Clinical Researcher—February 2018 (Volume 32, Issue 2)
Sara Spadoni, PhD
The changes brought by the International Council for Harmonization’s (ICH) E6(R2) addendum to its Guideline for Good Clinical Practice (GCP) and the subsequent adoption by the European Medicines Agency effective June 14, 2017, have had a significant impact on sponsors, contract research organizations (CROs), and clinical trial sites alike.
There now exist a number of requirements that are specific to investigators and clinical trial sites, such as those targeting source documents, essential documents, and delegation of authority. However, as explored below, when implementing the new regulation, sites should consider that while some E6(R2) updates require them to adapt their way of working on clinical trials, other changes that primarily impact sponsors and CROs still have an influence on site activities (e.g., implementation of risk-based monitoring [RBM]).
Source Documents: How to be Compliant to ICH E6(R2)?
Findings on source documentation are very common during inspections,1–3 and this may be due to the lack of formal ICH GCP guidance prior to the E6(R2) addendum, the complexity in creating source documents, and whether defined handling and storage processes are enforced at the site.
Source document–related changes introduced by the E6(R2) addendum serve to formalize requests that sponsors, CROs, and regulators have already been asking sites to comply with during clinical trials. For example, certified copies of source documents were provided to monitors and auditors in the past, but the E6(R2) addendum section 1.63 now defines what a certified copy is. Sites are required to verify that the process to generate copies of source documents is robust enough—and that systems used (e.g., scanners) are validated—to guarantee that the copy is identical to the original in every aspect.
Key attributes for good documentation were first described by U.S. Food and Drug Administration (FDA)4 in the form of the so-called ALCOA (Attributable, Legible, Contemporaneous, Original, Accurate) standards. With section 4.9.0, E6(R2) has formally adopted these requirements, and has gone even further by adding the “Complete” requirement (ALCOAC) for source documents and trial records.
In order to satisfy these requirements, sites are required to ensure that the source documents and trial records in all media type (e.g., paper, electronic) contain clear details about the following:
- Who has made or updated the entry (i.e., the name of the doctor or signature or initials are present)
- When the entry was made or updated (i.e., the date is present)
- The entry is readable and understandable (e.g., it features clear handwriting and is void of non-standard abbreviations)
- The entry must be the first place the information was recorded (i.e., not transcribed from another document)
- The entry must reflect what occurred and when, including all the relevant details
- An audit trail tracing the changes made by whom, when, and why must be available
Site monitors have always requested sites to comply with ALCOA requirements. Now these requirements have been formally adopted by the GCP as ALCOAC, and sites must adapt their processes and systems (if they use electronic medical records) to ensure compliance.
Patient medical records may be quite complex; in fact, they can be generated from different hospital departments and on different media type (e.g., paper, electronic). The new item 8.1 in E6(R2) requires the investigator to maintain, for each study, a record of the location(s) of the essential documents, including source documents. Item 8.1 also requires that the storage system used during the trial and for archiving after the trial (irrespective of the type of media used) provides clear document identification, version history, and search and retrieval functionalities.
Delegation of Tasks and Qualification—Investigator Responsibilities
Inadequate delegation and training continue to be major findings in GCP and regulatory inspections.1–3 ICH has added two new items (4.2.5 and 4.2.6 ) to the guideline pertaining to delegation of authority and training. These items should help the investigator understand that delegation of tasks in a clinical trial goes hand-in-hand with both the responsibility to ensure adequate qualification to conduct the delegated tasks, and the responsibility to supervise the delegated individuals. Delegating tasks to another individual in a clinical trial does not exempt the investigator from supervising that individual.
In addition, item 4.2.6. requires the implementation of procedures to ensure the integrity of the trial-related duties that are performed, and of any data that are generated during the trial. Investigators and their institutions should create appropriate (written) procedures to be followed by site personnel during the conduct of the trial.
RBM as Experienced by Sites
How are sites experiencing the implementation of E6(R2)? The Society of Clinical Research Sites (SCRS)5 reported that one challenge for sites is that RBM “is often defined to site personnel in different ways by sponsor and CRO representatives. As a result, site personnel are unclear what changes in monitoring tasks are related to [RBM], leading the term to become a catch-all for alternative monitoring practices. How these practices impact the site drives discussion linked to site leader perceptions about” RBM.
