Stakeholders’ views on the most and least helpful aspects of the ICH E6 GCP guideline and their aspirations for the revision of ICH E6(R2)

Background The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) has published the ICH E6(R2) Good Clinical Practice (GCP) guideline, which provides standards for the design, conduct, documentation, and reporting of clinical trials. Revision to E6(R2) is currently underway, aiming to adapt the guidance to the current regulatory environment. The Clinical Trials Transformation Initiative (CTTI) interviewed stakeholders, gathering their experiences implementing ICH E6 GCP and suggestions for revising the guidance. Methods We conducted a qualitative descriptive study using in-depth interviews. Participants were purposefully selected to ensure diversity in geography, research role, and type of institution. Participants reflected on their aspirations for the ICH E6 GCP revision and described sections of the guidance that they found most and least helpful. Narratives were analyzed using applied thematic analysis. Results Many participants found ICH E6 GCP generally clear and helpful. They appreciated that the guidance is globally accepted and serves as a common standard for research worldwide. Participants also noted opportunities for improvement, suggesting that the revised guidance should incorporate flexibility, simplify requirements, and accommodate advances in research conduct. They highlighted areas where language should be updated and concepts clarified and expressed a desire for transparency and inclusiveness in the revision process. Conclusion Our findings show that many participants view the ICH E6(R2) guidance as helpful overall, although substantial room for improvement remains. We have provided the full report of these findings to ICH in hopes that it will be useful as the E6 GCP guideline is revised.


Introduction
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) aims to achieve greater harmonization worldwide for developing safe, effective, and high-quality medicines [1]. ICH has published numerous guidelines to facilitate its mission, including the ICH E6 Good Clinical Practice (GCP) guideline [2], which provides standards for the design, conduct, documentation, and reporting of clinical trials. The guideline is intended for clinical trials with data collected for regulatory submission but states that the general principles "may also be applied to other clinical investigations." ICH E6 GCP was first released in 1996 as E6(R1), and an integrated addendum to the guidance, E6(R2), was issued in 2016. This addendum was intended to address evolutions in technology and clinical trial practices occurring since the (R1) release and to encourage greater efficiency in clinical trials.
Several critiques of ICH E6 GCP have been identified, including lack of flexibility [3,4], confusion around application of the guidelines to non-regulatory trials [3], inconsistencies between the original guidance and the (R2) addendum [3], challenges with implementing the guidance in low-and middle-income countries [4][5][6], and lack of transparency and stakeholder inclusiveness [3,7]. Updates to the E6(R2) guidance aimed at acknowledging and addressing many of these criticisms are currently underway [8]. ICH describes that the goal of this revision is to better adapt to the current regulatory environment by "addressing the application of GCP principles to the increasingly diverse trial types" and data sources being utilized and by providing "flexibility … to facilitate the use of technological innovations in clinical trials" [9]. Where appropriate, the revision will preserve concepts and guidance from the previous version but will include modifications aimed at providing guidance for a diversity of approaches to clinical trials, as well as address gaps and inconsistencies [9].
The Clinical Trials Transformation Initiative (CTTI) conducted a multi-method project aimed at providing ICH with recommendations on ICH E6 GCP from a diverse group of stakeholders representing academic, pharmaceutical, and other institutions engaged in the conduct of clinical trials. CTTI is a public-private partnership between Duke University and the United States (U.S.) Food and Drug Administration that develops and drives the adoption of practices to increase the quality and efficiency of clinical trials. CTTI independently conducted a 3-phase project consisting of (1) a global online survey, (2) qualitative, in-depth telephone interviews, and (3) an open comment platform [10]. The purpose of these activities was to gather stakeholders' perceptions of areas in ICH E6 GCP that are in greatest need of revision, their experiences with implementing ICH E6 GCP, and their suggestions for revising the guidance. This paper describes the findings from the in-depth qualitative interviews; the results from the other phases of the project are available elsewhere [11,12].

Study design
We conducted a qualitative descriptive study [13,14] using in-depth interviews (IDIs).

