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Risk Based Monitoring

For more than two decades clinical trials are monitored by sponsor’s and CRO’s clinical monitors by conducting periodic monitoring visits at the clinical investigator sites. The purpose of monitoring is to guarantee the authenticity and quality of the clinical trial data generated.The method commonly used is Source Data Verification(SDV), which consumes almost 46% of the time of the visit leaving little time for other constructive activity.

Current monitoring practices

The monitoring visit involves review of informed consent forms, patients medical files, case report forms, use of concomitant medications, laboratory reports, vigilance on the use of prohibited medications, investigational drug accountability, review of adverse events and serious adverse events, verification of calibration records of the equipments used for the trial, temperature records of the storage equipments, resolution of data queries, identification of the protocol deviations and violations and retraining of the site staff personnel on the problem areas identified. (1)

The monitoring plans are created in such a manner that a monitoring visit occurs at the investigator site after a particular period i.e. once in 4 weeks or in 8 weeks and also depending on the number of patients recruited at the site. There has been no change in this practice since the introduction of GCP in clinical trials.

Monitoring challenges

Inspite of repeated visits and 100% source data verification (SDV), there was no guarantee of absolutely clean data. In a retrospective analysis of 9 studies, it was found that SDV identified only 7.8% of total queries raised. The critical ones identified were only 2.4% of the total. (2) Latest new drug candidates for the management of rare diseases have increased complexity of clinical trial protocols and successful oversight becomes more challenging. There is also the concern over escalating costs of the monitoring visits because of multiple geographically dispersed investigator sites.

Evolving electronics and communication technologies have led to real time patient data capture and storage. Connectivity between devices has become more accurate, dependable and economical. These are being put to greater use for the effective monitoring of the clinical trial. One such approach is centralized or remote monitoring, a major component of risk based monitoring.

Use of alternative monitoring systems - FDA guidance

FDA has issued guidance for risk based monitoring and recommends a quality risk management approach. It describes strategies for monitoring activities that reflect a modern, risk-based approach that focuses on critical study parameters and relies on a combination of monitoring visits and remote monitoring to oversee a study effectively (4).

Risk based monitoring

Risk based monitoring is the process of identification of risks and employment of quality improvement principles to overcome anticipated failure. Critical data elements such as trial endpoints, safety assessments and data essential for trial integrity are identified. Risks such as fabrication of trial data, too many protocol violations and deviations, very high recruitment rate, too many screen failures, higher number of lost to follow up cases, inadequate documentation of source data, higher query rate in case report forms, wrong randomization of patient etc. are identified through central monitoring.. After identification of critical data and risks, risk assessment is performed for every investigator site. Data trends from all the sites are compared and chances of failure of the trial because of the involved risks are identified and corrected. This ensures higher protocol compliance eventually leading to the trial success.

Preparing a Monitoring Plan

A Monitoring plan for risk based monitoring has to take into account the critical elements to be monitored and the risk assessment

Some critical elements could be

  • Verification of informed consent documents to ensure that all the subjects recruited in the trial are informed and their consent has been taken properly.

  • Critical records such as blood sampling time points in pharmacokinetic studies, instrument reading records which are critical to determine subject’s eligibility criteria in the trial, diary data of symptom score, use of rescue medication during the placebo run in period, critical check on data for use of prohibited medications during the wash out period, inclusion / exclusion criteria of protocol, investigational products accountability records, assessments for study endpoint measurements, protocol violation / deviations, patients safety data have to be observed carefully by remote monitoring.

  • Ensuring that study blinding is maintained

Risk assessment is the most critical part after the potential risks are identified. Risks should be prioritized according to the occurrence of errors, the impact of such errors on the subject safety and reliability of the trial data generated.

Risks could be protocol and product related like therapeutic area, product safety profile, method of administration or investigations required. They could be site related like experience level of investigator and staff or location of site. They could be real time risks based on enrollment rates, adverse events, source data quality etc.

Monitoring plans should be structured to mitigate the risks, by detecting and correcting errors at an early stage and implementing preventive actions. Monitoring visits can be more focused on confirming the trends identified by doing a limited and specific SDV, satisfying specific queries, training of personnel, networking with the team and other more fruitful activities. Appropriate decisions should be taken by the sponsor after performing risk evaluation and focused monitoring.. For example if the trial data generated at a site has lot of errors and fabrications, sponsor should not hesitate to close out such a site.

Following are the few examples of the risks identified, anticipated result because of the involved risk and the possible risk mitigation strategy to overcome the risk in the following table.

Identified risks Anticipated result because of the involved risk Possible risk mitigation strategy to overcome the risk
Too many protocol deviations and violations noticed at an Investigator site. Objectionable quality of data, higher chances of trial not meeting the endpoints. Retraining of the site staff personnel
Very high recruitment rate at a particular site Virtual patient’s, falsified data, subject’s right of informed consent are not followed, study procedures not followed correctly leading to occurrence of protocol deviations / violations Checking the informed consent forms to ensure that the consent process is adequately documented for every subject. Checking all the subject’s eligibility criteria for inclusion in the study. Checking the laboratory reports of al subjects looking for patterns, repititions, to ensure that real subject’s are recruited in the trial
Higher number of lost to follow up cases Inadequate safety data, unreported adverse events and serious adverse events Training the site staff personnel. Highlighting the importance and mandatory regulatory requirements of documentation of the safety data.
Wrong randomization of patient Threat to the subjects health, violation of GCP guidelines, invalid study results Retraining the study staff again on the Protocol’s inclusion / exclusion criteria
Too many adverse events reported at a site Regulatory authorities will raise concern about the investigational study medication’s safety Retraining the principal investigator and the study team about anticipated adverse events from the investigators brochure, safety data reported from other sites, correct reporting of adverse events. Schedule a monitoring visit after the conduct of a few patient visits, to verify that the site staff are reporting right nature of adverse events
Minimal adverse events reported at a site Deficiency of safety data of the investigational drug, site staff not performing study assessments in a correct manner, lack of knowledge of reporting adverse events Retraining the principal investigator and the study team about anticipated adverse events from the investigators brochure. Stressing the importance of reporting the safety information in a correct manner.
Incomplete source documentation of patients Data integrity quiet often questionable, or vital information missing in case report form Training the site staff for correct source documentation practice and recording the patients data appropriately as per the protocol
Higher query rate / CRF page More time involved in data cleaning and validation, it may lead to extension of the timelines for the data base. Training the site staff for the correct documentation of data in the case report form.

Treatises could be written on centralized monitoring, risk evaluation, risk mitigation, focused monitoring visit planning etc; this was but a small summary


  1. Gupta A. Taking the ‘Risk’ out of risk-based monitoring, Perspect Clin Res. (2013) 4: 193–195.

  2. http://www.transceleratebiopharmainc.com/wp-content/uploads/2013/09/Risk-Based- Monitoring-Methodology-Position-Paper.pdf downloaded april 2014

  3. Morrison R. Pulling the trigger on risk based monitoring Journal for Clinical Studies,(2013) 5:12.

  4. Guidance for Industry: Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring. U.S. Department of Health and Human Services, Food and Drug Administration, August 2013, OMB Control No. 0910-0733, Expiration Date: 03/31/2016.

  5. http://www.iconplc.com/technology/iconik/Less-is-More-Risk-Based-Monitoring-of-Site-Performance.pdf downloaded april 2014

Dr. Vishwas Sovani (April 2014)


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