Need More EU Rules? Here's Another One

It may be known as "the old continent," but Europe sure as hell comes up with plenty of new rules. And as another old year blends into a new year, the international clinical trials community can look forward to plenty of regulatory novelty from Brussels.

For instance, anyone manufacturing investigational products in Europe-or doing trials with them there-has just a couple of months now to modify their operating systems if they want to avoid trouble with the new European Union rules for investigational medicines.1

Peter O'Donnell

EU member states are to bring these rules into force by 30 April 2004 at the latest. The new rules represent yet another small step in the EU's long and sometimes painful journey towards a harmonized framework for medicines and clinical trials. The foot soldiers of the clinical trials community might also be excused for feeling occasionally bruised by this relentless onward march.

This new milestone along the route is an update of good manufacturing practice (GMP), but with a particular focus on the new EU obligations on clinical trials,2 which provided for detailed guidance to be drawn up on the evaluation of investigational medicines for human use within the EU.

So, the EU has extended and adapted its existing provisions on GMP3 to cover GMP of investigational products, and most of the changes relate directly to this new area of regulation. The new rules also tighten up on GMP for authorized products, too (see sidebar).

But of most direct interest to readers of this publication, the new rules contain provisions explicitly "in order to protect the human beings involved in clinical trials." When investigational products are imported from outside the EU, "the importer shall ensure that the products have been manufactured in accordance with standards which are at least equivalent" to EU standards, and that the products "have been manufactured by manufacturers duly authorized to do so." In particular, "An importer of investigational medicinal products shall ensure that such products have been manufactured by a manufacturer notified to the competent authorities and accepted by them for that purpose."

For investigational products, the manufacturer is to ensure that all manufacturing operations are carried out in accordance with the information provided by the sponsor, in line with the requirements of the 2001 Clinical Trials Directive. And he or she must regularly review his or her manufacturing methods in the light of scientific and technical progress and the development of the investigational product.

Updating EU GMP Rules

The emphasis on training in the new rules, particularly on "the theory and application of the concept of quality assurance and good manufacturing practice," makes specific reference to "the particular requirements for the manufacture of investigational medicinal products."

To make sure the entire process can be effectively inspected, established procedures for general manufacturing operations and conditions are going to have to be kept available, together with specific documents for the manufacture of each batch. Those documents will provide the history of the manufacture of each batch and of any changes introduced during the development of an investigational medicinal product.

The rules on batch documentation are more demanding for investigational products than for authorized products. Batch documentation for authorized medicines will normally have to be retained for at least one year after the expiration date of the relevant batches, but in some circumstances this obligation may run to as much as five years. But for investigational products, "the batch documentation shall be retained for at least five years after the completion or formal discontinuation of the last clinical trial in which the batch was used." The sponsor (or, if different, the marketing authorization holder) will be responsible for ensuring that records are retained as required for marketing authorization.

Prescribing production rules

Production must be in line with pre-established instructions and procedures, with adequate in-process controls. All process deviations and product defects must be documented and thoroughly investigated, and appropriate technical or organizational measures shall be taken to avoid cross-contamination and mix-ups. In the case of investigational products, "particular attention shall be paid to the handling of products during and after any blinding operation."

The manufacturing process for investigational products "shall be validated in its entirety in so far as is appropriate, taking into account the stage of product development." At least the critical process steps, such as sterilization, must be validated. And all steps in the design and development of the manufacturing process must be fully documented.

A quality control system, under the authority of a qualified person independent of production, and with appropriately staffed and equipped testing laboratories, must be established. If a contract laboratory is used for investigational products, the sponsor must ensure that the contract laboratory complies with EU rules.

During the final control of the finished product before its release for sale or distribution or for use in clinical trials, the quality control system shall take into account, in addition to analytical results, essential information such as the production conditions, the results of in-process controls, the examination of the manufacturing documents, and the conformity of the product to its specifications, including the final finished pack.

Samples of each batch of finished medicinal product shall be retained for at least one year after the expiration date. For an investigational medicinal product, sufficient samples of each batch of bulk-formulated product and of key packaging components used for each finished product batch shall be retained for at least two years after completion or formal discontinuation of the last clinical trial in which the batch was used, whichever period is longer.

