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EU clinical trials directive: 0% inspiration, 100% perspiration?
The leading edge THE LANCET
Neurology EU clinical trials directive: 0% inspiration, 100% perspiration? The deadline for implementation of the European Union (EU) clinical trials directive passed on May 1. According to the European Commission, around half of the member states—including Spain, Sweden, and Greece—have introduced national legislation to implement the directive; the remainder, including the UK, have missed the deadline. When the UK Medicines & Healthcare Products Regulatory Agency (MHRA) opened up its proposed legislation to comment in March 2003, the reservations of the medical and research community—including NHS trusts, medical charities, and the pharmaceutical industry—were voiced loud and clear. As a result, “The medicines for human use (clinical trials) regulations 2004” was only laid before parliament on April 1 and will be debated by the end of May. The aim of the directive, which was adopted in April 2001, is to “simplify and harmonise the administrative provisions governing trials by establishing a clear, transparent procedure and creating conditions conducive to effective coordination of such clinical trials in the Community”. In doing so, the rights, safety, and wellbeing of participants in clinical trials will be protected, the legislators hope, with the added bonus that drug development and internal marketing of medicinal products within the EU will be facilitated. However, when a group of cancer researchers analysed the 149 publicly available responses to the MHRA’s proposed legislation (Lancet 2003; 362: 1415), they found that almost two thirds of responders expressed concern that the proposed legislation would slow or prevent trials or that costs would be increased. Three areas seem to be of particular concern: trial sponsorship, consent procedures, and pharmacovigilence. The directive specifies that a single “sponsor”—be that a person, a company, or an organisation—must take overall responsibility for the initiation, management, and financing of a trial. In practical terms, sponsors would deal with submission of trial applications (for both drug manufacturing and ethics approval), trial registration, and pharmacovigilance. For the pharmaceutical industry, this is not a new concept, but for publicly funded trials the practicalities are unworkable. How can a principal investigator take on the responsibility of pharmacovigilance across multiple trial sites in one country, let alone in a multicentre international trial? A way round this—and one now provided for in the UK regulations—would be for universities, NHS trusts, and funding bodies to collaborate and shoulder the sponsor’s responsibility THE LANCET Neurology Vol 3 June 2004
collectively. This apparently simple solution may sound good in theory but could prove difficult to negotiate in practice: some fear that the good relationships fostered by academic trialists with NHS trusts and funding bodies will quickly turn sour. Even if such disagreements can be settled, extra funding and armies of administrators will be required to get trials up and running. The concern over new consent procedures relates, in particular, to trials involving incapacitated adults (eg, patients with dementia, severe head injury, or a stroke that renders the person unable to communicate). If consent cannot be provided by the patient, a “legal representative” must take on the responsibility. Such legal representatives must not be involved in the trial— which rules out the treating doctor in most cases—and must make their decision on the basis of the “nature, significance, implications and risk of the clinical trial”. Many neurologists are concerned that the practical implications have not been properly thought through, and eligible patients will be excluded from valuable clinical research that could either benefit them directly or be of benefit to future patients. An additional concern is the necessity for increased data monitoring and pharmacovigilance. Regular site visits—already mandatory in the pharmaceutical industry—carry a heavy burden for publicly funded studies with limited financial and staff resources. Unless these concerns are taken into account before legislation to implement the directive is adopted in the UK, additional data monitoring and pharmacovigilance could send costs of trials rocketing sky high. The UK Medical Research Council estimates that an extra £500 000 per year will be needed to cover all publicly funded trials. All in all, the changes introduced by the directive mean that large international studies run by academics—such as the IMAGES trial of magnesium treatment in stroke (see commentary on page 330)— would be prohibitively expensive. The directive, the aim of which was to safeguard patients’ safety and to speed the development of drug treatments, is likely to have the opposite effect by reducing both the number of trials that public-funding bodies can afford to support and the number of patients enrolled in each study. This does not bode well for academic research in Europe or, indeed, for patients. The Lancet Neurology
http://neurology.thelancet.com
321
For personal use. Only reproduce with permission The Lancet Publishing Group.
