Earlier this year, the U.S. Food and Drug Administration (FDA) finalized changes to the “Good Clinical Practices” (GCP). The FDA was the latest in a string of countries to adopt and implement these revised GCP guidelines (e.g. EMA, Canada, Switzerland, and others). These new guidelines should encourage both sponsors and CROs to closely examine drug development processes to identify how they will be affected and how they can be improved. This opportunity will allow for the identification of new approaches to clinical trials that will be more time and cost efficient and safer for patients. This in turn will enliven the creative process that leads to significant innovations.
Here, we review several of the updated regulations and discuss the potential impact to our clients:
The set of standards generally considered GCP is formally codified in the International Conference on Harmonization Good Clinical Practices E6 (R1) – ICH GCP E6 (R1) – guidelines. They were formally adopted in 1996, after extensive work by the global regulatory community and pharmaceutical companies to identify and implement a common set of standards that could be used industry wide. These guidelines are used in the design and conduct of thousands of clinical trials and, subsequently, the arrival of numerous drugs into the hands of patients who need them.
Over the subsequent 20 years, the industry has evolved; outsourcing the conduct of clinical trials has become the norm, electronic data capture is now standard, and drug development has gotten more complex. These changes, combined with the major trends in inspection findings, prompted the need for an update.
In November of 2016, the ICH GCP E6 (R2) guidelines were approved and published by ICH as an addendum to the existing guidelines. This monumental revision to GCP resulted in far-reaching impacts, both expected and unexpected. What impact do these new standards have at the CRO, sponsor, and site level? And what strategies will be employed for taking on the challenges of implementing them?
Guidance Sections Relevant to Sponsors
A significant portion of the addendum is related to the Sponsor and its conduct of clinical trials, especially the outsourcing components. These updates likely reflect the volume of inspection findings relative to inadequate sponsor oversight. More than 180 FDA inspection findings over the last 10 years were related to sponsor oversight of clinical trials.
Quality Management (Guideline for Good Clinical Practice E6 (R2) 5.0)
- “ADDENDUM The sponsor should implement a system to manage quality throughout the design, conduct, recording, evaluation, reporting and archiving of clinical trials.
“Sponsors should focus on trial activities essential to ensuring human subject protection and the reliability of trial results. Quality management includes the efficient design of clinical trial protocols, data collection tools and procedures, and the collection of information that is essential to decision making.
“The methods used to assure and control the quality of the trial should be proportionate to the risks inherent in the trial and the importance of the information collected. The sponsor should ensure that all aspects of the trial are operationally feasible and should avoid unnecessary complexity, procedures and data collection. Protocols, case report forms, and other operational documents should be clear, concise and consistent.”
These quality management topics are important to the Sponsor/CRO relationship. The concept of “quality by design” is introduced in this guidance – the concept of designing a quality trial from the beginning, mapping assessments to endpoints, including risk-based approaches, structuring operationally feasible trials, etc.
As the cost of drug development increases, protocols have grown more complex as drug developers attempt to accomplish more in a single protocol. The revised language addresses this topic head-on: “…focus on trial activities essential to ensuring human subject protection…”, “…collection of information that is essential to decision making…”, and finally, “…that all aspects of the trial are operationally feasible and should avoid unnecessary complexity…”
The concept of developing “operationally feasible” trials as defined in ICH E6 (R2) puts increased importance on the period of “early engagement” between a CRO and sponsor. Many biopharma companies have shed their internal management structure, and much of this expertise now resides within CROs.
Historically, CROs were contracted at the time of a final protocol and were left solely with responsibility for operational execution. However, we’ve seen a recent trend toward an extended “early engagement” period before the protocol is finalized, where trial operations can be optimized around the trial’s objectives. Most of our trials contain some degree of early engagement, even in situations where PRA is not writing the protocol. We also have several unique partnerships where PRA owns or shares responsibility for the entire Clinical Development Plan/Target Product Profile and associated strategy.
Contract Research Organization (CRO) (Guideline for Good Clinical Practice E6 (R2) 5.2)
- 2.1 “A sponsor may transfer any or all of the sponsor's trial-related duties and functions to a CRO, but the ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor. The CRO should implement quality assurance and quality control.
- “ADDENDUM The sponsor should ensure oversight of any trial-related duties and functions carried out on its behalf.
- 2.2 “Any trial-related duty and function that is transferred to and assumed by a CRO should be specified in writing.
- “ADDENDUM The sponsor should document approval of any subcontracting of trial-related duties and functions by a CRO.”
