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For the EU, these new good clinical practice rules come not from Brussels, but Mt. Sinai.
The showers that swept across Europe in April brought out more than daffodils. The spring also saw the birth of what amounts to a new European Union bible on good clinical practice (GCP), in the shape of administrative rules governing the conduct of clinical trials.
The new rules1 give substance to some of the key principles set out in the EU's 2001 directive on clinical trials.2 Their impact will be felt indirectly as well as directly by the industry. As is normal for this type of legislation, the obligations are imposed primarily on the EU's member states. It is these 25 member states' regulatory authorities who will have to make sure that industry and researchers comply at local level (or 27 states starting in 2007, when Bulgaria and Romania will join the EU).
The underlying approach is in line with the International Conference on Harmonization's (ICH) 1995 consensus paper on a harmonized approach for GCP, which has already been endorsed by the European Medicines Agency. "Clinical trials shall be scientifically sound and guided by ethical principles in all their aspects," the new rules say. Sponsors, investigators, and other participants will have to take into account the scientific guidelines relating to the quality, safety, and efficacy of human use medicines as laid down in the EU's extensive rules governing medicinal products.
The overall objective is nobly linked to the good of the patient or subject. Notably, the new rules make clear that the principles and guidelines for good clinical practice should be such as to ensure that the conduct of clinical trials on investigational medicinal products is founded in the protection of human rights and the dignity of the human being. The safety and the protection of the rights of trial subjects should be ensured at all times, the new rules say. "The rights, safety and well being of the trial subjects shall prevail over the interests of science and society," they insist unambiguously. They also specify in particular that protection of individuals who are incapable of giving their informed consent should be extended to cover individuals temporarily incapable of giving their informed consent, such as in emergency situations. And the duty to protect subjects is itself extended into ensuring that unnecessary clinical trials are not conducted.
Reinventing the wheel?
Much of the substance of the new text is a codification of what has already become standard practice for much of the clinical trials community. Ensuring that information on an investigational product is adequate to support the proposed trial, that trials are conducted in accordance with the Helsinki Declaration, and specifying inclusion and exclusion criteria in the trial protocol is established in the new text. There is a strong sense of dj vu in the provisions that where sponsors delegate trial-related functions, they still remain responsible for the conduct of the trials and the final data, or that the information in the investigator's brochure must be "concise, simple, objective, balanced and non-promotional."
Most surprisingly, four years after the EU's GCP directive and 14 years after the EU started planning its approach to GCP, the new rules say there is still "a need to define principles and detailed guidelines of good clinical practice." In fact, the new rules tend largely to restate what has already been stated elsewhere in other EU requirements on pharmaceuticals. This is less a matter of reinventing the wheel, and more a question of defining more precisely the characteristics of the wheel.
So in addition to the priority given to the protection of trial subjects, most of the other elements in this refinement are related to quality and ensuring compliance with quality requirements. There is insistence on allowing the results of the trials to be documented for use in a later phase. There is emphasis on the duty to ensure that all experts and individuals involved in the design, initiation, conduct, and recording of clinical trials apply the same standards of good clinical practice. "Each individual involved in conducting a trial shall be qualified by education, training, and experience to perform his tasks," it reads. And the importance of meticulous observance of operating procedures is underlined, so "the necessary procedures to secure the quality of every aspect of the trials shall be complied with."
Ethics committee aspirations
The new rules aim to bring some order to the current diversity--and occasional anarchy--of ethics committee review across the EU. The proposed measures, though, are only the broadest of brush strokes and are hardly likely to overcome the persistent differences in approach from committee to committee and country to country. The new bible says little more than provisions for the functioning of ethics committees should be established in each member state on the basis of common detailed guidelines in order to ensure the protection of the trial subject. It does urge that these provisions should allow for "harmonised application in the different member states"--but that is little more than the expression of a pious hope, rather than a clear instruction. Elsewhere, the new bible demands little else of ethics committees other than that they shall adopt relevant rules of procedure, retain the essential documents relating to every clinical trial for at least three years, and assure the flow of information to and from the competent authorities.
Filling the gap on investigational products
A long-standing regulatory gap is also plugged by these new rules. The general EU rules on medicines, as last updated in 2004,3 impose conditions on the supply of authorized medicines, but none on the supply of products intended for research and development trials. So, the EU has now remedied this deficiency. There are now minimal requirements regarding applications for and management of authorizations to manufacture or import investigational medicinal products, as well as for the granting and the content of the authorizations, in order to guarantee the quality of the investigational products used in clinical trials.