And there are specific provisions on the labelling of investigational products. "Labelling shall ensure protection of the subject and traceability, to enable identification of the product and trial, and to facilitate proper use of the investigational medicinal product."

Elaborate arrangements for product recall are required. The manufacturer of investigational products must, in cooperation with the sponsor, "implement a system for recording and reviewing complaints together with an effective system for recalling promptly and at any time investigational medicinal products which have already entered the distribution network. The manufacturer shall record and investigate any complaint concerning a defect and shall inform the competent authority of any defect that could result in a recall or abnormal restriction on supply." All trial sites must be identified and, in so far as is possible, the countries of destination must be indicated. And if the investigational product already has a marketing authorization, the manufacturer, in cooperation with the sponsor, must inform the marketing authorization holder of any defect that could be related to the authorized product.

The sponsor must also implement a procedure for the rapid unblinding of blinded products-where this is necessary for a prompt recall-but the procedure must disclose the identity of the blinded product only in so far as is necessary.

From tactics to strategy

While the detailed regulations gradually fall into place on the more technical aspects of clinical trials-the tactics, as it were, of regulation-the European Union is also still deep in the throes of creating a new strategic framework for its pharmaceutical legislation, covering everything from the organization of the European Agency for the Evaluation of Medicinal Products (EMEA) to the handling of pharmacovigilance and the protection of intellectual property. This is a slow-moving process, which has been underway since 2000. This column last offered an update in the middle of last year (ACT, July 2003), and the exercise is still far from completed.

However, as 2003 drew to a close, at least one aspect of this huge debate was drawing attention to the significance of clinical trials. Much of the discussion in Brussels polarized around a high-profile dispute between the innovative pharmaceutical industry and generic manufacturers over access to data.

Regulatory data protection-an innovator's right to prevent copying of the information generated to support an application for marketing authorization-is "vital to stimulate research for the benefit of patients," insisted the European Federation of Pharmaceutical Industries and Associations (EFPIA), as EU legislators argued over how long an innovator should be able to keep a generic copier off its back.

And the European biotechnology industry association, EuropaBio, warned that any reduction in intellectual property protection in Europe would have a damaging effect on the European pharmaceutical industry as a whole. According to its secretary general, Hugo Schepens, intellectual property protection is "the lynchpin" of the current debate on pharmaceutical regulation-and the calls for cuts in protection coming from some parts of the EU legislative machinery must be resisted. "We can't accept that protection is cut back," he said.

What most of the debate comes down to is at what point generic firms should be entitled to make reference to an innovator's clinical trials data to support a marketing authorization application for a copy product. Hawks among the innovator camp want a blanket 10-year period of protection for such data (with the possibility of extensions to 11 years where new indications are found). Generic firms should be required to carry out adequate safety and efficacy testing themselves-particularly for biological or biotechnology-derived products. Preclinical tests and clinical trials are essential to demonstrate product safety and efficacy, EFPIA says, since "Biological medicinal products are not the same as chemical medicinal products and cannot be treated the same. Since they are very complex entities, even small differences in their physicochemical nature or production process can result in major differences in their biological properties...such differences could result in a loss of efficacy and/or emergence of clinical safety issues and therefore become a threat to public health."

Meanwhile, the hawks among the copyist camp say that three years is more than enough time for innovators to make profits out of exclusivity over such data. The European Generic Medicines Association rejects the innovative industry's calls for "restrictive changes to the definitions of a generic medicine and a bio-similar medicine, restrictions on the manufacturing of generic medicines in contradiction to current practice in international patent law," and "special protection periods for products." And it accuses big pharmaceutical firms of pushing for additional amendments "which would further increase the period of time generics must wait before authorization."

The end of 2004 should see a conclusion to this debate-and to the debates on the other issues in this major overhaul of the EU pharmaceutical framework. And you know what that means: more new rules!

1. Commission Directive 2003/94/EC laying down the principles and guidelines of Good Manufacturing Practice in respect of medicinal products for human use and investigational medicinal products for human use

2. Directive 2001/20/EC of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use.

3. Directive 91/356/EEC.