COVID-19 has disrupted the clinical trial landscape today. The situation has caused many patients not wanting to visit sites, resulting in multiple missed patient visits. The availability of sites and investigators themselves have been limited, since sites have been busy prioritizing COVID-19 patients and dealing with the current crisis. The unavailability of site staff has also resulted in delays in site initiation, delays in the processing of lab samples or receiving drug shipments. Labs, eCOA providers, and other vendors have also struggled with staff shortages, directly impacting the progress of the clinical trial and delaying critical milestones such as database lock. Delays in data entry and query resolution have presented an even greater challenge, since there is an urgent need to access data and monitor patient safety in real-time.
The industry has scrambled to find alternatives. It has made all efforts to ensure patient safety by avoiding calling patients to the site, implementing the remote monitoring of patients using solutions such as wearables, telehealth solutions, the DTP supply of the investigational product, using e-consenting tools, etc. The model of on-site monitoring has also been replaced by models such as remote monitoring visits. Many of these changes are being rapidly implemented to ensure continuity in ongoing clinical trials.
This has caused multiple protocol amendments, to address protocol deviations, such as delays in patient recruitment, missed patient visits and missed procedures, resulting in missing data points, the use of alternative monitoring models and technologies in clinical trials. Regulators across the globe have revised their guidances multiple times in a short time frame, to support these alternatives to enable continuity in drug development, while ensuring patient safety.
There has also been an urgent need to accelerate drug development for COVID-19 clinical trials, involving the use of innovative strategies such as leveraging novel adaptive designs enabling seamless transition across phases, while dealing with higher numbers of discontinued patients. These challenges have caused the industry to reflect on their strategy, to define and prioritize focus on critical data points, define how many missing visits equate to patient discontinuation, outline when post-production changes are required in an eCRF, have a flexible CRF design structure to adjust for the replacement of central labs with local labs which are manually updated. It is also desirable to update edit checks to identify which protocol deviations are COVID related and create flags to identify those which need to be reported to regulators.
A risk-based approach to the monitoring strategy adds significant value, clearly flagging new risks, and defining thresholds to detect what needs attention, without driving an unrealistic number of queries. Strategic decisions need to be made when identifying Key Risk Indicators (KRIs) to ensure that key data points of significance are not being missed. In addition, correlations between different KRIs need to be factored in, since risk needs to be evaluated in a holistic manner. To be able to analyze risk holistically, data from multiple sources needs to be integrated. Since COVID has been a propulsive force in the decentralization of clinical trials, data has been flowing in from diverse sources, in different formats. Interoperability is important to ensure the seamless flow and the real-time viewing of data. Risk cannot be managed retrospectively.
Efforts are also being made to recruit patients using tools such as social media, and by mining EHRs and claims databases. Additional attempts are being made to exploit RWD directly from EHRs and eliminate the need to re-enter data in database. However, data from healthcare systems and from clinical trials are quite different in format and structure. The industry is still battling to deal with these challenges. In addition, compliance with diverse regulations such as HIPAA and GDPR is essential. For example, the EU guidance for example, indicates that remote SDV (source data verification) can only be considered “during the public health crisis for trials involving COVID-19 treatment or prevention or in the final data cleaning steps before database lock in pivotal trials investigating serious or life-threatening conditions with no satisfactory treatment option.” Regulations within different countries in the EU vary, requiring sponsors to carefully understand the applicable regulations while implementing clinical trials. Apart from regulations, another factor is the sites openness to provide access to EMRs as well.
These challenges are resulting in the industry incorporating additional perspectives into the site qualification process addressing aspects such as the sites experience in using EMRs, e-consenting and other technology and platforms, their openness to remote site initiation and site monitoring visits, and their willingness to provide remote access to data. Efforts are also being made to incorporate these components into the protocol design to offer flexibility to modify processes, without having to create protocol amendments.
The reality is that the industry recognizes that it doesn’t have to only deal with this pandemic – it has to prepare for the future as well.