The Impact of ICH GCP E6 Guideline R2 Revisions on Sponsors, Sites, Contract Research Organizations and Vendors

Abstract

The ICH GCP E6 revised guideline was issued to reflect on the current research landscape: increase in globalization, studies complexity, and technological capabilities. The updated ICH GCP E6 (R2) Addendum is more descriptive than the previous version and contains 26 items of change. These changes consist of new items in definitions; new sections on investigator responsibilities, including oversight; a substantial new sponsor section on quality management, including risks assessment; monitoring plans defined and implemented; introducing risk-based quality management; serious breaches, and, a new section on computer validation and electronic records, etc. This review will explore the changes to provide a better understanding of how they impact conduct of clinical trials for sponsors, participating sites, CROs and vendors.

Introduction

Managing clinical trials, of any size and complexity, requires strategic planning and efficient execution. As scientific advances continue, the types of therapies being developed have higher potency and novel targets; and increased pressure to have study designs that speed up clinical development. In 2016, the International Council on Harmonization (ICH) revised the Good Clinical Practice (GCP) E6 guideline to further standardize processes in biomedical products development, decrease redundancies; and reflect the current research landscape such as increase in globalization, complexity of the studies, and technological capabilities.¹ The revised guideline is entitled “Integrated Addendum to ICH E6 (R1): Guideline for Good Clinical Practice E6 (R2).”¹ The ICH steering committee comprised of representatives from the pharmaceutical industry and the regulatory authorities of the United States, Japan, the European Union (EU), Canada, and Switzerland. In addition, observers included representatives from Brazil, China, South Korea, and the World Health Organization. The updated ICH GCP E6 R2 is more descriptive than the previous version and describes 26 items of change.¹ These changes consist of new items in definitions (e.g. certified copy irrespective of type of the media used, monitoring plan and validation of computerized systems); new sections on investigator responsibilities, specifying responsibilities and oversight; a substantial new sponsor section on quality management, including risk assessment; definition and implementation of monitoring plans, introducing risk-based quality management (RBQM); revisions addressing the reporting and follow up of significant noncompliance (including conducting a root cause analysis, and creating a corrective and preventative action plan), and a new section on computer validation and electronic records (e.g., specifying that electronic systems should be validated, backed-up, and safeguarded).¹ All changes are briefly summarized in Table 1. This review will explore the changes to provide a better understanding of how they impact conduct of clinical trials for sponsors, sites, CROs and vendors.

Since the development of the ICH GCP Guideline E6 (R1) in 1996, the scale, complexity, and cost of clinical trials have increased. Industry had to modernize according to advances in technology, complexity of clinical trials and globalization.² When the original ICH E6 (R1) guideline was prepared, clinical trials were performed in a largely paper-based process.2 Advances in use of electronic data recording and reporting facilitated implementation of other approaches (e.g. centralized monitoring can now offer a greater advantage to a broader range of trials than it was suggested in the original text). Evolution in technology and risk management processes offered new opportunities to increase efficiency and focus on relevant activities and critical aspects.

Therefore, this guideline has been amended to encourage implementation of improved and more efficient approaches to clinical trial design, conduct, oversight, recording and reporting, while continuing to ensure human subject protection and reliability of trial results.

The Impact of the ICH E6 (R2) Addendum on Investigator Sites

Requirements related to investigator’s qualification, delegation, and oversight of third parties, as well as requirements for records and reports are all reinforced by adding them directly to the investigator’s clinical research with certain phases of clinical trials (earlier phase of development is considered more risky since safety profile is not fully established, while later phase can be more complex to execute due to increased number of subjects and additional complexity of study procedures) and experience with investigational product in specific therapeutic area (e.g. biologics, devices or drugs)). Assessment of experience of site personnel by the sponsor/CRO is crucial to determine the level of support needed during execution phase.

