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International Clinical Trials

To e-Archiving and Beyond

Dimitri Stamatiadis at Merck Serono explains the benefits of e-archiving and shows how the transition from the use of hard copy records can be made most effectively

How long has it been since you last hand-wrote a document in your business, if ever? The paper paradigm for business documentation has all but disappeared in the industrialised countries during the first decade of the 21st century. Today, way beyond traditional word processing, we practice e-banking, e-tax filing and ecommerce, send e-Christmas cards and even the most archaic administrations offer elaborate websites where one can find eforms for just about everything. To this we should add the content of email, social media and other forms of communication that generate an impressive and ever-growing amount of electronic content. The pharmaceutical industry – the largest producer of regulated documentation – embraced e-technologies decades ago and has moved on to filing fully electronic marketing authorisation applications in most countries. But, paper has not disappeared from our lives and questions about the kind of records we retain and how we deal with regulatory and legal requirements, long-term retention or with business needs for knowledge management remain. In other words, how do we perform record management in today’s changing world, and has the landscape changed since the earlier assessments, five years ago (1,2)?

RECORDS MANAGEMENT IN 21ST CENTURY PHARMA

Records management is process based and begins with the definition of a record. According to the US National Archives and Records Administration (NARA): “Records include all books, papers, maps, photographs, machine-readable materials, or other documentary materials, regardless of physical form or characteristics, made or received by an organisation in connection with the transaction of business and preserved (or appropriate for preservation) by this organisation or its legitimate successor as evidence of the organisation, functions, policies, decisions, procedures, operations, or other activities or because of the informational value of the data in them” (1,3).

Electronic records can easily fit into the above definition, but have more features than their physical counterparts. For example, following a long legal battle, a 2009 decision of the Arizona State Supreme Court has defined that: “Metadata is an inherent part of any electronic document and thus discoverable as a part of a records request...”(4).

Metadata is a term describing the information about a record, or ‘data about data’. The consequence of the Supreme Court decision is that any electronic archive must not only store the content of records, but also a collection of metadata providing information about that particular record.

ARCHIVING

In the meantime, paper is still around, and there are several reasons for that – the first and foremost being our own former practices. We have paper archives in place, we know how to search and retrieve documents from them and we trust paper because it is familiar. In a highly regulated industry such as pharmaceuticals, one can not easily take the risk of losing documentation and, rightly or wrongly, a large paper archive that you can view every day on your way to the office offers some kind of comfort.

This is particularly true for records that originate as paper documents, such as the massive trial master files regrouping all the administrative documentation from clinical trials. Although turning these paper records into electronic images is possible and is practiced by a number of companies as a backup method, the paper still remains the official record.

On the other hand, an equally large mass of documents is now produced electronically and is stored in more or less elaborate electronic documentation management systems (EDMS). With a few exceptions, these are kept as electronic files, but can we consider them as archived? What drives the choice between paper and electronic archives? One of the principal reasons for paper still being used for archiving is related to signatures. Indeed, one may find electronic forms on the internet, but when it comes to signing a legally binding statement, most of the time the only way to do it is to print, sign and hand back or post the document. By doing just that, one generates a new paper record that will, of course, be fed to a paper archive. So the signature defines the nature of the record, regardless of the method used to generate its content.

e-RECORDS, e-SIGNATURES & 21 CFR PART 11

In the pharmaceutical industry, the undisputed reference in terms of electronic records and electronic signatures is the US legislation 21 CFR part 11, issued in 1997 (5). Unfortunately, while 21 CFR part 11 makes apparently reasonable assumptions and requirements, a strict interpretation of the text can lead to unreasonably complex solutions. During the first few years after it went into effect, pharmaceutical companies struggled to revise all their electronic systems and the FDA issued a series of increasingly complex and cryptic guidances interpreting 21 CFR part 11. Subsequently, we entered a sort of moratorium where common sense and predicate rules were used in absence of better solutions. To follow the predicate rules in essence means to handle electronic records as you did the paper ones. So all good clinical, manufacturing or laboratory practices (GxP) rules still apply, but there are no particular requirements linked to the electronic nature of the records. This is specifically true (and practical) when it comes to storing metadata. Today’s EDMS contain tenths of metadata allowing for navigation and retrieval as the volume of records they contain increases exponentially over time. Which of these should be considered part of the record and preserved along with the content? Predicate rules point to a limited set since the paper records mainly carry footer information (version, date, page numbers and so on), and of course signatures. On July 8, 2010 the FDA announced that they will resume auditing electronic records according to 21 CFR part 11 and the current FDA Guidance, which was issued in 2003 and replaced all the previous ones (6).

