Impact of the COVID-19 Pandemic on the Collection and Analysis of Exposure/Drug Accountability in Ongoing Clinical Trials

Subteam F: Exposure/Drug Accountability

Members:

As the COVID-19 pandemic severely impacts many facets of human activity around the world, the pharmaceutical industry is being presented with significant challenges related to the manufacturing and shipping of existing marketed products and to treatment development activities. Regulatory authorities have released guidance documents focussing on the impacts on study start-up activities, changes to ongoing study procedures, and items considered urgent safety matters during this pandemic. This paper considers the impacts of COVID-19 on the collection and analysis of exposure/drug accountability data, offering guidance from industry experts on what clinical data scientists can expect in the short term, as well as consideration of future implications.

REGULATORY BACKGROUND

In the current, constantly evolving atmosphere sponsors have been faced with urgent decisions regarding each clinical study in their portfolios, regardless of development stage. Challenging decisions based on mitigating the risks to study participants are being made on whether to delay initiation of new clinical studies, temporarily halt or terminate ongoing clinical studies, or update study protocols as necessary. These decisions must be based on the 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). Given the scope and breadth of the guidance documents, as well as the multiple changes required to be considered for any given study, it is essential to collaborate with all relevant team members to ensure all exposure/drug accountability updates are managed appropriately. Involvement in a COVID-19 task force will be helpful when communicating these types of challenges and developing decisions tailored to each study.

IMMEDIATE IMPACTS

The concept of exposure to study drug within protocol-defined windows is critical to all interventional clinical trials. The COVID-19 pandemic has affected the ability of clinical trial participants to attend sites and has interrupted the supply chain for drug products. The safety of clinical trial participants is the primary concern in conducting clinical trials, but the effects on the analysis from missed dosing or early discontinuation of study drug and impact on accountability from alternative sourcing of intervention must also be accounted for.

The FDA guidance [1] and the EMA guidance [2] on the conduct/management of clinical trials during the pandemic address issues that may arise due to interruptions to the protocol planned drug exposure and drug accountability during trials. These considerations include whether it is in the best interest of a clinical trial participant to continue drug exposure per protocol, or for the participant to discontinue study drug exposure, or end their participation in the trial entirely.

The statements “Ensuring the safety of clinical trial participants is paramount” [1] and “The ability to confirm eligibility and to conduct key safety assessments and trial evaluations is of particular importance” [2] both highlight the importance of safety monitoring of ongoing studies during the COVID-19 pandemic. How sponsors achieve this will differ, and different trials may require different approaches depending on the indication or the mode of action of the investigational or comparator drug(s). Several considerations are raised in both the FDA guidance [1] and the EMA guidance [2] relating to the conduct of the study. These include, but are not limited to, the conversion of physical visits into phone or video visits or utilising alternative locations for assessments, changes to the study visit schedule, pausing trial recruitment or withdrawing subjects from trials, missed dose or adjusted dosing, and/or changes to the dispensing of the study medication. Any steps taken by a clinical study sponsor may have an impact on the safety analysis of the study. Steps taken that result in changes to the number of participants dosed, or the amount of overall time spent by participants on the drug, may affect the analysable safety population of the study. Clinical data scientists will need to consider the actions taken by the sponsor when preparing to perform these analyses.

DATA COLLECTION and Mapping to SDTM

According to best practice stated by the PHUSE COVID-19 Task Force, sponsors should collect data for the ongoing study to support analysis. Analysis needs should determine whether additional data will be collected, the types of data that need to be collected, and flagging records for COVID-19 relationship, as proposed in the “Guidance for Ongoing Studies Disrupted by COVID-19 Pandemic Version 1.0” [3]. The CDISC guidance will detail how things are collected, but analysis should dictate what is collected.  

When determining what data should be collected, it is important for sponsors to consider that outside of trials in which COVID-19 is the indication, COVID-19 data is not the main topic of collection. Sponsors should take care not to collect data for which an analysis need has not been identified.

If analysis needs determine that COVID-19 related data is to be collected, then a sponsor’s data entry guidelines should clearly state at what timepoints the data should be collected, and when the data should be reviewed. Sponsors should also consider data consistency across all eCRFs for a trial as the COVID-19 impact will be the same for all data points. Historical data may need to be collected – for example, if a trial participant missed a dose because a site was closed, but the sponsor had not already updated data collection to note site closures related to COVID-19, it may be appropriate to query the site to determine whether the missed dose is considered COVID-19 related. If data collection methods for a particular CRF page cannot be easily changed, then other mechanisms should be evaluated to collect this data, such as updates to the protocol deviation data collection process.

As detailed in the “Guidance for Ongoing Studies Disrupted by COVID-19 Pandemic Version 1.0” [3], the variables below are SDTM variables that might be used to identify COVID-19 impacted records in the EC, EX and DA domains. 

