Holger Liebig

Proactive risk management is absolutely vital for every organization in today's fast moving global marketplace. As the recent worldwide financial crisis clearly demonstrated, companies that fail to properly anticipate and mitigate their risks are endangering their business assets, the jobs of their employees, and even their existence.   

 Photography: Getty Images   Illustration: Paul A. Belci  

For the biopharmaceutical industry, several well-publicized incidents in recent years involving the safety of marketed products have brought the issue of risk to the forefront of public awareness and regulatory scrutiny. While most of the industry's risk management efforts have focused on postmarketing drug safety, the clinical trial process holds a broad array of other potential risks that could jeopardize a company's multi-million-dollar product development investment—risks such as site staffing shortages, patient recruitment issues, logistical problems with drug supplies, or regulatory delays. 

These challenges are compounded by the increasing complexity of global clinical trials, as well as significant marketplace pressure to introduce new safe and effective treatments as quickly as possible. Without a comprehensive plan to identify, analyze, and manage potential risks, these issues could prevent important biopharmaceutical products from reaching the market in a timely fashion. 

A focus on risk management from the beginning of the development process encourages a company to examine the trial plan and identify potential challenges. With that information, trial managers can improve the study design to reduce risk and help the project team be better prepared to deal with issues when they occur. 

By integrating this proactive, qualitative risk assessment approach into every stage of development—and monitoring risk profiles as they change during the product lifecycle—a biopharmaceutical company can increase the probability of dealing successfully with both foreseeable and unforeseeable risks to minimize their impact on clinical development and protect the value of its product portfolio and future of the company. 

The first stage of risk management is to identify the risks. Many companies have set up general risk management plan templates that include common categorized risks and potential mitigation strategies. These templates allow project teams to learn from other teams' previous experience. Their quality depends largely on an efficient feedback process from finished trials. This can be achieved by a mandatory post-mortem assessment of trials. Templates do not replace a thorough risk assessment of individual studies. 

In addition to templates, the risk identification process can be enhanced by a review of information from previous studies and interviews with project managers who have worked on similar studies or in similar indications. It is important to take into account all sources for background data and prior experience. Ideally, the entire project team should brainstorm potential risks and openly identify issues of common concern. Given the combined experience of a typical study team, there should be ample input about potential risks and how they have impacted studies in the past. 

What types of risks are encountered during clinical trials? Although there is wide spectrum of potential issues, typical problems might include:  

Study sites with insufficient staff to perform all the necessary tasks required for the trial

Unsatisfactory compliance with patient diary requirements

Delays in study approvals by either regulatory agencies or ethics committees

Patient recruitment that is too slow or too fast

High volumes of data queries and re-queries      

Staff leaves the project team and needs to be replaced without a loss of project-specific knowledge. 

While these types of commonplace issues vary in significance, they all have the potential to delay or disrupt the start up or timely completion of a trial, which means they pose a degree of risk. The list of such risks for a particular trial forms the basis for the risk management plan. 

Once the risks have been identified, the next step in the risk management process is to qualitatively analyze each risk to determine its relative potential to impact the time or cost of the study (see Table 1). This process usually begins with a subjective, qualitative analysis that assigns an impact level of high, medium or low for each identified issue. 

The second part of the analysis quantitatively evaluates the probability that a particular risk will occur. For example, it is very common in larger studies for some sites to have insufficient staff to perform the required study functions, especially at the beginning of a study, so this risk would rank as a high probability. In most cases, the effect of staff shortages at a site would be significant, so this risk might also be designated as having a high impact potential. Other issues such as ethics committee delays are less common and might have low probabilities, but would have a high impact. 

When the analyses have been completed, the risks that have both high probability and high impact would obviously be the focus of the risk management and mitigation efforts. 

Although the risk analysis helps set priorities, all of the risks should be continuously monitored and reevaluated during the course of a study. Risk management must be an iterative process, because risk profiles inevitably change. The risks encountered at the beginning of trials are different than those in later stages, and new risks will appear as a study moves forward. The key for any successful risk management strategy is constant vigilance and adaptation as the circumstances surrounding a trial change and evolve. 

In addition, the risk analysis data determines the extent and direction of a trial's contingency planning, as well as the potential cost of those contingencies. A high probability, high impact risk would obviously require the most extensive contingency plans. If those contingency plans are likely to be necessary, then the trial's contingency reserve budget—which all studies should have—must be sized to accommodate those costs. 

Once the risks have been identified and analyzed, the next step is to develop appropriate risk response strategies. The common response is risk mitigation: to reduce the chance of a particular risk occurring, or to reduce the impact if it does occur. For the high-risk situations that have been identified during the initial analysis, the best response is to design the trial in such a way that risk mitigation is built into the plan. By anticipating and planning for those major risks as part of the trial process, the project team has a greater chance of reducing or avoiding those risks entirely. 

A well-designed risk mitigation strategy and solid contingency plans greatly increase the chances that the trial team will be prepared to respond quickly and appropriately when problems occur. It is expected that even unexpected issues can be handled successfully if well thought out risk management procedures have been built into the trial process. 

Another approach in the biopharmaceutical industry to dealing with risk is to transfer or share the risk with other parties involved in a trial. The most common way to accomplish this is through contractual arrangements. 

Typically, risk transference means that the party with the most control over a risk should be contractually responsible for managing that risk. For example, if a lab is handling patient samples for a trial, then the contract for those services should include specific language about responsibilities and contingencies for dealing with lab sample problems. If the lab has control over the shipment, analysis, and reporting of the samples, then the lab should be responsible for the risks associated with that process. 

