Graeme Downes, Senior Director, Clinical and PV QA, AstraZeneca
Anatoly Gorkun, Senior Manager, Scientific and Compliance Training, MedImmune
Abstract: The Good Clinical Practice (GCP) regulations require that each individual involved in conducting a clinical trial be qualified by education, training, and experience to perform the respective tasks. This article provides an overview of the purpose of GCP training, ways of delivering GCP training, and components of the GCP training package. An effective way to build a risk-based GCP training program is described.
Disclaimer: The views and opinions presented here are those of the authors and not of MedImmune or AstraZeneca.
GCP is an international standard for clinical trials that ensures that the rights, safety, and well-being of clinical trial subjects are protected and that the clinical trial data are credible. Various legislative requirements exist for GCP training from a country level to global. For example, in the United Kingdom, regulation 28 of the UK SI 2004/1031 states that, “no person shall conduct a clinical trial… otherwise than in accordance with the conditions and principles of GCP.” From a global perspective, the International Conference on Harmonisation (ICH) Guideline for Good Clinical Practice §2.8. states: “Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s).” This means that each individual involved in conducting a clinical trial must receive training in GCP.
Even though legislative requirements have been in effect for several years and most if not all companies claim to have GCP training programs in place, non-compliance with GCP is frequently identified, as evidenced through monitoring, audit, and inspection findings.
Case Study on Joint Assessment
This case study involves a rheumatoid arthritis trial in which joint assessment was used as a primary efficacy criterion. The results were recorded in the Electronic Data Capture (EDC) system. All clinical trial sites had a delegation of responsibilities log, which covered blinded, un-blinded, and joint assessment responsibilities.
The EDC vendor allocated a system log-in PIN, identical for all joint assessors at all clinical trial sites in all contributing countries. The joint assessors used a stylus to create their on-screen signatures. Later in the study, it was discovered that while signing into the system, some of the joint assessors significantly changed their signatures; as the result, some of the signatures appeared to be different from the initial ones captured on the delegation of responsibilities logs. When cross-checking the signatures from the EDC system against the delegation logs, it was not possible to identify who conducted the joint assessments and who entered the data. As a result, the auditor was not able to confirm that the joint assessments were completed by the appropriately-delegated blinded site team members.
Thus, it was not possible to confirm the quality of the joint assessment data, and some clusters of the data were rejected. The sponsor had to extend enrollment in the clinical trial.
This case raises several issues, and it highlights the importance of GCP training in the proper conduct of clinical trials. The sponsor, the contract research organization (CRO), and the investigator all contributed to the problem. GCP training could have included measures to prevent this problem.
Ways of Delivering GCP Training
There are different ways of delivering GCP training, ranging from a traditional approach through to a more modern risk-based approach (Table 1). Historically, GCP training has evolved from classroom-based instructor led training to eLearning (computer-based modules) supported by case studies, scenarios, and knowledge tests. These GCP training programs can be provided by internal training departments or by external providers. Also, cross-company initiatives such as TransCelerate BioPharma Inc. are helping sponsors to deliver consistent GCP training that is accepted by other members of the initiative. Functional GCP training, covering targeted areas, is mainly provided internally.
Risk-based approach is becoming common-place across the industry, for example, during clinical trial monitoring and auditing. This approach could also be used in provision of GCP training.
Risks exist at different levels in organization. They might be corporate-wide or related to a particular product. They may also relate to the operating model of the organization, for instance, when the activities are performed internally or outsourced. Changes within the organization or between the parties involved in activities may introduce the risk that needs to be mitigated and may require training intervention.
Based on the corporate risks, a risk-based assurance program can be developed. This includes observations and action items. The risk-based approach to GCP training is also used to predict study-specific risks, such as complex procedures, new technologies, or new vendors. Taking all of this into account, GCP training solutions can be developed to help prevent problems.
