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Throwing a wrench in the works?
Reflection & Reaction Throwing a wrench in the works? In May, 2004, Directive 2001/20/EC of The European Parliament1 will be adopted and applied by all member states of the European Union (EU). This directive outlines requirements for “the approximation of the laws, regulations, and administrative provisions of Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use”. The European Commission’s choice of the Enterprise Directorate-General, a specialist branch of the European Commission dedicated to improving the competitiveness of European endeavours, to drive the development of the Directive underscores why many people believe that the primary objectives of academic research organisations have been forgotten. Many research organisations involved in clinical trials are worried about how they will cope with the increased costs and administrative burdens that the Directive will bring and whether it will truly result in greater protection for the patient. For many years, a key element of patient protection has been the assessment of risk. Risk can be defined in many ways, but perhaps the most obvious would be an evaluation of the extent of patient exposure to an investigational drug whose toxicological profile is not fully known and whose manufacture is not done to the same controlled standards of commercially available drugs. But, it is important to remember that many clinical trials do not investigate new drugs. Indeed, many trials are actually driven by investigators and academic organisations aiming to improve therapeutic strategies and establish new state-of-the-art treatments; for example, organ preservation in patients with cancer is now a real possibility by use of a combination of commercially available chemotherapeutic agents and surgery or radiation therapy. But importantly, these types of trials are done without the involvement of the pharmaceutical sector. The toxicological profiles of marketed drugs have already been assessed in great detail to obtain marketing THE LANCET Oncology Vol 4 December 2003
authorisation, and extensive documented follow-up data from clinical practice is known thus negating the need for repetition of safety profiling as dictated by the new Directive. Without a doubt, minimising the risk is essential in any trial. The Directive aims to do this with a set of guidelines defining the content of a dossier that must accompany any request for clinical trial approval, manufacturing and labelling of investigational medicinal products, and notification of adverse events. Is the protection of patients and other study participants really improved by insisting on a heavy dossier full of information previously assessed by other authorities or by insisting on additional preclinical testing of drugs routinely used in medical practice? To insist that trials using commercially available drugs would need to be repackaged and relabelled introduces a process that investigators and academic organisations may not be able to fulfil. Furthermore, if the provision of investigational medicinal products for free by the sponsor is enforced, many trials run without the involvement of the pharmaceutical sector will be stopped in their tracks. Another concern for academic organisations is the increased administrative burden related to safety reporting. The Directive will force sponsors to introduce databases for efficient collection and analysis of safety information to provide detailed annual reports to various authorities. In addition, the ability to do expedited electronic reporting of Serious Unexpected Suspected Adverse Events could be a problem for some academic organisations. Indeed, the value of increasing the amount of reporting of such events, together with the perceived duplication of information submitted to various authorities and ethics committees, is questionable. Increasingly, academic research relies on international collaborations to ensure accrual targets are met in a timely fashion. This ‘intergroup’, often co-sponsored, approach strengthens national efforts by establishing an international network of excellence
and has proved particularly effective for clinical research investigating treatments for rare diseases and targeted therapies. The Directive’s definition of a sponsor leaves room for doubt over whether international cosponsorship could also mean coliability. The obligation of the sponsor to provide insurance or indemnity to cover the liability of the sponsor and the investigator is perfectly reasonable, however, if the sponsor has to accept liability for areas beyond its control, as would be the case in an intergroup trial involving international cooperation and different national laws, many academic organisations will not be prepared to take the risk. If we assume that a sponsor, such as an academic organisation, does actually have the organisational framework to fulfil the above criteria there will be other substantial associated costs. Multicentre, international trials may be jeopardised because it may be difficult for regulatory authorities and ethics committees to waive processing fees for academic clinical trials. Some academic organisations have estimated that overall costs will increase by a factor of four. And it is unlikely that money made available to academic organisations by their stakeholders will increase following the introduction of the Directive. If anything, the involvement of the pharmaceutical sector in helping to finance some areas of academic research may well decrease because of a reluctance to risk being defined as a sponsor if they provide funding or study drugs to an academic trial. So how will academia cope? Some academic organisations will not be able to withstand the impact of Directive 2001/20/EC. Others will be able to accommodate the new requirements, but will be forced to decrease their clinical research activities. May, 2004, is still a few months away but already The European Organisation for Research and Treatment of Cancer (EORTC) has seen an increase in the amount of administration associated with initiating and running clinical trials in a number of EU Member
http://oncology.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
717
Reflection & Reaction States without any notable improvement in patient safety. The run-up to May, 2004, will be a crucial period of time. With the exception of Denmark, most EU Member States have not yet published their new legislation incorporating Directive 2001/20/EC. It is difficult to estimate the true effect of the Directive until the wording of each country’s legislation becomes known but the Directive does leave some room for interpretation in certain areas and this in itself leaves hope that Member States will be able to introduce clauses favourable to academia. The future of academic research in Europe, and significant progress in patient care, is now largely in the hands of the national legislators. Françoise Meunier, Nathalie Dubois, Anastassia Negrouk, and Lesley-Ann Rea European Organisation for Research and Treatment of Cancer (EORTC), Brussels, Belgium.
