Art Gertel

The biopharmaceutical industry is, perhaps, the most heavily regulated industry outside of nuclear power and aerospace. For the most part, this is because human safety is at risk. There is a clear mandate to ensure there are adequate protections in place to best safeguard the welfare of those who participate as subjects in clinical studies. To accomplish this, regulations require the establishment of oversight committees, including institutional review boards (IRBs) and independent ethics committees (IECs)—collectively referred to as Ethics Committees (ECs)and other bodies such as Data Safety Monitoring Boards (DSMBs). We will focus on ECs and examine how to optimize their time and effort to efficiently and effectively fulfill their human subjects protection remit.

The elements of these protections are set forth in ICH E6 R2: Guideline on Good Clinical Practices.

, the International Council on Harmonization(ICH) points out that “clinical trials have evolved substantially, with increases in globalization, study complexity, and technological capabilities.” They recommend that “to keep pace with the scale and complexity of clinical trials and to ensure appropriate use of technology we should modernize our approach to GCP to enable implementation of innovative approaches to clinical trial design, management, oversight, conduct, documentation, and reporting that will better ensure human subject protection and data quality.”

Focusing efforts on aspects of clinical trials with the greatest potential impact and/or harm (e.g., misleading or confusing information that might inappropriately influence a patient’s decision-making) would be consistent with the existing standards for risk-based monitoring of clinical studies.

review by a learned committee of every data capture document may protect clinical study subjects from potentially misleading or otherwise deficient content, and including such content together with the trial protocol is in keeping with the mission of ECs. Is there significant additional benefit in supporting review of final screenshots? Obtaining, reviewing, and filing all such screenshots requires a significant commitment of the committee’s time and effort. It should also be considered whether further evaluation of these images is ethically substantive or, rather, more of a quality control task that is a formal responsibility of COA system providers and Sponsor study teams. Does such a review represent an optimum use of the EC time, possibly causing them to spend precious time reviewing screenshots which share content with other data collection documents already under review? Conceivably, this could result in more harm than good—ultimately more of a burden than a clearly beneficial exercise.

Just as with other “protective” activities conducted during the course of a clinical trial, for example, risk-based monitoring, determination of causality associated with adverse events, and, adjustment of acceptable risk according to disease, one must consider the balance of risk of harm to prospective benefit. Thus, the burdensome task of converting from paper formats the representations of all of the screens to be used for data entry on devices must be weighed against the potential patient harm and, not insignificantly, the likelihood of delaying initiation of a clinical study while awaiting EC approval while all electronic versions of COAs are generated in final form for their review.

This issue is at the crux of this discussion—how do we achieve the optimum balance between research subject protection and practicality of the process of bringing new medical products, vaccines, diagnostics, and medical devices to patients in need, as well as advancing healthcare knowledge? If we unnecessarily delay availability of new medicines, we do a disservice to patients who may require innovative therapies.

Perspectives of each of the stakeholders will be considered in evaluating these issues and, in doing so, we will discuss the potential consequences that may result in harm or benefit both to individual research subjects, to the broader population and, indeed, to the research and development enterprise.

Contract research organizations (CROs) and sponsors now often request that data capture forms such as patient diaries, electronic patient-reported outcome (ePRO) assessments and other eCOAs be submitted to the EC. The request seems to be based on a broad interpretation of “written material to be provided to the patient” in ICH E6 R2 guidance rather than justification of relevance to patient safety or burden. From our experience, with names changed and circumstances altered to maintain confidentiality, the following scenario illustrates points in the execution of a study where procedural delay and complexity can occur.

Implementing an eCOA solution in clinical studies requires a substantial amount of activity, as shown in 

Figure 1: general eCOA implementation lead time

During the planning phase, the patient-reported outcome (PRO) measures and clinician-reported outcome (ClinRO) assessments to be programmed into the eCOA system are selected as part of the study protocol. 

During the design phase, the eCOA system provider faithfully migrates these COAs, based on industry migration best practices and on authors’ instructions. This migration process ensures that there are no changes in content, and that participants will interpret and respond the same way regardless of the mode of data collection. Screenshots obtained because of this faithful migration need to be approved by the author and/or an expert screen reviewer. In some instances, additional evidence such as cognitive interviewing and usability testing may be needed to confirm measurement equivalence.

