In this report we are going to challenge the ‘requirement’ for finalized electronic Clinical Outcome Assessment (eCOA) screenshots and localized application (app) content as part of the Institutional Review Board (IRB) / Independent Ethics Committees (Ethics) approval process. By removing this inherent hurdle from the approval process, sponsors and vendors will be able to focus on study delivery which will get treatments to patients faster.
Clinical research is a heavily regulated industry, fundamentally because human safety is at risk. There are mandates in place to protect the welfare of those who volunteer in clinical studies and the elements of these protections are set forth in ICH E6 R2: Guideline on Good Clinical Practices1. One of the founding principles of the ICH Guidelines is the establishment of independent oversight committees in the form of IRBs (as termed in United States) and Ethics committees (as termed in the rest of the world).A key element of the IRB / Ethics process is the review of ‘Patient Facing Materials’ which relates to the informed consent process and any written information related to recruitment.
The requirement for IRB / Ethics oversight, predates the digital era, and to some reading this report it may be hard to believe but there was a time when clinical trials were done on paper, going electronic was something new and there was reticence and misunderstanding around what ‘going electronic’ meant. To address this, the industry (as was then), decided to promote an understanding within the IRB / Ethics community, of the ‘minimal impact’ that going electronic would have on patients that they would supplement the ‘Patient Facing Materials’ with screenshots of the electronic eCOA implementation. As clinical research expanded globally, and electronic adoption took off this then was extended to also include localised app content. Hence the industry inadvertently expanded the interpretation of the original GCP guidance to apply to ‘any’ written information which is presented to the patient which in turn has set expectations with Sponsors, Clinical Research Organizations, and IRB / Ethics boards around what is to be included in the submission packets for review. This is best summarized by Gartel et al2 in who in 2020 said, “Requiring screenshots of translations of all diaries and questionnaires into local languages is an expansive reading of ICH E6 Guidance.”
However, in 2022 both Advarra and WCG (two of the leading centralized IRBs in the United States) announced independently that they did not expect the submission of screenshots for standardized eCOA as part of the submissions process, which was a major step in resetting the interpretation.
In general, the United States (US) has evolved to a world where finalized eCOA screenshots are not required, but research is a global activity, so we have to consider other territories. There is still a perception that outside of the US, submissions need to follow the de facto assumptions around the need for finalized eCOA screenshots and localized app content, however recent changes in the global regulatory landscape may provide an opportunity for change and harmonization of processes between the US and European Union (EU).
Within the EU, as of the 31st of January 2023, all new clinical trials are governed by the Clinical Trials Regulation (CTR): REGULATION (EU) No 536/2014 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 16 April 2014 on clinical trials on medicinal products for human use3. So, the question is “Does the CTR provide an opportunity to reset perceptions around the need for finalized eCOA screenshots and localized app content?” To get an answer we must follow the definitions trail as described below.
Within the CTR under ANNEX I: APPLICATION DOSSIER FOR THE INITIAL APPLICATION in section L SUBJECT INFORMATION, INFORMED CONSENT FORM AND INFORMED CONSENT PROCEDURE (INFORMATION PER MEMBER STATE CONCERNED) under item 61, the CTR states:
61. “All information given to the subjects (or, where applicable, to their legally designated representatives) before their decision to participate or abstain from participation shall be submitted together with the form for written informed consent, or other alternative means according to Article 29(1) for recording informed consent.”
Based on this part of the regulation, it all comes down to the definition and interpretation of ‘All information’ and this has led to the assumption that eCOA screenshots should be part of “All information.” However, when you read the regulation itself, L.61 also uses the critical phrase “before their decision to participate or abstain….” This is referring to the Informed Consent process and participant facing materials, which are presented to participants for review, prior to their agreement to be part of the trial. If finalized eCOA screenshots and localized app content are included in the interpretation of L.61, then that means that they are both part of the Informed Consent Process. So, the question to ask is, “How many studies have you been involved in that include the finalized eCOA screenshots (or even a representation of the COA materials) and localized app content as part of the consenting process?” – and it is fair to assume that the answer is zero.
Next, when we look at how under the CTR studies are approved for implementation in the EU, we see that the process is split into 2 parts; Part I (Protocol approval) and Part II (Ethics approval).
Part I (Protocol approval) is akin to gaining approval from the FDA and under the CTR this approval can be obtained up to 2 years in advance of the start of the study. Under CTR, as with an FDA submission, the COA to be used is expected to be included as part of the Part 1 submission. As it is unlikely that a sponsor will know in advance which eCOA vendor they will use for the study, the CTR states that the submission process under the Clinical Trials Information System (CTIS) does not expect eCOA screenshots to be included as part of the Part 1 submission. Instead, as with an FDA submission paper versions of the COA can be submitted as part of the Part 1 process. Also, the Part I process is in English only, hence the COA does not need to be localized either.