Organisation of European Cancer Institutes says . . . When integrated in to the national laws governing member states of the European Union in May, 2004, European Directive 2001/20/EC aims to provide a general framework for good clinical practice in trials that test medicinal products for human use. The objective of the Directive is fundamental: the protection of study participants. Indeed, such an aim requires strict rules, defined procedures, and harmonisation in the European Research Area. And importantly, the Directive will introduce essential concepts: more professional and powerful ethics committees; authorisation of clinical trials following a thorough process of assessing the risks and benefits for trial participants; special consideration for paediatric trials; and, the establishment of a European database allowing real-time monitoring of clinical research. The Directive was inspired by the Loi Huriet (a French law requiring organisers of clinical trials to obtain informed consent from all participants), but it also attempts to combine many regulatory requirements
718
specific to other EU countries. Consequently, it introduces administrative procedures, infrastructure requirements, and financial commitments that many academic units will find challenging. Indeed, the large number of requirements is simply unrealistic in many academic settings. Understandably, it has become a major concern for research clinicians. The Directive seems tailored entirely for clinical research sponsored by industry and its implementation will require a gigantic step for those EU countries without strict clinical trial regulations. Undeniably, regulations governing clinical trials in Europe would benefit from harmonisation, but their implementation should be done in a way that is feasible for all countries and interested parties. Otherwise, clinical research in academic centres will be jeopardised: some countries may become totally deprived of such research, both nationally and through international collaboration—despite a growing need for better integration of the European research community. The objective of the Enterprise Directorate-General will not be achieved by this Directive because industry-sponsored trials will simply move to non-EU countries; a trend that is already evident. With academia unable to sponsor trials and industry moving elsewhere, will any clinical research survive in the EU? It is likely that the numbers of European trials will not only decrease but also large research centres might find difficulties sponsoring strategy-oriented studies. As a general framework to provide safeguards protecting patients enrolled in marketing-oriented trials, the Directive is an important piece of legislation. But, if implemented in its current form, the limitations on innovation and the ability for all academic centres to do clinical research will negatively effect long-term provision of high-quality health-care. Clearly, the Directive needs to be adapted to accommodate the infrastructure and diversity of nonprofit academic centres, and only with appropriate complementary measures and financing from the European Commission, along with considerate incorporation in to national laws,
will non-profit European clinical research centres find themselves internationally competitive. Mahasti Saghatchian and Thomas Tursz Organisation of European Cancer Institutes, Institut Gustave Roussy, Villejuif, France.
