Introduction

In all types of clinical research studies, risk management planning should take as much priority as project planning since the risks associated with clinical research are multi-faceted. Researchers are faced with the obvious risk of the intervention not being efficacious, but also the risk that the intervention, or indeed a study procedure (such as invasive sampling), may present a safety risk. In addition, the study needs to show that it has been conducted to acceptable standards and regulations to ensure that the data derived from the study is acceptable. Risk of inaccurate data is a very key consideration. Lastly ethical considerations are worth thinking about in terms of risk.

According to a recent FDA report, the most common compliance inspection deficiencies by clinical investigators include failure to follow the investigational plan, protocol deviations, inadequate record keeping, inadequate drug accountability and inadequate subject protection—including informed consent issues. Also the deficiencies for sponsors and monitors include inadequate monitoring, failure to bring investigators into compliance, and inadequate accountability for the investigational product. Whether your study is a regulatory pathway drug development clinical trial, or a cohort observational study that is gathering academic epidemiology data considering the risk and complexity of your study is important because building in a plan to manage risk will ensure that you protect the rights, safety and well-being of the participants, as well as the integrity of your data.

Another important reason for considering risk is to enable appropriate interpretation of ICH-GCP and other regulatory requirements for your planned study. For example a minimal risk short observational study will probably not need on site monitoring, whereas a complicated clinical trial may well.

Therefore, considering risk and complexity from the outset of planning a study can help identify potential challenges which could help improve the study design, reduce inaccurate data, protect the participants and help the project team be better prepared to deal with issues if and when they occur. Managing risk does not end with identifying them, but it also needs to be monitored on an ongoing basis and with the view to adjusting the impact of such risks at every stage of a study. For instance, the risks encountered at the beginning of studies are different from those experienced in later stages.

Identifying Risk and complexity Factors
The first step in enhancing risk mitigation involves a careful identification of factors that have the potential for noncompliance to the protocol or regulations. Such factors may include variables that are inherent in the study design, or may be ones that emerge in the conduct of the study. This includes the sample size, number of procedures, nature of the study procedures, number of study visits, inclusion/exclusion criteria, length of study, intervention administration, and study population. Often the risks from a data quality perspective comes down to ‘what are the possible risks that might make the data entered for this activity wrong or inaccurate’ or ‘can this task or activity vary between points in time or between operators such that the data that is entered could be inaccurate when comparing’

There are also operational risks which may seem trivial but could significantly delay the start of the trial, such as intervention supply chain issues, adequate monitoring plans, the use of vendors, and site-related issues. Many research teams use a general risk management plan template that include common categorised risks and potential mitigation strategies. These templates allow project teams to learn from other teams' previous experience and can be adapted for individual studies.

The quality of the templates however will depend largely on an efficient feedback process from finished trials and should be built into each research organisation’s SOP so that it doesn’t get neglected or forgotten. Another method of identifying risk is by interviewing project managers who have worked on similar studies or in similar indications. Additionally, the entire project team should brainstorm potential risks and openly identify common issues and how they have impacted studies in the past. Once the risks have been identified, the relative potential impact on data quality, safety and ethical conduct can be analysed. This process usually begins with a subjective analysis that assigns an impact level of high, medium or low for each identified issue and then evaluating the probability of each risk occurring. The risks that have both high probability and high impact should obviously be the focus of the risk management and mitigation efforts.

Assessing the complexity of a study is also important. Often it is assumed that just clinical trials where there is an intervention, are required to comply to good clinical practice and thus it is only clinical trials where many of the tools that are used to mitigate risk are applied. However, many trials can be low risk and very simple and on the other hand some epidemiology studies involve high risk sampling procedures combined with frequent and demanding follow up visits from the participant. All types of clinical studies should ensure that the question set is being answered, that the participants have their safety and well-being protected and that the study is conducted ethically.

Complexity in research studies increases the risks. For example a study with long term follow-up is likely to have a higher risk of losing participants in the follow-up stages. Loss to follow up drastically impacts the power of a study and its ability to answer the question that was set. Another example of complexity could be sampling scheduling in a pharmacokinetic study. Difficult timetables in taking samples on a busy hospital ward can risk missed samples, or wrong times recorded or wrong gaps between sampling, again risking the ability of the study to answer the question.

Even social science methodology clinical research studies can present risk. A survey--based study on sexual behaviour in teenage girls in a rural African village could present significant risk because the questions might upset the local community. This could impact the data in several ways, from limiting the number of recruits, to participants not answering all the questions. Ethically these types of studies present significant risk because they might create stigma. There might also be another outcome of causing hostility and suspicion about research generally, and this could negatively impact future studies.