The GCP Training Package
A GCP training package may include an introduction to GCP, targeted training, and focused risk-based learning (Table 2). Learners get a basic knowledge of the topic, learning about the history of GCP, the Declaration of Helsinki, GCP principles, and the basics of roles and responsibilities. eLearning modules from the Institute of Clinical Research (ICR) in the United Kingdom could serve as an example of the GCP training programs that cover:
- Principles of ICH GCP
- History and purpose of GCP
- Roles and responsibilities of clinical research staff
- Ethics committees
- Essential documentation
- GCP sponsor responsibilities
- ICH GCP requirements and their impact on the role of the sponsor
- Awareness of the proper procedures, systems, and regulatory requirements in clinical research
- GCP for investigators
- ICH GCP requirements and their impact on the role of the investigators
- Strategies for ensuring adherence to the protocol
- Communication with the ethics committee
- Informed consent
- Drug accountability
- Safety reports
Functional or targeted training provides a deeper understanding of the required subjects. Targeted training may cover the responsibilities of the sponsor and the investigator. For example, an individual in the sponsor organization who is involved in reviewing/approving investigational medical product labels must have training in EudraLex v.10 or Annex 13. EudraLex v.10 is a compilation of regulations on European clinical trials. Some of the investigator’s responsibilities may include obtaining ethics approval, investigational product handling, and safety reporting. Targeted training on these specific responsibilities will ensure that the staff has the required specific knowledge in these areas and will be able to conduct those activities appropriately.
New technologies, such as electronic source data capture and electronic informed consent management systems, can also be covered through targeted training. Targeted training in systems is usually done for company staff and clinical trial sites. The company staff training covers general systems such as the project management, the pharmacovigilance, and the electronic trial master file, as well as study-specific systems.
The Risk-Based Approach to GCP Training
Having provided introductory and targeted training, the goal of focused risk-based learning is to eliminate risk and increase success.
In the above joint assessment case study, training could have prevented the problems that occurred. Such training could have covered the following topics:
- For the Sponsor, GCP responsibilities include: Study design, study oversight, quality assurance, and electronic records/electronic signatures
- For the Sponsor/CRO: Training in the new electronic system
- For the CRO: GCP Sponsor responsibilities includes: Study oversight and quality assurance/quality control to ensure that all of the data are reliable
- For the site: Investigator’s responsibilities including records and reports.
When providing risk-based training, it is essential to identify the trigger for the training activities. Then, a training solution can be developed to manage the risk. With regards to the training delivery methods, such training can be provided in classroom settings or as eLearning, job shadowing, coaching, or self-learning (read, sign and date).
It was mentioned that risks exist at different levels. Company restructuring could represent an example of a risk at a company level. In such a case, training may be required to support staff members whose roles and responsibilities may be affected by boundary changes within the company. Restructuring may also result in functional level risks such as when activities are outsourced or brought back in-house. Groups within an organization may find that they require new skills and capabilities not possessed by staff who were previously considered to be highly knowledgeable and experienced.
A transition study problem (from one phase to the next one) could represent a program-level risk. The identification of a persistent informed consent problem could be an example of the risk at study level. In this case, the learning intervention should be developed in collaboration with the respective clinical trial team and, if applicable, site staff. In a situation like this, collaboration with management is important to decide whether the development of a training solution is needed to fix the problem or not.
There are different levels of training needs (Table 3). For a high risk, such as protocol development issues, training is mandatory. The training could be real scenarios through video clips, instructor-led training to do a knowledge check, or a booklet on a hot topic. For a medium risk, such as audit findings on safety reporting, training could be mandatory or optional. The training, for example, could be eLearning on periodic safety update reports based on the internal procedure. For a low risk, such as a few minor issues during day-to-day activities, the functional department will determine whether training is required or can be optional. This type of training could be reading the internal procedure for developing periodic safety update reports (self-learning).