Sites can also expect an increase in remote or centralized monitoring activities. That can raise expectations by the sponsors for sites regarding timely data entry in electronic data capture systems (EDC), expectations for quicker turnaround for data queries resolution, as well as provisions of source documentation and updates for essential regulatory documents to be submitted electronically.³ Heavy reliance on technology can raise specific concerns with internet access as a requirement for sites for clinical trials conducted on a global scale, where in some parts of the world stable internet connections may not always be possible. There is always a learning curve with implementation of new technology and/or new approach in utilization of existing systems. Training must be provided upfront to all parties involved with data management (e.g. site personnel, CROs, and vendors). Expectations need to be clearly defined and progress should be monitored to identify trends, and address any issues in a timely manner. Sponsors should discuss possibility of access to electronic medical records (EMRs) for source documentation verification upfront with sites and familiarize themselves with site’s specific policies and procedures for confidentiality of medical records and HIPAA compliance.

Hosting on-site monitoring visits is time consuming, and it has additional travel/accommodation costs for monitors associated with on-site visits. Therefore, sponsors will want to work with quality sites and reduce expenses, time and effort associated with this type of monitoring. The recommendation to the sponsors and CROs can be made to discuss upfront monitoring approach that will be utilized in a specific trial (e.g. planned frequency, utilization of on-site versus remote (centralized) monitoring practices and expectations of the sponsors for both); possibility of remote access to electronic medical records (EMRs), data security, exchange and confidentiality; and address in Clinical Trial Agreements (CTAs) that timely data entry and query resolution are critical, as well as indicate metrics that will be indicators for monitoring visits:

• Number of days from study visit to data entry (e.g. 2-3 working days)
• Number of data queries and time it takes to close queries (e.g. 48-72 hours)
• Number of significant protocol deviations (predefine level of tolerance)
• Unreported SAEs (predefine level of tolerance)

One thing to keep in mind, that in addition to entering data to EDCs, site personnel may need to maintain internal quality control (QC) tracking logs, as well as entering data into institution specific clinical trials data management systems (CTMS) such as Velos to track study related visits and completion of procedures. All these activities are important to be conducted at the site level for quality assurance and billing compliance. However, institution specific platforms will not be accessible to the sponsors/CROs. The variety of electronic platforms utilized in clinical research without them interfacing properly often presents a challenge for study personnel to learn how to use a new electronic tool, and also during execution phase they will need to duplicate their effort in entering information into different systems with the lack of synchronization, which can be time consuming, especially if they are running multiple studies.

In addition to clearly defining expectations to site personnel, establishing best practices for data management and monitoring practices; adequate effort allocation for physician investigators, coordinators and research nurses should be addressed in the study budget and contracts, since the burden of preparing and sharing a lot of documentation remotely between sites and the sponsors/CROs/data managers is shifting towards sites, and their effort must be evaluated based on increasing workload with implementation of centralized monitoring practices.

Investigator’s Responsibilities and Oversight in the ICH E6 (R2) Environment

The investigator continues to be ultimately responsible to provide an oversight for clinical trial conduct. There were no changes made to the “Investigator’s Qualifications” section, and the investigator is still allowed to delegate trial-related responsibilities.¹ “Adequate Resources” revisions in Section 4.2 specify that the investigator is responsible for supervision (oversight) of persons with delegated tasks.

Further, the investigator should ensure research staff are capable and trained for their assigned trial-related tasks. This is aligned with the U.S. Food and Drug Administration (FDA) regulations (Investigational New Drug Application 2016) and FDA (2009) guidance.^4,5 The added text in “Records and Reports” in Section 5.5 also mirrors the FDA in specifying that “source data should be attributable, legible, contemporaneous, original, accurate, and complete”.^1-3 The commonly used acronym is “ALCOAC”. Records and reporting may be hand written or electronic.

