With the goal of ensuring issues with site misconduct are identified and addressed before problems occur, clinical monitoring is an essential cog in the wheel of clinical research. When trials are outsourced to clinical research organizations (CROs), site monitoring becomes the CRO’s responsibility. Nevertheless, it is crucial for the sponsor to maintain oversight of monitoring operations and evaluate the quality of the service, since consequences can be severe if issues go unnoticed.
In 2022, at least 15 trials were terminated, suspended, or withdrawn due to protocol deviations and regulatory issues – problems that might have been prevented with better monitoring and oversight. The number of trials being terminated, suspended or withdrawn for these reasons has been steadily decreasing across the past ten years, although this trend is less convincing in the regulatory issues data.
“Regulatory issues may involve problems with meeting regulatory requirements or following clinical protocols,” says Priya Nair, Senior Analyst, Clinical Trials Intelligence at GlobalData. “Issues may also surround clinical trial operations or the trial site, especially site misconduct or not following practices needed for Good Clinical Practice. Changes in country regulations may also lead to regulatory issues.
“Protocol deviations can also affect the status of a trial,” Nair continues. “Key issues that may occur include failure to properly obtain informed consent from trial participants, non-compliance with the exclusion and inclusion criteria, incorrect administration of IMP, and monitoring of the trial.
“Suspension, termination or withdrawal for either reason can become a serious issue as it affects the scientific validity, participant safety, or ethical integrity of the clinical trial,” Nair adds.
Ensuring protocol compliance
To protect patient safety and avoid the delays and potentially much more serious repercussions that come with poor trial conduct, robust monitoring procedures are critical. In 2016, the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) updated its Good Clinical Practice (GCP) guidelines. Javier Engraff, Oversight Monitoring Manager at KPS Life, describes ICH GCP as “the bible of clinical research” since many international regulations are based upon the recommendations. The 2016 update stated that while sponsors may transfer study activities to service providers such as CROs, who may also subcontract themselves, the sponsor should retain overall responsibility for all study activities. They must therefore ensure appropriate oversight or supervision throughout the trial.
“The ICH GCP guidelines define monitoring as the act of overseeing the progress of a clinical trial, and of ensuring that everything is conducted, recorded and reported in accordance with the protocol, with the standard operating procedures, with GCP, and with the regulatory requirements,” explains Engraff. “Oversight is a critical element that ensures the protection of the research participants and the integrity of the data.”
How to oversee monitoring of a trial
So, what is actually involved in the oversight monitoring of a clinical trial? Firstly, a highly experienced monitor is trained on the study’s protocol, the sponsor’s internal processes, and all relevant regulations. They then review a sampling of the trial documentation from the site in question. An in-person visit to the site comes next, with some of the most important points to review including the informed consent process, the correct inclusion of the patients, the management of the investigational product, and essential documentation.
“During the on-site visit, the oversight monitor should review the source documents of the patients, the medical records, the databases, and the electronic case report forms,” says Engraff. “They must go to the pharmacy to review the medication stock and storage conditions and they must go to the laboratory to assess how the samples are being handled. If there are other facilities involved in the study, the oversight monitor must assess in addition to meeting with the principal investigator, study coordinator, and research nurses – everybody involved in the study – to have a complete picture of what is happening at this site.”
“Reports are then created using the agreed upon oversight monitoring plan. There is no general rule for how many oversight visits are required for each trial, and each sponsor has their own strategy for determining the appropriate number. Some choose to do one visit per clinical research associate (CRA) per protocol per year, while others do a percentage of all sites or perform one visit per country that the study is being conducted in. Some decide to oversee the trial with staff from their own headcount, while others rely on a partner’s specialist monitors.”
A range of factors can influence the level of oversight needed, including the complexity of the trial and the number of participants. Other factors include rapid enrollment, a large number of protocol deviations, or a high CRA turnover rate.
“We need to be able to oversee these trials,” Donna Cullen, Senior Director of Clinical Excellence at Intercept Pharmaceuticals said on a recent webinar. “You can do it internally within your own group or externally with a group like KPS Life. We have chosen the external route, and it has worked very well for us.”
Choosing a partner for clinical monitoring oversight
There are many reasons why pharma companies both large and small choose to outsource their clinical monitoring oversight, but what kinds of considerations should companies make when evaluating providers?
This was a key topic of discussion for the industry experts on the recent webinar hosted by KPS Life, an industry leading standalone functional service provider (FSP) and a specialist in clinical monitoring oversight. During the event, Brian Nugent, Senior Director of Clinical Compliance at Travere Therapeutics said that, for his company, it was most important to find a well-experienced partner and one that could offer a global service, with international monitors who speak the native language of each country.
Dr. Cornelis Winnips, Clinical Head of Novartis’ tropical disease program, listed similar requirements for his company, emphasizing the importance of a formal validation process for new partners. He added that while large organizations may have more flexibility over which oversight activities they choose to outsource and which to keep in-house, quality is always the most important consideration when working with a partner.
Cullen agreed that quality always comes first. She said her experiences using outsourced monitoring services with CROs haven’t always been positive, but her work with KPS Life has. This is thanks to the team’s level of knowledge and understanding, and the overall flexibility and adaptability of the company.
How KPS Life gets global oversight monitoring right
With headquarters based in Malvern, PA in the US and European headquarters in Warsaw, Poland, KPS Life’s fully global teams have excelled in providing global clinical monitoring oversight services since the inception of the FDA guidance in August 2013. The team takes every step to make sure the CRO’s monitoring of the clinical sites is being conducted per ICH/GCP and regulations, which aims to ensure that the clinical research associates are providing quality monitoring services and that the trial sites are following the protocol and agreed procedures. To do so, KPS Life relies on robust processes and experienced oversight monitors.
“KPS Life hires staff with many years of on-site and remote monitoring experience throughout the different regions,” says Engraff. “There is a very solid training curriculum for KPS employees. We are ACRP GCP certified every two years, and we have extensive training as it applies to personal data protection, GDPR, and cybersecurity.”
This approach is essential considering the importance of high-quality monitoring oversight services in clinical research. There can be no loose ends in a clinical trial, and any problems must be detected early before they have serious repercussions for patients, the sponsor, and the status of the trial.
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