ICH GCP Guidelines (E6) Addendum Now Available

So after securing approval at the November ICH meeting in Osaka, the revised text of the ICH guidelines for Good Clinical Practice – otherwise known as ICH E6(R2) – has been published on the ICH website….. and also available to download HERE. My previous blog posting highlighted some of the issues that I thought needed to be addressed. Although many were not resolved by the final approved wording of the guideline (no surprise there!), I was pleased to see some changes since the initial draft was circulated for consultation. I have these highlighted below.

The revised guideline now includes a definition for a “certified copy” and provides for such copies replacing the originals. Section 8.1 states:

“When a copy is used to replace an original document (e.g., source documents, CRF), the copy should fulfill the requirements for certified copies”.

This statement suggests strongly to me that it is acceptable to generate a certified copy (e.g. a digital scan of a paper document) and for the copy (the digital file) to completely replace the original paper version i.e. the paper copy can be destroyed. If the paper original is being retained, then the copy is not actually replacing anything….. it is being filed in addition to the original! You may want to retain originals for other reasons (e.g. originals may have greater evidential weight if relied upon in court) but this is not needed to comply with the guidelines here.

The final definition of a certified copy is slightly different from that first proposed but I think the subtle change is extremely important. The original wording proposed was:

“A paper or electronic copy of the original record that has been verified (e.g. by a dated signature) or has been generated through a validated process to produce an exact copy having all of the same attributes and information as the original.”

The two highlighted words are significant and were mentioned in my feedback to ICH during the consultation period. “Exact” is a very precise term, as is “all”. It is often the case that conversion of documents from one format to another results in a copy that is not 100% identical to the original in EVERY respect. But still, it contains all of the information, content and structure that is critical from a GCP compliance perspective and to support patient safety and data integrity. So the revised definition takes account of this nuance of document conversion:

“A copy (irrespective of the type of media used) of the original record that has been verified (i.e., by a dated signature or by generation through a validated process) to have the same information, including data that describe the context, content, and structure, as the original.”

So, I would argue that a PDF rendition of an email potentially loses some metadata components related to the email header (so is not an “exact copy” based on the original definition) but retains “the same information” contained within the email, the structure of the email and the context of the email, and would therefore constitute a certified copy (if produced through a validated process). And of course the ICH definition allows for certification via use of a validated process, not requiring a dated signature to certify each and every copy! It is worth noting that the current FDA definition of a certified copy differs from the ICH addendum definition but the FDA have stated that the “draft guidance, when finalized, will represent the current thinking of the Food and Drug Administration (FDA or Agency) on this topic”.

The second small but significant change that is of interest from a records management perspective is the specific inclusion of the requirement for “systems for archiving”. The original addendum included the following statement in section 8.1:

“The sponsor and investigator/institution should maintain a record of the location(s) of their respective essential documents. The storage system (irrespective of the media used) should provide for document identification, search and retrieval.”

The final text states:

“The sponsor and investigator/institution should maintain a record of the location(s) of their respective essential documents including source documents. The storage system used during the trial and for archiving (irrespective of the type of media used) should provide for document identification, version history, search, and retrieval.”

So there are three new concepts that are emphasised here:

  • The TMF inventory or index that is maintained both by the sponsor and by the investigator / institution must include all records considered part of the TMF, including source documents.
  • The issue of long-term retention and preservation of TMF content must be addressed and those systems selected for archival purposes must meet the same requirements for document identification, version control, search and retrieval as systems used during the trial.
  • The system for good version control and maintenance of an immutable audit trail of version history throughout the retention period must be assured – including those systems used for archiving.

The GCP addendum includes many other changes, some of which are directly relevant for records management and TMF management and can easily be found by reference to the additional sections in the guideline. I’ve just highlighted here what I consider to be two of the most significant ones for TMF management as they relate to concepts that are often misunderstood and variously interpreted across industry.

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What Impact for the Trial Master File (TMF) of ICH E6(R2)?

So we are now extremely close to Step 4 of the ICH E6 process, resulting in a final, approved revision of the guidelines for good clinical practice…. the first revision since the mid-1990’s. The draft was circulated for review (June 2015) and commented upon by regulators and industry (consultation closed January 2016) but we have yet to see the final text put forward by the Expert Group and voted upon most recently. I’m looking forward to seeing what the impact will be for the management of clinical trial records and whether any of the issues that I identified in the 2015 draft document will have been addressed during the final revision of the guideline. Here’s what I noted previously of interest to TMF colleagues:

Certified copy:
The inclusion of a definition for a certified copy is welcomed, especially as it provides for the production of copies via a validated process rather than mandating verification of the copy by use of signatures. However, the definition in the draft requires that a copy has “all of the same attributes” as the original. It must be acknowledged that electronic records contain data other than the information captured within a document (i.e. metadata) and often, this metadata is of inconsequential or no value with regards to trial conduct. Therefore, the requirement to maintain “all of the same attributes” as the original is often not necessary and could require an unnecessary burden and cost. For example, for many years, it was perfectly acceptable to retain printouts of emails in the trial master file despite these not containing all of the same attributes as the original. These retained the information and meaning of the original; retention of the internet metadata was deemed to be unnecessary.

