The clinical trials industry must prepare for a paradigm shift in good clinical practice (GCP) principles when two impending revisions of key International Council on Harmonization (ICH) guidelines are finalized in the coming months.

Regulators will expect quality and risk management principles to be weaved into trials from the beginning and sites and sponsors will have to abandon the traditional reactive approach of finding and fixing problems once they have occurred.

ICH’s forward-looking guidelines, ICH E6 — Good Clinical Practice and E8 — General Considerations for Clinical Trials, which lay out in detail the concepts of risk management and quality-by-design (QbD), will be finalized most likely in 2022. The documents will push GCP toward quality-based approaches on a massive scale, according to WCG Avoca Group Senior Consultant Janis Hall. The first revision of ICH E8 is much further along in the development process than ICH E6, but there are no set dates for either to be made final.

“Of the challenges that we’ve observed, certainly QbD involves definitely new, evolving thinking for the GCP space. These are new concepts and it’s a process, not a final destination, that calls for continuous improvements,” Hall told attendees at a WCG Avoca Group webinar last week.

A number of key challenges exist in implementing QbD, which has seen great success and incorporation into good manufacturing practices (GMP), she said. Sites, sponsors and CROs should be aware of these issues and know how to approach and prepare for them ahead of the release of the ICH guidelines.

For one, although QbD is firmly established within GMP, in the GCP realm it is still a fresh and unstandardized way of thinking. That means that an imbalance currently exists across functional areas, with methods not well-established in company standard operating procedures (SOPs) or staff expectations and concepts unevenly established across the end-to-end trial process, Hall said.

Right now, the clinical trial industry’s approach to quality looks more like a 1950s car factory than the modern, automated approach to quality that regulators are envisioning, according to Andy Lawton, a consultant with Risk-Based Approach. “It should be this automated factory of the future … relying on defined and measured quality,” Lawton told webinar attendees. “Our quality is [currently] relying on auditing, inspection and monitoring retrospective document checks,” he said. “You can’t go to an automated process until you measure quality, until you know what you’re going to get.”

Transitioning industry to a quality-oriented mindset and structure will be no easy lift, Hall added, but the benefits are increased patient safety, improved data integrity, higher-quality drug submissions and a better chance of approval.

Problems arise with stakeholders other than sites and sponsors that often may not all be present in discussions on implementing QbD elements into a trial. Some providers, including CROs, are more heavily involved in the ongoing development of methods, while “other niche providers and sites are often not part of the equation,” she said, and may struggle to understand or apply the concepts.

Similarly, clinical staff may be rooted to the traditional ways of operating and be hesitant or incapable of switching to new quality-based approaches. “Some people may lack the critical thinking skills to be able to make this transition, and companies may need to reassign or remove resources to fit new needs,” she said.

To overcome challenges to QbD implementation, it is critical to be transparent and evaluate the experience of outsourced providers used in a trial. For example, a vendor that’s more experienced in quality management than a site or sponsor may be able to help with staff training, whereas a less experienced one may not align well with a trial’s quality expectations. Hall recommends developing a comprehensive list of specific, relevant questions to use in the vendor selection process.

For example, considering if the vendor even mentions QbD approaches or proactive risk analysis is a good barometer, as is considering if a vendor’s approach is in line with regulators’ priorities. In addition, consider what data integration and analytic technologies vendors offer, if they offer tools to identify or track factors critical to quality, and if they share risk mitigation strategies, among other items.

Proactive vendor risk assessments also are important, Hall added. Sponsors, CROs and sites should discuss the vendors that will be used, what they will contribute to the trial and how critical those contributions are to trial quality. Also consider protocol-unique risks associated with providers, she advised. For instance, certain risks associated with an electronic patient reported outcome (ePRO) vendor could pose greater potential risks to a trial of a bipolar disorder drug that’s heavily reliant on PROs, she said. Similarly, an imaging provider could pose higher potential risk for a solid tumor cancer trial that depends largely on imaging data.

Additionally, sponsors that plan to outsource a trial to a CRO should clearly lay out the roles and responsibilities they intend to assign to the CRO. “When a sponsor collaborates with a CRO and plans to implement QbD, which is what is expected within the industry going forward, it’s really important to start by clarifying roles and responsibilities on what you want that CRO to do,” Hall said. “Are they going to develop an integrated risk management plan or elements of that plan? Do they identify factors critical to quality in quality tolerance limits, how to measure them, the frequency of measurement? Do they report the risks to governance committees? Are they training stakeholders in these QbD approaches?”

And lastly, Hall said it’s important to build QbD methodologies and expectations into vendor contract documentation. Capture such expectations into the trial’s responsibility matrix, the scope/statement of work documents and the contract itself, she said.

“We need to live continuous quality improvement rather than just having it as a statement in our philosophy documents. We need tools to avoid being such siloed organizations,” Lawton said. “Our data systems need to be integrated from source to the submission and we need integrated SOPs and a much-reduced set [of SOPs],” he said. “Risk management has to be the basis of all of our work and we also need some defined quality philosophy that we’re following [as an industry.]”