Impact of the COVID-19 Pandemic on the Collection and Analysis of Protocol Deviations in Ongoing Clinical Trials

The COVID-19 pandemic is an unprecedented event in the context of our clinical trials. It is, therefore, very important to understand the impact of the pandemic on our trials. Protocol Deviations are a key source of insight regarding the conduct of our trials related to ensuring patient safety and the integrity of our trial data. The details of definitions of protocol deviations may differ among sponsors. Below we propose classification from one of our member companies:

Protocol deviation is any non-adherence to the protocol-defined study conduct for a specific subject.

Major Protocol Deviations are any deviation which has the potential to impact or impacts subjects’ rights, safety or well-being, or the integrity and/or result of the clinical study. Typically, major protocol deviations are predefined on a protocol deviation criteria list.

Potential Major Protocol Deviations are the deviations not listed on a predefined criteria list but potentially meet criteria of a major protocol deviation. Such potential major protocol deviations require prompt review and documented confirmation of their classification.

The last category is Minor Protocol Deviations, which simply indicates a deviation not classified as major.

The data associated with these deviations is therefore an integral part in creating an overall picture that describes the impact of COVID-19 and the measures taken to manage and mitigate its effects within our trials. This blog considers the impacts of COVID-19 on the collection and analysis of protocol deviations and offers guidance from industry experts on what clinical data scientists can expect in the short term, as well as consideration of future implications.

Regulatory Background

Current regulatory guidance issued relevant to the COVID‑19 pandemic, including those published by the US Food and Drug Administration (FDA), the European Medicines Agency (EMA) and many other countries (including individual member states within the EU).

Health authorities recognise that the impact of the current COVID-19 pandemic will increase the number of protocol deviations observed in clinical trials and recommend that sponsors document the specific protocol deviation and the reason for the deviation using existing processes or alternative documentation approaches [1,2,3].

Immediate Impacts:

Data Collection

While the pandemic’s impact on the ability to conduct clinical trials is reflected in the rise of protocol deviations, all protocol deviations and issues, related and not related to COVID-19 impact, need to be documented and reviewed per your company’s standard procedures. Study teams may take this opportunity to review and possibly update their predefined criteria of major and potentially major protocol deviations in light of the pandemic.

To easily identify protocol deviations related to the pandemic, it is recommended site staff use a standard text string such as “COVID-19” at the beginning of the deviation description. Consistent labelling and adherence to the standard text string will also enable programmatic identification of pandemic-related records. In addition, monitors and site staff should ensure protocol deviations descriptions include the specific reason of relatedness [1] to COVID-19. 

Examples of protocol deviations related to COVID-19 impact are missed doses, impact to study procedures, out of window or missed subject visits, missed disease evaluation, visits using alternative modalities, etc. Study teams can consider doing a retrospective review of previously documented protocol deviations and/or issues for COVID-19 relatedness and, if appropriate, amend to add a prefix description as identified above. No new CRFs or modification to existing CRFs is recommended. 


Data Monitoring

The COVID-19 pandemic has created the situation when due to Shelter-in-Place and travel restrictions, monitors may face delays in visiting sites to gather additional details required, perform Source Data Verification (SDV) and/or Source Data Review (SDR). This may impact timely sponsor oversight of the study.

To help with oversight and future data reporting, proper identification of COVID-19 related PDs, a certain naming convention can be used. For example, COVID-19 related PDs could be marked as  prefix “COVID” or “COVID-related”, as mentioned above. This approach will help with future analytics and distinction between “standard” PDs (which would occur during “normal” study conduct) versus pandemic-related.

Although it is rather difficult to fully replace a clinical research associate’s work at the site in identifying PDs, a robust central monitoring can offer substantial support in oversight. For example, certain central monitoring techniques may be helpful in identifying data patterns indicating potential PD to further investigate. Also, using central analytics properly coded PDs could show patterns, distinction by priority or trending by deviation type for further analysis.

In scope of study conduct and following regulators’ recommendations, changes in protocol conduct necessary to assure patient safety can be immediately implemented with companies, ensuring the subsequent review by the IRB and notification to the FDA [1]. Also, companies must follow the rule that any necessary modification to protocol-specified procedures that occur prior to IRB approval and submission to the FDA must be reported as a protocol deviation. This approach allows for necessary flexibility when change needs to be implemented fast, but also ensures proper tracking of situation-driven introduced deviations.

Data Analysis

While it is the responsibility of monitors to appropriately capture and document all COVID-19 related PDs, review should take place to confirm relatedness. Clinical data scientists should work collaboratively across disciplines and within study teams to ensure any analysis variables needed to identify COVID-19 related protocol deviations and associated reasons follow CDISC guidelines (i.e. COVID-19 flag variable, Protocol Deviation reason variable).

If it is the company practice to only report major deviations, then it is recommended to explore the minor deviations for any textual mention of anything relating to COVID-19. It may also be necessary for minor deviations that refer to COVID-19 to be reported as major deviations, particularly if the deviation is relating to missing visits or assessments related to primary efficacy or safety parameters. It may be important to document the reasons for missing visits for future regulatory review. If the method of data capture does not support this, then alternative methods of collecting this data, such as protocol deviations, should be considered.

A potential approach for reviewing and reporting protocol deviations starts first with a manual review of the deviation descriptions at which time COVID-19 relatedness classification can be confirmed/updated. Among this subset, the associated reasons can also be identified and classified into the following 6 categories: (a) Confirmed epidemic/pandemic infection (b) Suspected epidemic/pandemic infection (c) Subject movement restricted due to epidemic/pandemic infection (d) IMP shipping delayed/blocked due to epidemic/pandemic infection (e) Sponsor action due to epidemic/pandemic infection (f) Site action due to epidemic/pandemic infection. This work occurs after data collection but before data transformation (SDTM).  

In many cases, sponsors will need to report summaries relating to the number of protocol deviations due to COVID-19 and the specific reasons for the deviations to help evaluate the impact of the pandemic on the study.

 

Conclusion

The COVID-19 pandemic has affected practically all aspects of life, work and clinical research specifically. It is highly probable that a certain form of epidemic risk will stay with us for a long time and the impact will continue. What will change over time is preparedness of societies and in our environment preparedness of sites and sponsors’ clinical operations. The sites may be better ready procedurally to ensure performing safe patients’ study visits. Sponsors are already introducing a lot of changes which will allow increase of remote oversight and more central analytics review. The importance of distance monitoring through EHRs will also grow providing technology and regulations allow. Specifically, for protocol deviations, what will remain important is understanding how the distinction between what epidemic-related vs what is typical error in the study conduct observed for years so far. Solid reporting of these will be meaningful for regulators reviewing submitted CSRs and making decisions on market authorisation.

 

Resources:

[1] FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public Health Emergency: Guidance for Industry, Investigators, and Institutional Review Boards – March 2020, Updated on June 3, 2020

  • Section(s) related to Protocol Deviations: Section III, Appendix: Questions 3, 4, 6, 7, 9, and 13,

https://www.fda.gov/media/136238/download

[2] Guidance on the Management of Clinical Trials During the COVID-19 (Coronavirus) Pandemic – Version 3 (28 April 2020)

https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/guidanceclinicaltrials_covid19_en.pdf

 [3] MHRA: Guidance – Managing clinical trials during Coronavirus (COVID-19)

https://www.gov.uk/guidance/managing-clinical-trials-during-coronavirus-covid-19

 

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