Language implementation activities can begin once faithful migration has been finalized.

Such activities often include translations, and possibly linguistic validation.

The eCOA system software is then developed, validated by the eCOA system provider, and the system then undergoes UAT by the Sponsor or its designee, such as a CRO. Once UAT has been approved by the Sponsor, the electronic system is ready to be deployed in the original language.

The full complement of screenshots only becomes final in each original language when development, faithful migration, and formal evaluation activities have been completed. This is 7-to-14 weeks after the initiation of the planning phase. An additional 8-to-12 weeks needs to be added should cognitive interviewing and usability testing be required. At that time, the final screenshots can be taken and submitted to an EC for review.

Screenshots in targeted languages only become available 4-to-12 weeks after the finalization of the original language, depending on availability as templates, or if linguistic validation is required.

eCOA-related documents required for submission to an ec

Regulatory authorities worldwide have agreed, in most cases, to abide by guidance issued by the International Council on Harmonization (ICH), particularly ICH E6 R21, which applies to clinical studies conducted in the United States (US), European Union (EU), Japan, Canada, and other nations recognizing ICH E6 Good Clinical Practices (GCP) standards. The 2005 European Directive mandates Member States to harmonize processes to the GCP.

 While each national or regional authority has the freedom to issue specific guidance and regulation for studies conducted under their jurisdiction, the predominant underlying standards are those established under ICH. There are national differences regarding protection of patient/subject privacy; however, these will not be addressed in this manuscript.

ICH E6 R2 addresses documents to be provided to ECs, as follows:

3.1.2 The IRB/IEC should obtain the following documents.

Trial protocol(s)/amendment(s), written informed consent form(s) and consent form updates that the investigator proposes for use in the trial, subject recruitment procedures (e.g., advertisements),

(emphasis added) to be provided to subjects, Investigator's Brochure (IB), available safety information, information about payments and compensation available to subjects, the investigator’s current curriculum vitae and/or other documentation evidencing qualifications, and any other documents that the IRB/IEC may require to fulfill its responsibilities.

Note that the provision concerning written information is in the context of consent and recruitment, and does not specifically recommend that ECs obtain ‘screenshot representations’ of diaries, questionnaires, and clinician interviews that will be used to capture information. In contrast to the informed consent form, such scientific content for data capture is not physically provided to subjects to review and retain in conjunction with deciding to participate in an investigation. 

When consent forms are submitted for EC review, the EC will most often apply the approach that FDA recommends regarding EC review of audio or visual advertising, per the FDA Information Sheet “

 This guidance recommends that the EC review the storyboards and proposed text to identify potentially unduly influential language or images prior to incurring the expense of recording the final version. The guidance recommends that the EC then review the final versions of these documents. Using this logic, when an eConsent is submitted to the EC, if early in document development, the EC may ask for a storyboard and proposed text to perform an evaluation on both the initial and final versions.

The GCP Guidance includes, in Section 8, considerations on the Essential Documents for a study to support the review of the study by regulatory authorities. Section 8.2 includes a list of documents associated with “

the period before the clinical phase of the trial commences

should be generated and should be on file before the trial formally starts.

”1It should be noted that there is no specification that evaluation checklists, questionnaires, or diaries be obtained in all languages for review and approval as part of the “planning stage” of a trial. 

Section 8.2.3 applies to the “Information Given to Trial Subject” in the planning stage of a trial, and refers to “any other written information,” clarifying the purpose of such information as “

to document that subjects will be given appropriate written information (content and wording) to support their ability to give fully informed consent.”

Thus, guidance to ECs is narrowly focused on informed consent and written information related to recruitment. Nonetheless, some sponsors, CROs and ECs interpret the GCP Guidance to apply to 

 written information, regardless of relationship to inducement of subjects or whether shown/presented versus literally “provided” to the subjects. In addition, the content of these may be duplicative of other documents provided to the study subjects, adding little, if any, value in terms of useful information or increased comprehension. ICH E6 R2, Sections 3.1.2 and 8.2, instructs ECs to obtain a range of essential documents for review. 

