ICH announces sign-off on good clinical practices guideline

Regulatory NewsRegulatory News | 07 October 2021 |  By 

The International Council for Harmonization (ICH) recently announced that the E8(R1) guideline on general considerations for clinical studies had reached Step 4 and is awaiting sign-off by regulators. The widely anticipated guideline modernizes the design, conduct and reporting of clinical trials by adopting quality by design principles. The guideline incorporates “current concepts achieving fit-for-purpose data quality.”
ICH announced that “the modernisation of ICH E8 is the first step toward [good clinical practice] renovation initiated in 2017.”
The guidance identifies critical to quality factors that can be adapted to different types of trials to “support the meaningfulness and reliability of trial results and to protect human subjects.”
A 2017 ICH concept paper on ICH E8(R1) said that such a guidance is needed as the parent E8 Guideline “has high level descriptions of trial objectives and design, but does not address how design or planning considerations can optimize trial and data quality. The set of trial designs described in E8 is limited and does not reflect the range of designs in use today.”
The ICH business plan for this guideline reiterates that the E8 parent guideline “does not put emphasis on the importance of prospective determination of critical-to-quality factors and does not reflect the range of designs in use today. These limitations may lead to costly and inefficient trials, trials that are not of sufficient quality to provide meaningful and actionable evidence, trials not being undertaken, or drugs not being developed.”
The guidance states that “the quality by design approach to clinical research…involves focusing on critical to quality factors to ensure the protection of the rights, safety, and well-being of study participants, the generation of reliable and meaningful results, and the management of risks to those factors using a risk-proportionate approach.”
The guidance outlines an approach to identity the critical to quality factors, advocating for an approach that includes establishing a culture that supports open dialogue, focusing on activities essential to the study, and engaging stakeholders in the design of the study.
The guideline also includes a set of principles for ensuring the quality of investigational products. It says that “more extensive characterization may be required for complex or biological products.” Also, changes in a product during the development stage should be supported by comparability data.
The guidance lists a set of 18 considerations in identifying critical to quality factors. Although the considerations are “not exhaustive and may not apply to all studies,” the factors range from engaging stakeholders to study planning and design, requiring competencies and training for the sponsor and investigator staff, and assessing the need for a data monitoring committee.
Drug development planning
In the section on drug development planning, the guidance encourages sponsors to consult the ICH M3 guidance on non-clinical safety studies to ensure the quality of the investigational product. The guidance states that “use of the drug in special populations (e.g., pregnant or breast-feeding women, children) may require additional non-clinical assessments,” also referencing ICH E11’s guidance on pediatric clinical trials.
For clinical studies, the guideline urges the use of biomarkers to ensure the availability of “safer and more effective drugs.” Sponsors are encouraged to consult the ICH E16 guidance on qualifying genomic biomarkers.
The guideline states that protecting study participants should be the “first priority” when designing human pharmacology studies, especially on first administration of a drug to humans, and encourages sponsors to enroll healthy participants for such studies.
Aafter clinical studies demonstrate drug safety, sponsors move to the conduct of exploratory (Phase 2) and confirmatory (Phase 3) studies to “further evaluate both the safety and efficacy of the drug.”
Phase 2 studies, according to the guideline, “may provide information on the identification and determination of factors that affect the treatment effect and, possibly combined with modelling and simulation, serve to support the design of later confirmatory studies.”
By the time the sponsor gets to Phase 3 trials, the studies “are often intended to provide an adequate basis for marketing approval, and to support adequate instructions for use of the drug and official product information.” Endpoints in these studies should thus have clinical relevance and take into account the disease burden of the drug’s intended indication.
The guideline addresses investigations in special populations such as pregnant and lactating women, children and geriatric populations, and directs sponsors to ICH E5 and E17 for consideration of ethnic factors, and to E6 and E11 for consent and other important issues in vulnerable populations.
After the drug is approved, post-approval studies may be needed to “further understand” the drug’s safety and efficacy. The guideline reviews commonly used study types to assess issues important in the post-market setting.
Data sources for clinical studies
The guideline reviews the necessary data elements to ensure robust study design as well as data sources that can be used.
Sponsors are encouraged to consult the ICH E9(R1) addendum on statistical principles for clinical trials to refine their study objectives through the specification of estimands.
The guideline also addresses the use of interventional studies and observational studies in drug development. For interventional studies such as randomized controlled trials — the backbone of drug development — master protocol studies and platform studies can be used to study multiple drugs under a “shared framework.”
Selecting study participants
The guideline gives considerations for selection of the study population in terms of the nature of the cohort and the sample size.
The control group should be chosen so the study can meet the desired end of seeing treatment effect as a separate outcome from other confounders or the natural course of the disease in the indicated population. The guideline refers to ICH E10’s cautionary note about the limitations in the use of external controls.
Randomization and blinding are important methods to reduce the risk of bias in clinical studies; the guideline covers these and other strategies to reduce bias.
Statistical analysis of a study should be pre-planned and pre-specified in the protocol, as laid out in ICH E9. The guideline recommends pre-specified sensitivity analyses, as well as a description in the study protocol of how hypotheses of the drug effect will be tested, and how the study sample size will be justified.
Study data, whether primary or secondary, should be guarded by protocols that make sure personal participant data are protected.
The guideline states that “the study data should contain the necessary information to conduct the statistical analysis specified in the protocol and statistical analysis plan, as well as to monitor for participant safety, protocol adherence, and data integrity.”
Study data can either be generated from the present study or can be obtained from external sources. External sources include “historical clinical studies, national death databases, disease and drug registries, claims data, and medical and administrative records from routine medical practice.”
If using secondary data, sponsors should ensure that such data are relevant and described in the study protocol.
Study Conduct and Monitoring
The guideline outlines a set of core principles for conducting and reporting clinical studies. The principles address adhering to the protocols, training, data management, and accessing interim data.
 An annex to the guideline outlines different types of clinical studies, identifying the objective of a particular study type and giving several examples of each type.
The revision contains very few changes from the Step 3 versions issued in May 2019. It adds an attachment on “critical to quality factors in operational practice” in the section on designing quality into clinical studies. It also adds language in the section on design elements and data sources for clinical studies.
Regulators last provided an update on the E8(R1) guideline E19 in November 2019, (RELATED: ICH Updates: What to Expect Through 2020, Regulatory Focus, 5 November 2019).
ICH E8(R1)


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