It’s Finally Here
On October 6, 2021, the International Council on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) announced that its long-awaited revision of ICH E8 “General Considerations for Clinical Trials” had reached its last step (Step 4) and now awaits regional regulator approval. The revision is part of a more general Good Clinical Practice (GCP) “Renovation” that involves the modernization of ICH E8 and subsequent renovation of ICH E6 “Guideline for Good Clinical Practice.”
The process of GCP renovation began in January 2017 – almost immediately after the revision of GCP E6 in 2016 (ICH E6(R2)) – with the ICH adoption of a “Reflection Paper.” The goal of the renovation, according to the paper, was to produce guidances that were “flexible enough to address the increasing diversity of study types and data sources” employed by contemporary studies (ICH 2021a).
ICH E8 was first adopted in 1997. In the intervening years since, clinical trial designs have become more complex, with an increase in time and cost required to develop drugs. The twenty-four-year-old document has not only become outdated, according to the ICH, but actually precludes the flexibility needed for effective and ethically sound clinical trials (ICH 2021a).
The ICH E8 renovation has four purposes (ICH 2021a):
- To describe the internationally accepted principles and practices that ensure protection of study participants while generating rigorous data and results accepted by regulators.
- To introduce quality by design practices in clinical studies across product lifecycles, including the “identification of factors critical to the quality of a study and the management of risks to those factors during study conduct.”
- To provide an “overview of the types of clinical studies performed during the product lifecycle” along with a description of study design elements that help identify “quality factors critical to ensuring the protection of study participants, the integrity of the data, the reliability of results, and the ability of the studies to meet their objectives.”
- To provide a guide to the different ICH efficacy documents.
An Emphasis on Quality
The revised ICH E8 offers new emphasis not found in its 1997 antecedent. It provides an introduction into “designing quality into clinical studies” and focuses on the factors that are most critical to a study’s quality. The guideline is not intended as cookbook of recipes. Instead, it is to be read as in an integrated, holistic document, one encouraging researchers to move beyond a limited focus on one guideline or subsection at a time (ICH 2021b).
The new E8(R1) defines quality as “fitness for purpose,” which in clinical studies involves producing reliable information while protecting research participants. The quality of information should be adequate to support “good decision making,” whether the decisions involve approval of a new drug or a change in clinical practice (ICH 2021b).
The document emphasizes “quality by design” in clinical research, which in practical terms involves using a multidisciplinary approach that prospectively builds quality into a clinical trial (ICH 2021b). Quality by design involves the early focus on all aspects of the study protocol, including such operational practices as staff training. The idea is that prospective quality measures are superior to those involved in typical quality assurance and quality control, which are only retrospective snapshots in time.
Critical to Quality Factors
The process of quality by design involves the determination of “critical to quality factors,” whose integrity is fundamental to the success of the trial. If these factors are undermined, so the definition goes, either the ethics of the trial or the results of the trial would be threatened. Having identified the critical to quality factors, the next step is determining the risks that threaten their integrity and supplying mechanisms to reduce those risks based upon their probability and importance (ICH 2021b). This is a fundamentally risk-based approach to quality by design.
Given that the precision of a study design comes with an inherent trade off in resources needed, ICH E8(R1) advocates a prioritization of quality factors and study procedures that are proportionate to the unavoidable risks in the study, measured against the importance of the collected information (ICH 2021b). The guideline warns that this risk-based approach is often threatened by unnecessary complexity in study designs, where processes are cluttered with minor issues and results clouded by extensive secondary objectives and unnecessary data collection.
The guideline calls for the establishment of a culture of open dialogue, one that moves beyond the excusive focus on checklists. While standard operating procedures are necessary, the new guideline warns that researchers need to be careful not to adopt a rigid one size fits all approach. The creation of a culture of openness also facilitates the identification of gaps in data or even conflicting data, thus helping researchers avoid rushing to unsupported claims (ICH 2021b).
New Voices, New Concerns
ICH E8(R1) places an emphasis on including patient (or patient organization) perspectives in study design. The logic is that involving patients early in the process likely increases trust in the study, encourages recruitment, and helps with protocol adherence (ICH 2021b). Incorporating patient perspectives can also help understand the lived experience of a condition, which can contribute to producing results that are meaningful to patients and support the creation of drugs better suited to patients’ needs. Including patient perspectives can also place treatments in the “context of ethical issues, culture, region, demographics, and other characteristics of subgroups within a targeted patient population” (ICH).
The inclusion of patient voices is part of ICH E8(R1)’s call for engaging a wide range of stakeholders in study design. The call includes stakeholders from the outside, such as healthcare providers and subject matter experts, as well as internal stakeholders such as research administrators, clinical investigators, study coordinators, and other site staff. These stakeholders can offer valuable insights into subject recruitment, study feasibility, and the factors leading to early dropouts. The guideline encourages early engagement with regulatory bodies, particularly if the study features new design elements critical to quality, and with health authorities, who may be concerned with health technology assessments (ICH 2021b).
The new E8(R1) calls for widening the notion of clinical trials to include study designs beyond the traditional randomized controlled interventional trial that was the focus in 1997. These can include:
- Observational trials
- Single blinded trials
- Trials with external controls
- Retrospective trials
- Adaptive design trials
Staged trials are now often combined and special populations traditionally excluded from clinical trials (for example, pregnant women) are increasingly included in clinical research. Among other new designs are “master protocol studies” that allow for multiple drugs or multiple conditions to be studied under a shared protocol and “platform studies” that study multiple drugs in a serial manner, with different drugs evaluated in the same trial (ICH 2021b).
Finally, the guideline points to new sources of data that were not common in 1997. Electronic health records, drug registries, networked claims data, and easily minable national death databases are all commonplace today. As a result, contemporary study designs often consider real world data in ways that were not possible a quarter century ago.
Something Old, Something New
The Step 4 iteration of the E8(R1) guideline was greatly foreshadowed by a 2019 draft revised guideline “General Considerations for Clinical Trials.” That was step 2 of the E8 renovation and its intent was to solicit input from a broad range of non-ICH observers. That draft guideline contains nearly all of the elements of the newly released revision (ICH 2019). As a result, this new E8(R1) document is not entirely new. Even so, its content features profound changes from the 1997 ICH E8 guideline as well as principles and practices now common to clinical research.
- International Conference on Harmonisation (ICH). 2019. “General Considerations for Clinical Studies E8(R1). Step 2 Document – to be Released for Comments.” Accessed October 11, 2021.
- International Conference on Harmonisation (ICH). 2021a. “ICH Reflection on ‘GCP Renovation’: Modernization of ICH E8 and Subsequent Renovation of ICH E6. Endorsed in January 2017. Revised in May 2021.” Accessed October 11, 2021.
- International Conference on Harmonisation (ICH). 2021b. “ICH Harmonized Guideline: General Considerations for Clinical Studies, E88(R1).” Accessed October 11, 2021.