Participant eligibility and selection
Stakeholders were eligible to participate in the IDIs if they completed the online survey and self-reported that they 1) regularly reference ICH E6 GCP to implement their research, 2) conduct research for registrational purposes, 3) were willing to have the information they provided in the IDI be linked to their name and organization, and 4) were interested in participating in a follow-up IDI and share their experiences with implementing ICH E6 GCP and suggestions for its improvement. Among these eligible stakeholders, we purposefully selected and invited participants for the IDIs to ensure that the sample was diverse in geographic location of employment, countries where participants conducted research, role in research (e.g., investigator, clinical operations personnel, quality assurance personnel), and type of institution (e.g., university/academic center, pharmaceutical company, contract research organization [CRO]).

Data collection
A trained qualitative interviewer conducted the IDIs in English and on the telephone from September 15 to November 29, 2019. Reflecting on the 2016 ICH E6(R2) addendum, participants were asked to describe (1) their overall hopes for what the revision to ICH E6 GCP will achieve, (2) sections of ICH E6 GCP that they have found most helpful and why, including examples of how they have applied the guidance, (3) sections of ICH E6 GCP that have been least helpful to them and why, including examples of difficulties encountered in applying the guidance, and (4) suggestions for how ICH E6 GCP guidance could be improved and how this would subsequently improve trial conduct. Although participants were not asked to reflect specifically on their survey responses, when requested by the participant, or if the participant needed encouragement to respond to the interview questions, the interviewer reminded participants about the areas of ICH E6 GCP they previously indicated in the survey were in need of revision.

Data analysis
We used descriptive statistics to summarize the demographic data and applied thematic analysis [15] to analyze participants' IDI narratives. All interviews were transcribed verbatim following a transcription protocol [16]. We used NVivo 12 [17], a qualitative data analysis software program, to organize the data and apply codes to the transcripts. First, two analysts developed and independently applied structural codes based upon the three primary research questions: 1) aspirations for the revision of ICH E6 GCP, 2) helpful sections, and 3) unhelpful sections and suggested revisions. These structural codes were further segmented into sub-codes for 1) each of the eight sections of ICH E6 GCP, and 2) general comments about each of the research questions. Inter-coder agreement was assessed on five interviews (22%), discrepancies in code application were resolved through discussion, and where necessary, structural coding was revised accordingly.
Next, the analysts identified content codes within each structural code that reflected participants' aspirations, experiences, and suggestions for updating ICH E6(R2). The sub-sections of ICH E6 GCP were used to categorize these content codes while general comments were coded separately. Analysts also identified overarching themes, content codes that emerged across numerous sub-sections of ICH E6 GCP. Code frequency was reviewed to identify participants' main experiences and suggestions. While several important themes were identified based on frequency, many valuable experiences and suggestions were shared by only a small number of individual participants. All IDI participants were well-positioned to provide helpful information based on their unique experiences and insights; therefore, we included most participant comments in the final CTTI report [18] and highlighted the most salient findings here.

Ethics
The Duke University Health System Institutional Review Board (IRB) determined that the research was exempt from further IRB review.

Participant characteristics
Of the 327 individuals who completed the survey, 75 agreed to be contacted for IDIs, and 23 participated in the IDIs. Participants were employed in 10 different countries (Table 1): Argentina, Australia, Belgium, Canada, France, Germany, Ireland, Switzerland, United Kingdom, and the US. Similar to the survey population [11], most interview participants were from Europe and North America. Participants conducted research in 124 countries worldwide (Supplemental Appendix A). Participants also held various research roles, including principal investigator, co-investigator, and clinical operations, quality assurance, and regulatory affairs personnel, and represented different types of institutions, such as academic research centers, pharmaceutical companies, CROs, and non-governmental organizations ( Table 1).

