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ICH E6: Teaching the World to Sing in Perfect Harmony

1 August 2018 No Comment

Lisa LaVange

Statisticians working in clinical trials will be familiar with the acronym GCP, denoting good clinical practice. What may be less well-known is the international regulatory guideline that defines GCP for drug trials, or the organization responsible for issuing that guideline. The International Conference for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) was convened in 1990 with the goal of bringing together pharmaceutical sponsors and regulators from the different regions of the world to develop harmonized guidelines for drug development.

ICH E8 Working Group in Kobe, Japan

One of the most widely used ICH documents issued early on was ICH E6 Good Clinical Practice. For the past 25 years, this guidance has formed the basis for training individuals of different backgrounds and disciplines working in regulatory clinical trials, especially clinical investigators, study managers, site monitors, and inspectors.

The ASA recognized a few years ago that formal GCP training could benefit the large number of statisticians involved in clinical trials—and not just those working in the pharmaceutical industry or at regulatory agencies. In collaboration with the Drug Information Association (DIA), an ad hoc committee was formed to develop a white paper on statistical training in GCP. Janet McDougall was appointed chair, and Aloka Chakravarty—deputy director of the Center for Drug Evaluation and Research’s (CDER) Office of Biostatistics—represented the FDA on the working group. The white paper and subsequent workshop presentations served as a valuable resource when offering preliminary training recommendations for statisticians working in regulatory and research clinical trials. A summary of the committee’s work is available.

The timing of this training initiative could not be better, due to changes in the works for E6. But first, a little history (which you know by now I cannot resist giving).

Ad Hoc Good Clinical Practices Committee Members
Janet McDougall, Chair
Scott Berry
Joan Buenconsejo
Aloka Chakravarty
Brenda Crowe
Debra Michaels
Eva Miller
Maria Matilde Sanchez-Kam
Nancy Smith
Terry Weber Sosa

ICH was initially based on the three major regulatory regions of the early 1990s: the US, Europe, and Japan. Representatives from the US Food and Drug Administration (FDA); the European Commission (EC); and Japan’s Ministry of Health, Labour, and Welfare (MHLW) and Pharmaceuticals and Medical Devices Agency (PMDA) joined representatives from regulated industry associations—namely the Pharmaceutical Manufacturers Association (PhRMA) in the US, European Federation of Pharmaceutical Industries and Associations EFPIA), and Japan Pharmaceutical Manufacturers Association (JPMA)—as founding ICH members. In 2015, the organization changed its name to the International Council on Harmonisation and adopted a new management structure. Membership has expanded over the years to include 16 members and an even larger number of observers. The Chinese regulatory agency, CFDA, joined in 2017, for example, and the International Generic and Biosimilar Medicines Association (IGBA) joined in 2018.

The early products of the ICH were a series of guidelines covering various aspects of trial design and conduct, manufacturing, and quality control. The regulatory agencies adopted the guidelines, which in the US involves an additional step for the FDA to issue formal guidance.

ICH E6 was published in 1996 and describes the responsibilities and expectations of clinical trial stakeholders, including clinical investigators, site monitors, sponsors, institutional review boards, and regulators. It covers the nuts and bolts of running a trial, including data collection, monitoring, reporting, and archiving trial materials. Protecting the safety and rights of patients is addressed through guidelines for the informed consent process and communication of risks (e.g., through investigator brochures).

E6 stood relatively untouched and broadly used for years. A proposal was made to revise it in 2014 to reflect changes that had occurred in clinical trial methodologies and technologies, such as the use of electronic data capture, centralized data monitoring, and risk-based clinical site monitoring. The revision included an integrated addendum and was adopted in 2016. The FDA’s corresponding guidance was issued earlier this year.

The ICH meets every six months and rotates meeting locales among the three founding regions. At the June 2016 meeting in Lisbon, Portugal, a group of clinical trialists met with ICH management committee representatives to discuss changes they would like to see in the newly revised E6 document. These suggested changes were outlined in an open letter to the European Medicines Agency (EMA) and ICH that was signed by several European research organizations and an international consortium of health researchers with experience in clinical trials from 19 countries.

As the FDA representative responsible for all ICH documents in the E series (efficacy), I had the opportunity to attend the Lisbon meeting and participate in the E6 discussion with the external stakeholders.

One major concern the stakeholders expressed was the scope of the guidance was too narrowly focused on clinical practice and should more broadly reflect the principles of trial design, conduct, and reporting. We noted during that discussion that E6 does not stand alone as a guide to good clinical trial practice, but rather is concerned primarily with practice at the clinical centers of the trial. ICH E9 Statistical Principles for Clinical Trials, for example, provides what could be termed good statistical practice, and many of the topics absent from E6 that were pointed out in the open letter could be found in that guideline.

Other deficiencies noted in the open letter and discussed at the meeting, however, would require a more comprehensive revision to address. In particular, it was thought the current E6 failed to acknowledge that different types of clinical trials posed different levels of risk for participants, and researchers needed to be able to exercise flexibility in managing those risks. Much of the material was pertinent to trials of investigational drugs and did not allow a fit-for-purpose approach for other types of trials. Clinical monitoring in a post-market trial of a marketed drug, for example, may not require the intensity of monitoring or scrutiny of source data that an early phase trial requires, when little is known about potential harm from the drug.

Shortly after the Lisbon meeting, we developed an FDA proposal to renovate E6 and revise the related document, E8 General Considerations for Clinical Trials, in response to the open letter and subsequent discussions with the authors. The proposal was accepted by the ICH, and a reflection paper describing the planned renovation and revision work was posted on the website in January of 2017, inviting public comment. As stated in the reflection paper, “The goal is to provide updated guidance that is both appropriate and flexible enough to address the increasing diversity of clinical trial designs and data sources that are being employed to support regulatory and other health policy decisions. The underlying principles of human subject protection and data quality would remain.

The revision of E8 was proposed to accomplish three goals: (i) introduce a quality by design approach to clinical trials; (ii) expand the scope to nontraditional trial designs and data sources; and (iii) provide a more comprehensive and updated guide to the full list of ICH guidelines pertinent to clinical trials, the complete set of which could be viewed as a reference for good clinical trial practice.

Following the E8 revision, the renovation of E6 would begin, further modernizing its approach to GCP. In the reflection paper, we had proposed a series of annexes to E6 corresponding to the use of different data sources (e.g., health care claims data or patient registries, etc.) and trial designs (e.g., pragmatic clinical trials, pharmaco-epidemiology studies, etc.), leaving the main body of the document to cover more traditional randomized clinical trials conducted for product registration.

The revision of E8 began with the ICH meeting in Geneva in June. The expert working group has 30 members from a variety of disciplines. I represent FDA as the rapporteur, and—along with the regulatory chair from the EMA—lead the working group. Mark Levenson, Biometrics Division director in CDER’s Office of Biostatistics is FDA’s topic lead.

Although not a statistical guideline per se, the importance of statistics in trial design, risk management, data quality, and many other elements of GCP is indisputable. Statisticians have an important role to play as GCP concepts continue to evolve, and the ASA’s leadership on the training initiative is timely indeed!

Lisa LaVange

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