Clinical Trials EU Regulation – Even More Bizarre

Following the recent vote of the ENVI Committee on the several hundred amendments put forward to the proposed EU Clinical Trial Regulation, the consolidated report containing all carried amendments has now been published. Report A7-0208/2013 entitled “Report on the proposal for a regulation of the European Parliament and of the Council on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC” can be downloaded HERE or from the European Parliament website.

You will remember that I noted only a few days ago my disappointment that the amendment which extended the mandatory retention period for trial master files to “indefinite” had been carried. Now that we have visibility of the final text being proposed, the amendments are even more bizarre! Amendment 222 proposes changing the wording of the draft Regulation from:

“The sponsor and the investigator shall keep a clinical trial master file” to

“The sponsor or the investigator shall keep a clinical trial master file”.

Given that the sponsor TMF and investigator TMF serve different purposes, have different contents and have their ownership defined quite separately from each other, I wonder how this is going to work. If the sponsor decides to keep the TMF – which they will need to protect themselves against product liability claims and to support regulatory activities – does this mean the investigator may destroy their TMF? What will happen when a health agency wants to conduct an inspection and finds the investigator has no TMF?

The wording of the amendment specifying retention times has changed slightly but with major impact. Amendment 223 changes the requirement to retain a trial master file for a minimum of five years to:

“The sponsor and the investigator shall archive the content of the clinical trial master file in electronic format for an indefinite period of time after concluding the clinical trial. However, the medical files of subjects shall be archived in accordance with national legislation. If the sponsor is unable to archive the master file, it may be archived in the EU database. The electronic master file shall be archived in a readable and easily searchable format.

My first observation is the inconsistency between this amendment and the prior amendment. We’ve just seen that either the sponsor or investigator may choose to retain the trial master file but we now have a requirement that both have to retain the file indefinitely! We also see a mandatory requirement for the TMF to be archived in electronic format. In one sense, I’m pleased about this change because industry is moving towards managing and archiving documents in digital form anyway. However, to mandate that all sponsors – including investigator-led trials – convert paper TMFs to electronic simply for archival purposes is astonishing. As we all know, scanning using a validated, quality process is an expensive operation and is rarely cost-effective simply for the purposes of archiving. This will place a HUGE burden on industry, and in particular on investigator sites for investigator-sponsored studies. And once again, we have this suggestion that there will exist an EU database that has the capability of managing the huge variety of documentation that makes up a trial master file…. across sponsors, investigators, CROs, EU member states…. all in “a readable and easily searchable format”.

I really do think it is time that members of the ENVI Committee took a step back and listened to one of two GCP records managers. The text now being proposed for the EU Regulation appears to me to highlight a lack of understanding in this area.

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Clinical Trials EU Regulation – An Update

You will remember that I wrote a few weeks ago about the proposed Clinical Trial Regulation which will replace EU Directive 2001/20/EC. Specifically, myself and many of my industry records management colleagues were extremely concerned about Amendment 60 which was being put forward by the UK Rapporteur, Ms. Glenis Willmott. Amendment 60 revised the wording of the proposed Regulation from:

“Unless other Union legislation requires archiving for a longer period, the sponsor and the investigator shall archive the content of the clinical trial master file for at least five years after the end of the clinical trial. However, the medical files of subjects shall be archived in accordance with national legislation.” to

The sponsor and the investigator shall archive the content of the clinical trial master file for an indefinite period of time after concluding the clinical trial. However, the medical files of subjects shall be archived in accordance with national legislation. If the sponsor is unable to archive the master file, it may be archived in the EU database.

At the ENVI Committee meeting on 29th May, a vote was passed which ACCEPTED amendment 60. Unless the wording is amended again as the draft Regulation passes through parliamentary scrutiny, we look forward to the prospect of ALL documents associated with a clinical trial (as defined in EU Directive 2005/28/EC) being retained permanently. Let’s just be clear about what this means. A fairly small-scale clinical trial that I was recently doing some work for involved about 500 patients spread across 50 trial sites. We estimated that this would generate in the region of 12,000 documents, totalling some 65,000 pages. Another study I was recently associated with – a large scale Phase III study – has generated in excess of 385,000 documents….. for a single study!!!