Under CTR, the COA piece has been separated out from the Ethics component (Part II), and the Part II submission is now all about the consent information (as detailed in L.61 above). This has not gone unnoticed by sponsors who have asked for clarity as detailed in the working group Question and Answers document4 and the European Medicines Agency has provided a ‘crystal clear’ answer [emphasis added.
“Question 23: According to Annex I of the CTR (L. 61.), all information given to the subjects (or, where applicable, to their legally designated representatives) before their decision to participate or abstain from participation, shall be submitted together with the form for written informed consent, or other alternative means according to Article 29 (1) for recording informed consent.
The CTR does not mention other patient-faced materials, such as diaries, patient reported outcome questionnaires, etc.
Should diaries, ePROs and similar patient-faced materials need to be included in the Part II dossier according to the CTR?
Answer: Refer to Q.1.24 EudraLex – Volume 10 and its Q&A document on patient facing documents.
Patient facing documents are documents, other than recruitment material or subject information sheets, presented to clinical trial participants during the conduct of the clinical trial. These can be questionnaires, patient diary, patient card or patient reported outcomes (PRO/ePRO).”
So, this answer is ambiguous and could be interpreted as screenshots should be included in a Part II submission. Let us now look at the referenced Question and Answer document in Q.1.24 Eurdex – Volume 105. When we do, we are presented with the following:
“1.24 Question: How are patient-facing documents expected to be submitted?
77. Answer: Patient facing documents are documents, other than recruitment material or subject information sheets, presented to clinical trial participants during the conduct of the clinical trial. These can be questionnaires, patient diary, patient card or patient reported outcomes (PRO/ePRO). Below, the text explains the difference between recruitment material and patient facing documents.
78. Annex I of the CTR describes the content of the clinical trial application part I and part II. Section K60 of annex I refers exclusively to recruitment material (copies of the advertising material, including any printed materials, and audio or visual recordings), and section L61 refers exclusively to all information given to the subjects together with the informed consent form (or, where applicable, to their legally designated representatives) before their decision to participate or abstain from participation in the clinical trial. Recruitment material or subject information sheets are to be submitted in part II, and no other documentation shall be submitted under these sections. If along the clinical trial duration specific concerns arise requiring informing the clinical trial participants or requiring a re- consent these materials should also be provided within a substantial modification as part II documents.
79. Patient facing documents that are linked to the endpoints of the clinical trial shall be provided together with the protocol in part I of the clinical trial application, in line with Annex I of the CTR (section D14 and D17l). These documents will be assessed during Part I assessment. See also Q1.5.
80. Patient facing documents will need to be submitted in line with Annex II of this document (i.e., for several Member States patient facing documents should be provided to the CT participants in a language understandable for the CT participants). Sponsors are responsible for ensuring the quality of the texts to be provided to the participants.
81. There is currently no legal basis in the CTR to request the submission of all patient facing documents in the part II documentation package and/or to require their translation.”
The key points here are items 79 and 81. They make it clear that because eCOA are endpoints they are not included in the Part II submission. There is no legal requirement for translated materials to be submitted under the CTR.
The advent of the CTR in the EU has resulted in the harmonization of the protocol approval processes within the US and EU. The main takeaway from this is that finalized screenshots are not required as part of the Ethics approval process in the US (when using Advarra or WCG as IRBs) or in the EU as part of the Part I or Part II submissions process. In an ideal world the above logic would be applied to data capture forms which are not endpoints, such as eDiaries. There is an argument that when an eDiary is mentioned in a protocol, if it is not associated with any endpoints, then it falls under the remit of Part II as it is patient facing materials. However, as detailed above, under the CTR these would still be provided in paper form rather than finalized screenshots.
While the CTR is clear about the requirements, Ethics committees may still rely on their ‘expectations’ rather than regulation as acceptance of the above is a seismic change in the EU submission processes. Change can be hard and even though finalized eCOA screenshots and localized app content are not required, a compromise (if requested) would be to supply paper versions of translated COA in this period of transition.
We hope that the new CTR and the use of CTIS will promote central adoption of the regulated standards by member state Ethics committees and if the above is reflected in future Ethics approval processes, then this can only be for the good of clinical research, removing an unnecessary burden from vendors and sponsors. Let us see how this plays out now that CTR and CTIS are the new normal for EU clinical research.
References:
- https://database.ich.org/sites/defauklt/files/E6_R2_Addendum.pdf
- https://www.appliedclinicaltrialsonline.com/view/demystifying-submissions-of-ecoa-documentation-for-ethics-review-are-we-making-submissions-more)
- https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=celex%3A32014R0536
- https://www.ema.europa.eu/en/documents/other/questions-answers-query-management-working-group-ctis-ctr_en.pdf
- https://health.ec.europa.eu/medicinal-products/eudralex/eudralex-volume-10_en