In addition, a certified copy is defined as being a “copy of the original record”. It should be noted that it need not necessarily be a copy of an original. A certified copy could be a copy of an existing copy.

The draft also states: “When a copy is used to replace an original document, the copy should fulfil the requirements for certified copies.” There has been much confusion within industry whether or not it is permissible to destroy original records following copying i.e. whether the certified copies can truly replace the originals. Given this ambiguity, it is recommended to provide explicit clarification here and change the text to: “It is permissible for an original trial record to be replaced with a copy and for the original record to be destroyed if so required, as long as the copy fulfils the requirements for certified copies.”

Terminology:
The draft guideline noted that the “terms clinical trial and clinical study are synonymous” but some jurisdictions (e.g. the EU) have already noted a distinction here. EU Regulation 536/2014 already includes a definition of these two terms so it might be preferable to adopt those definitions and not use the term interchangeably.

Within the guideline, “records”, “data” and “documents” are also used interchangeably. However, typically “documents” and “data” are considered separate entities. For example, subject data within an electronic case report form would be “data” and would not generally be considered to be a “document”, unless converted to PDF for example. It would however be considered to be a “record” and it would also meet the proposed definition of “documentation”. Given that absolute clarity should be the goal within the revised guideline and to remove ambiguity wherever possible, it is recommended that “document” only be used in the traditional meaning of the word…. to mean information that has been recorded in a structured format as a distinct document…. or avoid using the term completely. On this basis, the majority of the references to “documents” within the guideline should be changed to “records”, for example “essential records”.  In the same way, “Source Documents” change to “Source Records” or “Source Documentation”.

Investigator Records:
An assessment of an investigator site for suitable records storage facilities is often overlooked by a sponsor and may not be perceived as an issue until the trial has come to an end and the TMF is ready for archiving. It is recommended that filing/records storage is specifically included and could be accommodated in lines 479-481: “The investigator should have available an adequate number of qualified staff and adequate facilities for the foreseen duration of the trial to conduct the trial properly and safely, including storage of essential records during the trial/study and for the whole required retention period.”

Retention Times:
Retention of trial records for an appropriate length of time is critical. However, there are several factors that determine the most appropriate retention time, including ensuring records are available for inspection, potential litigation support and protecting the safety and welfare of subjects. The introduction to the draft guideline states that it “provides public assurance that the rights, safety and well-being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible.” Therefore, the mandatory, minimum retention period should be consistent with these aims alone, and should not support any business needs or commercial needs of the sponsor. On this basis, a fixed retention period as a number of years following completion of a study/trial would meet the requirement to ensure records were available. Linking the retention period to marketing applications (per the proposed revision and also the original wording) is surely a commercial decision for the sponsor. If a sponsor chooses to destroy records prematurely, it simply impacts the sponsor’s ability to support the marketing application; this is a commercial decision for the sponsor. Whilst most sponsors would in reality retain records for this period, it should not be mandated as part of GCP. Furthermore, it is impractical for an investigator to set a retention period based upon the marketing strategy of the sponsor! Alternative wording should be “Essential documents should be retained for a minimum of 15 years following completion or termination of the clinical study/trial. The sponsor may require the records to be retained for a longer period to support marketing applications.”

An aspect of electronic systems that is frequently over-looked is the long-term retention and preservation of digital content, particularly measures that need to be taken to mitigate against software obsolescence and file format obsolescence. It is recommended that this is addressed in lines 895-911: “(i) Take measures to mitigate against software, hardware and file format obsolescence over the retention period of the trial data and records to ensure their ongoing accessibility, readability and integrity.”

Essential Documents:
Across industry, the minimum list of documents has often been interpreted – incorrectly – as the required content for a trial master file. Although this opinion is decreasing in frequency, the wording here could help provide clarification. The following alternative wording is proposed: “A minimum list of essential records has been developed and is described here. However, this minimum list of records should be supplemented by additional records that collectively permit evaluation of the conduct of a trial and the quality of the data produced.”.

Let’s see what the final document looks like, though I’m not too optimistic that my wish list here will be delivered!

