The ICH GCP E6 R1 guidelines state that in

The ICH GCP E6 R1 guidelines state that in a clinical trial
there needs to be onsite monitoring before, during and after the trial. This is
so that sponsors ensure their trial is meeting regulatory guidelines, producing
reliable data and ensuring the trial participants are protected. Usual
monitoring approaches relied on regular consistent onsite visits and source
data verification (SDV), but this approach can require a considerable amount of
time and effort as the process requires data within the case report form (CRF)
to be compared to the original source of information such as consent forms and
laboratory notes. The process of SDV and onsite monitoring has been shown to be
resource intensive and recent studies has shown there is no evidence to suggest
SDV has a limited impact on the quality of the clinical trial. As a result of
SDV being quite inefficient, the ICH GCP made changes to the guidelines so to
encourage the development of a systematic risk based approach to monitoring
these trials.  An addendum to the ICH GCP
guidelines showed a drive towards the implementation of a risked based
approach. Risk based monitoring is a strategy used to monitor clinical trials
by focusing on critical study parameters. By focusing on these critical study parameters
it will mitigate the risks that could affect the quality and safety of the
study and also facilitate more effective monitoring. For sponsors to adopt a
risk based approach they need to adopt systems that will help them achieve the
risk based monitoring, this is usually carried out by a company’s Electronic
data capture (EDC) systems, electronic trial data is checked by these systems.
Using a risk based approach is likely to have a large impact on the
pharmaceutical industry due to the wide range of benefits it is likely to

What is driving
the adoption of a risk based approach?

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Changes to ICH GCP guidelines are encouraging a drive
towards the adoption of a risk-based approach to monitoring to adhere to the
principles of GCP. Good clinical practice’s (GCP) are internationally
recognised standards for carrying out clinical trials. To comply with ICH GCP
guidelines sponsors must implement a system for quality control of the study.
The aim of these quality control procedures is to ensure the safety of test
subjects and to ensure the results of the study are credible (EMA). However, the
current methods of quality control are time consuming and constitute a large
proportion of the cost in developing the drug. The current practices for monitoring
are not proportionate to the risks and therefore are not achieving their
desired goals, this is due to a multitude of reasons. The current practices are
not proportionate to the risks due to risk aversion as society is increasingly
risk averse, without knowing what the actual or relative risk of different
activities are, leading disproportionate risk mitigation. The globalisation of
clinical trials complicates the regulatory aspect, as it is a different patient
population and the regulatory standards maybe different which means that they
have a different perspective of quality control. In other countries the clinical
trial infrastructure and medical methods can be less established so would need
more intensive monitoring. By using risk-based monitoring, it can be
highlighted whether the quality control measures used by these sites are reliable
in comparison to other sites. By using risk based approach companies can save
money without affecting GCP’s and clinical quality.

Another driver of a risk-based approach is the fact that
this process can make the monitoring process less tedious. One of the main
aspects of risk based monitoring is the centralisation of the monitoring. Using
more centralised monitoring techniques means that there are fewer errors when
compared to on site monitoring. It lessens the risk of quality management concerns
by recognising risks and determining the reliability of clinical data
throughout the development of the drug. The Risk based approach uses more
automated reviews to look at data across several sites and from that, it can be
determined whether there is need for an intervention at specific site. Due to this,
only sites where problems are occurring the most can be monitored on site and
this brings the benefit of reducing the cost of monitoring. As all this data is
going into a centralised system, it allows cross-site comparison that could
identify any outliers. The centralised process will make the detection of fraud
easier and it allows the sponsors to see the effect of the fraud on the outcome
of the trial (Marc Buyse
et al). As all this data is easily accessible therefore any problems are
easily identified and resolved while the trial is occurring, giving more timely
results. By centralising the process, it is easier to see which sites are a
cause for concern and then onsite monitoring can be carried out on these
problematic sites. This allocates prioritised resources to identifiable risks.

What do sponsors
have to have in place to meet the requirements?

