In tactical terms, the next year, as the member states adapt their national rules, is going to demonstrate whether those anxieties are justified. And in more strategic terms, the next decade is going to reveal how far the EUs attempts to boost EU medicines research manage to keep the industry alive and activeand able to supply the new drugs patients need.

References
1. Communication from the Commission to the Council, the European Parliament, the Economic and Social Committee, and the Committee of the Regions, July 2 2003 (soon to be published in the EU Official Journal).

2. Council Regulation (EC) No 297195 (as amended) Articles 3 (4) and 5 (4) (human and veterinary sectors respectively), as amended by Council Regulation (EC) No 2743/98.