home > ict > summer 2011 > right place, right time
International Clinical Trials

Right Place, Right Time

Guy Patrick of Centrical Global Limited discusses operational risk management, its application in the delivery of clinical trials, and how it can help to facilitate faster and better quality results

In the increasingly complex world of clinical trials, shaped by ever evolving regulatory oversight, multiple stakeholder involvement and global delivery, the poor or inappropriate management of risks can have severely detrimental effects on the product under development, the trial participants or the outcome of an individual clinical trial. A number of pharmaceutical and biotechnology companies have established strategies for the management of developmental products and subject risk, and investigational institutions are increasingly beginning to focus on site and subject risk management plans. To date however, risk management has failed to comprehensively capture the actual process of clinical trial delivery, relying on a more ad hoc and generic approach, rather than an individual, tailored and structured approach. Appropriately and actively managing operational clinical trial risk can and will minimise time delays, budgetary over-runs and poor quality delivery, and also conflicts with outsourcing partners. In summary, acceptance of the statement ‘if it could go wrong, it will go wrong’ underpins the absolute necessity for risk management within a clinical trial.

In its broadest sense, risk can be simply defined as ‘the possibility of suffering harm or loss’. However, this can be further developed into ‘the potential that a chosen action or activity (including the choice of inaction) will lead to a loss (an undesirable outcome)’, and it is this definition that is most applicable to the delivery of clinical trials. Furthermore, given that planned actions (that is, those that form a clinical trial development plan) are subject to large cost and benefit risks, detailed assessment and management of the risks of all such actions is crucial to making them successful. This strategy forms the basis of operational risk management.

In adopting this approach, operational risk management becomes a continual cyclic process, which includes a formal risk assessment, risk decision-making and implementation of risk controls. By default, this results in the acceptance, mitigation or avoidance of risk from inadequate or failed internal processes and systems, human factors or external events. The fundamental principles of operational risk management include:
  • The acceptance of risk when the benefits outweigh the cost
  • The acceptance of no unnecessary risk
  • The anticipation and management of risk through appropriate planning
  • The making of risk decisions at the right level of operational expertise and responsibility
The structured processes underlying operational risk management include: identifying and assessing the risks; making risk decisions; implementing controls; and monitoring for change and outcomes. Its successful implementation leads to the reduction of operational loss, as well as compliance and auditing costs; the early detection of time delaying, cost increasing and unlawful activities; and the reduction of exposure to future risks. Operational risk management is therefore all about making and managing risk decisions, rather than simply taking risky decisions.


Managing and delivering a clinical trial is fundamentally driven by people and processes. The increasing pressure to deliver cost-effective, timely and quality results is driving change within the industry, and is leading to, for example, running larger and more complex clinical trials in emerging countries and regions, as well as the greater use of outsourced resources such as contract research organisations. While clinical trial management systems (CTMS) are useful tools in managing trials, they are not risk management tools. Comprehensive risk management requires a new and more structured approach to ensure successful trial delivery.

It can be argued that operational risk management is merely a more disciplined, formal approach to the everyday tasks that project managers already perform, albeit sometimes unconsciously. In part this may be correct, but risk management should be regarded as the umbrella of a clinical trial – its purpose, function and necessity understood by all parties involved. For a clinical trial to be run in its entirety by a single individual would be classified by most as being an extremely high risk proposition. However, paradoxically, the converse can also be true. More resources do not necessarily equate to less operational risk. Poor communication, for example, can amplify and even conceal risk within larger teams.

So, how can operational risk management plans work at a practical level without becoming an additional burden for already under pressure clinical operations teams, or incurring unacceptable additional layers of management? Lessons can be learnt from specific groups, such as pharmacovigilance teams, as well as other industry sectors, such as finance and construction. In the latter there is a strong focus on regulated processes and significant advantages have been gained by incorporating and integrating trained risk management personnel into delivery teams. The key message being, ‘new approaches do not require re-inventing the wheel’. Having said that, the implementation of operational risk management within a clinical trial will require planning, monitoring and time critical management.


Risk management should begin before a trial starts. This process includes:
  1. Establishing the framework and context for the plan
  2. A formal, documented risk assessment to include risk identification, analysis, and evaluation
  3. The development of individual risk treatment and handling
  4. Supervision and ongoing monitoring and review
This process is cyclical as changes acquired through the monitoring process will require ongoing re-evaluation. Based on stage two of this process, the following outputs can be constructed for each element of risk identified (see Tables 1 and 2).

