Filling in the EU Gaps on Clinical Trials Rules

The European Union is beginning to provide details about how it expects the pharmaceutical industry to meet the requirements of its clinical trials directive. It has released a series of consultation documents on good manufacturing practice and authorizations for manufacturers and importers of investigational medicinal products. At the same time, and separately, it has announced the requirements for its new common technical document for all applications for marketing authorizationwith extensive details of how to manage clinical trials data.

The gaps in the European Union rules about clinical trialsfor many months a subject of serious concern to the European pharmaceutical industryare starting to be filled in. Recently a series of drafts have emerged from the EUs internal consultation machinery into the public arena. The people who actually conduct clinical trials now have the opportunityuntil the end of Julyto give their views on whether these proposals make sense. The proposals cover good manufacturing practice for investigational medicinal products, authorizations to manufacture or import investigational medicinal products, and the format and contents of the application for such authorizations.

The gaps exist because the EUs clinical trials directive¹ left some key areas open to further definition when it was adopted. EU regulatory authorities have conducted lengthy consultations about how to phrase these refinements. All the while the deadline for implementation of the new directiveJune 2004is getting closer. So, with no time to lose, what do the draft new rules say?

GMP for clinical trials
The proposal for a Commission directive amending the 1991 EU rules for GMP² emphasizes that all medicines for human use manufactured or imported into the EU must be manufactured in line with GMP, including investigational medicinal products (IMPs) for use in clinical trials. Manufacturers of IMPs therefore should operate effective quality management of their manufacturing operations, including the implementation of a pharmaceutical quality assurance system. Officials from the competent national authorities will report on compliance, and these reports are to be available to other national authorities in the EU. In addition, the manufacturer or importer must regularly review its manufacturing methods in the light of scientific and technical progress and the development of IMPs.

The draft includes plenty of detail about personnel, premises and equipment, documentation, production, quality control, contracting out, complaints and product recall, and self-inspection.

For instance, the function of quality control is to be established and maintained distinct from other functions and placed under the authority of a person who has the required qualifications and is independent of production. The quality control department must have quality control laboratories that are appropriately staffed and equipped to carry out the necessary examination and testing of starting materials, packaging materials, and intermediate and finished products. Contracting out may be permitted, but only to duly authorized laboratories. The manufacturer or importer must ensure that all manufacturing operations subject to an authorization for marketing are carried out in accordance with the information given in the application for marketing authorization as accepted by the competent authorities or in accordance with the information given by the sponsor. Each manufacturing site or site of importation must have competent and appropriately qualified personnel in sufficient number to achieve the pharmaceutical quality assurance objective.

Manufacturers or importers also must use a system of documentation that is based upon specifications, manufacturing formulae, processing and packaging instructions, procedures, and records covering the various manufacturing operations that they perform. According to the clinical trials directive, documents shall be clear, free from errors, and kept up to date. Preestablished procedures for general manufacturing operations and conditions shall be available, together with specific documents for the manufacture of each batch. This set of documents shall make it possible to trace the history of the manufacture of each batch and, where appropriate, the changes introduced during the development of the investigational medicinal product. For a medicinal product, the batch documentation shall be retained for at least one year after the expiry date of the batches to which it relates or at least five years after the certification.

Batch documentation must be retained for at least five years after the completion or formal discontinuation of a trial. Sufficient samples of each batch of bulk formulated products and of the packaging components used for each finished product batch must be retained by the manufacturer or importer for at least two years after completion or formal discontinuation of the clinical trial, whichever is the longer. However, in certain cases (for example, products manufactured individually or in small quantities or whose storage could raise special problems), other sampling and retaining conditions may be defined in agreement with the competent authority.

The use of electronic, photographic, or other data processing systems instead of written documents requires validation and proof that the data will be appropriately stored during the anticipated period of storage. Data stored by these systems shall be made readily available in legible form and shall be provided on demand to the competent authorities.Manufacturers/importers/sponsors are obligated to institute systems for recording and reviewing complaints and for prompt recall at any time during which IMPs are distributed for use in a clinical trial. Any complaint concerning a defect, as well as details of the centers and countries of destination, must be recorded, investigated, and reported to the competent authority if it could result in a recall. Comparator products must also be included in this system. And the sponsor must maintain and, when necessary, implement a procedure for the rapid identification of blinded products in an emergency. The procedure may not permit undetectable breaks of the blinding. Labeling must ensure protection of the subject and traceability, allow identification of the product and trial, and facilitate proper use of the product.

The drafts text also creates new definitions:

• Blinding, in relation to the labeling and packaging of an investigational medicinal product, shall mean the deliberate disguising of the identity of the product in accordance with the instructions of the sponsor. Unblinding shall mean the disclosure of the identity of blinded products.
• Investigational medicinal product shall mean a pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial, including products already with a marketing authorization but used or assembled (formulated or packaged) in a way different from the authorized form, or when used for an unauthorized indication, or when used to gain further information about the authorized form.

Applying for authorization for IMPs
The new draft guidance on obtaining an authorization to manufacture or import IMPs describes the requirements to be met. As with most EU rules, the obligations are in fact placed on the member states rather than on the companies involved. The Commissions proposed text makes it the responsibility of the member states to take all appropriate measures to ensure that the manufacture or import of IMPs is subject to authorization, even when the products are intended for export. The authorization covers both total and partial manufacture and the various processes of dividing up, packaging, or presentation (although changing the packaging of investigational medicinal products in hospitals, health centers, or clinics where the IMP is to be used may be exempted).

Applications must specify the products to be manufactured or imported, the operations concerned, the manufacturing process, and the place where these products are to be manufactured and/or controlled. The applicant must be able to demonstrate suitable and sufficient premises, technical equipment and control facilities as well as the services of at least one qualified person, and the member state must verify these details. The time limit in which member states must complete the processing of applications must not exceed 90 days from the day on which the competent authority receives the application. When the holder of an authorization requests a change in any of the details supplied, the time taken for the procedure relating to this request must not exceed 30 days (or, in exceptional cases, 90 days).