When a sponsor decides to carry out risk based monitoring on
their clinical trial there are requirements set out by the food and drug
administration (FDA). The FDA have set out a guidance to assist sponsors into
adopting a risk-based approach. A study needs a well-designed case report form
(CRF) or electronic CRF to collect data. Someone within the company needs to
identify the critical data, which is the high-risk data. This is high-risk data
if inaccurate would impede the safety of trial subject’s or the integrity of
the results. High-risk data includes subject eligibility, which looks at the
inclusion and exclusion criteria, serious adverse effect (SAE) data and
treatment discontinuation data, informed consent and agreement to extra visits.
Less critical data can be identified as age, concomitant medications and
concomitant illnesses. The less critical data would be monitored less and have
reduced SDV. When the critical data has been has been identified a risk
assessment is carried out to understand how this risk can affect the results of
the data, by understanding this the sponsor organisation can mitigate the

The FDA encourages sponsors to tailor monitoring plans to
the need of the clinical trial by focusing on the critical data. The monitoring
plan should utilise both centralised and onsite monitoring. With risk based
monitoring likely to reduce the occurrence of onsite monitoring, the sponsors
need to set critical values for the study, these values are key risk indicator’s
(KRIs) and would be indicated in the monitoring plan. Key risk indicators can
be the number of adverse effects per patient or the number of data
clarification forms (DCFs) per patient. If these values are exceeded, then
there is an escalation in the monitoring process and a monitor is sent to the
site to see why the values were exceeded. However, the concern with setting
KRIs is that if there is a new type of study occurring how will the sponsor
organisation know what level to set the critical values for the KRI’s. As there
is no previous data for a new type of study, there is not enough clinical data
to set objective thresholds. The sponsor would have to rely on experience from
previous studies to set subjective critical values and change these values
throughout the duration of the study. (Clue points)

When creating a study plan there are factors to consider
such the complexity of the study design. If a study is more complex then it may
be necessary to increase the intensity of the monitoring. In addition, the type
of endpoint needs to be considered as objective endpoints such as death or
hospitalisation can be verified remotely. However, endpoints that are interpretative
would require on site monitoring.  The study
also needs highly trained site staff as with a risk based approach there is not
going to be routine checks so well trained staff are required to trials are
being carried out properly and according to GCP.     

The use of technology is vital in implementing risk based
monitoring into the pharmaceutical industry as without technology risk based
approach would be difficult to carry out. EData technologies facilitate
effective centralised monitoring as they bring all the data from different
sites and departments together. An example of a risk based monitoring tool used
in the industry is JMP clinical software. This tool allows the sponsor
organisation to review clinical trial data efficiently. What the software does
is it flows all study data into an interpretable dashboard. The dashboard gives
visual indication of which sites are high risk. In the monitoring plan, KRI
values were set and when values exceed the KRI then the dashboard will provide

What do you think
the impact is likely to be on the industry as a whole?

From the consensus risk based monitoring will have a
positive impact on the pharmaceutical industry. The economic impacts are huge
as using a risk-based approach can save between 15-20% as a consequence of less
frequent on site monitoring. Risk based monitoring improves the efficiency of
clinical research associates (CRAs) as they are able to focus on incompetent
sites. The risked based approach is more efficient which allows trials to be
completed quicker and the pharmaceutical company is able to market the drug earlier
without affecting the quality of the study. Because of this pharmaceutical
companies will have a longer time period to reap the financial benefits of
their drugs before the patent finishes. As more resources are available to the
companies they are able to invest this money into more research which could
potentially aid the advancement of medicine.

Clinical trial studies have become accustomed to CRAs
supporting them in assessing the quality of their data, but using risk based
monitoring will reduce the CRAs activity. Risk based monitoring encourages
sites to form their own standard operating procedures (SOPs) which will allow
them to have their own form of quality control on data that goes into the CRFs.
This means that the CRA can focus on the review of source documentation, and how
well the sponsor has adhered to GCPs. By focusing on these areas it will benefit
the study as it will improve the quality of the data.