GCP Snippets: Copies Without Originals ??

ICH E6 (R3) features an inconspicuous, but troublesome concept called “certified copy”. The glossary defines:

??“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 as the original, including relevant metadata, where applicable.”

Despite sounding boring, it gains momentum in section C.2.9:

?? “When a copy is used to permanently replace the original essential record, the copy should fulfil the requirements for certified copies.”

First, you might realise that production of certified copies will be a time-consuming task if you apply it to every single essential record in the Trial Master File and Investigator Site File - which you probably have to do, despite the lip-service that ICH E6 (R3) pays (in section 3.10 and elsewhere) to the “proportionate and risk-based approach to quality management”.

Moreover, in the computer age, differentiating between an original and its copy is not an easy task. In the 1970s, a letter from the ethics committee would be a paper with letters printed on it, whereas in 2025 the ethics committee might send an PDF file via e-mail. Is the PDF file the original and a paper printout a copy? Is the downloaded PDF file still the original? Or was the Word version of the PDF file the original and we should ask the ethics committee for a certificate that the PDF file is actually a copy?

ICH E6 (R3) does not define what “the original” is and for many documents it is hard to classify them as originals or copies. E.g., for clinical trials that are subject to the EU Clinical Trials Regulation, the interaction between the involved parties is accomplished via the online portal CTIS. CTIS can be used to transfer and store previously produced PDF files, while some documents are generated by and in CTIS, for example the list with requests for information. Is the PDF version of this list the original? Or is the data set in CTIS the original? If yes, who could produce a validation of the generation of the PDF file? A data set, a PDF file and a paper printout are very different things when you look at their materiality. Some of the meta data of the CTIS data set might be lost when you generate the PDF file and some of the PDF file data are lost when you produce a paper printout. Given that, is the PDF file or the paper printout still a copy of the CTIS data set? Perhaps there is more than one original? ??????

Even if the generation of PDF files from CTIS would somehow be validated by the EMA it would be meaningless, since data handling in CTIS is not 100% reliable for some circumstances: The EMA published a 20 page booklet called “Clinical Trials Information System (CTIS) List of known issues for Sponsor Users”, whose February 2025 version features, among many others, the following bug: “When a temporary halt is submitted, in the CT summary screen, the end of trial date is updated with the temporary halt date”. Starting from August 2022, the EMA presents the workaround “There is no workaround until the issue is fixed”…

If CTIS is unable to capture and display such a simple piece of information correctly, can you trust in accurate production of originals or copies? The EMA “Guideline on computerised systems and electronic data in clinical trials” tries to illuminate how certified copies are produced, but that does not help if you have no access to the original or to one of the originals.

Thankfully, the human factor and along with it the rational judgement is not yet overwritten by AI.

For many documents in the clinical trials context it is hard to define whether they are originals or copies and whether the copy, if classifies as such, is certified. For documents generated by the online portal CTIS this is hardly possible.

How to cope with this confusion? Perhaps a “Plan about originals and copies” helps, which lists the files that are regarded as originals, defines qualifications for a copy and how to ensure that copies are certified.

You might submit this plan as part of the application. ??

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https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/guideline-computerised-systems-and-electronic-data-clinical-trials_en.pdf

Amrei Bahr: Was ist eine Kopie? ISBN 978-3-7873-4056-9.