Helpful aspects of the ICH E6 GCP guidance
Many participants stated that ICH E6 GCP is helpful, generally clear, and useful for training. Participants described that ICH E6 GCP represents the only globally accepted guidance, serving as a common standard for research worldwide, and they stated that it is particularly useful for establishing a research framework in countries with underdeveloped legal or regulatory requirements for trials, or where variation in regulations exists between countries. They explained that having this common framework is helpful for ensuring that globally generated trial data complies with requirements for product registration and is meaningful for marketing organization applications. Participants also emphasized that information on human subjects protections sets an effective standard for protecting participants' rights, safety, and welfare. Participants noted that they found the sections on GCP principles, investigator and sponsor responsibilities, and essential documents to be particularly helpful, stating that these sections contain especially clear guidance, as well as templates and checklists of essential elements. Within the sponsor section, participants said they particularly appreciated the guidance on quality management using a risk-based approach, stating that this has been useful to their work, and some found the shift to risk-based monitoring established in the (R2) revision to be clear and helpful (see Table 2, Section 1 for participant quotes).

Aspirations for revision of the ICH E6 GCP guidance
Five themes emerged from participants' narratives on their aspirations for the revision: incorporate flexibility, simplify the guidance, accommodate advances in research conduct, update and clarify language, and be transparent and inclusive (see Table 2, Section 2 for participant quotes about aspirations). Many participants' narratives about unhelpful sections of the guidance also reflected these themes; thus, participants' comments about suggested revisions for sections considered unhelpful are discussed here in conjunction with their aspirations for what revisions to the guidance should achieve ( Table 2, Section 3 lists participant quotes on unhelpful aspects of ICH E6 GCP).

Incorporate flexibility
Participants expressed a desire for flexibility in applying ICH E6 GCP. Many participants described uncertainty about whether or how the guidelines are intended to accommodate non-drug trials and other types of trials not intended for regulatory submission and discussed that globally, the guidelines are being strictly applied to many different types of research, including studies for which they may not be appropriate. As examples, participants mentioned non-Investigational Medicinal Product (IMP) trials for standard of care, post-marketing trials, post-authorization safety trials, pragmatic trials, and procedural studies. Because of this, participants described that the ICH E6 GCP revision should 1) be very specific about the types of research for which the full gamut of ICH E6 GCP is a requirement, 2) clarify when use of the full ICH E6 GCP is optional and therefore which components may be selected as appropriate for the needs of a particular study, and 3) provide a framework for adapting the GCP guidance to other types of research by identifying the minimum requirements necessary for different types of trials and setting quality standards that encompass non-interventional and non-drug studies.
Participants also described that as ICH E6 GCP is used globally, it would be helpful to acknowledge in the update that flexibility may be required when working in low-and middle-income countries. For example, they stated that it may be difficult to implement the full ICH E6 GCP in remote or under-resourced areas or in emergency settings. Likewise, participants explained that certain aspects of GCP may need to be adapted to accommodate the needs of vulnerable populations, such as informed consent with orphans or indigenous communities. An additional challenge to implementing GCP within these contexts includes a dearth of properly qualified and trained individuals who may be needed to compose an IRB in under-resourced countries or countries where few studies are conducted. To address this issue, participants suggested expanding the IRB and independent ethics committee (IEC) guidance to allow for collaborative IRB reviews, teleconferenced IRB meetings, and flexibility in training requirements for IRB members.

Simplify the guidance
Participants described a desire for the updated guidance to be more user-friendly, including simplifying requirements for GCP refresher training and eliminating duplicative trainings required by sponsors. Participants commented that the complexity of the guidelines can serve as a disincentive for investigators and that the burden of trial complexity is viewed as particularly high by potential investigators, small single-site trials, and investigator-initiated studies. In their discussions of both aspirations for revision and unhelpful aspects of the guidance, participants emphasized that ICH E6 GCP should no longer be viewed as a highly prescriptive "checklist" that must be applied to all studies, which encourages it being used as a policing tool for audits and inspections, and viewed instead as a document based on the "spirit of GCP" that elucidates the organizing principles for research. Thus, participants suggested that an introductory preamble to the guidance, clearly stating that the intent is not prescriptive and reminding end users of the fundamental purposes of research and GCP-improving patient outcomes while protecting research participants and ensuring data integrity-would be helpful for arriving at a common understanding across users. Participants also requested that ICH E6 GCP provide templates, examples, scenarios, and best practices throughout its sections; provide additional direction on how to make protocols simpler and more feasible; and provide training materials focused on implementing the guideline.

