FDA, ICH Seek Comments on “Quality by Design” Draft Guideline

August 5, 2019

Sponsors, CROs and other stakeholders have until September 30 to help shape a critical trial design guideline, according to the FDA’s call for public comment on the revision of ICH E8 last week.

The ICH E8 revision is the latest step in the International Council on Harmonisation’s (ICH) efforts to update trial standards, following the revision of ICH E6 — Good Clinical Practices in 2016.

Publishing the document as an FDA draft guidance, the agency last week requested input on the near-total overhaul of the guideline, which was originally issued in 1997.

A brief 17 pages when it was first published, the revised ICH E8 weighs in at 40 pages and is an almost-total rewrite of the original guideline.

The primary theme of the new document is “quality by design,” an approach built on identifying factors critical to the quality of a clinical study, as well as their risks, beginning in the design stage.

“Quality should rely on good design and its execution rather than overreliance on retrospective document checking, monitoring, auditing or inspection,” the guidance says. “These activities are an important part of a quality assurance process but are not sufficient to ensure quality of a clinical study.”

Examples of critical quality factors listed in ICH E8(R1) include:

  • Eligibility criteria;
  • Randomization;
  • Blinding/Masking;
  • Types of controls;
  • Data quality;
  • Endpoints; and
  • Procedures supporting endpoints and data integrity.

To help identify quality factors, ICH E8(R1) recommends:

  • Engaging all relevant stakeholders, including patients, in study planning and design;
  • Ensuring study objectives address relevant scientific questions appropriate for a given study;
  • Designing a meaningful comparison of the effects of a drug to the trial’s chosen control groups;
  • Conducting a feasibility study to ensure the study is operationally viable;
  • Choosing well-defined response variables and assessment methods; and
  • Specifying in the protocol information about study subjects that may be important to understanding the benefit/risk of the drug.

The update also addresses the diversity of clinical study designs and data sources, encouraging trials to think outside the traditional box of phases 1-4. “The phase concept is a description, not a set of requirements,” the draft guidance says, and categorizing trials by study objective also is an option. For example, a progression of studies could be categorized as nonclinical testing, human pharmacology, exploratory, confirmatory and postapproval.

In addition to recommendations on incorporating quality into clinical studies, ICH
E8(R1) includes suggestions on study design elements, study conduct and reporting.

For example, it stresses the importance of patient centricity — designing the trial around the patient. By involving patients in the early stage of study design, researchers are likely to “increase trust in the study, facilitate recruitment and promote adherence, which should continue throughout the duration of the study,” ICH says.

The FDA will accept comments on the draft until September 30, and ICH will hold a public meeting to solicit input on Oct. 31 in Silver Spring, Maryland. ICH hopes to have final guidance ready to publish by June 2020.

ICH also is in the process of developing another clinical trial-related guideline, E19 — Optimization of Safety Data Collection, aiming to publish it in 2021 (CenterWatch, July 1, 2019). And the organization is in the initial planning stages for a revision of E20 — Adaptive Clinical Trials.

Read the draft ICH E8(R1) here:

By Leslie Ramsey and James Miessler