If electronic systems are utilized for records and reports on a clinical trial, evidence of compliance and validation of such systems with Title 21 CFR, Part 11 needs to be presented by the site at qualification visits, and sponsor must ensure that data were collected on a clinical trial in accordance with the Food and Drug Administration’s (FDA) Guidance for Industry: Computerized Systems Used in Clinical Trials.^6,7 Principal Investigator (PI) or designated co-Investigator must perform within study review and within site review for GCP and study protocol compliance review, according to designated roles/responsibilities of site personnel. PI needs to assess the following to determine impact of subject safety, impact on data quality and integrity and ensure research subject protection on a clinical trial:

• Screening data with formal, documented approval for enrollment
• Diagnostic reports for clinical significance
• Adverse events and assignment of causality
• All notes to file
• All protocol deviations

In addition, ICH E6 (R2) revisions address investigator’s oversight responsibilities of third parties in Addendum, Section 4.2.6: “If the investigator/institution retains the services of any individual or party to perform trial-related duties and functions, the investigator/institution should ensure this individual or party is qualified to perform those trial-related duties and functions and should implement procedures to ensure the integrity of the trial-related duties and functions performed and any data generated.”¹

In order to comply with this new requirement, investigators/institutions should retain in their files evidence that the third parties are qualified to assume responsibilities for the specific study procedures and the contractual agreements with the third parties. Where the third parties are individuals, these should be listed in the site’s delegation of authority log. Where the third parties are entities (e.g., pharmacy, blood bank, pathology ancillary services), a responsible party of that entity should be listed in the site’s delegation of authority log, and the entity should maintain its own internal delegation of authority log. It is also essential that all site personnel and the third parties receive and document any study-specific training as it applies to their roles and responsibilities. To enable site personnel to perform the assigned functions correctly on a clinical trial the following aspects should be addressed: adequate education and training needs to be provided upfront on GCP, study protocol, and role-specific as it pertains to their role/responsibilities on this study. This can be done as on-site or remote (e.g. webinar, etc.) training, which should aim to explain critical aspects of the study protocol and procedures based on risk analysis and critical factors of the specific study.

Prior experience with investigational product within the same therapeutic class is desired for site personnel (e.g. investigators, study coordinators, research nurses, any ancillary services) to prepare investigational product and be familiar with Quality Control (QC) principles and acceptable methods for complying with the statutory requirements of cGMP, GLP, and GCP.

Furthermore, it is not adequate for investigators/institutions to assume that the services performed by the third parties and the data generated will meet integrity expectations. The investigator/institution should put in place a process for assuring themselves of this throughout the study, and should retain evidence that the process has been followed. In some settings the investigator will contract with the third party, while in other instances the institution will assume the obligation. Even if the institution holds the contract, the investigator is ultimately accountable for the quality of the services being provided by any third parties on their studies.

It is important for the sponsors and their representatives (e.g. CRO) to understand the site processes of review and approvals for contracts and budgets. Who else besides the Principal Investigator team at the participating site needs to review study protocols, procedures, operational manuals; as well as review and approve CTA/budget on an organizational level (e.g. ancillary services as internal third party vendors at that institution – Pharmacy, Blood Bank, Radiology, etc.; Clinical Trials Office, Legal Counsel, etc.) ? Understanding of site policies, standard operating procedures (SOPs) and process will help sponsors/CRO to streamline review and approval process of study protocols, informed consents, contracts, budgets and any other study related documentation. The key point is to build strong relationships with all site staff. Site personnel is a “workhorse” of clinical trials, and they play a critical role in the study conduct, while being on the front line in dealing with research subjects.

They are essentially key stakeholders. Therefore, it is important for the sponsors to invest heavily in building relationships with sites and not necessarily delegate them in full to their CRO partners.

Also, with so many different parties contacting sites (e.g. CROs, centralized laboratory vendors, sponsors, suppliers, etc.), it is crucial to develop a clear communications plan to decrease number of communication channels, avoid duplication of effort and streamline process of information exchange, especially when it comes to critical values, processes and assessments.

Changes Affecting Sponsors and Their Representatives in the ICH E6 (R2) Environment

The areas of the ICF GCP E6 (R2) addendum with the biggest impact on the sponsors and their representatives are those related to “Quality Management” in Section 5.0 and the “Extent and Nature of Monitoring” in Section 5.18.1 Organizations should consider the readiness of their risk-based quality management systems (RBQM) and the extent to which Quality by Design (QbD) principals are implemented in their clinical trials.³ How sensitive technologies utilized by sponsor/CRO organizations are to detect data outliers remotely by monitoring data patterns on centralized electronic platforms and inform that on-site monitoring or inquiry to the site is needed to be performed?

