Separate comments were also received from three of the official bodies of the European Medicines Evaluation Agency, and even the EMEA executive director has responded in person. Other observations have come from a health insurance organization, and from several individuals and companies. The European Commission’s own departments responsible for research, competition, and the EU internal market have also commented.

Incentives are welcomed
All of the comments welcome the Commission’s consultation paper and indicate support for most of the ideas expressed in it. Several of the comments provide ideas on how to expand on the suggestions in a practical manner. All responders recognize the need to take specific regulatory measures to improve the availability of suitable adapted medicines for children. The urgency of promoting clinical trials for medicines for children, and the need to ensure that any framework put in place was underpinned by adequate resources and funding to meet its objectives, were frequently mentioned.

The comments show considerable support for the idea of incentives to encourage the development of new products. Respondents who expressed views on the duration of the market exclusivity provision, which was suggested in the EU consultation paper, recommended that it should last for 12 months. The idea of a “kid marketing authorization” as a mechanism for offering exclusivity was supported in principle—but questions were raised as to whether this would be sufficient to generate the necessary studies.

Patient or health professional associations, with particular interests in specific therapeutic areas, tended to stress the specific needs of children suffering from these diseases—such as eczema or diabetes. Several respondents indicated childhood cancers as priority areas. The need for multidisciplinary involvement in any expert group or pediatric network to include patient support groups, pharmacists, nurses, and parents was emphasized by several respondents. But some respondents expressed concerns that incentives might result in medicines being developed for financial gain, rather than for the benefit of children.

Duplication must be avoided Many of the comments focused on technical aspects of the EU’s outline proposals. Putting mechanisms in place to avoid two companies embarking on the same set of studies was seen as essential. Most respondents underlined the need to improve and disseminate information on medicines authorized in some countries but not in others, and to ensure feedback on empirical success or failures from treatment with unauthorized medicinal products and/or medicinal products used off-label. The development of a central database received significant support. Also highlighted was the need for negative as well as positive results of trials to be made available, as a way to avoid unnecessary trials.

Most respondents stressed the need for specific and adapted pharmacovigilance systems, although most noted the high cost and risk of creating disincentives for industry. Industry respondents tended to recommend targeting these studies carefully. With some exceptions respondents supported establishing a pediatric expert group or committee within the European Medicines Evaluation Agency. However the importance of clearly defining the role and mandate of this group and of allocating sufficient resources for its operation was highlighted. Creating a network of excellence for the performance of pediatric studies, ranging from non-clinical to dose ranging, and from observational to pharmacovigilance, received wide support. Several organizations indicated examples of existing networks which could be integrated or used as models. It was also suggested that such a network could be used to develop specific methodologies.

There were also calls for training needs to be met—and creating a steering committee to manage this was proposed—and for setting up a register of pediatric studies. Several respondents also mentioned the challenge of generating information for pediatric sub-populations, in particular, neonates.

The likely outcome will be the drafting of a formal EU proposal for legislation—but this is unlikely to emerge until sometime in 2003, and could take another two years to be agreed upon and come into effect.

The fate of files
Meanwhile, the EU is pushing ahead with filling in some of the gaps in its new clinical trials rules—the set of rules formally adopted in 2001 (Directive 2001/20/EC), which still needs a series of technical details to be put in place before it can become effective. During June it started consultations on one of the many missing pieces of the jigsaw puzzle by finalizing its proposals for detailed guidelines on the trial master file and archiving.

Not always the most exciting aspect of clinical trials, the question of archiving and retention of documents received a new topicality by the controversy over Enron and the shredding of documents by its auditor, Andersen. This new EU guidance on clinical trials eschews all flamboyance, and makes no reference to the wider world—except for a reminder that storage of personal data is also subject to the relevant parts of the EU rules on data protection (Directive 95/46/EC).

But its deadpan treatment of the question of document destruction nonetheless carries inevitable—if unwitting—resonances of the recent high-profile discussions of when to shred.

The reasons for destruction of essential documents should be documented and signed by a person with appropriate authority. This record should be retained for a further five years from the date that the essential documents were destroyed. The sponsor should notify investigators in writing when their trial records can be destroyed, it intones quietly.

Overall, the new draft EU document provides guidance for sponsors and investigators on requirements on trial master files. Basing itself on the existing EU and ICH definitions of “essential documents” (as the documents which individually and collectively permit evaluation of the conduct of a clinical trial and the quality of the data produced), the new guidance says these documents, which serve to demonstrate the compliance of the investigator, sponsor, and monitor with the standards of GCP and with applicable regulatory requirements, “should be filed in an organized way that will facilitate management of the clinical trial, audit and inspection” to constitute the trial master file.

