Impacts of the COVID-19 Pandemic on the Collection and Analysis of Disposition and Concomitant Medications

While 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 clinical trial research and development activities. Regulatory authorities have released guidance documents focussed on the impacts to study start-up activities, changes to ongoing study procedures, and items considered urgent safety matters during this pandemic.

This blog considers the impacts of COVID-19 on the collection and analysis of disposition and concomitant medications, offering guidance from industry experts on what clinical data scientists [1] (i.e. those who analyse data collected in clinical trials) can expect in the short term relating to the studies impacted by the COVID-19 pandemic, 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 patient disposition and concomitant medication 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 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). A number of 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. Any steps taken by a clinical study sponsor may have an impact on the safety analysis of the study. Clinical data scientists will need to consider the actions taken by the sponsor when preparing to perform these analyses.

 

Patient Disposition:

As studies are taking place concurrent with the COVID-19 pandemic, participants may discontinue study or study treatment due to the COVID-19 illness or COVID-19 impact (travel restriction, quarantine, site closure). Since the COVID-19 pandemic will hopefully end at some time in the near future, the recommendation is to add additional CRF pages where needed to collect COVID-related information rather than amending the existing CRF to minimise the updates to already collected data.

 

Data Collection:

Based on the study design, we may see several changes or updates to disposition pages including enrolment, treatment disposition, study disposition, investigation period disposition, follow-up period. Changes or updates to each disposition type are summarised below:

DSTERM in general is sufficient to collect discontinuation related to COVID-19. To capture whether the primary reason for discontinuation is due to COVID-19, some sponsors have added more instructions to the pre-text of the DSTERM fields on the disposition forms. For example, instructions to add the pre-fix “COVID-19:” and to specify detail such as illness, quarantine and control measures have been incorporated.

Randomisation/Enrolment discontinuation – Some sponsors have added an additional question “COVID-19 related – Yes/No” to the CRF if the subject screen fails due to a reason of COVID-19. Reason for screen fail is recommended to be captured in Screen fail domain SF. SFEPRELI (NSV).

Treatment Discontinuation – Some sponsors have added an additional question “Did COVID-19 impact discontinuation status – Yes/No” to CRF pages that collected information about unplanned discontinuation of study treatment, or unplanned overall discontinuation of a participant from a study. When collected, this information should be captured in the DS domain. This may be achieved by adding a DSSCAT of “COVID-19 DISCONTINUATION” to the record of the participant’s discontinuation of treatment of study.

Because it may not be possible to update existing CRFs on ongoing studies with additional questions, or it may impose too much site burden, some sponsors may collect treatment discontinuation in relation to COVID-19 by adding codelist items to existing treatment discontinuation questions rather than adding a question. In this case, “COVID-19” would appear in the codelist item text. A DSSCAT could be used to group those codelist items that included “COVID-19”, for ease of analysis.

Data Monitoring:

Sites and data management cleaning must be cautious in how free text is entered and cleaned, if DSTERM is utilised to capture impact of the COVID-19 pandemic. For example, “Not related to COVID-19” is not an efficient way of capturing discontinuation term. Instead, guidance to an alternate or more detailed explanation should be provided to the data entry personnel. Designated study team members (some sponsors have study statistician leads and programming leads) work in conjunction with the study team to closely monitor:

  • Number of participants enrolling
  • Number of participants completing the study
  • Number of participants who discontinued the study with a reason clearly capturing COVID-related, not COVID-related.

Data Transformation:

If careful instructions are not followed, we might be in a manual review situation, which could be strenuous for Phase III or IV studies. Programming should be cautious in scanning the free text for flagging – “Not related to COVID-19” should not be flagged as a COVID-related event. In case manual review is required, teams could consider creating results of the review in an Excel spreadsheet and the converted SAS dataset could be used for data transformation and analysis. The non-standard variable (NSV) DS.DSEPRELI [3] could be added to the dataset to indicate that the disposition reason is related to COVID-19.

  • No change to the DSCAT/DSSCAT codelist.
  • Additional disposition CRF pages could be added to capture whether COVID-19 did impact the discontinuation status (data transformation decision pending).
  • If the SAP requires that the COVID disposition reason is due to Death and DSTERM indicates COVID-related, then ADaM time to event data (ADTTE) should indicate censoring the record.
  • The recommendation is to create a PANDEM ADaM dataset to capture all COVID-related information.


Data Analysis
:

It is important to understand that the COVID-19 pandemic is not the featured discussion and for updates to the analysis to be kept minimal [4]. Study discontinuation/treatment discontinuation/delayed reason can be captured depending on recommended scenarios presented below. Scenarios 1, 2 and 3 are recommended to be considered for studies with minimal disruptions (i.e. last few patients remaining in the trial). Studies with substantial disruptions might consider the 4th Scenario.