In an ideal operational risk management environment, risks are simply prioritised using a structured process, with those with the greatest probability of occurring and the greatest impact handled first. In practice, the risks that are most often mishandled are those where the risk has a high probability of occurring but a lower direct or indirect impact, or a high direct or indirect impact but a lower probability of occurring. In these cases, the experience in determining how best to handle such risks becomes critical.

In itself, managing risks may identify a further risk, namely one that is almost certain to occur but is ignored by the delivery team due to an inability to identify it. Examples of this are when deficient knowledge is applied to a situation; when ineffective collaboration occurs; or when ineffective operational procedures are applied, resulting in new risks materialising. These additional and not immediately quantifiable risks can directly reduce the cost-effectiveness, service and quality within a clinical trial. Nevertheless, when assessed by experienced risk managers, calculations of the level of risk can be compiled for all operational risks across a clinical trial (see Table 3).


Time critical risk management relates to clinical trial delivery performance and ensures the monitoring and review process functions in such a way as to respond to changes identified in the operational risk management plan in a timely and appropriate manner. This is critical to successfully managing risks in a clinical trial, and four key areas of activity can be identified:

Assessing the Situation
In assessing the situation, three conditions are relevant and include task loading, additive and human factors. Task loading refers to the negative effect of increased workload on performance of the tasks. Additive factors refers to having a situational awareness of the cumulative effect of multiple variables; while human factors refers to the limitations of an individual or individuals to adapt to the work environment – for example, stress, attention impairment, and deliberate or unknowing violations of regulations.

Balancing Resources
This refers to the balancing of resources in two different ways. The first way is balancing resources and available options, namely evaluating and leveraging all the informational, labour, equipment and material resources available. Secondly, one can balance resources versus risks. This means estimating how well prepared you are to safely accomplish a task and making a risk decision. Individual efforts must be balanced with that of the team. This means observing individual risk warning signs, such as observing how well the team is communicating, understanding the roles that each member is supposed to play, and recognising the stress level and participation level of each team member.

Communicate Risks and Intentions
Risks and intentions should be communicated to the right people. Use the appropriate communication style; asking questions is a technique to opening the lines of communication, and a direct and forceful style of communication is more likely to get a specific result from a specific situation.

Take Action and Monitor for Change
This can be accomplished in three different phases. The first phase involves executing and gauging the risks involved, as well as managing change and risk while the trial is in progress. This requires risk trigger plans (that is, what will identify a particular risk as requiring a particular action) and risk response plans (including such actions as avoidance, mitigation, contingency or observation) together with a wider assessment of overall risk impact. The second phase is at the completion of the project and this is a point where the trial can be evaluated and reviewed in full. Finally, future performance improvements are discussed, involving the preparation of a ‘lessons learnt’ report for the next team that plans or executes a similar trial.

The risk management planning and response processes are linked in a structured way, as shown in Figure 1.


Detailed feasibility is an integral part of operational risk management for a clinical trial. However, it is more than simply identifying a list of investigators either de novo or from pre-existing database lists. Commonly documented or inferred risks and their management tends to focus on the obvious at a high level and simply invokes contingency planning rather than detailed and formal assessments, monitoring and response. Indeed, risks assessed in isolation and at a high level may be under- or over-weighted if taken out of the context of the wider trial environment. In reality, for example, identification and selection of a suitable number of investigator sites should always rank as an ‘extreme’ risk as the consequences of failure have a wider impact on overall trial performance.

Operational risk management of feasibility can therefore be regarded as a two-dimensional matrix with risks associated with the group or sub-group of investigative sites as a whole and those associated with individual sites. Importantly, both dimensions can act in synergy or independently of each other. For example, the risks of not meeting the anticipated group recruitment rates can be influenced by either individual and discrete risks at each site (for example, the lack of appropriately trained personnel, the lack of availability of suitable subjects and so on) or factors that affect all sites globally (such as inappropriate protocol design or failure to gain regulatory approval). This further highlights the observation that managing a single clinical trial’s operational risk within a sub-group, such as an individual site, can have much wider implications. Therefore, clinical trial operational risks as a whole need to be managed as such (see Figure 2). Within individual sites, operational risk management includes:
  • Overall site qualifications
  • Access to target subject population
  • Individual qualifications and available resource (the principal investigator or research co-ordinator, for example)
  • Site facilities
  • Site administration (for example, local approval requirements)

Similarly, within the group as a whole, operational risk management encompasses factors such as the total number of sites; predicted group recruitment; and regulatory and ethics approval planning strategy.

