Whether you are developing, manufacturing or conducting research on drug products, biologics, or medical devices, minimizing waste while maximizing benefit is the goal of industry leaders and regulatory agencies alike. The following are highlights covered in this review of modern approaches to pharmaceutical and medical device research:
- Quality not Quantity – producing results without duplicating efforts
- Quality Risk Management Guidance
- QRM Tool Overview
- Risk-based Approach to Clinical Trial Monitoring
Quality, not Quantity
The FDA has adopted the practical position that the number of the steps in a process, or the number of processes overall, does not precisely correlate to the quality of a drug product or medical device. In short, the complexity of the lifecycle does not ensure the safety or efficacy of the product.
Quality Risk Management (QRM) applied to all aspects of new and integrated into current research and manufacturing processes facilitates proper resource usage for both industry and regulatory agencies. By assessing potential risks and assigning a risk level to procedures, pharmaceutical and device manufacturers and researchers engage in informed decision-making, assurance of process control and may be offered manageable and less intrusive regulatory oversight.
Quality Risk Management Guidance
When evaluating and implementing risk management strategies, there is no need to recreate the wheel at every turn. For decades, the FDA has devoted resources to researching the impact of risk assessment on public safety. The administration has made it clear in action and writing that they are responsible for not only policing industry, but also acting as both partner and mentor in QRM process development.
The FDA has adopted the International Conference on Harmonisation (ICH) document that provides form and allows for intelligent structure of quality processes and decision-making. In June 2006, the FDA published the Quality Risk Management guidance (ICH Q9) to help clarify QRM processes and expectations.
The first steps to developing QRM processes are defining the terms:
- Risk Assessment: estimation and evaluation of risk (identification, analysis, evaluation)
- Risk Intervention: risk control action (reduction, acceptance)
- Risk Management Evaluation: measure and ensure effectiveness of risk management efforts (review)
- Risk Communication: interactive process of exchanging risk information – throughout the QRM process
To the right is an example of the process and how these puzzle pieces fit together. They divide smoothly in three major action categories: Assessment, Control (or Intervention) and Review.
The ability to decipher and translate this process map into standard operating procedures can determine the level of scrutiny required by agency auditors on manufacturing processes. A closer look at the guidance provides a detailed outline of each action for industry representatives involved in risk management.
QRM Tool Overview
In risk management, the right action toolbox is priceless. The current guidance identifies the assessment tools as “assessing the probability, severity, and detectability of the risk.” The FDA defines these actions as follows:
Risk Identification discerns the specific hazards and addresses the “What might go wrong?” question, including identifying the possible consequences. This provides the basis for further steps in the QRM process.
Risk Analysis is the qualitative/quantitative estimation and then linking the likelihood of occurrence and severity of harms, which may include detectability.
In practice, this step assigns values from a scale to the variables and then evaluates them individually and combined versus predetermined criteria.
Risk Evaluation considers the strength of evidence for all three of the fundamental questions:
1. What might go wrong?
2. What is the likelihood (probability) it will go wrong?
3. What are the consequences (severity)?
For the control action toolbox, the goal is to reduce the risk to an acceptable level. The FDA emphasizes the importance of proportionality between the effort used for risk control and the significance of the risk. These actions are enacted based on the assessment of the risk and include:
Risk reduction focuses on mitigation or avoidance of quality risk when it exceeds a predetermined acceptable level
Risk acceptance can be a formal decision to accept residual risk or a passive decision in which residual risks are not specified.
All efforts are employed to define risks in order to assess, mitigate, eliminate, and then finally review the results. When risk is identified after assessment or develops based on the control actions, the review action may lead back to the assessment process. This leads to the final tool:
Result Review is the mechanism used to evaluate and monitor events, planned or unplanned, occurring as a result of the risk management process. The intensity and frequency of review are related to the level of risk.
Overall, in risk management procedures look for the “three C” rule:
CAREFUL PLANNING, COMMUNICATION, AND CONTINUING REVIEW ENSURE QRM SUCCESS
Risk-based Approach to Clinical Monitoring
As further evidence of the FDA’s stance on quality versus quantity, they have even weighed in on risk
management as it pertains to clinical trial oversight. In August 2013, the FDA published a guidance entitled “Oversight of Clinical Investigations – A Risk-based Approach to Monitoring”, offering a renewed perspective and understanding of the modernization occurring in trial data collection and investigator site review. The FDA acknowledges the burden and challenges that a full-review on-site monitoring program for each trial can pose, as evident in the following statement:
“There is a growing consensus that risk-based approaches to monitoring, … are more likely to ensure subject protection and overall study quality, and will permit sponsors to monitor the conduct of clinical investigations more effectively than routine visits to all clinical sites and 100% data verification.”
The guidance proceeds in encouraging Sponsors to develop a monitoring program based on trial protocol requirements, along with specific data collection and storage techniques utilized during the clinical trial. This involves a healthy evaluation of the following factors:
- Complexity of Trial Design including trial end points, participant population and trial stage
- Geographic concerns
- Sponsor/Investigator clinical experience
- Electronic Data Capture (EDC) technique and quantity of data transmitted
- Relative safety of the investigational product
The guidance outlines monitoring styles and ultimately offers Sponsors and Clinical Research Organizations (CROs) more freedom to develop review procedures on a per trial basis. A centralized and on-site monitoring hybrid approach is encouraged to allow for less travel and time expenditure with little impact on data integrity. An emphasis is placed on ensuring clinical sites have quality procedures in place prior to conducting the trial, allowing for less on-site review of trial documentation by monitors.
In summary, the overall message of this and other agency guidance documents on managing the risks involved in drug development and manufacturing is intelligent and prudent process evaluation versus a bunker buster approach – quality over quantity.