Now, how about we take a look at the EU Clinical Trials Registry to see how this extrapolates across Europe. There were 2,348 Phase I – Phase III clinical trials registered during 2012. Let’s say for argument’s sake that across these 3 phases an average clinical trial generates 10,000 documents (not an unreasonable estimate), we have a storage requirement for nearly 25 million documents. To be kept ‘in perpetuity’ just for a single years’ clinical trials. Will this make Europe a competitive place to run clinical trials when the FDA have a records retention requirement of 2 years following drug approval?

As with many other sectors of industry, clinical trials are becoming increasingly digital in format. So just how exactly do the ENVI committee propose that these 25 million documents are going to be managed electronically in excess of 50 years? Have they not heard of software obsolescence? It is impossible to open a Microsoft Powerpoint file created just a few years ago in Powerpoint 95 due to software/file format obsolescence issues! I love the throw-away line at the end of the amended text “If the sponsor is unable to archive the master file, it may be archived in the EU database”. I can’t wait for the EU to create a database that is capable of (a) managing this volume of data, (b) managing trial master files containing the enormous variation of documents, file formats, naming conventions etc that exist across the industry, and (c) maintaining the content in accessible and readable format in perpetuity.

Come on guys, I think it is time for a re-think!

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An eTMF is For Life, Not Just For Christmas! Achieving Archive Compliance

This is the title of the next webinar that we are involved with.

This topical webinar will be structured as follows:

karenreddingKaren Redding of Phlexglobal will present the current eTMF industry status and how eArchiving is not being addressed;

 

 

Eldin RammellEldin Rammell of Rammell Consulting will explain why an eArchiving strategy is so important, especially in light of the EMA TMF Reflection Paper and proposed EU Clinical Trial Regulation, the benefits of eArchiving and the various approaches; and

 

matthewaddisMatthew Addis of Arkivum will talk about the challenges of meeting regulatory requirements, and how to meet these challenges through an active archiving strategy.

 

 

In conclusion, Karen will give a brief overview of the integration between PhlexEview, (Phlexglobal’s eTMF) and the Arkivum digital preservation solution to provide an effective long-term e-Archiving solution.

Don’t miss this FREE webinar on Wednesday June 19th 2013 at 4pm BST. Space is limited so please reserve your seat now. If you have any queries about the event, please do contact us.

Posted in e-records, Technology, TMF, Training

Why are Signatures Missing from the Average Office Computer Desktop?

Have you ever thought about the decision-making process for the purchase of office desktop software? I’ve never been involved in this activity so it is something I admit to knowing almost nothing about! However, there is one aspect that has intrigued me for a while. Let me explain.

The provision of office productivity software to all office-based employees is taken for granted these days. Certainly in the business sectors that I work, it is a given that every new employee will be given a computer (desktop or laptop, sometimes both) which has an office productivity suite pre-installed. This is more often than not Microsoft Office, which comprises a word processor (Word), a spreadsheet (Excel), a presentation package (Powerpoint) and electronic mail (Outlook) together with various related utilities. This is a significant cost to the employer; for a company employing 1,000 staff, they are spending around £5000,000 on desktop software. I see very little evidence of this purchase being justified…. what is the software being used for; are all components necessary; is the company getting value for money. Now, I’m taking a very simplistic view and I’m sure some of these discussions do go on but the fact is, it is taken as a given that everyone “needs” these products installed on their computer. And for the most part, I’d agree.

However, there is one significant component missing. We create documents electronically…. a report, a proposal, a letter. We create data files electronically….a budget, a costing proposal, an expenditure analysis. We create presentations electronically…. a conference lecture, a presentation to our department. And we use electronic mail to send all of these documents to our colleagues for input, information, review etc. The guys who have provided the tools to do all of this seem to have forgotten that a significant number of these documents then have to be signed once they have been reviewed and approved for use. Or at least, need some way of authenticating the origin and/or status of the document. So what do we do? Our desktop productivity suite does not include digital signatures so we have to print out the document and use a handwritten signature. Old-fashioned or what!!