The list does not mandate screenshots of 

that subjects will see during participation in a trial where eCOA is used to capture eSource records. Requiring screenshots of 

of all diaries and questionnaires into local languages is an expansive reading of ICH E6 Guidance.

For example, “Other written information to be provided to the subject” is a phrase used throughout ICH E6 R2 Guidance (Sections 3.1.2; 3.1.9; 4.4.1; 4.8.1-2; 4.8.9-11; 5.11.c; 5.11.2; 5.18.2; 8.2.3; 8.2.7; 8.3.2-3).1 The context is always limited to informed consent or incentives to subjects in recruitment, and never refers to the diaries, questionnaires, or other forms to be used for data collection, or to device instructions.

The provisions in the ICH GCP Guidance that identify “any other written information to be provided to the subject(s)” do not specifically mandate review of diaries and questionnaires.

 Nonetheless, providing the content and wording of such eCOA content to ECs in English is useful in determining the nature of the data that will be collected, its relevance to the objective of the trial (Section 2.5), and the possible burden on the subjects who will complete the questionnaires (Section 2.2).

 The scientists on the EC boards may also be interested in assessing the pertinence of any sensitive information that may be sought (Sections 2.2; 2.5; 3.1.2).

Specific national laws affirm the concept that it is not necessary to provide any COA instruments to the EC. For example, in French law there is no requirement that the CRF or any COA instruments be part of the dossier provided. The guidance is also silent as to whether the research documents are provided on paper or in electronic format.

The EC is primarily concerned with the protection of the rights, safety and/or well-being of the subjects (Section 3.1.5). Thus, an EC may request more information be given to subjects than is outlined in Paragraph 4.8.10 when, in the judgment of the EC, the additional information would add meaningfully to these protections.

Regulatory perspective (FDA’s office of GCP/EMAs IWG GCP)

GCP Inspectors do cover ECdocumentation during GCP-inspections and often request the documentation that was provided to the ECs and designated to be given to trial subjects.

Several inspectors have indicated that the ECs can decide whether screenshots should be sent separately or as part of the clinical trial protocol. However, the opinion of inspectors is that details about diaries belong in the protocol (appendix) or a related document – in which case it would also be provided to the EC and the competent authorities. We are in agreement with this process and believe that a paper version of the content of a diary or other COA should be part of the information submitted with the clinical trial application.

To our knowledge, after hundreds of inspections and audits of sites, sponsors, eCOA/ ePRO system providers, the provision of eCOAs only in English and only on paper as part of a protocol has never been identified as inadequate provision of “written materials.”


Based on the guidance from regulators and ECs, our understanding of the purpose of ethical review, as well as previous examples describing potential consequences of requiring a plethora of eCOA documentation, we are proposing the following framework for documentation to be provided to ECs, including both local and central IRBs:

Paper documents that convey the content and wording (but no need for final screenshots showing layout and appearance) of measures the subject is to complete as well as any COA forms to be entered by clinicians on the eCOA system; include a description of the Time-and-Event schedule, and planned schedule for the

 Often these capture instruments themselves and the scientific rationale for collecting associated data are already included in the protocol; however, if absent from the protocol, they should be listed in the EC submission. 

Descriptions of data capture devices to be used in the study, including any regulatory approvals (e.g., for medical devices such as glucometers and peak expiratory flow meters); summary of training for the subject on the devices; privacy and security protections; and summary of administrative functions required to implement the eSource data capture forms for entry, transmission, maintenance, and retention in the provider’s system

. This would provide a better sense of what the subjects would experience in the study and how the electronic systems would maintain security and privacy of data. It would supplant the need to show and explain every administrative screen, and their translations. This then obviates the need to generate and review potentially thousands of pages of documentation for global studies. Even if screenshots are reviewed, they do not typically include discussion of how the implementation of the system for capture may contribute to the scientific and ethical merit of the study.

The description of the processes followed to ensure appropriate translations are being obtained

. Certificates of translations may be provided, if requested, when completed. 

Screenshots of eCOA questionnaires as they appear on the devices, together with their translations. Requiring screenshots would be redundant, as eCOA system providers do not change the content and meaning of data collection forms when implementing electronic capture. Further, eCOA system providers perform “faithful migration” of the COA content and follow requirements of the COA instrument developer if the content is already developed for use electronically. To require screenshots – and translations - puts undue pressure on up-front timelines for study start-up, while not providing further information of value to ECs for their review.

