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Overcoming Risks to Clinical Trials during Pandemics

April 2, 2021

The COVID-19 pandemic has caused widespread disruptions in the healthcare sector. While many industries faced unprecedented challenges, the clinical trial industry was uniquely affected, given the nature of this crisis. \(^1\)

Though the pandemic caused tremendous upheaval, it also provided an opportunity for redesigning the way clinical research is conducted.  In this article, we discuss the key issues arising in the management of clinical trials during pandemics and what measures can be taken to overcome the situation. We also discuss the various strategies which could lead to post-pandemic trial success.

Conducting clinical trials during the COVID-19 pandemic - What are the main challenges?

As the pandemic continues, clinical trials face many uncertainties and obstacles in conducting various activities. Following are the main challenges arising in the management of clinical trials due to COVID-19:


- Difficulties in accessing trial sites

Organizations are compelled to temporarily pause enrollment due to travel restrictions and concerns that the patients would not be able to reach trial sites safely. These concerns are more relevant to high-risk patients such as those with cardiac issues, cancer, and patients with impaired mobility such as those with neurodegenerative conditions.\(^2\)

- Limited trial site and staff availability

The need to reduce physical contact with the study participants and the divergence of staff to focus on COVID-19 patients also contributed to slower enrolment and delayed trial completion. Hospitals have restructured their services and trained staff to adapt and work in a new way quickly. Many hospitals that served as trial sites are packed with COVID-19 patients and hence are unavailable, whereas many have been entirely repurposed into COVID hospitals and do not admit any other patients. \(^{1,3}\)  

- Disruptions in the global supply chain

The restrictions caused by the pandemic have led to logistical challenges, which have impacted the clinical trial supply chain to some extent. Disruptions in the supply chain can hamper the delivery of investigational medicinal products (IMPs) and laboratory supplies to clinical sites. Receiving patient samples and transferring them back to central labs may also be a challenge.\(^3\)

- Risk that ongoing trials might be delayed

Though the industry is re-emerging from the crisis, there remains a risk that trials outside of life-threatening indications will be delayed or hampered to some extent.\(^4\)

Conducting clinical research during the COVID-19 pandemic - What measures can be taken to overcome the situation?

As the pandemic progressed, health regulatory agencies across the globe issued guidance to assist the companies and trial investigators in continuing with the trials while ensuring subject safety and data integrity. Healthcare agencies also encouraged the adoption of remote monitoring and e-communications wherever possible.\(^{5,6}\)  

Though each trial is different, companies can consider the following common measures to ensure trial continuity:

- Transfer of trial subjects

In exceptional cases, after assessing the personal benefit-risk ratio for the individual trial subject, trial subjects can be transferred to clinical sites away from risk zones or closer to their home. These may be sites already participating in the trial or new ones.\(^6\) 

- Ensuring IMP distribution

As per the EMA guidance, “Changes in the distribution of the investigational medicinal products (IMP) may be necessary to prevent avoidable visits to sites and provide the trial participants with needed treatments. Larger amounts of IMP than normally foreseen can be provided to the trial participant”. However, this should be in accordance with the applicable regulatory requirements and protocol. \(^{5,6}\)

- Remote monitoring

Sponsors can adopt remote monitoring strategies using a risk-based approach. Before implementing remote solutions, sponsors should consider the applicable regulatory framework and the rationale and feasibility of such assessments.\(^{5,6}\)


- Utilizing alternate laboratory or imaging center

In case the trial subject cannot travel to the site, laboratory tests and imaging tests may be done at an authorized local laboratory or clinical facility provided that patient facing documents are amended/approved as appropriate.\(^{5,6}\)  


- Maintaining IMP adherence

Meticulous attention to the administration of IMPs is needed to reduce the risk of bias from nonadherence. Strategies to increasing adherence without increasing the risk of COVID-19 infection could include:\(^4\)

  • Enabling study medications to be taken at home by the patient.
  • Home visits by healthcare workers.
  • Facilitating administration of injections in clinical facilities capable of following COVID-19 norms.

- Completeness of data collection

During the pandemic, ensuring data collection completeness is crucial to increase the validity efficacy and safety assessments. The use of electronic data capture, telemedicine, or teleconferencing can help.\(^4\)  

Building risk assessment and mitigation strategies

Managing clinical trials efficiently during the pandemic warrants continuous critical risk assessment and prudent actions in the best interest of trial subjects.\(^7\)  

The ICH E6 R2 recommends that the sponsor implement a risk-based quality management system that covers all stages of clinical trials and focuses on trial activities essential to ensuring human subject protection and the reliability of trial results. The key is to apply critical reasoning and implement learning from past experience.\(^7\)

Clinical trial implementation should be supported by tools and processes that utilize real-life data and past experience to avoid protocol amendments and protocol non-compliance.\(^7\)

Adopting a risk-based approach in monitoring

Health authorities worldwide encourage remote access for vital data during the pandemic. A systematic, risk-based approach should be implemented when adapting to remote monitoring.\(^7\)

A risk-based decision should be taken while selecting the data to be monitored. Ensuring subject safety and reliability and trustworthiness of data should hold paramount importance.\(^7\)

The remote review should focus on critical data and processes, like primary efficacy data and important safety data, informed consent, adherence to protocol eligibility requirements, patient compliance to investigational products, and identification and reporting of adverse events.\(^7\)

A combination of on-site, remote, and centralized monitoring can be used for effective oversight, monitoring, and the protection of data integrity and patient safety.\(^7\)