I’m still struggling to understand why in the 21st century when we have legislation that supports digital signatures and we have technological solutions for digital signatures that have been tried and tested for years, we still don’t have the technology FULLY INTEGRATED into the desktop productivity suites we’re using and they’re pre-installed by our IT departments BY DEFAULT. So this is a plea to our IT colleagues. If you are spending upwards of £300+ on a desktop productivity suite for each of your staff, don’t miss one of the most vital components of the document life-cycle – review/approval. Let’s get the tools to keep our documents electronic across the whole of the life-cycle. When a large pharmaceutical company estimates the cost of obtaining one wet-ink signature from an external approver as $25 (printing, courier, processing, scanning), the cost of installing a digital signature solution pales into insignificance. Time for another paradigm shift??

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Migration Options for SharePoint 2013: Consider Your Options Carefully

This is the title of a blog posted recently on the AIIM website and I’d encourage you to take a look. The reason that I’m highlighting this link is because it is just so relevant given the presentation that I gave recently during a webinar run jointly with colleagues at Arkivum. Archiving requires the management and preservation of authenticity, integrity, reliability and usability of records over the complete record lifecycle. For this reason, we concluded that enterprise records management systems were probably not the most appropriate tool to consider for electronic acrhiving purposes. Just consider the migration needs not only for the documents but also for the attributes, transactions, audit trails and data dictionaries. The AIIM article highlights some of these issues in the context of attempting to migrate from SharePoint 2007 or 2010 to SharePoint 2013. Extrapolate those problems over a 15-25 year retention period and you’ll begin to imagine the difficulties!! If you are considering e-Archiving, ensure you do this as part of a comprehensive digital preservation strategy.

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Should Legislation Mandate Specific Minimum Retention Periods for Documents?

If we consider a variety of legislation on the statute book in the UK for example, it is more often the case that citizens and corporations are left to define their own retention period that is consistent with both the statute of limitations (Limitations Act 1980 in the UK) and any inspection or audit requirements. There is, for example, no mandated minimum retention period for personal financial records within the Finance Act but the legislation does provide for the possibility of an inspection by HMRC within six years of the end of the financial year. There is no mandated minimum retention period for documents that demonstrate compliance with the Race Relations Act 1976 but action cannot be brought once a period of six years has expired. Similarly, there is no mandated minimum retention period for workplace health assessment records within the Management of Health and Safety at Work Regulations 1999, but action cannot be brought once a period of six years has expired. There are exceptions to these general rules but explicit retention periods in legislation are usually consistent with the relevant period described in the Limitations Act.

Why is this relevant? Well last week, the rapporteur for the new draft Clinical Trials Regulation in the European Union (Glenis Willmott glenis.willmott@europarl.europa.eu) published her draft report on the proposals. The report includes 74 amendments to the draft regulation text, including a suggested amendment regarding retention times for clinical trial records (the trial master file). The original draft regulation stated the following:

 “Unless other Union legislation requires archiving for a longer period, the sponsor and the investigator shall archive the content of the clinical trial master file for at least five years after the end of the clinical trial. However, the medical files of subjects shall be archived in accordance with national legislation.”

This provides adequate time for regulatory agencies to conduct inspections of both the sponsor documents and investigator site documents. Clearly, if the sponsor’s timeline for marketing authorisation application extends beyond this five year period, the retention time would be extended in order to support the application. However, that is a decision for the sponsor.

The draft regulation has now been amended as follows:

“The sponsor and the investigator shall archive the content of the clinical trial master file for an indefinite period of time after concluding the clinical trial. However, the medical files of subjects shall be archived in accordance with national legislation. If the sponsor is unable to archive the master file, it may be archived in the EU database.”

The rationale for extending the retention period to indefinite is given as:

“Should a sponsor come under investigation for misconduct, the clinical trial master file would be vital. Therefore the master file should be archived indefinitely unless national legislation states otherwise. The master file can be stored in the EU database if necessary.”

