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Our Clinical Research 101 series takes an in-depth look at key steps and tips for navigating the clinical research process. The fifteenth installment in our Clinical Research 101 series is by Dana Nohynek, Director of Regulatory Affairs and Quality Assurance.

Dana Nohynek is the Director of Regulatory Affairs and Quality Assurance at the CIHR Canadian HIV Trials Network (CTN) at CHÉOS. She leads the regulatory and quality affairs functions through the management of infrastructure and guidelines for creating, maintaining, and enhancing administrative, regulatory, and quality assurance systems associated with conducting clinical trials.

Clinical Research 101 Series

1. Navigating a Successful Clinical Trial Application

2. A primer on Good Clinical Practice

3. Clinical Trial Monitoring 101

4. Investigator Responsibilities 101

5. Sponsor Responsibilities

6. Clinical Trial Registration 101

7. Clinical Data Management 101

8. Grant Writing 101

9. GCP Changes 101

10. Clinical Research with Medical Devices 101

11. Regulatory Inspection 101

12. Evaluation Studies 101

13. Sex and Gender 101

14. Informed Consent 101

15. Risk Management 101

16. Research with Vulnerable Participants 101

What is Risk Management?

You wouldn’t pack for a vacation without checking the weather.

If the forecast calls for rain, you plan to bring a waterproof jacket. If it starts to pour while you’re sightseeing and you’re unprepared, you evaluate if you need to pick up an umbrella or change your plans to stay indoors. Checking your itineraries, flight times, bus tour locations – all require continuous evaluation to make sure everything stays on track.

Whether you’re planning a trip, writing a grocery list, or mapping out the fastest route to your workplace, we are all participating in some type of risk-based monitoring in our daily lives.

In 2013, the concept of risk-based monitoring was introduced to the world of research in a guidance issued by the US Food and Drug Administration and a reflection paper by the European Medicines Agency. Since then, risk-based monitoring has shifted from monitoring data to management of all factors that could jeopardize the conduct of a trial.

Put simply, risk management is using resources intelligently and identifying risks on an ongoing basis for all trial related activities from design to reporting.  It’s taking the time to understand the protocol, the study objective and study sites, to assure that the rights, safety and well-being of trial subjects are protected, and the results of clinical trials are credible.

As soon as protocol design beings, so does the risk mitigation process as it’s built into the protocol and other trial documents.

Why do you need to manage risk?

Protecting your research participants and your results just makes good sense.The 2016 ICH E6 (R2) Addendum to Good Clinical Practice guideline requires clinical trial sponsors to develop processes and technology that support a more active risk-based study oversight approach. The guideline directs sponsors to “…identify those processes and data that are critical to assure human subject protection and the reliability of study results.”

Specifically, the guideline requires clinical trial sponsor to incorporate risk management plan as part of clinical trial activities. This creates an opportunity for sponsors to improve data quality, increase patient safety, and achieve trial outcomes more quickly.

ICH E6(R2) also guides that “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.” In other words, use methods that make sense for the scope and scale of the trial’s risks.

A Team Effort

Risk Management involves the whole study team. Early in the process, at the trial conception or draft protocol stage, assemble a team to ensure that risk is considered over the entire lifecycle of the trial.

This interdisciplinary risk management team may consist of members working in diverse areas including clinical operations, project management, data collection, data management, regulatory affairs, quality affairs, pharmacovigilance/drug safety, medical affairs, and statistics.

How Do You Manage Risk?

The major concepts of a risk-based approach to quality management are:

Identify Critical Processes and Data

Determine critical data and processes based on the unique trial design including:

  • Type of study participants, 
  • Interventions, and 
  • Trial design complexity 
  • Number of sites

Examples of Critical data and processes include:

  • Primary study objectives 
  • SEA’s (collection, timing reporting to Sponsor, adequate management by Sponsor) 
  • Informed consent process 
  • The timely reporting of serious adverse events to the sponsor 
  • Selection of participants in compliance eligibility criteria 

Critical processes include:

  • The timely reporting of serious adverse events to the sponsor 
  • The adequate management by the sponsor 

Risk Identification and Evaluation

Idenfify all of the potential risks that may impact:

  • Patient safety
  • Data quality
  • The operational success of the study

Evaluate risk by ranking and prioritizing all risks based on three factors: 

  1. Likelihood: how likely it is that a specific risk will occur? 
  2. Impact: if the risk does occur, what is the potential damage? 
  3. Detectability: is there a chance to detect the occurrence or the risk on time or even at all? 

Risk Control

  • Identify appropriate risk indicators
  • Set thresholds/limits to help decide when to initiate corrective/mitigation measures during the study
  • Assign personnel to manage each risk

Indicators are metrics/tools used to monitor the risk exposure over time:

  • Quality Tolerance Limits (QTLs) are a pre-determined level, point, or value associated with a risk indicator that will trigger an action  
  • QTLs will vary risk to risk and study to study for the same risk
  • Example: for patient recruitment rate, in one study the QTL could be set at >20% sites below expected recruitment rate in the first 2 months of recruitment, while in a different study, the QTL may be set at zero enrollment at any 1 site during any 1 month over the enrollment period

Risk Documentation

Document all risk management and critical processes activities.

There are many ways to document risk management activities: 

  1. Prepare a risk management and treatment plan; 
  2. Capture risk strategies in the study protocol; 
  3. Describe risk mitigation in the study monitoring, data management and statistical analysis plans; 
  4. Maintain a risk register

Risk Review

Review risks, mitigation actions, and subsequent results throughout the coures of the study or trial

During a risk review following questions should be considered:

  • Is the pre-defined QTL for the risk still appropriate?
  • Is the risk above an acceptable level?
  • What can be done to reduce or eliminate an identified risk? 
  • Are new risks introduced as a result of the identified risk being controlled?

Outcomes of review meeting may include:

  • Develop alternative risk responses and mitigation strategies
  • Implement a contingency plan 
  • Take corrective actions 
  • Change the project objectives

Reporting

  • Report risk management activities to the relevant stakeholders over the entire course of the study. 
  • The final clinical study report should also describe the quality management and risk management approach.

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