There are pros and cons of traditional and risk-based approaches to training. Traditional training is easy to do and can be re-used many times; however, it may not prevent specific problems. Risk-based training can solve or prevent problems; however, it requires more time and resources to develop and can sometimes only be used once.
Practical Considerations in Training
Practical considerations include reactive versus proactive approaches to training provision, decentralized or centralized training, and maintenance of training records. It is always better to be proactive than reactive. Proactive training addresses foreseen risks and planned activities (e.g. a clinical trial), anticipated problems, new or updated regulations, and new or updated procedures. In some cases, such as to respond to audit or inspection findings or day-to-day issues, training may need to be reactive.
In decentralized training, each clinical project team is responsible for its own training. Training is done by one team at a time, it is not aligned vertically or horizontally, and it is not shared. In this scenario, there is no opportunity for cross-functional learning, sharing of expertise, or learning from other’s mistakes or problems. Centralized training involves the training department and offers transparency and consistency. If one team faces some problems, the outcome and solution will be shared with other teams to learn from their experience. Centralized training allows knowledge transfer, sharing of expertise, and cross-functional learning, and it includes professional training support.
Training records are extremely important to maintain to prove to the regulatory authorities that the training has taken place. Training records can also include curricula, resumes, job descriptions, and GCP training certificates. They are usually kept in learning management systems, trial master files, and for investigator sites, in on-site study files.
There are three major pillars of GCP training: GCP fundamentals, functional training, and risk-based training.
The purpose of GCP training is to support clinical development of new medicines for patients in an ethical, effective, and cost-effective way.
As we could see from the joint assessment case study, due to the major issues that might be prevented by a risk-focused approach to training, enrollment had to be extended, increasing the cost of the study.
GCP training supports clinical development of new medicines by:
- Educating staff in the fundamentals of ethical research
- Ensuring that the work is done in accordance with standards
- Ensuring that staff members know their roles and responsibilities
- Ensuring the quality, accuracy, and credibility of the data
And finally, remember the 5 “Ps:” Poor practice produces poor performance.
TABLE 1: Traditional and Risk-based GCP Training
Traditional GCP training:
- Introduction and GCP principles
- Regular GCP refresher training
- U.S. Food and Drug Administration regulations
- The European Union Clinical Trial Directives
- Country-specific regulations (e.g., the United Kingdom Statutory Instruments)
- Training in targeted areas (functional)
Risk-based GCP training:
- Assesses the corporate risks:
- New therapy areas
- Risk-based assurance program:
- Action items
- Study-specific risk:
- Complex procedures
- New technologies
- New vendors
Components of a GCP Training Package
- Introduction to GCP:
- GCP history
- Declaration of Helsinki
- GCP principles
- Roles and responsibilities
- Subject protection and medical care
- Safety reporting
- Protocol and investigator brochure
- Essential documents
- Targeted areas training:
- Company staff: General systems and study-specific systems
- Investigational sites: Study-specific systems
- New technologies:
- Electronic source data capture
- Electronic informed consent management system
- Focused risk-based learning:
- Eliminating risk and increasing success:
- New therapy areas
- New procedures or regulations
- Corrective action/preventive action
- Eliminating risk and increasing success:
Sample Learning Solutions by Risk
- High risk:
- High impact/high likelihood or high impact/medium likelihood
- Training is mandatory and recommended
- Example: Protocol development issues:
- Real scenarios: Video clips with interviews with the investigator, monitor, and nurse
- Knowledge check: What to do when things go wrong?
- Hot Topic: a booklet on non-eligible patients
- Medium risk:
- Medium impact/high likelihood or medium impact/medium likelihood
- Training may be mandatory or optional
- Example: Audit findings on safety reporting:
- Developing and delivering eLearning on periodic safety update reports based on the internal procedure
- Low risk:
- Low impact/medium likelihood or low impact/low likelihood
- Function determines whether training is mandatory or optional
- Example: A few minor issues during day-to-day activities:
- Reading the internal procedure for periodic safety update reports (self-learning)