I believe there are several significant problems with this new burden, not least of which is outlined in my introduction…. an indefinite retention period should not be mandated by legislation.

1. The existing retention period (minimum of 5 years after clinical trial completion and longer if the trial data supports a marketing application) should be sufficient to support the identification of misconduct.

2. If the reason for an indefinite retention is to help identify misconduct, it is questionable why the revised text permits reversion to national legislation with a shorter retention period be followed in preference to an indefinite period.

3. Given that a significant majority of clinical research misconduct is practiced by the clinical trial investigator site and not the sponsor, it is not understood why the sponsor’s retention period has been extended to indefinite but the subject files (source records) are only retained ih naccordance with national legislation, typically 5-10 years. It is usually the source records which help to confirm the presence of misconduct by the investigator.

4. The suggestion that the sponsor may archive the master file “in the EU database” is unworkable from a number of perspectives. Firstly, existing EU Directives and ICH GCP make it clear that the sponsor is responsible for retention of the sponsor trial master file. It is therefore inconsistent to suggest that if the sponsor cannot achieve this (or chooses not to), they may store the master file with the EMA in an EU database. The proposed wording suggests that it would be acceptable for the sponsor to transfer custodianship of the master file immediately a trial has closed. Secondly, it took several years for the development of a consistent content, structure and format for the clinical study report. Given the huge scope of the trial master file, it will take an age to agree the content, structure and format for master files to be submitted to the EU database. And finally, it is not clear what the “EU database” is that will be storing the trial master files. If it is the same database that is described in Recital 52, this significantly broadens the scope of this database and calls into question the requirement for its contents to be publicly available. This would open up the whole content of the trial master file to the general public.

5. No distinction is made between industry-sponsored clinical trials and investigator-sponsored clinical trials. The implication therefore is that the investigator site will similarly be required to retain their trial master files for an indefinite period. The implications of this burden cannot be under-estimated, both for industry and for investigators. Such a requirement may drive more clinical trials away from Europe.

And finally, this critique would not be complete without also commenting on Amendment 59, proposed text for Article 53, paragraph 1. The original text stated:

“All clinical trial information shall be recorded, processed, handled, and stored in such a way that it can be accurately reported, interpreted and verified while the confidentiality of records and the personal data of the subjects remain protected in accordance with the applicable legislation on personal data protection.”

This is now stated as:

“All clinical trial information shall be recorded, processed, handled, and stored in the format of a clinical study report, in such a way that it can be accurately reported, interpreted and verified while the confidentiality of records and the personal data of the subjects remain protected in accordance with the applicable legislation on personal data protection.”

The original wording referred to ALL clinical trial information in a wide variety of documents e.g. correspondence, monitoring reports, source data etc. However, the revised wording bizarrely suggests that all clinical trial information should be written in a clinical study report. Unless I’ve misinterpreted the text, this just doesn’t make sense.

If you are in agreement with my comments, I strongly urge you to read the draft report and submit a written response to Ms Willmott (glenis.willmott@europarl.europa.eu) as soon as possible.

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Update: MHRA GCP Guide Now Available in Electronic Format

Further to my posting in September to alert you to the availability of a new guide to Good Clinical Practice (GCP) from the MHRA, this guide is now also available electronically in Kindle format. Please note: it appears that currently the existence of this Kindle version is not highlighted on the MHRA website neither is it evident if you click on the link to purchase the guide. The purchase link only takes you to The Stationery Office (TSO) website to purchase a hard-copy version at £45.

To find the Kindle version, you need to go to the Amazon website and search for “good clinical practice guide” in the Books section. The search should reveal the hard-copy version (available at £42.75 / $85.00 plus p+p) but should also show the Kindle version at £32.06 / $59.99 (no postage fees!).

Don’t have a Kindle? Software is available to read Kindle books on PC’s, Apple devices (iPod, iPad and iPhone) and Android devices. If you prefer an iPad version, I believe that this is also being planned and should be published shortly. One of the advantages of the electronic version – other than not have to carry around a book that weighs 1.25kg – is that you can search easily for specific words and you can highlight and annotate sections.

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