Regulators, Industry Still Have Not Reached Consensus on Risk-Based Monitoring

July 22, 2019

Despite more than six years of regulators’ encouragement to adopt risk-based monitoring (RBM) of trials, the industry still has concerns about compliance.

Attendees at a recent FDA workshop question whether RBM is appropriate for small and complex studies, the appropriateness of sampling techniques for source data review (SDR) and source data verification (SDV) and how data privacy regulations might impact transmission and review of trial subject data.

But RBM has been shown to improve data quality, David Burrow, director of CDER’s Office of Scientific Investigations, told attendees at the workshop, also sponsored by Duke University. With companies that have implemented true RBM programs, Burrow said, the FDA has seen a great correlation between issues caught by those plans and problems often flagged in new drug applications.

But challenges — such as customization of RBM to individual trials and regulatory consistency — remain, leaving the industry lukewarm, industry speakers and workshop attendees agreed.

One problem that comes up frequently is a lack of understanding of what RBM means from the FDA’s perspective. RBM is part of an overall quality management plan, not just a component of study monitoring, Burrow said. Companies need to look at RBM as both a whole system and as part of an overall quality-by-design approach to clinical trial development and conduct. He outlined a three-stage approach to developing an RBM plan:

  • Risk assessment for each discrete clinical trial;
  • An appropriate and well-articulated study protocol that considers the identified risks; and
  • An RBM plan that focuses on the highest study-specific risks.

Monitoring activities should focus on processes and procedures deemed most critical for protection of trial subjects and ensuring data integrity, Burrow said.

Most EU regulators have adopted risk-based quality standards and encourage RBM, said EMA scientific administrator Camelia Mihaescu. Aside from minor language differences, the EMA approach under EU regulation 536/2014 is very similar to the FDA’s. The EMA, like the FDA, encourages sponsors to position their RBM strategy within the broader quality concept, Mihaescu said.

One area that has proven confusing to sponsors is how centralized or remote monitoring should relate relative to the more traditional on-site monitoring. SDR and SDV, for instance, traditionally have been conducted via on-site visits, and it is unclear whether a sampling approach, which could be conducted under a more centralized monitoring scheme, would be acceptable for these activities.

Nicole Stansbury, vice president of global centralized monitoring at CRO Syneos Health Clinical Solutions noted that SDR and SDV have been combined with medical reviews over the years, but the items have not been tightly connected. The FDA could help drug sponsors by providing clearer guidance on how to achieve that balance.

On-site monitoring likely will always have a role, Burrow added, but RBM strategies will need to involve greater use of centralized and remote tools, as well as various analytical tools to identify trends, missing or inconsistent data, variable data or outliers, protocol deviations and systemic errors. The idea is that RBM can better target risks to the most critical data elements and procedures of a trial, including SDV, SDR and evaluation of study conduct.

Sampling alone does not qualify as an RBM plan, Burrow cautioned. Sampling can be an important part of RBM, but must be included as part of a broader risk mitigation system.

Another key factor is change management. RBM is not a “set it and forget it” process, Burrow said. Because risk is complex and can change as a study progresses, companies must not consider RBM as a single risk assessment, but a continuous improvement concept.

And regulators, sponsors, CROs and sites all agree that companies cannot take a blanket monitoring approach to all studies regardless of design and risk factors. RBM must be tailored to match the specific risks of each individual study.

The FDA issued draft guidance, A Risk-Based Approach to Monitoring of Clinical Investigations — Questions and Answers, on March 19 and is currently reviewing comments on the guidance. There is no date set to make the draft guidance final.

Read the FDA guidance and public comments here: 


-By Elizabeth Hinkle