As implied from the above, performing a feasibility analysis and managing the associated operational risk requires a clear and structured process to not only be in place, but to be active as well. Identifying operational risk is relatively easy and regularly occurs in clinical trials. However, assessing these risks requires a clear map as to where each risk arises and how these risks relate and impact on the global risk profile. Figure 3 shows how different groups of risk inter-relate, influence and impact on others within the operational risk management of a clinical trial. Feasibility risk management (shown in purple) and overall subject recruitment (shown in red) form two such overlapping risk groups within the overall risks associated with a clinical trial (shown in grey). Such a construct readily allows risk to be managed appropriately. This approach both empowers and enables the making and taking of risk decisions at both predefined and ad hoc time-points.


Experience has demonstrated that serious consequences can arise from poorly managing the risks of clinical trial operational activities. They may have far reaching repercussions, bring disrepute to an entire development programme, and possibly compromise activities across an organisation. Active, rather than passive, risk management is therefore important and, despite not necessarily having prescriptive standards in the pharmaceutical industry, is a universal concept. As regulatory authorities embrace risk management strategies for investigational medicinal products and subject protection, it is inevitable that risk management will become an increasingly important aspect of clinical trial operational delivery.

Operational risk is best managed in a framework of responsibility and communication. These are within the domain of all those involved in clinical trial activities and should be managed in the same way as, for example, clinical monitoring or biometrics. Upward communication within a team is also critical, and fostering such a culture will ensure that risk decisions are made by the right person at the right time.

Undoubtedly scepticism abounds, largely as a result of a perceived complexity of the risk management process and subsequent increased workload. However, operational risk management is not difficult and, with relatively little effort, can be readily embedded within clinical operations in pharmaceutical companies and contract research organisations alike. The consequences of this approach will not only support faster, more cost-effective and better quality results, but will also facilitate better team work and more informed and structured responses to those events that will undoubtedly arise in any clinical trial.

Read full article from PDF >>

Rate this article You must be a member of the site to make a vote.  
Average rating:

There are no comments in regards to this article.

Guy Patrick is a co-founder of Centrical Global Limited, a specialist operational risk management and clinical trial feasibility company providing services to a broad range of pharmaceutical and biotechnology companies. Having trained as a Consultant Nephrologist and Renal Transplant Immunologist, he formerly worked for Omnicare Clinical Research prior to co-founding Premier Research Group plc, a leading full service CRO. Email:
Guy Patrick
Print this page
Send to a friend
Privacy statement
News and Press Releases

Veristat Joins Decentralized Trials & Research Alliance (DTRA) to Improve the Patient Experience

SOUTHBOROUGH, MA – October 13, 2022 – Veristat, announced that it has joined an alliance of over 120 life sciences and healthcare organizations whose mission is to accelerate the broad adoption of patient-focused, decentralized clinical trials and research. The Decentralized Trials & Research Alliance (DTRA) unites industry stakeholders which include healthcare companies, regulators, patient groups, clinical research and development organizations. The Alliance is dedicated to making clinical trial participation widely accessible by advancing policies, research practices and new technologies in decentralized clinical research.
More info >>

White Papers

Advantages of Quantitative NMR for the Determination of Relative Response Factors

Novatia, LLC

Quantitative NMR (qNMR) is a technique that is being applied broadly and at an increasing rate in the field of pharmaceutical analysis (1). This white paper highlights the advantages of using qNMR to determine Relative Response Factors (RRFs) for pharmaceutical impurities detectable by HPLC. A single determination of RRFs using qNMR allows for simple and accurate quantitation of impurities which eliminates the need for preparation, qualification, and storage of reference standards. An example is presented here, which demonstrates quantitation of known impurities that have variable responses to UV-VIS detection, thereby providing a more accurate assessment of impurity levels than UV-VIS response alone.
More info >>




©2000-2011 Samedan Ltd.
Add to favourites

Print this page

Send to a friend
Privacy statement