Some organizations are still utilizing on-site monitoring techniques predominantly. There is a heavy reliance on technology with remote and risk-based monitoring (RBM) approach. Organizations must assess their Trial Master File (TMF) and Computerized Systems Validation (CSV) processes with regards to their alignment with the new addendum requirements.^1,3 If a company decides to focus monitoring on the critical values and processes with a high risk profile, then effort can be spent on other activities that can directly impact subjects’ safety and reliability of trial results. Advantages in technology allow us to monitor data in real time to assess evolvement of trends, analyze patterns, meaning that any safety concerns and/or data integrity issues that can affect reliability of study results can be pro-actively assessed and addressed earlier during the lifecycle of the project.

One of the barriers to the adoption of a risk-based remote monitoring approach was resistance from organizations to move away from 100% source verification of the data. Focusing on the critical data and process evaluation and determining which data are of most importance and identifying the best way to monitor these data throughout the lifecycle of the clinical trial, can help to make some strategic decisions at the leadership level of the organization to reassure their staff, site personnel, auditors and regulatory authorities that the appropriate control measures are put in place and consideration for critical values and processes are adequate to provide effective monitoring on a clinical trial to ensure subjects safety and preserve data integrity. Change management is critical to successful implementation of the ICH GCP E6 (R2) addendum and can only be achieved through effective communication of sponsor’s expectations for monitoring, sharing assessments and assumptions for critical values and processes selection with the site personnel, CROs and third party vendors. Regulators are deliberately leaving some room for interpretation in the section pertaining to monitoring, which allows industry to move forward and select their approaches as long as choices for monitoring strategy and techniques utilized are justified in the monitoring plan, based on risk analysis for specific class of products and supported by scientific knowledge. Of course, it is also crucial that auditors and inspectors also adopt a risk-based approach in their evaluation of monitoring strategy, data validation, and compliance of the organization/site/CRO with the proposed monitoring plan, study protocol and applicable regulations. The mind set for auditors/inspectors have to also shift towards critical data and processes as check points to support the efforts of the industry to modernize how we manage clinical trials and successfully implement new amended regulations.

Sponsor Oversight of CROs in the ICH E6 (R2) Environment

In the prior version of ICH E6 in Section 5.2. it was stated that sponsors may transfer responsibilities to CROs, and the transfer should be in writing, and any responsibilities not specifically transferred should be retained by the sponsor.² In addition, this section states that where responsibilities are delegated to CROs, the CROs are responsible for complying with all ICH requirements related to those sponsor responsibilities.² According to ICH GCP, Section 5.2.1. sponsor transfers any or all of the sponsor’s trial related duties and functions to a CRO, but the ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor as a party who holds Investigational New Drug (IND), Investigational Device Exemption (IDE) or 510K designation of regulatory authorities and therefore, is responsible to trial conduct oversight, quality and integrity of data produced.^1,2

In the revised ICH E6 (R2) version there is an additional requirement under section 5.2.2 that, “The sponsor should ensure oversight of any trial-related duties and functions carried out on its behalf, including trial-related duties and functions that are subcontracted to another party by the sponsor’s contracted CRO(s).”¹ Similar to Section 4.2.6 “Investigator” of the amended guideline, it is not sufficient for sponsors to assume that because they have subcontracted services, the services performed by their third parties are being performed according to the revised guideline.¹ Sponsors need to ensure that there is appropriate oversight, and the evidence of the oversight needs to be retained (e.g. documentation of the third party vendor qualification and selection process, as well as training on sponsor’s/CRO’s SOPs, study protocol and procedures; and evidence of ongoing oversight throughout lifecycle of the project must be maintained by the sponsor).

