Understanding the Importance of a Clinical Trial Protocol
The fundamental objective of a clinical trial protocol is to provide common scientific guidance on how to conduct the clinical study in a regulatory-compliant manner and gather data that will ultimately provide answers on the safety and efficacy of the investigational medicinal product.
The Guidelines for Good Clinical Practice of the International Council on Harmonization (ICH GCP) define the protocol as “A document that describes the objectives, design, and methodology, statistical considerations, and organization of a clinical trial.”
Therefore, its critical to ensure that all key stakeholders are aware of the clinical study objectives and have a thorough understanding of study procedures as detailed in the clinical trial protocol to avoid risks related to patient safety, regulatory compliance, and overall study completion.
Protocol Deviations & Protocol Violations – What are the key differences
In simple words, both the terms mean that there has been a study conduct mistake and requires immediate attention to safeguard the rights and protection of clinical trial subjects. Many times these terms are interchanged when the differences are not understood. So, here is a closer look to get better clarity on the definition with relevant contextual examples.
A protocol deviation is an accidental or unintentional action where a study activity was performed inconsistently or incorrectly against the IRB-approved study protocol.
The action itself does not increase or decrease the risk or benefit nor it has a significant effect on the subject’s rights, overall safety, and the integrity of the study data.
A protocol violation is a more serious action which may have been performed accidentally, intentionally, or unintentionally where a study activity was completely not followed or performed incorrectly against the IRB-approved study protocol.
The action performed adversely impacts the subject’s rights, overall safety and the study data integrity and results in non-compliance with the actual study procedures.
Examples of protocol deviations may include any of the following actions:
Examples of protocol violations may include the any of the following actions:
Common Reasons for Protocol Deviations & Protocol Violations
Although pharmaceutical and medical device sponsors, and CROs follow a meticulous risk-based approach, protocol deviations and violations occur almost in every clinical trial due to:
- Poor study design with unclear or insufficient explanation of study procedures in the clinical trial protocol and related artifacts
- The study visit schedule is too rigid without any window visits to handle random study interventions
- Incomplete or incorrect understanding of study procedures where a method or scientific information was misinterpreted and performed in the wrong manner
- Deficiencies in Site Personnel Training that leads to mistakes in subject enrolment and randomization
- Lack of proper infrastructure and quality measures at the clinical site
- Inconsistencies in source data and study data collection (Eg: Mistakes in measurement units, dates, order of procedure completion, etc.)
- Lack of trial conduct oversight to monitor trial progress right from screening, subject enrolment, randomization, dosing until trial completion
- Failure in educating trial participants on critical study procedure requirements that they need to fulfill during the trial
Consequences of Improper Protocol Deviations & Violations Management
a. Patient Safety-Related Regulatory Non-Compliance
Irrespective of the cause, all protocol deviations and protocol violations require documentation and reporting. If a variance from the protocol is discovered during a regulatory audit and was not previously reported, the FDA would consider it “non-compliant”. Significant or persistent noncompliance may result in penalties, including a warning letter posted on the FDA website, disqualification/restriction/disbarment (also posted on the FDA website), or, in worst-case scenarios, criminal prosecution. Per ICH GCP regulations, sponsors should view non-compliance as a violation of the investigators’ responsibilities.
b. Increased Study Costs & Timelines
Both protocol deviations and violations can significantly increase clinical trial costs because the study duration may get extended to complete new subject enrolments to meet targeted sample size. Additionally, the expenditure to perform data collection, managing site & subject payments, handling trial supply logistics, etc. results in crossing planned study R&D budgets.
c. Poor Study Data Quality
When a clinical study has too many protocol deviations and violations, it has a direct impact on study data quality that ultimately has long-term implications on product approval. The resulting data variations for unique study procedures are the most difficult to address unless the procedures themselves are performed once again which in turn has a cascading effect on study timelines.
