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The EU’s newest draft legislation contains GCP rules that somehow aren’t already law.
The EU's newest draft legislation contains GCP rules that somehow aren't already law.
Almost 15 years ago, European Union officials started work on new clinical trials rules that would govern not only on how medicines were to be tested, but also on the requirements for the medicines. This summer, what may be the final elements of the draft legislation appeared at long last?and it covers much more than investigational products. It's taking some time, but inch by inch the EU is getting there.
The new text is a draft European Commission rule "laying down principles and detailed guidelines for good clinical practice as regards investigational medicinal products for human use, as well as the requirements for authorisation of manufacturing or importation of such products."1
This is another of the long-awaited pieces of secondary legislation implementing the 2001 clinical trials directive2 and the Council of 4 April 2001. It addresses the laws, regulations, and administrative provisions of the Member States relating to the implementation of good clinical practice (GCP) in the conduct of clinical trials on medicinal products for human use.3
It will, when finalized, give shape to the directive's requirements which state that principles of GCP and minimum standards shall apply to the authorization of manufacture and import of investigational products. Manufacturing requirements have already been laid down in another piece of secondary EU legislation4 regarding medicinal products and investigational medicinal products for human use.5 But because the general EU rules on authorization of pharmaceuticals (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 use6) does not cover medicines intended for research and development trials, the EU wants to establish minimal requirements to guarantee the quality of investigational products used in clinical trials. So the draft text covers applications for authorizations to manufacture and/or import investigational products, the management of applications, and the granting and the content of the authorizations.
Flexibility for noncommercial trials
Special provision has been made to ease requirements for noncommercial clinical trials, following intensive lobbying by the nonprofit sector.7 As the new text notes, a trial conducted by researchers without the participation of the pharmaceutical industry "may be of great benefit to the patients concerned." When non-commercial clinical trials are conducted with authorized products and on patients with the same characteristics as those covered by the indication, manufacturing or importation requirements already fulfilled by the authorized products are to be taken into consideration.
Furthermore, EU countries may choose to apply "specific modalities"?Eurospeak, in this case, for a more flexible approach?to these trials even when the patients do not necessarily have the same characteristics, "due to the specific conditions under which non-commercial trials are conducted...in particular as far as the manufacturing or import requirements for authorisation and the documentation to be submitted and archived for the trial master file are concerned." To justify this exception, the text acknowledges that "the conditions under which the non-commercial research is conducted by public researchers and the places where this research takes place make the application of certain of the principles of good clinical practice unnecessary or guaranteed by other means."
There is another area of flexibility, too. The regulatory authorities in the EU "may also take into account the special position of the trials whose planning does not require particular manufacturing or packaging processes." Labeling of investigational medicinal products intended for trials of this nature may be subject to simplified provisions.
The new rule is extensive and detailed. But its essence is that an authorization to manufacture or import investigational products will be required for both total and partial manufacture, and for processes of dividing up, packaging, or presentation?even if the products manufactured are intended for export. Authorization will also be required for imports from non-EU countries. This authorization will not, however, be required where pharmacists in dispensing pharmacies are carrying out the preparation, dividing up, or changing of packaging and presentation solely for retail supply.
The authorization application has to provide details of the product and pharmaceutical forms; the relevant manufacture or import operations and, where relevant, the manufacturing process; the suitability of the premises and equipment at the place of manufacture or import; and staff qualifications. And the nonclinical and clinical information available on an investigational product "shall be adequate to support the proposed clinical trial."
Wider than investigational products
This new piece of draft legislation does more than merely set out product-related rules, however. It insists that trials with investigational products for human use must comply with the international principles and the EU guidelines relating to GCP in their design, conduct, and reporting. It is also the vehicle for detailed EU guidance complementing the outline of the general EU rule on clinical trials8?a sort of mopping-up exercise for a number of areas where industry, the EU, and the clinical trials community had all been looking for clarification.