When inspecting sponsors, regulatory authorities are increasingly assessing the sponsor’s oversight of the services outsourced to the CROs. The types of evidence that inspectors are looking for include the following:

• Selection and qualification process of the CRO to ensure that the selected CRO meets the requirements of the sponsor.
• A written and signed contract that makes it clear which tasks exactly have been delegated to the CRO and the expectations of the sponsor are specified.
• Documentation of CRO’s personnel training on sponsor’s SOPs, operational manual for the study, study protocol and procedures.
• Ongoing oversight of the CRO to confirm throughout the study that the CRO continues to meet the sponsor’s requirements.

Ongoing oversight has been handled differently by sponsors: some have chosen a “hands-off” approach while others adopted “hands on” micromanagement strategy of the CRO. The challenge sponsors currently face is in finding reassurance that they have sufficient evidence to be confident that they have appropriate oversight and confidence in the services being provided by the CRO.

Many sponsors have traditionally relied on contractual agreements to document expectations of quality assurance to be met by the CRO. Such agreements may include, but are not limited to, reports required from the CRO, communications plan outlining criteria/frequency of information exchange with the sponsor, and details on the handling of escalations (e.g., regarding quality issues, protocol adherence, safety concerns, etc.). However these types of agreements, even if they contain a detailed quality section, have typically been more reactive than proactive and their focus has been more on issues management, audits, and inspections rather than on proactive risk management. We all have different tolerance level for risks. In order to standardize processes and improve communications between sponsors and CRO, as well as to comply with current regulatory requirements, it will be useful to share upfront between all stakeholders involved at least the following:

• Critical data and processes to monitor (refer to Figure 1 for some examples),
• Assumptions made,
• Key milestones,
• Risk identification and evaluation analysis,
• Expectations for communications and escalation process, if any issues evolve and pre-defined triggers are met.

According to revised ICH GCP E6 (R2) addendum guideline, Section 5.0.1-5.0.3 “Sponsor” during protocol development, the sponsor should identify those processes and data that are critical to ensure human subject protection and the reliability of trial results (Figure 1).¹ The sponsor should identify risks to critical trial processes and data. Risks should be considered at both the system level (e.g., standard operating procedures, computerized systems, personnel) and clinical trial level (e.g., trial design, data collection, informed consent process) (Figure 2). Also, the sponsor should evaluate the identified risks against existing risk controls, the likelihood of errors occurring, the extent to which such errors would be detectable, and the impact of such errors on human subject protection and reliability of trial results.³ The sponsor should decide which risks to reduce and/or which risks to accept. Newly updated regulations call for the approach used to reduce risk to be at an acceptable level, which should be proportionate to the significance of the risk. Risk reduction activities can include the following: protocol design and implementation, monitoring plans, agreements between parties defining roles and responsibilities, systematic safeguards to ensure adherence to standard operating procedures. Quality tolerance limits must be pre-defined and based on: medical and statistical characteristics of the variables, statistical design of the trial and systematic issues that can impact subject safety or reliability of trial results. Risk-based quality management (RBQM), which includes key risk indicators (KRIs) assessment, monitoring, control and communications with all stakeholders should be an iterative process throughout the lifecycle of the project, as risks can evolve and change as compared to initial assessment (Figure 2).

Oversight of CRO Subcontractors and Third Party Vendors

ICH GCP E6 (R2) Addendum, Section 5.2.2 states: “The sponsor should ensure oversight of any trial-related duties and functions carried out on its behalf, including trial-related duties and functions that are subcontracted to another party by the sponsor’s contracted CRO(s).”¹

In the past, it was widely accepted in the industry for a sponsor not to intervene greatly with CRO subcontractor arrangements, since the contract was between the CRO and its subcontractor. Most sponsors limited their oversight to assuring themselves through audits that their CROs had a process in place for qualifying their subcontractors, while some others went a bit further by requiring their CROs to seek sponsor’s pre-approval of their third party vendors. This level of oversight is no longer adequate under revised ICH GCP guideline, as responsibility has been put solely on sponsors to ensure oversight of services, which CROs subcontract to third party vendors. In order to be compliant with current regulatory requirements, sponsors will most likely require that all subcontractors must be pre-approved by them, and they will expect to be provided with more details on the results of the qualifications performed by the CROs. In addition, sponsors will also want evidence that the CROs are actively managing their subcontractors throughout their studies. Furthermore, sponsors most likely will be including some provisions regarding third party vendors into agreements with the CROs, in order to allow themselves to have more direct oversight of these subcontractors and their functions on a clinical study. In addition to Clinical Trials Agreements (CTAs) between sponsors and participating sites, Business Associates Agreements may be needed to be signed between investigator sites and third party vendors, if identifiable information will be released outside of investigator’s institution, in order to ensure HIPAA compliance and protect research subject’s privacy.