It is suggested that sponsors and CROs should increase their communication about the alternative monitoring strategies, the roles involved, and the reasons for the strategy being implemented. This will allow sites, CROs, and sponsors to better partner together during the design, planning, and conduct of clinical trials.
In some cases, the RBM approach may result in less frequent onsite visits and in an increased number of centralized/remote activities. This may be perceived by site personnel as receiving less in‑person support, and instead needing to spend more time on the phone or over the Internet connecting with unknown individuals from the sponsor/CRO as part of the remote activities.
In recognition of this perception and potential concern, some companies have been conducting site surveys to monitor directly or indirectly the impact of RBM at the site level, as well as if/how this has evolved as the industry (including clinical trial sites) gain experience with the centralized monitoring model. Initial results were shared during the TransCelerate RBM Open House event in Copenhagen in October 2017, suggesting that some sites may prefer more frequent visits—especially at the study start—and would better accept reduction in visit frequency when the study is ongoing.
Additional experience in the implementation of RBM is required in order to fully evaluate the impact on site personnel, and in general on site practices.
Audits and Inspections Results
Audits and inspection trends have been considered by the industry as good indicators for areas of improvement; however, it is still early to have an analysis of the trends from audits and inspections with regard to site compliance to the E6(R2) addendum. During the aforementioned TransCelerate event, sponsors and CROs shared preliminary information on audit and inspection findings focusing on the implementation of the RBM, and one of the TransCelerate member companies indicated its data showed a reduced number of major/critical findings reported on studies that had implemented the RBM approach.
Extensive and detailed information to identify the challenging areas for the implementation of the new regulation by the sites is not yet available, and it is expected that initial information on the most common findings related to the site compliance to the E6(R2) updates will be available in late 2018. As sites are going through their learning curve with the new regulation, in parallel sponsors, CROs, and auditors and inspectors are also learning about its correct interpretation and implementation. As a result, there may be a level of confusion among site personnel, who may receive different guidance on the same topic from various parties while the industry is still learning.
Sites are impacted by the E6(R2) changes both directly and indirectly, therefore all sites around the world participating in a clinical trial should be fully trained on the E6(R2) content irrespective of whether their country has formally adopted the addendum. The training on the “why” and the “how” should be provided by regulators/government officials, as this would reduce the variable interpretation of the E6(R2) regulation and its implementation.
Sites should seek to adapt their clinical trial processes and systems to ensure compliance, and in so doing further increase overall quality and reduce risk to patients. Sites, sponsors, CROs and regulators should also expect a transition period while countries and regions formally adopt the guideline, and as the industry (including regulators) seek to reach consensus on how to interpret and implement the new requirements.
- European Medicines Agency. 2014. INS/GCP/46309/2012. Compliance and Inspections. Classification and analysis of the GCP inspection findings of GCP inspections conducted at the request of the CHMP (Inspection reports to EMA 2000-2012). ema.europa.eu/docs/en_GB/document_library/Other/2014/12/WC500178525.pdf
- European Medicines Agency. 2015. EMA/INS/GCP/434373/2014. Compliance and Inspections. Annual report of the Good Clinical Practice Inspectors Working Group 2014 (Adopted by the GCP IWG on 05 March 2015). ema.europa.eu/docs/en_GB/document_library/Annual_report/2015/07/WC500189186.pdf
- European Medicines Agency. 2017. EMA/INS/GCP/763873/2016. Committees and Inspections. Annual report of the Good Clinical Practice Inspectors Working Group 2016 (Adopted by the GCP IWG on 2 June 2017). ema.europa.eu/docs/en_GB/document_library/Report/2017/08/WC500233740.pdf
- U.S. Food and Drug Administration. 2013. Guidance for Industry—Electronic Source Data in Clinical Investigations. https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm328691.pdf
- Society for Clinical Research Sites. 2017. SCRS InFocus. http://myscrs.org/assets/infocus_archive/InFocus_Archive_November_2017-updated.pdf
Sara Spadoni, PhD, (email@example.com) is Director of Clinical and Project Support Services for Syneos Health.