PRA-sponsor relationships are comprised of a range of outsourced services: full-service, single service, clinical-only, embedded staff, early development, etc. Even among trials with the same service offering, the operational set-up may be different based on client needs, therapeutic area, geographical spread, etc. We structure our larger study teams to maximize oversight of any subcontracted services, or third-party services (e.g., niche providers in certain regions or radiology vendors). We also leverage a strong centralized vendor management team to aid in governance relationships with our vendor partners, consistent structuring of commercial terms, and support project teams in oversight. These steps seek to protect the sponsor, the vendor partner, and PRA, and ensure everyone’s best interests are protected and are compliant.
Monitoring (Guideline for Good Clinical Practice E6 (R2) 5.18)
- 18.3 “The sponsor should ensure that the trials are adequately monitored. The sponsor should determine the appropriate extent and nature of monitoring. The determination of the extent and nature of monitoring should be based on considerations such as the objective, purpose, design, complexity, blinding, size, and endpoints of the trial. In general there is a need for on-site monitoring, before, during, and after the trial; however in exceptional circumstances the sponsor may determine that central monitoring in conjunction with procedures such as investigators’ training and meetings, and extensive written guidance can assure appropriate conduct of the trial in accordance with GCP. Statistically controlled sampling may be an acceptable method for selecting the data to be verified.
ADDENDUM The sponsor should develop a systematic, prioritized, risk-based approach to monitoring clinical trials. The flexibility in the extent and nature of monitoring described in this section is intended to permit varied approaches that improve the effectiveness and efficiency of monitoring. A combination of on-site and centralized monitoring activities may be appropriate. The sponsor should document the rationale for the chosen monitoring strategy (e.g., in the monitoring plan).
On-site monitoring is performed at the sites at which the clinical trial is being conducted.
Centralized monitoring is a remote evaluation of ongoing and/or cumulative data collected from trial sites, in a timely manner. Centralized monitoring processes provide additional monitoring capabilities that can complement and reduce the extent and/or frequency of on-site monitoring by such methods as:
(a) Routine review of submitted data.
(b) Identification of missing data, inconsistent data, data outliers or unexpected lack of variability and protocol deviations that may be indicative of systematic of significant errors in data collection and reporting at a site or across sites, or may be indicative of potential data manipulation or data integrity problems.
(c) Using statistical analyses to identify data trends such as the range and consistency of data within and across sites.
(d) Analyzing site characteristics and performance metrics.
(e) Selection of sites and/or processes for targeted on-site monitoring.”
These monitoring guidelines specify designing trials that can use risk-based approaches to monitoring, emphasizes the use of a monitoring plan to outline how the monitoring will occur, and emphasizes the importance of the monitoring report in this risk-based process. Risk-based monitoring is not about throwing risk into a trial; rather, it’s a way to design trials in ways that can detect risk in an objective fashion.
Technologies that focus on the most significant data and processes that will have direct effects on patient safety and data reliability should be introduced when employing risk-based monitoring strategies. The use of technological approaches to monitoring data gives PRA the ability to address potential risks/issues and identify abnormalities in the data before this risk is passed on to the trial and the patient.
PRA has invested heavily in our risk-based monitoring solution, termed Adaptive Trial Management and Monitoring. This name and approach embodies our view that risk-based monitoring is a mindset for the management of the entire trial. PRA has developed risk assessment tools from this guidance which form the basis of risk review triggers (e.g., SDV percentage, on-site monitoring, monitoring frequency, etc.). Risk assessment at the beginning of a trial is vital to risk-based monitoring -- identifying where areas of potential risk are, what actions will be taken if risk triggers are observed, and how each of these actions are documented. These steps also require new technologies to assess risk and document the associated action. Risk-based monitoring is a cultural shift. Historically, some industry professionals have associated greater SDV with greater quality, and E6 R2 putting additional pressure on this area may change some of this mindset. The best way to implement this shift will be training staff to use these new technologies and to show that risk-based monitoring strategies are best for data quality, patient safety, and monitoring effectiveness.
There will also be more ancillary effects for the site due to the move towards risk-based monitoring. This will mainly be a noticeable change in interactions with the Sponsor/CRO as there is a shift away from fixed-interval monitoring. Communication between the sponsor/CRO and the site on the reasons behind the new strategy and how it will manifest will be an important aspect of the implementation of the new monitoring strategies. These changes will have an impact on Clinical Trial Agreements with sites, ensuring the relationship is fair and reasonable for investigational sites.
A unique opportunity for the clinical trial industry
While the addendum presents some challenges, it provides a needed modernization to guidelines in use for more than 20 years. It also provides CROs, sponsors, and Investigators an opportunity—an opportunity to make significant changes to an industry that faces increasing complexity and rising costs for clinical trials. These guidelines should encourage both sponsors and CROs to closely examine internal processes in order to identify how they will collaborate on process improvement, information sharing and decision making. The implementation of these new guidelines will energize innovation within the industry and allow for significant growth to occur. At PRA, we welcome these changes and this opportunity to work even more closely with our clients to further innovation within the drug development industry.