In line with the existing rules, it spells out that essential documents must be retained (or “archived”) for sufficient periods to allow for audit and inspection by regulatory authorities and should be readily available upon request. The guideline gives details on the minimum set of documents to be retained; the quality of documents to be archived; the minimum standards for storage conditions; media transfer and certified copies, and retention times.

As the guidance notes, existing rules (notably the EU/ICH guidance CPMP/ICH/135/95 on Good Clinical Practice) already define the minimum set of documents to be archived. But it makes particular reference to the investigator site delegation list/log, quality control records, and statements that independent ethics committees are organized and operate in accordance with GCP.

As to quality of essential documents, they should be “complete, legible, accurate, unambiguous, authentic and, as appropriate, certified after verification.” Existing rules also, the new document recalls, state the responsibilities of the sponsor for implementing quality assurance and quality control to assure the quality of essential documents.

The media used to store essential documents should ensure that these documents will be promptly available, complete, and legible throughout the required period of retention. Any alteration to records should be traceable, and particular attention needs to be paid to records stored on electronic, magnetic, optical, or other non-indelible media, in which case suitable controls should be implemented to ensure that these records cannot be altered without appropriate authorization and the creation of an audit trail.

When original records are copied or transferred to other media for archiving, the system of copying or transfer should be validated to ensure that information will not be lost or altered. Copies or transfers should be certified for accuracy and completeness by someone with appropriate authority, as part of the quality control procedure. For media that require processing in order to turn records into a readable format, appropriate equipment must be available so that this processing can be done.

Storage facilities and their maintenance should reflect “relevant EU and national standards,” says the new draft guidance. They should ensure that essential records are maintained in a legible condition and can be retrieved promptly. Any change in the ownership and location of the documentation should be documented in order to allow tracking of the stored records. Adequate and suitable space should be provided for the secure storage of all essential records from completed studies. The facilities should be secure, with appropriate environmental controls and adequate protection from fire, flood, and unauthorized access. The storage of the sponsor’s documentation may be transferred to a subcontractor (such as a commercial archive), but the ultimate responsibility for the quality, integrity, confidentiality, and retrievability of the documents resides with the sponsor.

The function of storage and archiving should be specified and the role assigned to identified archivists. Access to archives should be restricted to authorized personnel. An archive index or log should be maintained by the archivists to record all essential documents that have been entered into the archive, and to track and retrieve documents on loan from the archive.

The investigator should make the sponsor aware of the storage arrangements for the documents. If the investigator becomes unable to store the essential documents, the sponsor should be notified in writing so that alternative storage arrangements can be agreed. Similarly, if the investigator is no longer able to maintain custody of their essential documents, the sponsor should also be notified in writing, and the investigator/institution should see to it that appropriate arrangements can be made.

The documents to be retained by the investigator may be stored in commercial archives. This may also be an option in some member states for source data, when the hospital or institution is unable to retain subjects’ trial records relating to clinical trials for a sufficient length of time.

The sponsor should retain all sponsor-specific essential documents so as to meet all applicable regulatory requirements of the countries where the product is approved, and where the sponsor intends to apply for approvals. If the sponsor discontinues the clinical development of an investigational medicinal product for any or all indications, routes of administration, or dosage forms, the sponsor should maintain all sponsor-specific essential documents for at least two years after formal discontinuation or in line with applicable regulatory requirements. Sponsor-specific essential documents should be retained until at least two years after the last approval of a marketing application in the EU and until no pending or contemplated marketing applications in the EU remain, or at least two years have elapsed since the formal discontinuation of clinical development of the investigational product.

These documents should be retained for a longer period if applicable regulatory requirements say so, or if the sponsor needs them. Record retention times for sponsors also apply to the records retained by contract research organizations or other agents of the sponsor, unless arrangements have been made to transfer the documents to the sponsor. Any transfer of ownership should be documented. It is the responsibility of the sponsor to inform the investigator/institution as to when these documents no longer need to be retained.

For trials that will not be used in regulatory submissions, it is the responsibility of the sponsor to consider whether the results will or may be included in a marketing authorization application, and to take the necessary steps to ensure appropriate retention of the essential documents. Essential documents of the sponsor and investigator from trials that are not to be used in regulatory submissions should be retained for at least five years after completion of the trial, and for a longer period if laid down in local regulatory requirements, or by agreement with the sponsor.

Finally, independent ethics committees should retain all relevant records for a period of at least three years after completion of the trial and make them available on request from the regulatory authorities. The documents should be retained for a longer period if local regulatory requirements so demand.

The draft document is open for consultation until the end of September—so interested parties who wish to use their summer vacation for making their own comments have time to do so.