Speakers

Prof Sir Martin Landray, FMedSci
Professor of Medicine & Epidemiology
University of Oxford
Chief Executive, Protas

Khair ElZarrad, PhD, MPH
Director, Office of Medical Policy
Center for Drug Evaluation and Research (CDER)
U.S. Food and Drug Administration (FDA)

Slides

Keywords

Pragmatic trials; Research; Guidance, Regulatory, Data Governance

Key Points

• The clinical trial enterprise needs modernization. Time, cost and failure to recruit trial participants are significant barriers that must be addressed. The rapidly evolving ecosystem now relies on real-world data, which is becoming increasingly more advanced, and clinical trial design is becoming more complex and innovative.
• The International Council for Harmonisation of Technical Requirements for Human Use (ICH) is a unique harmonization organization involving regulators and the pharmaceutical industry. Its objective is to improve efficiency of new drug development and registration processes, in addition to promoting public health, preventing duplication of clinical trial in humans and minimizing the use of animal testing without compromising safety and effectiveness.
• The E6 Good Clinical Practice clinical trial conduct principles was intended to be an improvement of the G8 clinical trial design principles. The working group is engaging with academic stakeholders to determine new approaches to enhance transparency. An extensive training program with use-cases focused on trial designs still needs to be developed in the application of GCP guidelines.
• The new structure aims to provide clarity and better readability. The scope is focused, and the language aims to facilitate innovation in trial design. It also aims to set a foundation for practical and feasible expectations around the responsibilities from the sponsor and investigator, encourage a fit-for-purpose approach and incorporate learning from innovative trial design. Annex-2 of E6(R3) will include additional considerations of GCP principles focused on decentralized elements, pragmatic elements and real-world data sources.
• The principles aim to promote good science and ethics, be clear and concise, be inclusively developed and be progressive and durable.
• While E6(R3) provides a foundation for GCP expectations, guidelines alone are not adequate. The field will also need to collaborate on implementation and capacity building, develop responsive and accessible training and avoid all-or-nothing approaches on design and technologies.
• Better guidelines are needed to promote better trials, which will promote better health. Clinical trials should incorporate quality in their scientific and operational design, conduct and analysis.
• The principles focus on the concepts that “Good Trials” produce a scientifically sound answer to a relevant question through the principles: Principle 01) Informative and relevant; Principle 02) Respectful of participants; Principle 03) Collaborative and transparent; Principle 04) Feasible for their context; and Principle 05) Efficient and well managed.
• The current 11 ICH principles are generally sound, and the structure of Introduction > Principles > Annexes support critical application. However, improvements can be made, and further modifications are needed to ensure that the annexes are treated as implementation guides and not rules.
• Current proposed modifications include grouping principles into overarching themes, restructuring each principle and explicitly cross-referencing principles in Annex-1. There are also concerns that the ICH document fails to include scientific issues encountered quite often, such as allocation concealment, randomization, loss-to-follow-up, blinded evaluation of endpoints and others.
• There are also some excessive details on data, records and computer systems, which are unlikely to stand the test of time. This could stifle innovation and quality when new and different technologies are more relevant. Unnecessary, irrelevant, or ultra-specific guidance can cause more harm than good.
• GCTC will publish its comments at goodtrials.org and the public is encouraged to submit feedback as the work continues to improve the guidance.

Discussion Themes

–How much work was needed to get to this stage where the revisions are up for public comment? The work started before COVID-19, and the idea was to meet every six months. We had an opportunity to meet once, and then everything became virtual. The amount of work that went into the gap analysis alone was several months because we needed to have a thorough understanding of where the community is coming from, especially in areas that we knew were seeing advancements in design. We wanted to make sure we were encouraging flexibility of design and use of technology, while still highlighting what people need to be careful with. We also included multiple meetings with our academic stakeholders. We need to be clearer and more concise, while making sure that the statement fits with the needs of researchers. Training is also going to be essential to move this forward.   

–How did the pandemic impact the updates to the guidance? COVID-19 made us think about things differently, because one couldn’t apply rules, one had to apply principles. You must apply what really matters regarding the critical quality factors – for example, you can’t disrupt critical health care. The principles were the only thing we could fall back on, so I think that’s why it’s so important to get the principles right and lean on the trainings in all of our department.

–How do you balance precision and fit-for-purpose quality checks with more situations in which investigators are conducting trials using data from entire systems of health care? We need to create a space where this is an open dialogue and these kinds of conversations can happen. I think collectively, we want to promote the utilization of health care in research. We see that as an important part of the future. It would be such a waste of valuable data, valuable approaches, and valuable infrastructure to not embed clinical trials effectively into health care systems.

–What are the next steps? We encourage people to review the guidance and provide feedback. One important note is that we specifically moved away from a checklist approach. The guidance should not remove the need to think. Even when we have a guideline, we want to lead investigators to think based on the principles of this guidance.

Tags

#pctGR, @Collaboratory1