EX and EC domains:

  • --ADJ
  • --RSDISC

Non-Standard Variable in the SUPPEX

Variable

Label

Type

Codelist

Role

Origin

EXRSINT

Reason for interruption

text

 

Non-standard Record Qualifier

CRF

EXEPADJI

Epi/Pandemic Related Adjustment Reas Ind

text

NY

Non-standard Record Qualifier

CRF

EXEPINTI

Epi/Pandemic Related Interrupt Reas Ind

text

NY

Non-standard Record Qualifier

CRF

EXEPDSCI

Epi/Pandemic Related Discontin Reas Ind

text

NY

Non-standard Record Qualifier

CRF

 

Non-Standard Variable in the SUPPEC

Variable

Label

Type

Codelist

Role

Origin

ECREASOC

Reason for Occur Value

text

 

Non-standard Record Qualifier

CRF

ECEPADJI

Epi/Pandemic Related Adjustment Reas Ind

text

NY

Non-standard Record Qualifier

CRF

ECEPDSCI

/Pandemic Related Discontin Reas Ind

text

NY

Non-standard Record Qualifier

CRF

Studies where exposure records as collected contain missed visits or missed doses should follow SDTM implementation guidance to include an EC domain to contain this data. The EX domain is not intended to contain records of interventions which did not occur, only interventions which did occur.

An example of how a team may choose to capture study treatment interruption is by adding the below to the Control Terminology list for ECADJ (EC Reason for dose adjustment): SUBJECT RELATED IMPACT; SITE RELATED IMPACT; SUBJECT DIAGNOSED WITH COVID-19 INFECTION.  

DA domain:

Non-Standard Variable in the SUPPDA

Variable

Label

Type

Codelist

Role

Origin

DACNTMOD

Contact Mode

text

CNTMODE

Non-standard Record Qualifier

CRF

DAEPCHGI

Epi/Pandemic Related Change Indicato

text

NY

Non-standard Record Qualifier

CRF

DATA MONITORING

Due to the pandemic, both the FDA [1] and EMA [2] have highlighted that different approaches to monitor both the completeness and quality of data collected as part of clinical trials may be impacted. It is the responsibility of the sponsor to ensure that this is carefully monitored to ensure patient safety. This may include the “optimizing of central or remote monitoring programs to maintain oversight of clinical sites” [1]. Much of the impact of COVID-19 on a clinical study will be identified by protocol deviations and protocol amendments. Missing data and protocol deviations will be discussed in separate blogs, but these will potentially be important to establish whether this impact is balanced across treatment arms.

Additional data monitoring considerations should be put in place if other eCRF forms related to the study medication are built into your trial. For example, if you have a form to collect the status of study medication at the end of the trial in addition to the study medication eCRF form, then you must monitor the data collection in both eCRF forms for consistency.

Sponsors conducting interim analyses to be included in regulatory submissions may need to account for incomplete data verification and explain when data verification will be completed, particularly for studies where the protocol is not amended, to reduce the percentage of source data verification required.

During the COVID-19 era, drug accountability may pose special data monitoring and collection challenges for IPs that are normally administered in a healthcare setting. The FDA states: “In all cases, existing regulatory requirements for maintaining investigational product accountability remain and should be addressed and documented” [1]. Thus, teams will need to carefully assess how they can monitor actual Investigational Product (IP) use, as well as give ample thought to how COVID-19 may affect IP storage conditions. For example, if the protocol indicates pharmacy dispensing for self-administration at home, and this is changed to direct-to-patient shipments, then a protocol amendment would be required to permit home delivery of investigational product [1].

DATA ANALYSIS

Sponsors should collect data for the ongoing study to support the analysis. Clinical data scientists (clinical and statisticians in particular) should be driving the discussion on what will be included in the Clinical Study Report (CSR) and how newly collected COVID-19 data will impact it. Impacts on investigational product that affect analysis include:

  • missed dose, delayed dose, incorrect dose
  • dose obtained outside of the study
  • non-centrally dispensed dose.

Consideration should be given to categorising these occurrences, as related to COVID-19, to allow for analysis flexibility. For example, it may be important to understand and analyse missed doses due to non-COVID-19 related site closure vs. COVID-19 related site closure. It may also be important to determine whether significant number of dose changes occurred, thus impacting analysis populations or sub-populations. If this occurs, the team will need to carefully evaluate potential need for protocol amendments.

Studies may also deem it important to drill down to actual COVID-19 status, with categories such as Confirmed COVID-19, Probable for COVID-19, Negative for COVID-19. The number of impacted subjects and types of analyses to be performed will drive whether this level of detail is needed.

Finally, the impact on time-dependent variables and outputs needs to be evaluated. Each study should review displays to determine whether algorithm updates are necessary for variables such as time on treatment, duration of exposure, time since last dose, and time to event.

CONCLUSION

Study teams will need to determine the impact of COVID-19 on exposure and drug accountability related datasets and outputs. Potential updates to data collection methods and SDTM mapping need to be considered, to determine whether additional analysis is required at the individual study level or at the compound level.

REFERENCES

[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 May 14, 2020

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] Guidance for Ongoing Studies Disrupted by the COVID-19 Pandemic

http://www.cdisc.org/system/files/members/standard/ta/COVID-19/Guidance%2520for%2520Ongoing%2520Studies%2520Disrupted%2520by%2520COVID-19.pdf

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Tags: COVID-19

Categories: Working Groups News

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