The concept of "risk triggers" is also essential to timely risk response and mitigation. In addition to identifying potential risks and developing contingency plans, a trial team must have a way to predict when a particular risk is increasingly likely to occur. Just as a meteorologist can check a barometer to anticipate changes in the weather, trial managers need effective metrics and milestones for key aspects of a study that are predictors of potential problems. For example, if the data management group is validating fewer case report forms every day, that statistic could indicate a problem with monitors who are not collecting as many pages as needed. 

Whatever the problem, the deviation from the expected metrics would be a trigger for a trial manager to investigate the issue and address it before it becomes a serious risk. For this system of risk triggers to be effective, however, extensive trial metrics must be in place and must be closely monitored. Effective, proactive risk management will not only ensure those trigger levels are in place, but ensure that someone is assigned responsibility to monitor them and that sufficient tools exist to allow such monitoring and layout specific actions to take as well as escalation procedures. 

How does risk management work in clinical trials? Following are some typical risk situations that occur regularly in the course of clinical trials, and some possible scenarios for managing those risks. 

Insufficient staff to complete required work at a site.

 If this is a high probability and high impact risk, then more extensive screening at site qualification visits could be built into the site selection process to reduce the probability of staffing issues. After the study begins, managers should stay in touch with the data staff to monitor on-going workloads. If staffing issues still occur, a potential contingency plan could be to offer the site additional funding to recruit needed personnel, or provide additional contract resources. In addition, it is helpful to collect metrics about the sites for future use, which may help to mitigate problems in the future. 

Unsatisfactory compliance with patient diary requirements.

 Problems with the completion of manual patient diaries are commonplace, and this can impact data collection and data quality. One possible mitigation solution is to design studies that utilize electronic diaries, which improve compliance by prompting patients to enter data at the correct times. These systems can also check data as it is entered to minimize improper or incomplete entries. Staff training at the time of study start-up can also be useful to make the site staff aware of typical diary shortcomings so they can help patients comply with the requirements. If problems with diary data become evident during a trial, the situation could be improved by identifying areas with persistent data issues and bringing those issues to the attention of the CRAs and investigators. 

Approval problems with regulatory agencies or ethics committees.

 One way to avoid this issue could be arranging a sponsor meeting with FDA or MHRA personnel early in the trial planning process to discuss potential protocols and gather regulatory input. If the trial team is aware of regulatory or ethics committee issues with similar trials in the past—such as questions about patient care or the selection of a comparator drug—these concerns should be preempted by addressing them in the trial plan. The most reliable contingency plan would have back-up sites, and even back-up countries, identified during the planning process. This is so critical a component that it may be worthwhile to have prequalified alternate sites available to avoid study delays. It is also helpful to involve the principal investigator (PI) at predeployment meetings to address some issues. This is important because the PI will appear before the IRB and should be prepared. 

Patient recruitment success outstrips the capacity of site data team.

 While patient recruitment shortcomings are more typical—and thus more frequently accounted for in risk mitigation plans—rapid patient recruitment can also present risks by overwhelming the data management staff. To avoid this risk, the recruitment forecasts as developed within the project team can be given to the data management personnel so they can build the required capacity into their resource planning process. The contingency plan for a data overload at a particular site is to identify and train back-up data entry and data management resources in advance who can be quickly assigned to the site to meet peak demands. 

 This is another common problem, especially in global trials where language issues can often contribute to poor data quality if not managed properly. To minimize this potential problem, the clinical team should review the data validation specifications and wording to ensure that they are easy to understand, even for those whom English is not the primary language. Training for data management personnel should include a clear process and explanation of the types and timing of responses that are expected for data queries. If repeated queries become a problem during a study, retraining that focuses on specific response shortcomings would be an appropriate contingency. 

Staff leaves the project team and needs to be replaced without a loss of project-specific knowledge.

 The most important mitigation task for this risk should be that a strategy for the training of new staff during the project lifetime is already developed at project initiation. When project staff changes, transition periods need to be put in place where old and new staff work together on the same tasks. Project Coaching, understood as the assignment of an existing team member as a direct coach, is another effective way of dealing with this risk. 

The final step in the risk management process is to continuously monitor risk throughout the clinical development process. Risks change over time, and new risks may arise during the course of a trial, so constant vigilance is required to maintain a strong focus on risk mitigation during the course of a clinical study. 

To meet the challenge of risk management in clinical programs, senior executives need to invest in the people, processes, and technology required to maintain a strong risk management process. Although this process requires investment, the potential costs of trial delays or more significant costs of regulatory failure because of trial issues could be avoided with the right risk management plan. 

A proactive approach to risk management can greatly reduce the chances of a biopharmaceutical company falling victim to a catastrophic risk that could jeopardize its future. A company with a strong focus on risk management will be able to bring its products to market successfully, enhance its reputation among regulators, physicians, insurers, and the other key constituencies, and most importantly get important new safe and effective treatments to the patients who need them. 

1. S. Hanna-Leena, "Risk Management in Drug Development Projects, Helsinki University of Technology," Laboratory of Industrial Management, Report 2004. 

Risk Management: Tricks of the Trade for Project Managers: A Course in a Book

 (RMC Publications Inc, Minnetonka, MN, 2003). 

3. Treasury Board of Canada Secretariat, Integrated Risk Management Framework, 

http://www.tbs-sct.gc.ca/pol/doc-eng.aspx?id=12254&section=text#cha2

* is senior director, project management, and 

 is project director for Parexel International, 200 West Street, Waltham, MA 02451, email: 

*To whom all correspondence should be addressed. 

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