Authorization is required for total or partial manufacture of investigational products, and for dividing up, packaging or presentation, even if the products are intended for export. It will not be required for reconstitution prior to use or packaging if this is done in hospitals, health centers or clinics by pharmacists or qualified persons.
The national competent authority issues the authorization for manufacturing or importing investigational products after its agents have verified the accuracy of the applicant's particulars. They have a maximum of 90 days to do it. And member states are required to ensure compliance with all the conditions imposed on trials, including sending in their inspectors. They will be obliged to suspend or revoke authorizations if there is any failure in compliance.
Relief for noncommercial trials
In parallel to the reinforcement that the new rules bring, there is also explicit recognition that excessive regulation may be counterproductive or excessively prudent for noncommercial clinical trials. This response to energetic lobbying by many research institutes and organizations makes some generous concessions to them. Noncommercial clinical trials conducted by researchers without the participation of the pharmaceutical industry "may be of great benefit to the patients concerned," the new rules concede. So when non-commercial trials are conducted with authorized medicines and on patients with the same characteristics as those covered by the authorized indication, it should be possible to simply make reference to the manufacturing or importation requirements already fulfilled by these authorized products.
The generosity goes further. The new rules encourage member states to "foresee specific modalities"--which translates into making additional concessions for noncommercial trials. Noncommercial trials are often not being conducted with authorized products and on patients with the same characteristics. Given the "specific conditions under which they are conducted," member states could disregard some of the other rules for these trials, such as the manufacturing or import requirements for authorization and the documentation to be submitted and archived for the trial master file. The reasoning is that some of the details of good clinical practice will not need to be applied in the conditions under which noncommercial research is conducted by public researchers. And in the places where this research takes place, the principles are "guaranteed by other means."
There is also some scope for easing labeling requirements. Simplified provisions may be applied to investigational products intended for trials whose planning does not require particular manufacturing or packaging processes. They could be carried out with products with marketing authorizations, manufactured or imported in accordance with EU rules, and conducted on patients with the same characteristics as those covered by the indication specified in the marketing authorization. But the process will be carefully controlled: member states will have to inform the Commission and the other member states of any specific measures they take in this respect.
Key roles for inspectors and experts
To make sure everything covered by the new rules is not only done, but witnessed, a more detailed legal framework is created for inspections--and inspectors. "To secure the compliance of clinical trials with the provisions on good clinical practice, it is necessary that inspectors ensure the practical effectiveness of such provisions. It is essential therefore to provide detailed guidelines on the minimum standards for the qualification of inspectors, in particular as regards their education and training. For the same reason, detailed guidelines on inspection procedures, in particular on the cooperation of the various agencies, and the follow-up to the inspections, should be laid down," the new rules say.
Member states shall ensure that inspectors receive appropriate training, that their training needs are assessed regularly, and that appropriate action is taken to maintain and improve their skills. In order to ensure the presence of skills necessary for specific inspections, they may appoint teams not only of inspectors, but also additional experts with appropriate qualifications and experience. This way, they can collectively meet the requirements necessary for conducting adequate inspections.
This new bible is not up for discussion--even if some of its elements will themselves require further detailed guidelines from the EU. It is now established fact: it appeared in the EU's official journal on 9 April, and member states are required to bring into force "the laws, regulations and administrative provisions" necessary to comply with it by 29 January 2006 at the latest.
1. Commission Directive 2005/28/EC, 8 April 2005, European Commission, Brussels; http://pharmacos.eudra.org/F2/eudralex/vol-1/DIR_2005_28/DIR_2005_28_EN.pdf.
2. Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 European Union, OJ L 121, 5 January 2001, p. 34.
3. Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use, OJ L 311, 28 November 2003, p. 67, and amended by Directive 2004/27/EC; OJ L 136, 4 April 2004, p. 34.
Sidebar: The Trial Master File and Archiving
The essence of the new rules on documentation are as follows:
The trial master file shall consist of essential documents which enable both the conduct of a clinical trial and the quality of the data produced to be evaluated. Those documents shall show whether the investigator and the sponsor have complied with the principles and guidelines of good clinical practice and with the applicable requirements. The trial master file shall provide the basis for the audit by the sponsor's independent auditor and for the inspection by the competent authority. The content of the essential documents shall be in accordance with the specificities of each phase of the clinical trial.
The sponsor and the investigator shall retain the essential documents relating to a clinical trial for at least five years after its completion. They shall retain the documents for a longer period, where so required by other applicable requirements or by an agreement between the sponsor and the investigator. Essential documents shall be archived in a way that ensures that they are readily available, upon request, to the competent authorities. The medical files of trial subjects shall be retained in accordance with national legislation and in accordance with the maximum period of time permitted by the hospital, institution or private practice.--PO