Administrative screens that may appear before, or during, the COAs and screens that appear to direct the subject to complete items or advance to the next screen; rules for moving from one screen to the next, or how to transmit a questionnaire after it is completed. Administrative screens do not change the scientific nature or the meaning of the questionnaires. To include these screens requires much of the up-front programming and translations to be completed, again placing undue pressure on already compressed study start-up timelines. 

Actual devices for review by the EC. If well-described summaries of the descriptions of the devices are provided, this should be adequate.

With recent Patient-Focused Drug Development deliberations and the passing of the 21stCentury Cures Act

 in the US, there has been more focus on risk-based, patient-centric drug development to help patients benefit from newly developed drugs sooner. Creating documentation that may not protect clinical trial subjects, is time-consuming and costly to produce, and that ultimately does not benefit subjects should be discouraged. After review of applicable regulations and guidance documents, along with many discussions among stakeholders across the clinical development process, we believe our proposal for a simplified way to look at EC submissions for eCOA documentation reflects best practices. For pharmaceutical sponsors, our proposal would reduce the complexity, costs, and timelines associated with such submissions without increasing potential risk or compromising subject protection. For eCOA system providers, it reduces unnecessary and time-consuming paperwork, and alleviates the timeline pressure to generate screenshots before the electronic implementation of the study is completed. For ECs, our proposal would reduce paperwork submissions for review that are not essential and may not even be reviewed. Ultimately, our justification and recommendations stand to support subjects through reducing timelines and costs of drug development. If we unnecessarily delay innovative medicines, we do a disservice to patients-in-need. Limitations to this proposal include instances of regional/cultural differences or therapeutic areas that may require additional documentation.

Based on our review of the guidances that govern submissions to ECs, we find no evidence that there is a specific requirement to submit for review the actual devices that will be used during the trial; screenshots of electronically implemented questionnaires as they appear on the devices; administrative screens that may appear before or during the entry of eCOA data, nor corresponding translations. Further, we believe requests for these screenshots would be an expansive interpretation of the ICH guidance. Such requests lead to unnecessary delays in the drug development process, as well as increased costs for sponsors and, ultimately, consumers. They do not provide additional human subject protection for clinical trial participants. As ICH GCP guidelines are reviewed, clarification on this matter would provide further support for simpler and more streamlined EC submissions of eCOA questionnaires to be used in a clinical trial.

, MBA, MAis the Executive Director of patient centered at

, DrPH, JD, LLM, is the Public Health & Outcomes Project Director at the

International Drug Development Institute.

MA is Associate Director of Critical Path Institute’s Patient-Reported Outcome Consortium and Acting Director of the Electronic Patient-Reported Outcome Consortium.

Views expressed in this manuscript do not necessarily reflect the official policies of the Department of Health and Human Services nor does any mention of trade names, commercial practices, or organizations imply endorsement by the United States Government. Support for the Electronic Patient-Reported Outcome (ePRO) Consortium comes from membership fees paid by members of the 

Bhatt A. International Council for Harmonisation E6 (R2) addendum: Challenges of implementation. Perspectives in Clinical Research. 2017; 8:162.

International Council for Harmonization (ICH) Steering Committee. Final Concept Paper Addendum for ICH E6: Guideline for Good Clinical Practice. 2014. Available at 

https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2_Concept_Paper_July_2014.pdf. Accessed 8/7/19

Commission of the European Communities. Commission Directive 2005/28/EC of 8 April 2005 laying down principles and detailed guidelines for good clinical practice as regards investigational medicinal products for human use, as well as the requirements for authorization of the manufacturing or importation of such products. Official Journal of the European Union. 2005;91:13-9.

U. S. Food and Drug Administration. Office of Good Clinical Practice. (1998). Recruiting Study Subjects Guidance for Institutional Review Boards and Clinical Investigators. Washington, DC.