Cancer Research UK says . . . Academia, patient groups, and industry have all voiced substantial criticism of the ‘Clinical Trials’ Directive (2001/20/EC). The publicfunders of clinical trials have been particularly incensed by what they see as legislation reducing patient access to high-quality trials. The cost of implementing this legislation will increase the cost of trials without any discernible improvements in patient safety. And, unlike industry, which will simply increase drug prices to cover the new costs, public-funders will have to find the additional money from existing budgets. Responses to the UK’s consultation on national legislation (MLX 287) implementing this Directive have identified serious problems, many of which were entirely foreseeable.2 The Directive’s definition of a trial sponsor is one of the most serious treats to European clinical studies because it is commercially driven. It fails entirely to recognise a partnership, characteristic of most publicly funded trials, in which the funder, host institution, and chief investigation, data monitoring, and trial steering committees cooperate to ensure highquality patient protection and science. As Françoise Meunier and colleagues explain in the commentary above, the potential to increase the amount of data reporting for clinical trials using licensed chemotherapy drugs is considerable and, moreover, simply not justified. Likewise, the requirements on safety-data reporting will not decrease patient risk in many oncology trials. For instance, the requirement for annual reports to be sent to a “competent authority” and the lead ethics committee for all serious adverse reactions is simply meaningless data in academic studies using licensed drugs. Causality is extremely hard to judge in
THE LANCET Oncology Vol 4 December 2003
http://oncology.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
authorisation, and extensive documented follow-up data from clinical practice is known thus negating the need for repetition of safety profiling as dictated by the new Directive. Without a doubt, minimising the risk is essential in any trial. The Directive aims to do this with a set of guidelines defining the content of a dossier that must accompany any request for clinical trial approval, manufacturing and labelling of investigational medicinal products, and notification of adverse events. Is the protection of patients and other study participants really improved by insisting on a heavy dossier full of information previously assessed by other authorities or by insisting on additional preclinical testing of drugs routinely used in medical practice? To insist that trials using commercially available drugs would need to be repackaged and relabelled introduces a process that investigators and academic organisations may not be able to fulfil. Furthermore, if the provision of investigational medicinal products for free by the sponsor is enforced, many trials run without the involvement of the pharmaceutical sector will be stopped in their tracks. Another concern for academic organisations is the increased administrative burden related to safety reporting. The Directive will force sponsors to introduce databases for efficient collection and analysis of safety information to provide detailed annual reports to various authorities. In addition, the ability to do expedited electronic reporting of Serious Unexpected Suspected Adverse Events could be a problem for some academic organisations. Indeed, the value of increasing the amount of reporting of such events, together with the perceived duplication of information submitted to various authorities and ethics committees, is questionable. Increasingly, academic research relies on international collaborations to ensure accrual targets are met in a timely fashion. This ‘intergroup’, often co-sponsored, approach strengthens national efforts by establishing an international network of excellence
and has proved particularly effective for clinical research investigating treatments for rare diseases and targeted therapies. The Directive’s definition of a sponsor leaves room for doubt over whether international cosponsorship could also mean coliability. The obligation of the sponsor to provide insurance or indemnity to cover the liability of the sponsor and the investigator is perfectly reasonable, however, if the sponsor has to accept liability for areas beyond its control, as would be the case in an intergroup trial involving international cooperation and different national laws, many academic organisations will not be prepared to take the risk. If we assume that a sponsor, such as an academic organisation, does actually have the organisational framework to fulfil the above criteria there will be other substantial associated costs. Multicentre, international trials may be jeopardised because it may be difficult for regulatory authorities and ethics committees to waive processing fees for academic clinical trials. Some academic organisations have estimated that overall costs will increase by a factor of four. And it is unlikely that money made available to academic organisations by their stakeholders will increase following the introduction of the Directive. If anything, the involvement of the pharmaceutical sector in helping to finance some areas of academic research may well decrease because of a reluctance to risk being defined as a sponsor if they provide funding or study drugs to an academic trial. So how will academia cope? Some academic organisations will not be able to withstand the impact of Directive 2001/20/EC. Others will be able to accommodate the new requirements, but will be forced to decrease their clinical research activities. May, 2004, is still a few months away but already The European Organisation for Research and Treatment of Cancer (EORTC) has seen an increase in the amount of administration associated with initiating and running clinical trials in a number of EU Member
http://oncology.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
717
Reflection & Reaction States without any notable improvement in patient safety. The run-up to May, 2004, will be a crucial period of time. With the exception of Denmark, most EU Member States have not yet published their new legislation incorporating Directive 2001/20/EC. It is difficult to estimate the true effect of the Directive until the wording of each country’s legislation becomes known but the Directive does leave some room for interpretation in certain areas and this in itself leaves hope that Member States will be able to introduce clauses favourable to academia. The future of academic research in Europe, and significant progress in patient care, is now largely in the hands of the national legislators. Françoise Meunier, Nathalie Dubois, Anastassia Negrouk, and Lesley-Ann Rea European Organisation for Research and Treatment of Cancer (EORTC), Brussels, Belgium.