Best practices to Reduce and Avoid Protocol Deviations and Violations
Ensure Accurate Clinical Trial Protocol Authoring
- Clinical Trial Protocols should be written in a clear and concise manner without any ambiguity so that there is common understanding amongst all stakeholders. It must provide detailed information about the nature of the disease, characteristics of the study population, and the investigational product
- Clearly stating study objectives and drafting a risk-based study design accordingly helps a lot to proactively identify opportunities to maximize patient safety, regulatory compliance, and data quality
- The clinical trial visit schedule needs to have appropriate ‘window visits’ timeframe that sites and subjects can leverage for missed visits
- For long-term clinical studies, consider having a ‘Study Run-in Phase’ prior to enrolment with a placebo to determine potential non-compliant subjects
Provide Site Personnel with Contextual Protocol Training and Engage with Empathetic Feedback
- Protocol trainings must be delivered to all stakeholders by explaining the context of study objectives, anticipated outcomes, potential areas for non-compliance and proactive measures to follow for the welfare of study participants
- Sponsors and CROs should ensure that Site Personnel receive periodic trainings on how to avoid protocol deviations and violations that were observed in other sites
- Unique study procedures and expanded eligibility criteria increase the complexity of protocols. These sections need to be given extra importance to clarify timing, explain detailed methodology and the right process for data collection
- Incorporate a positive feedback loop with Principal Investigators and Site Coordinators to engage them with empathetic trial support
- Ensure that all stakeholders are timely trained after all mid-study protocol changes
- With advancements in technology, Sponsors and CROs can choose provide study procedure instructions through hands-on interactive videos and web-based training
Implement a Risk-based Collaborative Trial Conduct Process with Proactive Oversight
- Sponsors and CROs must perform a rigorous risk management exercise and implement study-specific tools such as trackers and checklists that could serve as qualitative check points for ensuring patient safety and compliance
- Establish regular open communication between the sponsor, CRO, and investigational sites to relay information on unanticipated outcomes
- To ensure patient safety and wellness, site personnel should engage with subjects by providing proper counselling during each subject visit
- Sites must be encouraged to send subject reminders and alerts for offsite procedures such as timely medication intake, recording patient diaries, planning next site visit, etc.
- Developing a time-bound oversight framework with qualitative and quantitative measures of quality and compliance will certainly help Sponsors and CROs to recognize patterns of protocol adherence across sites
- The oversight plan should have periodic assessments of all the protocol deviations and violations that were observed, reported, and documented to timely implement necessary corrective and preventive measures
The successful completion of a clinical study requires tremendous collaboration and communication between various stakeholders starting from Principal Investigators, Site Staff, Clinical Project Managers from CROs, IRB Representatives, Sponsor Personnel and most importantly study subjects. Therefore, its extremely important that all these members have a common understanding of the study objectives and continuously work towards subject safety and regulatory compliance throughout the trial duration.
From our experience, we have seen that long-term clinical studies always have considerable scope for protocol deviations and violations for obvious reasons. Here are some of the approaches that Techsol Life Sciences has implemented across our clinical operations to significantly reduce the occurrence of protocol deviations and violations.
- Incorporating risk-based study design while authoring clinical trial protocols and related artifacts
- Usage of e-Consent with video support at Sites to ensure that informed consent is obtained from the trial subject after thoroughly going through the study procedures
- Use a robust Electronic Data Capture (EDC) and a Clinical Trial Management System (CTMS) to timely report, document and resolve all reported protocol deviations and violations
- Conduct risk-based monitoring using pre-defined questionnaires that auto-calculates risk scores for each site
- Delivering timely training with follow-ups for clarifying mid-study protocol changes
- Providing periodic feedback to sites based on observed study performance and compliance adherence
- Continuously observe clinical study data trends to detect anomalies and outliers that indirectly could be a result of protocol deviations
- We have a robust clinical trial oversight system has helps us to continuously gain insights on the overall trial progress and discover patterns of protocol deviations and violations across sites
To learn more about our capabilities in conducting clinical trials for Biopharma and Medical Device companies, please visit our website and send us a message with your business needs. We will schedule a meeting to discuss our clinical solutions that can align towards your business goals.