Successful implementation of newly revised guideline will require transparency, sharing of assumptions and expectations, continuous holistic approach to data collection and monitoring of key risk and performance indicators throughout study conduct. Evolving trends, indicators and errors should be assessed systematically and proactively, communicated in a timely manner to involved stakeholders whose functions and processes are affected to stay focused on reinforcement of quality by design or preventing rather than correcting issues after they occurred.

Conclusions

ICH E6 (R2) provides an opportunity for enhancing sponsor’s oversight by implementing collaborative risk-based quality management approach in conducted clinical trials. The revised guideline invites sponsors to partner with their CROs early in the development process, and adopt proactive approach to identify the critical data and processes associated with their study protocol and procedures, in order to assess the associated risks that will provided risk-based strategy for monitoring, and to perform ongoing risk management throughout the lifecycle of the project. If these steps are performed in a transparent manner as part of strategic partnership, sponsors will benefit by having the data they need to feel confident they have adequate oversight of their services outsourced to the CROs. It will also provide assurance to them that the CRO is not just informing them post-factum of issues that need to be corrected/addressed once they have already occurred, but instead CRO is engaged in preventing the issues from occurring in a proactive fashion.

Advantages in technology can also significantly assist in enabling sponsor’s oversight by creating a holistic approach to data collection and monitoring of any outliers in the data trend analysis. By monitoring key risk indicators and sharing the data with their sponsors, CROs can provide real-time data and evidence of proactive risk-based quality management on the study.

Based on the increasing level of outsourcing in biomedical product development field and facing globalization, it is not surprising that regulators in ICH GCP E6 (R2) revisions have addressed in more specific details the third-party vendor oversight expectations of both investigators and sponsors. This revised guideline will have an impact on changes in contractual agreements between sponsors, CROs, investigator sites and third party vendors. The ICH GCP E6 (R2) revisions are intended to modernize according to advances in technology, complexity and globalization; and based on regulatory authorities’ current state of knowledge to provide an updated guideline for investigators, sponsors, and CROs on how to develop processes that will enable effective risk-based quality management critical to the protection of human subjects and reliability of trial results.

References

1. Integrated Addendum to ICH E6 (R1): Guideline for Good Clinical Practice E6 (R2). 2016. https://www.ich.org/fileadmin/Public_Web.../E6/E6_R2__Step_4_2016_1109.pdf
2. Guideline for Good Clinical Practice E6 (R1).1996. http://academy.gmp-compliance.org/guidemgr/fi les/E6_R1_GUIDELINE.PDF
3. U.S. Food and Drug Administration (FDA). 2013. “Guidance for Industry: Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring.”
4. U.S. Food and Drug Administration (FDA) regulations (Investigational New Drug Application. 2016. https://www.fda.gov/drugs/types-applications/investigational-newdrug-ind-application
5. Investigator Responsibilities — Protecting the Rights, Safety, and Welfare of Study Subjects Guidance for Industry. 2009. https://www.fda.gov/regulatory-information/search-fdaguidance-documents/investigator-responsibilities-protecting-rights-safety-and-welfarestudy-subjects
6. Code of Federal Regulation, Title 21, Volume 1, Part 11: Electronic Records, ElectronicSignatures. Washington, DC: Government Printing Office; 1998. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/part-11-electronic-recordselectronic-signatures-scope-and-application
7. Computerized Systems Used in Clinical Investigations Guidance for Industry. 2007. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/computerizedsystems-used-clinical-investigations