Volume 18, Number 8 August 2009

You r P eer -r e v ie w ed G u ide

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G l ob a l C l iniCa l t r i a l s M a naGeM en t

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Reducing Risk Through Mitigation Strategies

Proactive risk management helps pharma protect their product development investments and future.
brought the issue of risk to the forefront of public awareness and regulatory scrutiny. While most of the industrys 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 companys multi-million-dollar product development investmentrisks such as site staffing shortages, paroactive risk management is absolutely tient recruitment issues, logistical problems with vital for every organization in todays drug supplies, or regulatory delays. fast moving global marketplace. As These challenges are compounded by the inthe recent worldwide financial creasing complexity of global clinical crisis clearly demonstrated, trials, as well as significant marketplace companies that fail to properly anticipate pressure to introduce new safe and efand mitigate their risks are endangering fective treatments as quickly as possible. their business assets, the jobs of their Without a comprehensive plan to idenemployees, and even their existence. REVIEWED tify, analyze, and manage potential risks, For the biopharmaceutical industry, these issues could prevent important bioseveral well-publicized incidents in recent years pharmaceutical products from reaching the marinvolving the safety of marketed products have ket in a timely fashion.

Holger Liebig and Rebecca Hastings

PhotograPhy: getty Images IllustratIon: Paul a. BelcI

PEER

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 developmentand monitoring risk profiles as they change during the product lifecyclea 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.

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.

Analyzing the risks

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 func-

Identifying risks

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 poThe risk identification process tential mitigation strategies. These templates allow project teams to learn from other teams previous experience. Their can be enhanced by a review of quality depends largely on an efficient feedback process previous studies and interviews from finished trials. This can be achieved by a mandatory with project managers. 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 tions, especially at the beginning of a study, so this risk be enhanced by a review of information from previous studwould rank as a high probability. In most cases, the effect ies and interviews with project managers who have worked of staff shortages at a site would be significant, so this risk on similar studies or in similar indications. It is important to might also be designated as having a high impact potential. take into account all sources for background data and prior Other issues such as ethics committee delays are less comexperience. Ideally, the entire project team should brainmon and might have low probabilities, but would have a storm potential risks and openly identify issues of common high impact. concern. Given the combined experience of a typical study When the analyses have been completed, the risks that team, there should be ample input about potential risks and have both high probability and high impact would obviously how they have impacted studies in the past. be the focus of the risk management and mitigation efforts. What types of risks are encountered during clinical trials? Although the risk analysis helps set priorities, all of the Although there is wide spectrum of potential issues, typical risks should be continuously monitored and reevaluated problems might include: during the course of a study. Risk management must be an Study sites with insufficient staff to perform all the iterative process, because risk profiles inevitably change. necessary tasks required for the trial Suggested Actions for Risk Management Unsatisfactor y compliance with patient diary Impact Risk Management Actions requirements Considerable management Must manage and Extensive management Delays in study approvSignificant required monitor risks essential a ls by eit her reg ula tory agencies or ethics Risk may be worth Management effort Management effort Moderate accepting with monitoring worthwhile required committees Patient recruitment that is Accept, but monitor Manage and monitor Minor Accept risks too slow or too fast risks risks High volumes of data queHigh Low Medium ries and re-queries Staff leaves the project Likelihood team and needs to be reSource: treasury Board of canada secretariat. placed without a loss of project-specific knowlTable 1. Managing risk based on its likelihood to occur and its expected impact. edge.
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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 trials 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 trials contingency reserve budgetwhich all studies should havemust be sized to accommodate those costs.

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.

Responding to risks

Once the risks have been Typical risk is to transfer or share the ident i f ied a nd a na lyzed, management scenarios the next step is to develop risk with other parties...most commonly How does r isk ma nage appropriate risk response ment work in clinical trials? through contractual arrangements. st rateg ies. T he common Following are some typical response is risk mitigation: risk situations that occur to reduce the chance of a regularly in the course of particular risk occurring, or to reduce the impact if it does clinical trials, and some possible scenarios for managing occur. For the high-risk situations that have been identified those risks. during the initial analysis, the best response is to design Insufficient staff to complete required work at a site. If this is the trial in such a way that risk mitigation is built into the a high probability and high impact risk, then more extensive plan. By anticipating and planning for those major risks screening at site qualification visits could be built into the as part of the trial process, the project team has a greater site selection process to reduce the probability of staffing ischance of reducing or avoiding those risks entirely. sues. After the study begins, managers should stay in touch A well-designed risk mitigation strategy and solid continwith the data staff to monitor on-going workloads. If staffing gency plans greatly increase the chances that the trial team issues still occur, a potential contingency plan could be to will be prepared to respond quickly and appropriately when offer the site additional funding to recruit needed personnel, problems occur. It is expected that even unexpected issues or provide additional contract resources. In addition, it is can be handled successfully if well thought out risk manhelpful to collect metrics about the sites for future use, which agement procedures have been built into the trial process. may help to mitigate problems in the future. Another approach in the biopharmaceutical industry to Unsatisfactory compliance with patient diary requirements. dealing with risk is to transfer or share the risk with other Problems with the completion of manual patient diaries are parties involved in a trial. The most common way to accomcommonplace, and this can impact data collection and data plish this is through contractual arrangements. quality. One possible mitigation solution is to design studies Typically, risk transference means that the party with the that utilize electronic diaries, which improve compliance by most control over a risk should be contractually responsible prompting patients to enter data at the correct times. These for managing that risk. For example, if a lab is handling pasystems can also check data as it is entered to minimize tient samples for a trial, then the contract for those services improper or incomplete entries. Staff training at the time of should include specific language about responsibilities and study start-up can also be useful to make the site staff aware contingencies for dealing with lab sample problems. If the of typical diary shortcomings so they can help patients comlab has control over the shipment, analysis, and reporting ply with the requirements. If problems with diary data beof the samples, then the lab should be responsible for the come evident during a trial, the situation could be improved risks associated with that process. by identifying areas with persistent data issues and bringing The concept of risk triggers is also essential to timely those issues to the attention of the CRAs and investigators. risk response and mitigation. In addition to identifying poApproval problems with regulatory agencies or ethics comtential risks and developing contingency plans, a trial team mittees. One way to avoid this issue could be arranging a must have a way to predict when a particular risk is increassponsor meeting with FDA or MHR A personnel early in ingly likely to occur. Just as a meteorologist can check a the trial planning process to discuss potential protocols and barometer to anticipate changes in the weather, trial mangather regulatory input. If the trial team is aware of regulaagers need effective metrics and milestones for key aspects tory or ethics committee issues with similar trials in the of a study that are predictors of potential problems. For pastsuch as questions about patient care or the selection example, if the data management group is validating fewer of a comparator drugthese concerns should be preempted

Another approach to dealing with risk

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 typ-

icaland thus more frequently accounted for in risk mitigation plansrapid 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. High volumes of repeated data queries. 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

ously 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

Ethics committee issues with similar trials in the past should be addressed in the trial plan.
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.

References
1. S. Hanna-Leena, Risk Management in Drug Development Projects, Helsinki University of Technology, Laboratory of Industrial Management, Report 2004. 2. M. Rita, 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.

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.

Holger Liebig* is senior director, project management, and Rebecca Hastings is project director for Parexel International, 195 West Street, Waltham, MA 02451, email: Holger.Liebig@ parexel.com.

Meeting the challenge

The final step in the risk management process is to continu Reprinted from Applied Clinical Trials, August 2009

*To whom all correspondence should be addressed.

Printed in U.S.A.

www.parexel.com