Neurology EU clinical trials directive: 0% inspiration, 100% perspiration? The deadline for implementation of the European Union (EU) clinical trials directive passed on May 1. According to the European Commission, around half of the member states—including Spain, Sweden, and Greece—have introduced national legislation to implement the directive; the remainder, including the UK, have missed the deadline. When the UK Medicines & Healthcare Products Regulatory Agency (MHRA) opened up its proposed legislation to comment in March 2003, the reservations of the medical and research community—including NHS trusts, medical charities, and the pharmaceutical industry—were voiced loud and clear. As a result, “The medicines for human use (clinical trials) regulations 2004” was only laid before parliament on April 1 and will be debated by the end of May. The aim of the directive, which was adopted in April 2001, is to “simplify and harmonise the administrative provisions governing trials by establishing a clear, transparent procedure and creating conditions conducive to effective coordination of such clinical trials in the Community”. In doing so, the rights, safety, and wellbeing of participants in clinical trials will be protected, the legislators hope, with the added bonus that drug development and internal marketing of medicinal products within the EU will be facilitated. However, when a group of cancer researchers analysed the 149 publicly available responses to the MHRA’s proposed legislation (Lancet 2003; 362: 1415), they found that almost two thirds of responders expressed concern that the proposed legislation would slow or prevent trials or that costs would be increased. Three areas seem to be of particular concern: trial sponsorship, consent procedures, and pharmacovigilence. The directive specifies that a single “sponsor”—be that a person, a company, or an organisation—must take overall responsibility for the initiation, management, and financing of a trial. In practical terms, sponsors would deal with submission of trial applications (for both drug manufacturing and ethics approval), trial registration, and pharmacovigilance. For the pharmaceutical industry, this is not a new concept, but for publicly funded trials the practicalities are unworkable. How can a principal investigator take on the responsibility of pharmacovigilance across multiple trial sites in one country, let alone in a multicentre international trial? A way round this—and one now provided for in the UK regulations—would be for universities, NHS trusts, and funding bodies to collaborate and shoulder the sponsor’s responsibility THE LANCET Neurology Vol 3 June 2004
collectively. This apparently simple solution may sound good in theory but could prove difficult to negotiate in practice: some fear that the good relationships fostered by academic trialists with NHS trusts and funding bodies will quickly turn sour. Even if such disagreements can be settled, extra funding and armies of administrators will be required to get trials up and running. The concern over new consent procedures relates, in particular, to trials involving incapacitated adults (eg, patients with dementia, severe head injury, or a stroke that renders the person unable to communicate). If consent cannot be provided by the patient, a “legal representative” must take on the responsibility. Such legal representatives must not be involved in the trial— which rules out the treating doctor in most cases—and must make their decision on the basis of the “nature, significance, implications and risk of the clinical trial”. Many neurologists are concerned that the practical implications have not been properly thought through, and eligible patients will be excluded from valuable clinical research that could either benefit them directly or be of benefit to future patients. An additional concern is the necessity for increased data monitoring and pharmacovigilance. Regular site visits—already mandatory in the pharmaceutical industry—carry a heavy burden for publicly funded studies with limited financial and staff resources. Unless these concerns are taken into account before legislation to implement the directive is adopted in the UK, additional data monitoring and pharmacovigilance could send costs of trials rocketing sky high. The UK Medical Research Council estimates that an extra £500 000 per year will be needed to cover all publicly funded trials. All in all, the changes introduced by the directive mean that large international studies run by academics—such as the IMAGES trial of magnesium treatment in stroke (see commentary on page 330)— would be prohibitively expensive. The directive, the aim of which was to safeguard patients’ safety and to speed the development of drug treatments, is likely to have the opposite effect by reducing both the number of trials that public-funding bodies can afford to support and the number of patients enrolled in each study. This does not bode well for academic research in Europe or, indeed, for patients. The Lancet Neurology
http://neurology.thelancet.com
321
For personal use. Only reproduce with permission The Lancet Publishing Group.