Organisation of European Cancer Institutes says . . . When integrated in to the national laws governing member states of the European Union in May, 2004, European Directive 2001/20/EC aims to provide a general framework for good clinical practice in trials that test medicinal products for human use. The objective of the Directive is fundamental: the protection of study participants. Indeed, such an aim requires strict rules, defined procedures, and harmonisation in the European Research Area. And importantly, the Directive will introduce essential concepts: more professional and powerful ethics committees; authorisation of clinical trials following a thorough process of assessing the risks and benefits for trial participants; special consideration for paediatric trials; and, the establishment of a European database allowing real-time monitoring of clinical research. The Directive was inspired by the Loi Huriet (a French law requiring organisers of clinical trials to obtain informed consent from all participants), but it also attempts to combine many regulatory requirements
718
specific to other EU countries. Consequently, it introduces administrative procedures, infrastructure requirements, and financial commitments that many academic units will find challenging. Indeed, the large number of requirements is simply unrealistic in many academic settings. Understandably, it has become a major concern for research clinicians. The Directive seems tailored entirely for clinical research sponsored by industry and its implementation will require a gigantic step for those EU countries without strict clinical trial regulations. Undeniably, regulations governing clinical trials in Europe would benefit from harmonisation, but their implementation should be done in a way that is feasible for all countries and interested parties. Otherwise, clinical research in academic centres will be jeopardised: some countries may become totally deprived of such research, both nationally and through international collaboration—despite a growing need for better integration of the European research community. The objective of the Enterprise Directorate-General will not be achieved by this Directive because industry-sponsored trials will simply move to non-EU countries; a trend that is already evident. With academia unable to sponsor trials and industry moving elsewhere, will any clinical research survive in the EU? It is likely that the numbers of European trials will not only decrease but also large research centres might find difficulties sponsoring strategy-oriented studies. As a general framework to provide safeguards protecting patients enrolled in marketing-oriented trials, the Directive is an important piece of legislation. But, if implemented in its current form, the limitations on innovation and the ability for all academic centres to do clinical research will negatively effect long-term provision of high-quality health-care. Clearly, the Directive needs to be adapted to accommodate the infrastructure and diversity of nonprofit academic centres, and only with appropriate complementary measures and financing from the European Commission, along with considerate incorporation in to national laws,
will non-profit European clinical research centres find themselves internationally competitive. Mahasti Saghatchian and Thomas Tursz Organisation of European Cancer Institutes, Institut Gustave Roussy, Villejuif, France.
Cancer Research UK says . . . Academia, patient groups, and industry have all voiced substantial criticism of the ‘Clinical Trials’ Directive (2001/20/EC). The publicfunders of clinical trials have been particularly incensed by what they see as legislation reducing patient access to high-quality trials. The cost of implementing this legislation will increase the cost of trials without any discernible improvements in patient safety. And, unlike industry, which will simply increase drug prices to cover the new costs, public-funders will have to find the additional money from existing budgets. Responses to the UK’s consultation on national legislation (MLX 287) implementing this Directive have identified serious problems, many of which were entirely foreseeable.2 The Directive’s definition of a trial sponsor is one of the most serious treats to European clinical studies because it is commercially driven. It fails entirely to recognise a partnership, characteristic of most publicly funded trials, in which the funder, host institution, and chief investigation, data monitoring, and trial steering committees cooperate to ensure highquality patient protection and science. As Françoise Meunier and colleagues explain in the commentary above, the potential to increase the amount of data reporting for clinical trials using licensed chemotherapy drugs is considerable and, moreover, simply not justified. Likewise, the requirements on safety-data reporting will not decrease patient risk in many oncology trials. For instance, the requirement for annual reports to be sent to a “competent authority” and the lead ethics committee for all serious adverse reactions is simply meaningless data in academic studies using licensed drugs. Causality is extremely hard to judge in
THE LANCET Oncology Vol 4 December 2003
http://oncology.thelancet.com
For personal use. Only reproduce with permission from The Lancet.