Conversely simple trials might present minimal risk and complexity. A clinical trial that trains nurses in two different ways is still a trial because one set of participants will be exposed to the intervention of ‘trained nurses’ and the other set to ‘nurses with no extra training’. Depending on the topic in question this might be a low-risk study that is collecting one simple outcome measure at one point in time (number of mothers presenting in hospital to give birth rather that in the village, for example).

Common Risks

Site Staff Resource and Training
Many clinical research sites are under-staffed and over-stretched, and often not all staff have been fully trained in the requirements of each study. Well trained and motivated research staff are fundamental in running a successful study; so too few staff and lack of training represents a high probability, high impact risk.
If possible, more staff should be deployed to mitigate this risk. Elements such as supporting on-site monitoring can also help ensure the team understand the protocol and the SOPs, and help them work within them.

Appropriate training for all research team members is essential, and a documented hand-over process for new staff is often omitted from studies. A good solution is identifying back-up staff up front so that they can be trained alongside core staff. The research coordinator in turn could have copies of training sessions recorded in modules that can be used as a tool for staff. Everyone should receive training in the overall aim of the study and the protocol, which ensures that staff of all levels and roles understand the importance of the research, and will make them feel recognised and valued as an integral part of the study. Staff should also help turn the protocols into standard operating procedures that everyone is trained in.

Regulatory and Ethics Committee Approvals
The globalisation of clinical trials means that there are complex regulatory and Ethics Committee (EC) requirements that need planning to ensure that sufficient sites are able to start recruitment as planned. This is always not straight forward as regulatory authorities or ECs could over interpret or misinterpret standard regulations, and therefore delay approvals or even reject the application entirely. This can be avoided by pre-empting potential questions or looking for trends in similar studies/countries. For instance, some countries are keen to ensure patients recruited into trials are offered the study drug at the end of the trial if it proves to be beneficial. If the sponsor is unable to fulfil this requirement for whatever reason, providing a justification at the time of the application may mean that the approval process is much quicker. Some ECs on the other hand, are quite happy for sponsors or their representatives to attend EC meetings to discuss the study. By identifying back-up sites/countries and including these sites/countries in the original submission, it will help minimise the delay in starting these site following non-approval.

Study Planning and Conduct
Poor design of studies or over-complicating studies is another risk that is often not acknowledged enough. Often research teams will design a study to answer as many questions as possible, so to minimise the number of studies needed to address a set of questions. A significant consequence of this action is that the study objective is blurred and the end point unachievable. Being realistic with what can be achieved within a certain time point will significantly reduce this risk.

Quality tolerance limits

Establishing the acceptable variation or tolerance limits for study procedures is very important at the start of the study. This should be done with consideration to the statistical design of the study and the potential impact of the different levels of variability on the power of the study. This means if a deviation is introduced and it is within the tolerance range, the test is considered to be “per protocol” and therefore not classified as a “protocol deviation”. Another advantage is that it allows for a better focus on data measurement, collection and reporting. It also allows the researcher to focus on monitoring the clinical data that matter to the study endpoints or to safety. For instance, it may be important in some cases to accurately measure a procedure, 60 minutes post dose for pharmacokinetic studies but a tolerance of 60 minutes plus or minus 5 minutes may be acceptable and reduce the amount of “deviations”.

Managing Risks
This represents the plans required to prevent or to limit risk from happening. For high-risk and / or complex situations, the best response is to design the study in such a way that risk mitigation is built into the plan. By anticipating and planning for those major risks as part of the study process, the research team has a greater chance of reducing or avoiding those risks entirely. Another key step in the risk management process is to continuously monitor risk throughout the study. Risks change over time, and new risks may arise during the course of a study, so constant vigilance and the ability to respond to varying levels of risk is necessary to mitigate risk. The deviation from the expected metrics can also be used as a trigger for the study manager to investigate and address an issue before it becomes a serious risk in terms of data quality, ethical conduct or safety.

Conclusion
Poor risk identification and management is often associated with a reactive, fire-fighting approach to challenges and issues that typically and commonly occur in research studies. A proactive approach to risk management can therefore result in research teams being able to conduct high quality research studies where those who later depend upon the data (because it is being applied to change practice, support a regulatory approval, or to inform a further study) can use the data with confidence because there have been steps put in place to assure that the answer is correct and accurate. Furthermore those conducting the study, and most importantly of course those who volunteer to take part in the research, are assured of their safety and well-being are protected, along with their rights and best interests.

References

Alemayehu Demissie, Alvir Jose, Chappell Phillip, Knirsch Charles “Risk Assessment and Mitigation: A quantitative approach to enhancing risk assessment and mitigation in drug development”. Applied Clinical Trials Apr 2012

Liebig Holger and Hastings Rebecca “Reducing Risk Through Mitigation Strategies - Proactive risk management helps pharma protect their product development investments and future”. Applied clinical trials Aug 2009