Accommodate advances in research conduct
Participants discussed that the update should accommodate changes in research conduct and technological innovations that have emerged since the guidelines were created. For example, participants suggested that the guidance should address different types of informed consent (e. g., delayed consent, waiver of consent, opt-out consent, e-consent) and different types of trials (e.g., multi-modality trials, such as those that incorporate both drugs and devices). Participants also requested guidance for working within new research frameworks enabled by advances in technology, such as paperless trials and remote data collection. For example, they expressed confusion about how to adapt ICH E6 GCP guidelines on investigator oversight, monitoring, and record-keeping to these new circumstances. Participants further expressed concern that inspections are not yet being conducted in accordance with E6(R2) but are still based on the 1996 criteria, leading to questions about whether Table 1 Participants' engagement in research (n = 23).

Geographic location of employment n (%)
East  sponsors have interpreted the (R2) guidance correctly. Participants felt ICH E6 GCP should also be updated to account for new or substantially altered study roles and responsibilities since the guidance was created (e.g., monitor, sponsor liaison, study coordinator) and should specifically include patients and community representatives as stakeholders. Participants further suggested that revisions be written at a sufficiently high level to ensure continued applicability in the future, given that technologies and processes continue to evolve rapidly.

Update and clarify language
Participants pointed out the need to update and clarify terms or provide additional guidance within several sections of ICH E6 GCP. For example, within the section on GCP principles, participants suggested clarifying the meaning of retention requirements for the length of storage and the retention of different types of media. In the IRB/IEC section, they proposed additional guidance focusing on oversight of ethics committees, allocation of responsibility for monitoring site compliance between IRBs and sponsors, challenges related to composing and training IRBs in countries with low study density, and standards for conducting clinical research in public health emergencies. Participants additionally requested clarification of central terms and concepts, such as quality management using a risk-based approach and quality tolerance limits.
Participants noted that allocation of both investigator and sponsor responsibilities should be more clearly specified in the update, perhaps by adding individual subsections to their respective chapters. Some expansion of the investigator guidance was requested: for example, participants suggested updating the section on adequate resources to incorporate more flexibility in staff member roles and address the consequences of having inadequate resources. Lack of clarity was also perceived in the sponsor guidance, where participants described that individual sponsors variously interpret ICH E6 GCP, leading to overresourcing both low-and high-impact risks to ensure GCP compliance and leading sponsors to implement increasingly complex quality control, quality management, and documentation requirements. Participants further requested updates to data privacy and record-keeping guidelines. Within the essential documents section, participants noted challenges related to guidance about the trial master file (TMF), including the challenge of creating and archiving a TMF in underresourced countries, and requested further definitions and clarification of certain requirements. Participants additionally pointed out inconsistencies in terminology, noted where definitions in the ICH E6 GCP do not match definitions in other commonly accepted documents (e.g., "trial" vs. "study"), and requested that the E6 guidance be more fully integrated with other GCP "E" documents.

Be transparent and inclusive
Participants emphasized a desire for transparency and inclusion in the revision process, stressing that it is important to include a wide variety of stakeholders, representing perspectives across the gamut of trials, to create guidance that is operationally feasible. As such, participants said patients and their communities should be included in the process of updating ICH GCP and stressed the importance of having sufficient numbers of stakeholders from each geographic region included. Participants also requested transparency surrounding creation of the revision, including in the process that will be followed, the rationale behind decisions, the stakeholders who are involved and how they were selected, the process for soliciting feedback throughout the revision, and what is done with any feedback received.

