With new regulations taking effect this fall and more advanced technologies now available, the state of clinical development of new drugs and devices is definitely changing for the better.
On November 1, 2016, revisions to the Good Clinical Practice (GCP) addendum E6 (R2), from the International Conference on Harmonization (ICH) Working Group, will take effect. This will increase the adoption of Quality by- Design (QbD) and Quality Risk Management (QRM) principles in clinical development.
There are three big changes in store for pharmaceutical companies, but first, let’s revisit QbD and QRM and give some historical perspective.
QbD builds quality into the pharmaceutical manufacturing process, using a systematic approach to product design, process design and control, process performance, and continuous improvement. In embracing QbD, the FDA recognized that increased testing doesn’t necessarily improve product quality; it must be built into the product.
QRM, meanwhile, is a systematic process to assess, control, communicate and review possible risks to the quality of drug products across the product lifecycle. Quality should be based on scientific knowledge and the protection of patients. The effort, formality, and documentation involved in QRM should be commensurate with the level of risk.
A Bit of Clinical Development History
To appreciate the improvements these practices have made to date, it’s important to remember what the clinical development world was like before QbD and QRM first emerged. Back when ICH GCP E6 (R1) was released, in the mid-1990s, clinical trials were nowhere near as costly and complex as they are today - nor were the regulatory, ethical and quality standards as high.
From a technology perspective, two-plus decades ago the data from clinical trials was still mostly captured on paper. The most innovative companies were using Clinical Data Management Systems (CDMS) to perform heads-down double-data entry to produce paper Case Report Forms (CRF), which were then mailed from the clinical sites to the sponsor. Data clarification reports were mailed back and forth to resolve discrepancies. The process was amazingly inefficient.
ICH GCP E6 (R2) was an effort to modernize the process, and improvements continue to this day.
Changing Clinical Trial Data for the Better: E6 (R2)
The latest addendum, GCP E6 (R2), which applies to clinical trial data being submitted to regulatory authorities, provides “a unified standard for the E.U., Japan and U.S. to facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictions.”
Importantly, it encourages the “implementation of improved and more efficient approaches to clinical trial design, conduct, oversight, recording and reporting while continuing to ensure human subject protection and data integrity.”
Today’s life science industry has much better technological tools at its disposal, allowing for implementation of more efficient approaches in clinical development to meet the goals of protecting human subjects and data integrity. Unlike the ‘90s, when electronic data capture wasn’t available and the Internet was still a mystery, we now have ePRO, CTMS, IWRS, IRT, eTMF, and slick visual analytics for the analysis of clinical, operational, and safety data.
Realizing the technological advances, regulators are encouraging pharmaceutical sponsors and their CRO partners to use technology to achieve numerous goals:
• Identify and mitigate areas of high risk prior to conducting a trial
• Monitor risks during the trial
• Improve trial oversight
• Ensure data integrity and data quality
Three Big Changes for Clinical Development Pharma Sponsors
The revised E6 guidance places three main areas of responsibility with the pharmaceutical sponsors: riskbased quality management, risk-based monitoring, and CRO oversight.
1. Risk-Based Quality Management
New ICH guidance states that quality management is expected to be risk-based, and should be applied to monitoring and auditing tasks. Quality management involves efficient protocol design, data collection tools and procedures, and information collection that’s essential to decision making.
A risk-based quality management system should be implemented to manage quality throughout the clinical trial, including: design, conduct, recording, evaluation, reporting, and archiving. Activities should focus on human subject protection and the integrity of trial results. Methods to assure trial quality must be equally weighted with trial risks and the importance of the information collected. The trial must be operationally feasible, and operational documents such as protocols and CRFs should be clear, concise, and consistent.Anything unnecessary – think of certain procedures or data collected – should be avoided.
2. Risk-Based Monitoring (RBM)
The monitoring portion of the guideline had major additions, including an addendum calling for a risk-based approach to monitoring clinical trials by leveraging a combination of onsite and centralized monitoring. Centralized monitoring was called out as a method to “complement and reduce the extent and/or frequency of onsite monitoring.”
Monitoring activity results should be “documented in sufficient detail to allow verification of compliance with the monitoring plan.” The monitoring plan should be “tailored to the specific human subject protection and data integrity risks of the trial.”
Such a centralized monitoring strategy requires, from a technology standpoint, three capabilities for RBM:
1. Data integration
2. Visualization-based data discovery
3. Predictive analytics
These lead to fast, actionable insight; visibility into the unknown; self-service discovery; and universal adaptability.
3. CRO Oversight
For QbD and QRM to be more successful in clinical development, regulators are asking sponsors to take on a more active role; they can’t completely hand over trial responsibility to the CROs. “The sponsor should ensure oversight of any trial-related duties and functions carried out on its behalf,” ICH guidance states.
Achieving Clinical Trial Goals
With better technologies and updated regulations – like the addendum to ICH CGP E6 – working in tandem, life sciences companies are able to improve clinical development and achieve many important goals:
• Better trial oversight
• Reliable data quality
• Lower monitoring costs
• Faster study cycle times
• Patient safety
What would a Phase III project manager from 1996 (talking on a Motorola StarTAC!) think about the technological advancements - and better guidance - available for clinical development in 2016?
Are you working with the best solutions for QbD and QRM in your clinical trials?