  • 1st Scenario:
    • The standard disposition table is sufficient for reporting data as collected [5].
    • A supporting listing detailing the reason for discontinuation could be used to identify COVID-related discontinuation.
  • 2nd Scenario:
    • If the COVID-19 related reason is not collected on the CRF but derived using programming, then one option is to include an additional column in the existing standard disposition table. For instance, disposition table for 2 treatment groups, A and B, along with Total column, could possibly include an additional COVID-19 related column.
  • 3rd Scenario:
    • The standard disposition table can be altered to include specific reasons of “COVID-19-related” study discontinuation. A similar table could be included for treatment discontinuation.
  • 4th Scenario:

     

  • Teams might consider adding a separate table for Deaths due to COVID-19 as part of the COVID-19 impact analysis.
  • If the CSR has a special section for COVID-19 impact tables, then teams can decide whether to add a separate summary table of subjects who discontinued due to COVID-19.

Non-standard variable (NSV) logic added to DS and SF domains (DSEPRELI/SFEPRELI) [3] could potentially be used for efficacy/impact analysis by imputing values which are still considered collected values.


Concomitant Medications:

For ongoing studies, if the subjects are impacted by COVID-19, the medications helpful for treating the COVID-19 illness are collected under concomitant medications. As the COVID-19 pandemic is uncertain and there is no clear understanding of how a subject reacts to a drug, many approved drugs are being tested for efficacy in alleviating the symptoms caused by COVID-19, for example anti-malarial drugs, hydroxychloroquine and oxygen therapy.


Data Collection:

Concomitant medications can be captured depending on recommended scenarios presented below. Scenario 1 is recommended to be considered for studies with minimal disruption. Studies with substantial disruption or subjects who are vulnerable to COVID-19 due to pre-existing conditions such as asthma, cancer or any kind of pulmonary/respiratory diseases might consider the 2nd or 3rd scenario.

1st scenario

Existing CRF in general is sufficient to collect concomitant medications used to treat COVID-19 and add more instructions to the pre-text of the INDICATIONS on medications forms. For example, add an instruction to add the pre-fix “COVID-19:” to indications like “COVID-19: Infections”.

2nd scenario

Few sponsors have considered updating the CRF by adding fields such as

  1. “Due to COVID-19” Yes/No response on medications forms to see if the medication given was due to the COVID-19 indication.
  2. Add pre-specified questions asking

  (a) whether the subject received high-flow nasal cannula oxygen therapy during hospitalisation

  (b) whether the subject received non-invasive mechanical ventilation during hospitalisation (including oxygen therapy) and

 (c) whether types of non-invasive mechanical ventilation treatments were used.

3rd scenario

Few sponsors also considered adding a new CRF page to collect all medications used to treat COVID-19.

Data Monitoring:

Designated study team members (some sponsors have study statistician leads and programming leads) work in conjunction with the study team to closely monitor medications used for treating COVID-19.

Data Transformation:

  • The non-standard variable (NSV) CM. CMEPRELI could be added to the dataset to indicate the medication used to treat COVID-19 (if a new CRF page or new fields are added to collect in relation to COVID-19).
  • Use the existing standard variable Indication (--INDC) to know what treatments were given for COVID-19.
  • The Sponsor Device Identifier (SPDEVID) can be used in Concomitant Medications (CMs) and Procedures (PRs) to link to the Device Identifiers (DI) dataset.
  • CMEVLINT (Evaluation Interval) is used to indicate that only medications in the last 7 days are of interest.

Data Analysis:

For most studies, we might not need to add any changes to standard reports, but for studies where there is a substantial number of subjects who are impacted by the COVID-19 illness, or for studies like asthma or respiratory diseases, we might need a separate list of summary tables to distinguish the medications/procedures used due to the COVID-19 illness.

Conclusion:

For ongoing studies concurrent with the COVID-19 pandemic, changes in disposition and concomitant medication collection and analysis will generally be minimal. For collection, instructions may be updated to provide clarity as to how to capture COVID-related information. In some cases, CRF pages might be updated. In most cases, the already planned analyses for disposition and concomitant medication data will be sufficient. However, for studies in which many participants discontinue due to COVID-19 disruption or infection, different or additional disposition summaries may be helpful. For studies in which many participants became infected with COVID-19, a separate summary table of concomitant medications used to treat the COVID-19 illness might be desired, but the data on concomitant medication use will be most useful in the context of case reviews.

REFERENCES

[1] PHUSE Data to Knowledge: https://www.phuse.eu/d2k

[2] 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

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

[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

[4] https://transceleratebiopharmainc.com/

[5] Clinical Trial Drug Safety Assessment for Studies and Submissions Impacted by COVID-19 – Mary Nilsson, Brenda Crowe, Greg Anglin, Greg Ball, Melvin Munsaka, Seta Shahin, Wei Wang http://arxiv.org/abs/2006.05502

 

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