Adopting the virtual model to enable continuative research

The pandemic has accelerated the shift to adopt remote technologies in clinical trials. New avenues for using remote healthcare, such as virtual or “site-less” trials, telemedicine and remote monitoring and data management are now being adopted.  Companies that adopted remote technologies and services before COVID transitioned more quickly to the “virtual” model. \(^{8,9}\)

- Telemedicine

As the pandemic gained momentum, many in-person visits for checkups and other aspects of trials were managed via telemedicine. With telemedicine, investigators could remotely gain information regarding a patients’ health and decide if there is a need or urgency to intervene.\(^9\)

- eConsent

With eConsent, informed consent can be achieved remotely using a secure digital platform on an electronic device, thus eliminating paper forms. eConsent facilitates communication with patients by leveraging novel modalities such as video explanations and knowledge checks, or quizzes to assess understanding.\(^{10}\)

- Electronic patient-reported outcomes (ePRO)

The use of electronic PROs (ePROs) is another smart strategy that can be integrated into the virtual model. Patient-reported outcomes (PROs) are currently considered the standard assessment of patient experience of the disease and its treatment.\(^3\)

- Purpose-built remote trial monitoring solutions

Purpose-built remote trial monitoring solutions can enable clinical research associates (CRAs) to review documents and conduct oversight activities remotely. With purpose-built remote trial monitoring solutions, the CRA can directly access regulatory and source content and detect issues and trends effortlessly.\(^{11}\) 

COVID-19 has increased the demand for remote trials and solutions for preserving trial integrity. But, not all assessments may support remote implementation. Hence, it is essential that the sponsors consider the rationale and practicality of such evaluations, by using clinical outcome assessment tools. Formulating systems to ensure subject compliance and consistency in data collection is also important.\(^8\)  

The time for change is now

The pandemic has presented unique challenges for the clinical trial community. But, now is the time to redesign the old ways and prioritize the use of innovative and alternative approaches to conducting clinical trials.

Dokumeds – Helping companies re-evaluate their trial management strategies

In this unprecedented time, not all companies are in a position to pause their trial programs. Minimizing trial disruption is critical to avoid ethical and commercial risks.

It may be time for companies to re-evaluate their risk management methodologies, risk management tools, and methods of collecting key data points. 

Dokumeds, with its diverse expertise, can help companies navigate this critical phase. We thoroughly review COVID-19 country status and provide regular updates to the sponsor, aiding to rapid decision making. 

We can help assess risks and develop solutions for mitigation to facilitate the best decisions around implementing clinical trials. We are experts in the countries of our operations and are well versed with the regulatory framework and health care systems in each country. Get in touch with us to see how we can help your company minimize trial distruptions.

 

References

  1. Lorusso D, Ray-Coquard I, Oaknin A, Banerjee S. Clinical research disruption in the post-COVID-19 era: will the pandemic lead to change?. ESMO Open. 2020;5(5):e000924. 
  2. van Dorn A. COVID-19 and readjusting clinical trials. Lancet. 2020;396(10250):523-524. 
  3. Marandino L, Necchi A, Aglietta M, Massimo Di Maio MD. COVID-19 Emergency and the Need to Speed Up the Adoption of Electronic Patient-Reported Outcomes in Cancer Clinical Practice. JCO Oncology Practice 2020 16:6, 295-298. Available at: https://ascopubs.org/doi/full/10.1200/OP.20.00237. Accessed on: 12 March 2021. 
  4. Fleming TR, Labriola D, Wittes J. Conducting Clinical Research During the COVID-19 Pandemic: Protecting Scientific Integrity. JAMA. 2020;324(1):33–34.
  5. FDA Guidance on Conduct of Clinical Trials of Medical Products During the COVID-19 Public Health Emergency. US FDA. 2020. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/fda-guidance-conduct-clinical-trials-medical-products-during-covid-19-public-health-emergency#:~:text=FDA%20is%20issuing%20this%20guidance,COVID%2D19%20public%20health%20emergency. Accessed on: 12 March 2021.
  6. Guidance on managing clinical trials during the coronavirus disease (COVID-19) pandemic. EMA. 2020. Available at: https://www.ema.europa.eu/documents/press-release/guidance-sponsors-how-manage-clinical-trials-during-covid-19-pandemic_en.pdf. Accessed on: 12 March 2021.
  7. Integrated Addendum to ICH E6 (R1): Guideline for Good Clinical Practice E6(R2). November 2016.
  8. Izmailova ES, Ellis R, Benko C. Remote Monitoring in Clinical Trials During the COVID‐19 Pandemic. Clinical and translational science. 13:5, 838-841. Available at: https://ascpt.onlinelibrary.wiley.com/doi/10.1111/cts.12834. Accessed on: 12 March 2021. 
  9. Clement KD, Zimmermann EF, Bhatt NR, et al. Communication tools in the COVID-19 era and beyond which can optimise professional practice and patient care. BMJ Innovations. 2021;7:217-223.
  10. Skelton E, Drey N, Rutherford M, Ayers S, Malamateniou C. Electronic consenting for conducting research remotely: A review of current practice and key recommendations for using e-consenting. Int J Med Inform. 2020;143:104271. 
  11. COVID-19 Creates Urgent Need for Remote Monitoring in Clinical Trials. ACRP. 2020. Available at: https://acrpnet.org/2020/05/12/covid-19-creates-urgent-need-for-remote-monitoring-in-clinical-trials/#:~:text=Purpose%2Dbuilt%20remote%20trial%20monitoring,foot%20in%20the%20physical%20site. Accessed on: 12 March 2021.



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