Coons SJ, Gwaltney CJ, Hays RD, et al. Recommendations on evidence needed to support measurement equivalence between electronic and paper-based patient-reported outcome (PRO) measures: ISPOR ePRO Good Research Practices Task Force Report. Value in Health. 2009; 12:419–29

Wild D, Grove A, Martin M, et al. Principles of good practice for the translation and cultural adaptation process for patient‐reported outcomes (PRO) measures: report of the ISPOR Task Force for Translation and Cultural Adaptation. Value in health. 2005; 8:94-104.

Wild D, Eremenco S, Mear I, et al. Multinational trials—recommendations on the translations required, approaches to using the same language in different countries, and the approaches to support pooling the data: the ISPOR patient-reported outcomes translation and linguistic validation good research practices task force report. Value in Health. 2009; 12:430-40.

Raymond S, Gertel A, Barrasso B, Hackett A. Optimizing Electronic Clinical Outcome Assessment Materials Required for IRB/EC Review. Medical Research Law & Policy Report. 2016; 15 MRLR 159.

AFSP1635538A, Order of December 2, 2016 setting the content, the format and the modalities of presentation of the file of request of opinion to the committee of protection of the people on a research project mentioned in 1 ° of the article L. 1121-1 of the code of Public Health Concerning a Drug for Human Use. Available at 

https://www.legifrance.gouv.fr/affichTexte.do?cidTexte=JORFTEXT000033545400&categorieLien=id

21stCentury Cures Act. United States PUBLIC LAW 114–255—DEC. 13, 2016. 

https://www.congress.gov/114/plaws/publ255/PLAW-114publ255.pdf

Articles

Examining how to optimizing the time and effort of Ethics Committees to efficiently and effectively fulfill their human subjects protection remit. 

Demystifying Submissions of eCOA Documentation for Ethics Review: Are We Making Submissions More Difficult than Necessary?

	The world of clinical research includes participants from many sectors: the pharmaceutical industry, government agencies, academia, healthcare providers, subjects, patients, technology providers, and many others. While there may be the perception that a

 has evolved through common usage, this is not the case. We may find ourselves using common terminology, yet the strict definitions and interpretations of these words often differ markedly. This is not due solely to differences in native language or culture, but to the multiple “authoritative sources” of clinical research applicable definitions, including FDA, EMA, ICH, WHO, International Organization for Standardization (ISO), and specialty groups that code and use terminology for healthcare, payers, hospitals, and other stakeholders. While, in principle, the Glossary addresses global use, the primary sources of definitions are based on those derived from U.S. and European standards organizations and regulatory authorities.  

	Add to this scenario the need to ensure that information provided is both human- and machine-readable-a concept called “interoperability.” This really was the genesis point for CDISC-evolving, of necessity, as a standards organization at the beginning of the age of electronic data collection, analysis, and submission to regulatory authorities in support of new drug applications for marketing approval.  

	The long-standing Mission Statement for CDISC’s Glossary Group-the longest-serving working group under the CDISC umbrella (convening for the first time in 2002)-echoes these origins:

CDISC Glossary seeks to harmonize definitions (including acronyms, abbreviations, and initials) used in the various standards initiatives undertaken by CDISC in clinical research. Glossary also serves the community of clinical researchers by selecting and defining terms pertaining to clinical research, particularly eClinical investigations, sponsored by the pharmaceutical industry or a federal agency.

	Recently, it has become apparent that the clarity and comprehension provided by the Glossary supports colocation and translation of the concepts in the many countries where research is done, and the resulting products are used. 

	Thus, the Glossary is intended to serve both novice and experienced users as an authoritative advisory resource in the context of clinical research and development.  To accomplish this, it was necessary to identify recognized sources of definitions, clarify differing contextual interpretations, and, as much as possible, harmonize across a global landscape of word usage. It should be emphasized that the Glossary Group is not a standards development body but, rather, one that has developed an aid to better understanding the terminology.

	Occasionally, the members of the group made modifications to definitions in order to better represent the most common use or, when no authoritative source was identified, defined the term, based on their extensive collective experience in the conduct of clinical studies; collection, analysis, and interpretation of data derived from those studies; and long-standing roles in the development of CDISC models for protocols, data standards, and collaboration with regulatory authorities worldwide.

