Archiving Approach in the UK

Clinical trials involve a complex series of steps from inception through protocol design, recruitment, follow-up, data collection, analysis, and the final presentation of results. An important final component of this process is the archiving of the trial documents. Unfortunately, this is an often neglected function that is dealt with as an afterthought. Despite this, archiving is a legal and regulatory requirement that should be planned and carried out with the same attention to detail as every other aspect of the trial. It can also be a very labor intensive and expensive exercise. In this article what exactly is meant by archiving, what needs to be done to archive, and how it should be executed will be examined. We will focus on the practicalities and will draw upon our experience of archiving large clinical trials in the United Kingdom.

Background

Within the context of clinical research, archiving is the safe and secure storage of essential documents. In the United Kingdom, these documents are those that throughout a clinical trial have demonstrated the compliance of the investigator, sponsor, and monitor with the standards of Good Clinical Practice and with The Medicines for Human Use (Clinical Trials) Amendment Regulations 2006.¹ These essential documents, and therefore their safe storage, are the only means that can be used to reconstruct the study after its completion, enabling the information contained in the final report to be verified.

Regulatory background

All clinical trials of investigational medicinal products carried out within the United Kingdom must meet the requirements of the UK Medicines for Human Use (Clinical Trials) Regulations which became law in May 2004, and its associated amendments in 2006 and 2008. These regulations implement the EU Clinical Trials Directive in the UK.

The 2006 amendments have had the greatest impact on the archiving of clinical trial documentation. In particular, these regulations define the length of time documents are to be stored, and specify the appointment of a named individual responsible for the recovery and retention of the archive. The main changes to the 2004 Regulations regarding archiving are detailed below.

Recommendations

Duration. Essential documents must now be retained by the investigator or sponsor for a minimum of five years after trial completion. This has increased from two to five years although the industry standard is still 10 to 15 years, and beyond for some products.¹ Some documents may need to be retained for longer if it is specified in the contract between sponsor and investigator. For example, in the United Kingdom, general practice files are retained for 10 years after death, hospital files are kept for seven years, and the medical files of members of the armed forces and prisoners are kept indefinitely. Maternity records are kept for 25 years after the last live birth and oncology records are retained for 30 years, as are all blood transfusion records.² Individual research organizations, funders, and journals may also have their own policies for archiving trial documents, in particular in relation to the duration of archiving.³

Although it is common practice for records to be kept for variable lengths of time, it is not legitimate for records to be archived simply for historical purposes without patient consent or support under the UK Health and Social Care Act 2001.⁴ Principle 5 of the UK Data Protection Act also states "Personal data processed for any purpose or purposes shall not be kept for longer than is necessary for that purpose or those purposes."⁵

Named archivist. The sponsor is now also responsible for appointing named individuals within their organization to be responsible for archives, and access to these archives is now restricted to those individuals. In addition, essential documents must be archived in a way as to be readily accessible to competent authorities on request. Thus, a process must be in place for recovery of documents as well as retention.¹

Any transfer of ownership of the data or of the documents shall be documented. The new owner shall assume responsibility for archiving. The 2006 Regulations state:

If there is transfer of ownership of data or documents connected with the clinical trial the sponsor shall record the transfer; and the new owner shall be responsible for data retention and archiving.

Archiving in practice

Planning the archive. The importance of planning cannot be over-emphasized when it comes to archiving. However, often decisions of what, when, and how to archive are left until the study is completed. Ideally, archiving should be planned at the outset along with other aspects of the practical conduct of the trial.

When planning, it is important to identify which of the many different types of trial paperwork and other forms of documentation are to be archived. This means, in practice, identifying those that are essential documents. A full list of essential documents for archiving can be found in Section 8 of ICH GCP.⁶ For example, source documents (or certified copies), all documents contained in the Trial Master File and Investigator Site File, data forms, case report forms, and research records from support departments involved in the study are required to be archived.

Departments such as pharmacy will keep their own original records, but copies of these documents need to be archived. Laboratories involved in clinical studies also need secure archiving of biological materials and test facility records. Guidance on these is outside the scope of this article, however, regulations governing these come under the remit of Good Laboratory Practice. In the UK, these regulations implement the requirements of European Directives (2004/9/EC and 2004/10/EC) and are consistent with the OECD Principles of Good Laboratory Practice (ENV/MC/CHEM(98)17). ⁷

Other supporting documentation generated during the life of the study may include minutes of meetings, correspondence, status reports, safety updates, contact details, and e-mails. These documents should also be archived.

The next stage of planning is deciding where the documents will be archived. The archiving facility may be a designated building built for purpose, it may be a secure room, a fireproof safe, or a lockable secure cabinet. The archive, however, must prevent:

• Unauthorized access

• Destruction due to weather elements

• Flooding and fire

• Insect and rodent infestation

A major issue that is routinely overlooked, even by those who do plan their archiving process, is who will fund it. The potential costs of archiving a large study may be significant, and should be included within the study budget. It is also important to note that the contract for archiving a commercial trial should be between the pharmaceutical company in question and the archiving facility, although this may be arranged by a third party.