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Update: EMA Reflection Paper on Trial Master Files

A while ago I posted information here regarding the draft reflection paper from the EMA on trial master files (TMF). At that point, the intention was to bring the contents of the reflection paper along with other related guidance into a single document supporting the new Clinical Trial Regulation 536/2014 and published by the European Commission / Parliament. This would be a Regulation.

It appears that the draft reflection paper will now stay with the EMA and will be issued as a guidance document in EudraLex Volume 10 (Clinical Trials Guidelines). I understand that following the prior consultation on the draft, a revised draft will be posted for final consultation in the next few weeks and will be finalised as an EMA guidance document early in 2017.

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Case study-led agenda develops for TMF Europe

If you work with Trial Master Files, you might be interested to hear about IQPC’s TMF Europe conference. Now in its second year, this is highly interactive and case study driven. The agenda does away with your usual mix of classroom-style presentations and includes a live inspection simulation, people bingo, campfire round-table discussions, live debate and pub-style quiz! There will also be a keynote session from an EU regulatory agency on inspector expectations (TMF accessibility and availability). With an optional Cava tasting, what is there not to like!!

Thinking about implementing an eTMF solution but not sure what the issues are? Do have lots of questions about managing TMFs? This is certainly the conference for you. And in a great location too!

Please see IQPC’s conference website at http://www.tmfeurope.com for more details or view a draft agenda here.

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Training Course: Managing Electronic Records

This is a just a quick promo for a one-day training course that I am running with my colleague, Russell Joyce, on behalf of the Scientific Archivists Group. The course is aimed at anyone with responsibility for electronic records….. for those managing systems such as electronic trial master files or SharePoint-based solutions, those responsible for electronic records processes and policies, or those responsible for establishing electronic archives.

The Scientific Archivists Group (SAG) is focussed on management of records in a scientific research environment but the course content would also be applicable to other regulated industries.

The booking deadline is coming up in a couple of weeks so if this is of interest to yourself or a colleague, please make your reservation as soon as possible to ensure you get a place. The course is taking place just outside the perimeter of London’s Heathrow Airport – so great for accessibility – and is scheduled for Wednesday 15th June. For booking and further details, please see https://sagroup.eventhq.co.uk/mer. There is a discount for SAG members; if you are not currently a member, please consider taking up membership as the discount almost covers the membership fee.

 

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Wingspan eTMF

We are pleased to announce the addition of Wingspan eTMF to our list of featured advertisers. Wingspan – founded in 1996 by CEO Troy Deck – has been in the electronic document management business for many years, with its suite of DocWay products being very familiar to Documentum and SharePoint users (amongst others).

Wingspan eTMF – first released in 2009 – was developed in partnership with the life sciences industry. Refined based on feedback from daily use by thousands of users from around the world, Wingspan eTMF has been used to facilitate a number of successful health authority inspections from a variety of agencies.

Wingspan will be exhibiting at the upcoming 5th eTMF Summit, Arlington VA, USA (20-22 January 2016), with Kathie Clark, VP Product Management also presenting on development of an eTMF business case. Make time to catch up with Kathie and her colleagues if you are attending the summit. For more information about Wingspan eTMF, please see their feature HERE.

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Booking Now Open for SAG Conference (April 2016)

Just a quick note to mention that bookings are now being taken for the next Conference of the Scientific Archivists Group (SAG). This will be of interest to anyone who is involved in the management and/or archiving of scientific records, especially those working in the pharmaceutical, biotechnology and healthcare sectors.

For the first time, the conference will include parallel “clinical” and “pre-clinical” tracks, with topics that should be of particular interest to those specialist areas. So in the clinical track the sessions include an update on the TMF Reference Model and selecting an eTMF solution, whilst the pre-clinical track includes managing GLP/GMP samples and how to prepare for GLP/GMP compliance audits. We also have keynote sessions from the National Institute of Health and Clinical Excellence (NICE) and the Medicines and Healthcare products Regulatory Agency (MHRA). Added to this are updates from the two Special Interest Groups – Electronic Records and Good Clinical Practice – and various networking sessions (including drinks reception and gala dinner), and it all makes for a fabulous event!

This is going to be a sell-out event and ticket numbers are limited so please make sure you book early. The dates are 21-22 April 2016. The venue is the Crowne Plaza City Centre Hotel, Birmingham, UK. Prices go up by 15% once the Early Bird booking period closes and SAG members benefit from a 15% discount on the displayed prices. For further details, including the provisional agenda, prices, and booking process, go to the SAG website at http://www.sagroup.org.uk/events/2016conference.  Online booking is open at https://sagroup-2016.eventbrite.co.uk

Posted in Records management practice, Training