The text reiterates many of the familiar concepts underlying GCP-qualified staff, scientifically sound and ethically well-defined trials, quality assurance, data management. And it puts an emphasis on the individual?for instance, "the rights, safety and interests of the trial subjects shall prevail over those of science and society." But it also extends the existing EU legislation on matters ranging from archiving to qualifications of inspectors and inspection procedures.
Regarding ethics committees, for instance, the new text recalls the duty on each committee to adopt rules of procedure to meet the 2001 directive. It requires committees "in every case" to retain the essential documents on each clinical trial for at least three years after its completion. And it obliges regulatory authorities to set up "appropriate and efficient systems" for communication of information with ethics committees.
Similarly, for sponsors, it provides for delegation of "any or all of his trial-related functions to an individual, a company, an institution or an organisation," but makes clear that "the sponsor shall remain responsible for ensuring that the conduct of the trials and the final data generated by those trials" comply with the clinical trials directive. And it adds the clarification that "the investigator and the sponsor may be the same person."
On the investigator's brochure, it demands a presentation which is "concise, simple, objective, balanced and non-promotional," in a form "that enables a clinician or potential investigator to understand it and make an unbiased risk-benefit assessment of the appropriateness of the proposed clinical trial."
Details are also provided on the Trial Master File, defined as the essential documents which enable evaluation of both the conduct of a clinical trial and the quality of the data produced.
The sponsor and the investigator are required, in every case, to retain the essential documents for at least five years after completion of a trial, "in a way that ensures that they are readily available, upon request, to the competent authorities." Trial subjects' medical files "are to be retained in accordance with national legislation and in accordance with the maximum period of time permitted by the hospital, institution or private practice."
Inspecting the inspectors
But perhaps the most extensive complementary regulation relates to the processes of inspection. The nature of some of this draft legislation speaks volumes about some of the difficulties that the pharmaceutical industry and clinical trials professionals have been running into in the past?and fear they may run into even more in the future. Incredible as it may seem, the EU is only now attempting to require that clinical trials inspectors should know anything at all about what they are inspecting!
The section on qualifications of member states' inspectors says that they will have to be suitably qualified and experienced in medicine, pharmacy, pharmacology, toxicology, or other relevant fields, and receive appropriate training within systems that "maintain and improve their skills."
At the same time, demonstrating how little this has been guaranteed so far, inspectors are to be provided with means of identification, and will have to be "made aware of and maintain confidentiality whenever they gain access to confidential information as a result of good clinical practice inspections."
Each EU country will have to establish a legal and administrative framework within which its GCP inspections operate, which will define inspectors' powers for entry into clinical trial sites and access to data. And it is the responsibility of each individual state to provide sufficient inspection resources and appoint enough inspectors so that compliance with GCP is adequately checked.
Now, 15 years after the idea was sown, many of the EU's clinical trials rules have been adopted, and some have been implemented. But not all of the necessary legislative texts are in place?as this latest proposal demonstrates. Over the coming months, in the light of comments received on this proposal, EU officials will formalize this text'or something like it. And then there will be a further six months before it comes into effect across the 25 EU member states. So until then, in theory at least, the compliance of clinical trials with GCP could continue to be assessed by national officials with no training, no knowledge of medicine or medicine development, and nothing to stop them telling everyone they know about whatever they found at the latest inspection they carried out.
1.http://pharmacos.eudra.org/F2/pharmacos/news/DirectiveGCP20040614.pdf2. Directive 2001/20/EC of the European Parliament.3. EU Official Journal L 121, 1.5.2001, p. 34.4. Commission Directive 2003/94/EC of 8 October 2003.5. EU Official Journal, L 262, 14.10.2003, p. 22.6. EU Official Journal, 311, 28.11.2003, p. 67.7. P. O'Donnell, "View from Brussels," Applied Clinical Trials (April 2004). 8. Directive 2001/20/EC.