The new article addresses the aspects related to the content of a monitoring plan, as well as the follow-up procedures and the way they should be documented.

The Food and Drug Administration (FDA or the Agency), the US regulating authority in the sphere of healthcare products, has published a guidance document dedicated to the risk-based approach and the way it should be applied in the context of monitoring clinical investigations. The document is intended to provide additional clarifications regarding the applicable regulatory requirements, as well as recommendations to be taken into consideration by medical device manufacturers, study sponsors, and other parties involved in order to ensure compliance thereto. At the same time, the authority explicitly states that recommendations provided in the document are non-binding in their legal nature, nor are intended to introduce new rules or impose new obligations. Moreover, an alternative approach could be applied, provided such an approach is in line with the existing regulatory framework and has been agreed with the authority in advance. 

The scope of the guidance covers, inter alia, the aspects related to the content of the monitoring plan.

Monitoring Plan: Elements

First of all, the document outlines the elements to be included in a monitoring plan to ensure compliance with the respective regulatory requirements. Under the general rule, such a plan should be developed considering the risk assessment for a specific study, ensuring that study- and site-specific risks are duly addressed. Furthermore, a monitoring plan should prove how anticipated and newly identified risks will be addressed. According to the guidance, sponsors are encouraged to develop risk-based monitoring plans that emphasize crucial risks with the most significant potential to affect investigation quality, including: adversely

  1. The rights, safety, and welfare of participants in a clinical investigation; and
  2. The collection or analysis of critical clinical data such as safety and efficacy/effectiveness endpoints. 

Additional details are also provided in a separate guidance document dedicated to risk-based monitoring. The authority also mentions that a monitoring plan can reference other plans containing the necessary components. 

Apart from the elements described in the abovementioned guidance on risk-based monitoring, issued by the authority earlier in 2013, the FDA encourages the parties responsible for clinical trials to include other elements describing the risks potentially affecting the trial will be addressed, namely:

  • A description of the investigation design, including the blinding and randomization procedures, if applicable;
  • Processes for confirming that randomization is performed according to the protocol and investigational plan or plans;
  • The sampling plan or plans that will be used to identify the specific records and data that will be monitored, including (1) the rationale for how the sampling plan provides a representative picture of the overall information and (2) how the sampling plan will be implemented;
  • A description of the types of issues identified through monitoring that would trigger immediate issue escalation;
  • An approach for determining whether (1) an important issue detected at a clinical site may also be present at other clinical sites; and (2) the findings suggest a systemic problem with the protocol or associated investigational plans that requires remediation.  

Follow-up and Communication

Another important aspect addressed in the guidance relates to follow-up and communication of monitoring results. In particular, the authority explains the way the parties responsible for clinical trials should follow up regarding important issues. According to the guidance, significant issues identified in the course of monitoring should be subject to a rigorous evaluation to be carried out in a timely manner and in accordance with the respective monitoring plan. It is stated that study sponsors should conduct a rigorous root cause analysis, as well as take all the necessary corrective and preventive actions to ensure the impact of the issue in question is reduced to the extent possible in terms of the rights of study subjects, their safety and welfare, as well as data integrity. The FDA also mentions that risk assessment and monitoring plans could be subject to review and revision, should it be reasonably necessary to reflect the new risks identified or anticipated, preventing the associated events from reoccurring. This includes corresponding changes to be implemented to the protocols and investigation plans describing the way an investigation should be carried out. 

According to the guidance, examples of preventive and corrective actions that may be warranted include but are not limited to:

  1. Improved training for the clinical investigator and site staff;
  2. Halting enrolment at a clinical site pending resolution of identified issues;
  3. Clarifying or revising the protocol and/or other related investigational plans and documents; and/or 
  4. Modifying vendor service agreements to ensure adequate trial support. 

Any and all significant issues identified in the course of monitoring and oversight activities should be duly documented, while the information about such issues should be communicated to the parties involved, including management and teams of a sponsor, as well as clinical sites and institutional review boards. For further recommendations on follow-up and communication, the authority refers to the aforementioned guidance document dedicated to risk-based monitoring.  

Documentation Requirement

As it was mentioned before, it is important to ensure the monitoring activities related to the clinical investigation are duly documented. According to the relevant guidance, this should include the indication of the date when the activities took place, the names of the individuals involved, the summary, as well as the details of any noncompliances identified together with the information on actions taken in this respect. The level of detail should be sufficient for the authority to be able to verify whether the activities conducted are in line with the monitoring plan. The authority also mentions that monitoring activities to be documented should include on-site and remote monitoring of clinical sites and centralized monitoring across clinical sites. 

In summary, the present FDA guidance outlines the main elements to be included in a monitoring plan and provides additional clarifications in this respect. Apart from that, the document contains recommendations regarding the follow-up and documentation requirements to be followed in the course of a clinical investigation. 

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