Doing it. With a clear plan in hand the actual process of preparing the archive material and sending it for safe storage should be relatively straightforward. That said, between the early planning stages and the completion of the study many things may have changed. This includes turnover of study personnel both at the sponsor organization and at the study site, updates of the archive provider's policies, or regulations regarding archive contents and time-scales for storage. All these have to be taken into account and any plan amended accordingly. Archiving a large study may require a number of staff working full time. At the end of a study, site staff may come to the ends of their contracts and be unavailable for this task. This is important to plan for and should be anticipated because without site staff it will be close to impossible to complete the necessary tasks in a timely fashion.

We have always used a study specific archive checklist in order to ensure that all appropriate documents have been included in the archiving process. This should be agreed upon between the sponsor and the site before archiving commences.

If the storage is to take place at the site, then it is essential that an inspection has been undertaken by the sponsor to ensure the suitability of the archiving facility. If the storage is to be undertaken by a commercial organization in an off-site facility, again it is essential that an audit of the archive facility should be carried out to ensure the facility meets expected standards.

Finally, an inventory of the archive should be generated by the designated person or appointed archivist to record all essential documents that have been archived.

Retrieval. As noted above, a named archivist is responsible for the safe and secure archiving of the clinical trial data. This individual is also responsible for any requests for retrieval of the data for re-analysis, or in the event of an audit or regulatory inspection. The inventory generated when the archive was created should also be used by the archivist to track and trace documents retrieved from the archive and any items on loan should be checked by the archivist prior to returning them to the archive facility.

Retrieving documents from an archive is costly. Therefore, any requests for retrieval should not be made without good reason.

Specific issues

Health and safety. Use of a commercial archive facility ensures that the moving and handling of archive boxes will be undertaken by packers expertly trained in all aspects of the moving and handling process. For the archiving of smaller academic studies where research staff are undertaking the archiving themselves, it is essential and sensible that they undergo a moving and handling course before attempting to archive weighty study document boxes.

Paper vs. electronic. Regardless of which method of capturing data is used during a trial (paper or electronic), clinical trial information must be stored for a minimum of five years. Large paper based studies will involve a high archive cost and an ongoing monthly storage fee. Archiving electronic records also has its own difficulties. Data stored on an electronic storage medium such as floppy disk, CD, or flash drive, can quickly become obsolete and devices in common use today may be unavailable in the future, making retrieving the electronic data difficult. Archiving procedures should take this into consideration when deciding to retain records electronically.

One alternative may be for the electronic archive to be stored on a defined partitioned area of a computerized hard drive system. Records and data stored by this method would be "locked" in order that they could not be tampered with or altered in any way and would come under the control of the archivist who would follow documented procedures.⁷

ECGs and thermal paper. Thermal paper used in electrocardiography (ECG) monitors, and other devices that produce a print-out, can fade after time in storage. This can create difficulties for essential documents being kept for a minimum of five years. Thermal paper is sensitive to light, temperature, and humidity and therefore it may be invaluable to keep a photocopy of the ECG, along with the original record being archived.⁸

Labels, tape, plastic folders, and rubber bands. There are ways of delaying the aging process for archive material. Temperature control and humidity in the storage area is important as is suitable lighting to avoid light damage.⁹

Materials to be avoided within the archive box include the use of rubber bands, tape, labels, and some plastic folders. The rubber bands once stretched perish over time, while adhesive labels and sellotape may detach from their source and some plastic materials such as polythene pockets may lead to deterioration of printed material. It is important that if adhesive labels are affixed to the outside of boxes that the archive boxes are marked additionally with indelible markers—inside and out.

Elizabeth S. Ronald* is Network Coordinator at Scottish Stroke Research Network, 4th Floor, Walton Building, Glasgow Royal Infirmary, Glasgow, G4 0SF, United Kingdom, e-mail: liz.ronald@nhs.net. Eleanor M. Dinnett is Pharmacovigilance Officer at Pharmacovigilance Office, Robertson Centre for Biostatistics, Boyd Orr Building, Glasgow, United Kingdom. Elizabeth P. Tolmie is Education Officer, and Allan Gaw is Director of Operations, both at Glasgow Clinical Research Facility, Tennent Building, Western Infirmary, Glasgow, United Kingdom.

*To whom all correspondence should be addressed.

References

1. Department of Health, The Medicines for Human Use (Clinical Trials) Amendment Regulations 2006, (DH, London, UK, 2010).

2. Department of Health, Records Management: NHS Code of Practice: Annex D1: Health Records Retention Schedule, (DH, London, UK, 2009).

3. Clinical Trials Tool Kit, http://www.ct-toolkit.ac.uk/

4. Department of Health, Research Involving the NHS: Retention of Records (DH, London, UK, 2007).

5. Data Protection Act 1998, (The National Archives, London, UK).

6. European Medicines Agency, ICH-GCP E6 Section 8, (EMA, London, 2002), http://www.ema.europa.eu/pdfs/human/ich/013595en.pdf.

7. Medicines and Healthcare Products Regulatory Agency, Good Laboratory Practice—Guidance on Archiving, (MHRA, London, 2006).

8. ECRI Institute, "User Experience Network," Health Devices, 19 (10) 374-375 (October 1990), http://www.mdsr.ecri.org/summary/detail.aspx?doc_id=8155.

9. British Standards Institution, Storage & Exhibition of Archival Documents, (BSI, London, 2005).