	The CDISC Glossary Version 11.0 adds to the four groups of new terms included in last year’s update: Milestones, eSource, Transparency, and Clinical Trial & Clinical Study. This year’s Glossary expands the Outcomes Assessment (and eCOA) and endpoints; and includes some new terms from ISO for the identification of medicinal products (IDMP), the ICH E6 update, and elements from the Common Protocol. The NIH-FDA BEST (Biomarkers, Endpoints, and other Tools) Resource, which contains FDA-NIH harmonized terms used in translational science, is included the Glossary’s Reference Citations section. Specific terms are included in this year’s update.

	An additional technical update made this year is that the CDISC glossary content will be integrated into the NCI Thesaurus (NCIt; ncit.nci.nih.gov), an open source, publicly available biomedical coding terminology developed by the U.S. National Cancer Institute’s Enterprise vocabulary services (NCI-EVS).

	Examples of operational issues addressed in the course of the Glossary development include: 

Providing useful resources beyond the term definition

 Although the focus of the Glossary is to define commonly-used terms, the group determined that there would be great added value in providing links to associated information. These allow the user to further explore context and nuance that cannot be accommodated in the Glossary itself. Table 1 shows an example of the Excel table.

 On occasion, there were multiple legitimate definitions that needed to be considered. These definitions usually differed due to associated context. Thus, in order to recognize this, we provided these definitions with explanatory notes that conveyed the rationale and appropriate use. Older versions of the Glossary were organized like a dictionary of terms, without supporting the sorting and searching utilities that enhance review of a tabular format. This year, for the first time, the Glossary and its many formats can be filtered and the terms are unique (see Table 2). Each unique term has a single definition and synonyms, or similar terms, are noted.

 Adding this new and long-awaited feature to enable easier searching and readability, the Glossary has been updated to a PDF-based tabular format with searchable functionality. Terms can be sorted and filtered. Thus, it is truly sortable, linkable, and serviceable as a “go-to” reference tool. This version is remarkable in that it will be available in six different formats and more suited for digital download and use. These are Excel, Windows text file (.txt), odm.xml, pdf, html, and OWL/RDF formats. 

 Terms were carefully selected to ensure that they were germane to clinical R&D. We provide definitions that are, hopefully, sufficient to gain a basic understanding of the term and context. As noted earlier, the links to the source(s) are provided should the user wish to go into more depth. Terms are co-located and electronic searching is augmented by “child-parent” term organization.

Some terms carry with them long-standing confusion among users. We have addressed, as much as possible, ambiguity in existing reference source definitions and provided clarification. Some examples are the often synonymous but confusing use of “dose” and “dosage”, as well as “study” and “trial.” An example of the Excel table is shown in Table 3.

 Links will also be provided in the Glossary to access acronyms, abbreviations, and initials. The 

 list was not comprehensively updated during the Glossary update cycle for Version 11.0.

	Next year, the CDISC Glossary Group will continue to address concepts introduced and presented in new guidelines. As technology and globalization continue to evolve, we will be taking on the impact of guidances like the EU Clinical Trials Regulation (CTR) that goes into effect when the European database is operational. We will also continue to address concepts around transparency and disclosure as the pharmaceutical industry and regulators wrestle with the pragmatic logistics of providing timely and useful information to the research community, while protecting patient privacy.

	We test links to sources for individual terms and, while not all terms are updated each year, we will reassess terms periodically to ensure currency. Although the Glossary is now available in six formats, we will be exploring how to optimize it for use on handheld devices.

- Authors of this report and Glossary Team members: 

 (Team Chair), MA, Sr. Director, Janssen R&D Companies of J&J; 

, PhD, Chief Scientist, Scientific Affairs, ERT; 

, PhD, Clinical/Biomedical Information Specialist, Enterprise Vocabulary Services, National Cancer Institute

, Director, Master Data Standards, Global Clinical Development Operations, Janssen R&D Companies; 

, Senior Management Consultant, MC Consulting; 

, Global Data Standards Manager, F. Hoffmann-La Roche Ltd

We would also like to acknowledge the assistance of CDISC staff and SIRO Clinpharm

Reference tool is a Rosetta Stone for clinical research. A look at the updates and enhancements in latest version.

Art Gertel

Articles

Demystifying Submissions of eCOA Documentation for Ethics Review: Are We Making Submissions More Difficult than Necessary?

CDISC Glossary of Clinical Research Terminology