ACT Reducing Risk August 09

8/3/2019 ACT Reducing Risk August 09

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Proactive risk management is absolutely

vital for every organization in todays

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.

For the biopharmaceutical industry,

several well-publicized incidents in recent yearsinvolving the safety of marketed products have

brought the issue of risk to the forefront of pub-

lic 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 invest-mentrisks such as site staffing shortages, pa-

tient recruitment issues, logistical problems with

drug supplies, or regulatory delays.

These challenges are compounded by the in-

creasing complexity of global clinical

trials, as well as significant marketplace

pressure to introduce new safe and ef-

fective treatments as quickly as possible.

Without a comprehensive plan to iden-

tify, analyze, and manage potential risks,

these issues could prevent important bio -

pharmaceutical products from reaching the mar-ket in a timely fashion.

Holger Liebig and Rebecca Hastings

Reducing Risk ThroughMitigation StrategiesProactive risk management helpspharma protect their productdevelopment investments and future.

PhotograPhy: getty Images IllustratIon: Paul a. BelcI

PEERREVIEWED

Volume 18, Number 8 August 2009

YourPeer-reviewed Guideto GlobalCliniCaltrials ManaGeMent appliedclinicaltrialsonline.com


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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 lifecycleabiopharmaceutical company can increase the probability of

dealing successfully with both foreseeable and unforesee-

able risks to minimize their impact on clinical development

and protect the value of its product portfolio and future of

the company.

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 po-

tential mitigation strategies. These templates allow project

teams to learn from other teams previous experience. Theirquality 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 stud-

ies 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 brain-

storm 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 compli-

ance with patient diary

requirementsDelays in study approv-

als by either regula-

tory agencies or ethics

committees

Patient recruitment that is

too slow or too fast

High volumes of data que-

ries and re-queries

Staff leaves the project

team and needs to be re-

placed without a loss of

project-specific knowl-edge.

While these types of commonplace issues vary in sig-

nificance, 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 risksOnce the risks have been identified, the next step in the

risk management process is to qualitatively analyze eachrisk 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 ex-

ample, it is very common in larger studies for some sites to

have insufficient staff to perform the required study func-

tions, 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 com-

mon 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.

Impact Risk Management Actions

SignificantConsiderable management

requiredMust manage and

monitor risksExtensive management

essential

ModerateRisk may be worth

accepting with monitoringManagement effort

worthwhileManagement effort

required

Minor Accept risksAccept, but monitor

risksManage and monitor

risks

Low Medium High

Likelihood

Suggested Actions for Risk Management

Source:t Bd f cd si.3

Table 1. Managing risk based on its likelihood to occur and its expected impact.

The risk identification process

can be enhanced by a review ofprevious studies and interviewswith project managers.


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The risks encountered at the beginning of trials are differ-

ent than those in later stages, and new risks will appear as a

study moves forward. The key for any successful risk man-

agement strategy is constant vigilance and adaptation as

the circumstances surrounding a tr ial 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 prob-

ability, high impact risk would obviously require the mostextensive 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.

Responding to risksOnce 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-r isk 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 contin-

gency plans greatly increase the chances that the tria l 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 man-

agement 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 tr ial. The most common way to accom-

plish this is through contractual arrangements.

Typically, risk transference means that the party with the

most control over a r isk should be contractually responsible

for managing that risk. For example, if a lab is handling pa-

tient samples for a trial, then the contract for those services

should include specific language about responsibilities andcontingencies 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 po-

tential risks and developing contingency plans, a trial team

must have a way to predict when a particular r isk is increas-

ingly likely to occur. Just as a meteorologist can check a

barometer to anticipate changes in the weather, trial man-

agers need effective metrics and milestones for key aspects

of a study that are predictors of potential problems. Forexample, 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 notonly 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 proce-

dures.

Typical riskmanagement scenariosHow does risk manage-

ment work in clinical trials?

Following are some typical

risk situations that occurregularly 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 is-

sues. 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 awareof typical diary shortcomings so they can help patients com-

ply with the requirements. If problems with diary data be-

come 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 com-

mittees. 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 regula-

tory or ethics committee issues with similar trials in the

pastsuch as questions about patient care or the selectionof a comparator drugthese concerns should be preempted

Another approach to dealing with riskis to transfer or share the

risk with other parties...most commonlythrough contractual arrangements.


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by addressing them in the trial plan. The most reliable con-

tingency 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 mitiga-

tion plansrapid patient recruitment can also present risks

by overwhelming the data management staff. To avoid this

risk, the recruitment forecasts as developed within the proj-

ect team can be given to the data management personnel so

they can build the required capacity into their resource plan-

ning 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 man-

aged properly. To minimize this potential problem, the clini-

cal 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 pro-

cess and explanation of the types and timing of responses

that are expected for data queries. If repeated queries be-

come 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 with-

out 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.

Meeting the challengeThe final step in the risk management process is to continu-

ously monitor risk throughout the clinical development pro-

cess. Risks change over time, and new risks may arise dur-

ing 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 requiresinvestment, the potential costs of trial delays or more signifi-

cant 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 fallingvictim 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 impor-

tant new safe and effective treatments to the patients who

need them.

ReferencesS. Hanna-Leena, Risk Management in Drug Development Proj-

ects, Helsinki University of Technology, Laboratory of Indus-

trial Management, Report 2004.

M. Rita,Risk Management: Tricks of the Trade for Project Manag-

ers: A Course in a Book (RMC Publications Inc, Minnetonka,

MN, 2003).

Treasury Board of Canada Secretariat, Integrated Risk Manage-

ment Framework, http://www.tbs-sct .gc.ca/pol/doc-eng.aspx?id

=12254&section=text#cha2.

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.

*To whom all correspondence should be addressed.

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2.

3.

Ethics committee issues withsimilar trials in the past should beaddressed in the trial plan.

Reprinted from Applied Clinical Trials, August 2009 Printed in U.S.A.

www.parexel.com

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ACT Reducing Risk August 09