Electronic signatures do exist with various degrees of authentication. The most frequent type links the signatory’s information to the document within a closed system, allowing for identification by username and password in normal business conditions, but will not follow if the document is taken out of the system and may not stand in court as a legally binding signature. The more robust forms called ‘digital signatures’ (such as the one supported by the SAFE Biopharma Association) involve third party identification and a combination of codes and physical tokens, and is usually recognised as equivalent to a paper signature. The latter involves additional per user cost.

ARE WE READY FOR e-ARCHIVING?

Today, all major pharmaceutical companies and many others have in place large validated EDMS that follow robust rules for the classification and preservation of records and metadata. These systems include automated management of audit trail information that largely covers the predicate rule requirements for metadata (and probably any other reasonable request). They also frequently include e-signature functionality, allowing for unequivocal identification of signatories within the organisations. They are able to generate non-editable file formats (mostly PDF files) that are difficult to tamper with. Physically, files are stored on ever-growing hard disks and replicated in several remote locations, thus ensuring adequate disaster protection. Additionally, there is today an ISO archiving standard based on the PDF called PDF-A which offers a quasi-guarantee of accessibility for the foreseeable future. If your organisation possesses one of these systems, you probably have the basic components allowing you to embark in e-archiving.

So, 13 years after the publication of 21 CFR part 11, is the pharmaceutical industry finally ready to implement full electronic archiving? Such a decision naturally falls on the executives of each company to take, but in any case the following should be taken into consideration:

  • Issue a statement or position paper describing the company’s definition of e-records with reference to existing rules and regulations (for example, specify that only PDF-A compliant PDF versions of approved documents are considered official records, all drafts and editable forms being considered working documents)
  • Define groups of similar records (records series) and set clear rules for their retention and disposal
  • Define handling of working copies (such as drafts being deleted upon approval, editable versions of approved documents used only as templates for the generation of other documents or versions)
  • Verify that your EDMS includes adequate audit trail management that can not be tampered with
  • If implementing e-signatures, issue a company statement acknowledging e-signatures as having the same validity as physical ones (if you do not implement e-signatures, you will have to retain the signature pages in a physical archive with adequate information to unequivocally link it to the electronic record)
  • Ask potential signatories to sign a statement of understanding and approval of the e-signature rules (legal validity, confidential handling of passwords and so on)
  • Systematically follow all the above rules (it is the best way to show that you are taking records management seriously)
  • Exercise technological outlook to allow for hardware or software changes that may affect your e-archive

Other considerations, such as internal and external access control, primary records definition or the records held procedures are needed as part of good record management, but they do not directly affect the validity of the archive.

References

  1. Stamatiadis D, Digital archiving in the pharmaceutical industry, IMJ: pp54-59, July 2005
  2. Stamatiadis D, Electronic archiving: a new paradigm, APR 8:5 pp10-16
  3. NARA, http://www.archives.gov/midatlantic/agencies/ records-mgmt/definitions.html
  4. Klingler EC, Arizona declares metadata is fair game for open records requests, Litigation News, 29 December 2009
  5. Title 21, Food and Drugs Chapter I, Food and Drug Administration Department of Health and Human Services Subchapter A, General Part 11 Electronic Records, Electronic Signatures, http://www.accessdata.fda.gov/ scripts/cdrh/ cfdocs/cfCFR/ CFRSearch.cfm?CFRPart=11&showFR=1
  6. Guidance for Industry, Part 11, Electronic Records, Electronic Signatures – Scope and Application, August 2003, Pharmaceutical CGMPs

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Dimitri Stamatiadis, PhD, has more than 15 years’ experience in the pharmaceutical industry, working for both CROs and industrial corporations such as Boehringer Ingelheim, Lederle and Aventis in Europe and the Schering-Plough Research Institute in the US. In 2005 he moved to Geneva, Switzerland, where he headed up the EDMS replacement project at Merck Serono. He was involved very early on with introducing technology in pharmaceutical R&D. He is an active member of the DIA, European chair of the Document and Records Management SIAC and author of several articles on the introduction of digital technology in pharmaceutical R&D. He graduated from the University of Patras with a BSc in Biology and continued his MSc and PhD at the University of Paris Pierre et Marie Curie. Subsequently, he obtained an MBA in Pharmaceutical Business from the University La Sorbonne, Paris.
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