Denmark Finds Sponsors ‘Overburdening’ Study Sites To Support Decentralized Trials

A senior Danish GCP Inspector highlights instances of clinical trial sites facing burdensome procedures to support decentralized trials and discusses other challenges posed by such studies.

Source: Alamy

DCTs should neither compromise patient safety and data integrity, nor result in increased burden at trial sites

Decentralized trials (DCTs) can make research faster and more efficient as they allow all or most trial activities to be done remotely in or near a patient’s home. However, if not designed or executed well, such studies can miss the efficiency goal.

The Danish Medicines Agency has come across several instances of clinical trial sites being placed under “undue pressure” to support the deployment of decentralized solutions and remote ways of working. Also, DCTs are posing new concerns around data privacy and data integrity, said Lisbeth Bregnhoj, a good clinical practice (GCP) inspector at the agency.

Bregnhoj was speaking at the recent Drug Information Association Europe 2022 conference where she discussed the DMA’s experience with scientific advice applications covering different DCT models and the inspection of such trials during the COVID-19 pandemic.

In one case, Bregnhoj recalled, the DMA had issued a critical deviation to a trial site where things were set up in such a way that the trial’s principal investigator (PI) had no control over the site trial master file (TMF) and had in addition given inappropriate access to the sponsor staff.

In this instance, she explained, the sponsor had “coerced” the PI to replace their usual paper-based TMF with an electronic TMF that could be downloaded license free from the internet. Despite initial objections raised by the site, the sponsor had insisted on the eTMF because it would make things “so much better” for everyone during COVID-19, she noted.

The site eventually agreed on using the eTMF but did not take responsibility for its content. The sponsor promised to help with the eTMF if access was provided to its staff. This resulted in more people getting access to the eTMF than needed, and the site had no control over the documents that were uploaded, changed or deleted by the sponsor staff.

Moreover, as this eTMF did not support electronic signatures, the sponsor had insisted that for all documents that needed to be signed, the site staff should print these, get them signed and then upload them back into the eTMF. As expected, the site staff “were not too happy” about this, noted Bregnhoj.

In this case, the DMA held the sponsor “co-responsible” for the site deviation because the sponsor had put “undue pressure” on the site to implement systems that were “far away from usual practice” and had not provided any assistance or training to deal with the new setup.

The case also highlights how DCTs are “blurring” the traditional division of roles between sponsors and trial investigators, with sponsors trying to take on responsibility for tasks that traditionally rest with PIs. ([Link to part 1 article])

Other DCT inspections by the DMA have revealed more instances of sponsors imposing unreasonable burden on trial sites, including cases where:

• The sponsor – instead of sending in monitors at the trial site to verify source data – asked the site staff to “perform self-monitoring” without providing guidance on what to look at. This resulted in the site staff performing 100% source data verification even though the EU COVID-19 guidance is to only look at critical data, noted Bregnhoj.

• The sponsor had implemented remote monitoring of the trial even though on-site monitoring was still possible, and used video conferencing to exchange non-critical documents which needed to be translated in the process.

• The sponsor had requested the site staff to walk around with a video camera to verify tasks that should usually be performed by the trial monitor on site.

• The sponsor had systematically requested provision of redacted medical records to support central monitoring. “That is not really how central monitoring” should be done as this can jeopardize data protection, Bregnhoj noted.

Other Challenges

DCTs are also posing other challenges for companies, especially since such trials involve the increased use of computerized systems. During the scientific advice process on DCTs, the DMA came across instances where:

• The suggested process/standard for e-signature did not provide an assurance of the trial participant’s identification. Bregnhoj said ensuring that the participant is someone who he/she is claiming to be was especially relevant in cases where participants are recruited via social media and the PI does not know them and would potentially never meet them.

• There were concerns that the medical records may be “depleted” as a result of the proposed data collection methods, eg electronic patient-reported outcome data relevant for patient safety. In this case, the sponsor was asked to submit an updated protocol. In another case, the DMA sought confirmation from the PI’s institution that trial notes and documents could be generated and stored for a period in systems outside the institution’s infrastructure.

• No risk-based approach was provided to oversee trial safety data that were to be available to the PI and the sponsor 24/7. (Also see "Digital Data Deluge Can Affect Oversight Of Patient Safety In Trials" - Pink Sheet, 16 May, 2022.)

• The sponsor had failed to confirm whether the data protection officer at the PI’s institution had ensured that access to medical records/medical record‐like notes would only be controlled by the investigator and given in accordance with the data protection legislation. Bregnhoj said her “personal wish” on this front was to see some data protection agencies entering the scene to offer good advice on how the data protection officer should carry out this task.

• No justification was offered by the sponsor as to why no on-site monitoring was needed for the proposed trial, which relied only on centralized monitoring. The DMA asked the sponsor to either initiate some on-site monitoring or to justify why that was not necessary based on the types of data, trial sites, etc.

• Issues around the retention of photographs taken by the trial participants on their own devices and to be used for future research were not clearly flagged to the ethics committees and appropriately consented to by trial participants.