Discussion
Our findings show that while there is substantial room for improvement, many stakeholders view the GCP guidance in ICH E6(R2) as helpful overall. The global nature of the guidance provides a standard research framework that can be applied when working in countries with limited or varying research guidelines to ensure trial participant protections. IDI participants felt that ICH E6(R2) GCP clearly lays out how to establish an evidence base to ensure that trial data comply with regulatory requirements for product approval and helpfully delineates investigator and sponsor responsibilities and oversight. In particular, the transition in E6(R2) to risk-based monitoring was appreciated by participants.
However, participants also identified several ways in which the guidance can be further improved. Many of these points elaborate on previous criticisms of ICH E6 GCP [3] and reflect issues which are acknowledged in the pending E6(R2) revision [8]. Participants' aspirations for the ICH E6 GCP revision include incorporating more details about the types of research for which full GCP is recommended and supplying the minimum standards that should be met for trials that do not fit those criteria, including non-interventional and non-drug studies in which researchers currently struggle to apply GCP. Updates designed to acknowledge current and future changes in technology, trial types, informed consent, study roles and responsibilities, data collection methods, and data sources since the original guidance was created would also render the revision more applicable to real-world settings. Participants stated that the revision should strive for better integration with other GCP "E" documents and aim to further increase usability by decreasing complexity, with an overall goal of moving toward the spirit of guiding principles of GCP and away from a strict checklist approach.
Participants further highlighted several inconsistencies and points of confusion around central concepts and terms that ICH should seek to clarify in the next iteration of the guidance, including principles around data privacy and retention requirements, investigators' responsibility for adequate resources, best practices for monitoring, and quality management using a risk-based approach. The guidance should also encourage regulatory authorities to base inspections on the most recent version of GCP. Finally, participants discussed their concerns, echoed in the literature [3,7], that the revision of ICH E6 GCP should be transparent in its operations and encompassing of a wide variety of stakeholders, including patients, geographically diverse communities, and representatives across the trial spectrum, to achieve inclusive and operationally feasible guidance.
Independent of these research findings, steps have already been taken to address some of these issues. As part of the planned (R3) revision, ICH has committed [9] to addressing advances in technology and trial design and incorporating considerations for non-traditional trials while aligning with the principles and objectives of the existing guidance and addressing identified gaps and inconsistencies. The end result will take into account the diversity of clinical trials and will highlight both that "achieving GCP principles and objectives can be accomplished through the use of multiple tools and methods," and that "implementation of GCP principles should be a thoughtful, deliberative, and risk-based process as clinical trials can vary greatly and certain aspects of GCP may not be applicable to every trial" [19]. A draft version of the ICH E6(R3) principles is now available, which addresses the need for greater flexibility in the current research environment [20].
Our study has several strengths, including the composition of our sample, with participants who represented global professional clinical research networks and who were purposefully selected based on geographic diversity, professional role, and institutional type. Our work also includes the perspectives of commercial trialists, extending previously voiced critiques of ICH E6 GCP [3] by non-commercial trialists. In addition, diversity in the location of clinical trials is another strength, with participants representing clinical research efforts in 124 different countries.
Conversely, the geographic origin of our participant sample represents a limitation, as the bulk of IDI participants were from Europe and North America. Only a small percentage of IDI participants represented Asia and Latin America, and none were from African nations. However, a recent survey on the ICH E6 GCP revision among stakeholders in Japan [21] elicited similar findings to our interviews, including the need to clarify the scope of E6 GCP, modernize monitoring methods, and allow for flexibility in requirements for quality and procedures. This survey was based on the survey conducted by CTTI for the initial phase of this project [10]. An additional limitation of our study is that participants in the original CTTI survey who expressed interest in participating in the interview were quite invested in improvements to ICH E6 GCP. Therefore, a sample of participants less interested in improving ICH E6 GCP may have voiced different aspirations for amending the guidance.
CTTI provided the full report on the project's findings to ICH in March 2020 for their consideration. It is our hope that with revision to ICH E6 GCP actively underway, these findings will contribute to further refinement of the E6 GCP guidelines.