COVID-19 must catalyse changes to clinical development

Mackenzie, Rod; Honig, Peter K.; Sewards, Judy; Goodwin, Robert R.; Hellio, Marie-Pierre

doi:10.1038/d41573-020-00149-2

Cited by 15 publications

(8 citation statements)

References 2 publications

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“…Indeed, Phase 2 studies have now commenced (clinicaltrials.gov identifier NCT04405570 and NCT04405739). This case study demonstrates that urgent, coordinated efforts to support expedited study start-up and execution, including collaboration between sponsor, CRO and regulatory authorities, can greatly accelerate early clinical development of promising drug therapies under extraordinary circumstances, such as the SARS-CoV-2 pandemic [26].…”

Section: Discussionmentioning

confidence: 97%

Accelerated First-in-Human Clinical Trial of EIDD-2801/MK-4482 (molnupiravir), a Ribonucleoside Analogue with Potent Antiviral Activity Against SARS-CoV-2

Cohen

Holman

et al. 2021

Preprint

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A recently published article described the safety, tolerability and pharmacokinetic profile of molnupiravir, a novel antiviral agent with potent activity against SARS-CoV-2, the causative agent of COVID-19. Here, we report an unprecedented collaboration between sponsor, contract research organization (CRO) and regulatory authorities that enabled accelerated generation of these phase I data, including administration of the first-in-human (FIH) dose of molnupiravir within 5 days of receiving approval from the Research Ethics Committee (REC) and the Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom (UK). Frequent, direct communication with regulatory authorities and parallel, streamlined sponsor-CRO working groups facilitated this accelerated timeline. Dosing in healthy volunteers was completed for eight single ascending dose (SAD) cohorts, seven multiple ascending dose (MAD) cohorts, and one food-effect (FE) cohort within approximately 16 weeks of initial protocol submission to the REC and MHRA. Working to standard industry timelines, the FIH study would have normally taken approximately 46 weeks to complete and 33 weeks to enable Phase 2 dosing. Data from this study supported submission of a Phase 2/3 clinical trial protocol to the US Food and Drug Administration (FDA) within eight weeks of initial protocol submission, with FDA comments permitting phase 2 study initiation within two additional weeks. In the setting of a global pandemic, this model of collaboration allows for accelerated generation of clinical data compared to standard processes, without compromising safety.

show abstract

Section: Discussionmentioning

confidence: 97%

Accelerated First-in-Human Clinical Trial of EIDD-2801/MK-4482 (molnupiravir), a Ribonucleoside Analogue with Potent Antiviral Activity Against SARS-CoV-2

Cohen

Holman

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Indeed, phase 2 studies have now commenced ( ClinicalTrials.gov identifier NCT04405570 and NCT04405739), and study NCT04405570 completed in February, 2021. This case study demonstrates that urgent, coordinated efforts to support expedited study start-up and execution, including collaboration between sponsor, CRO, and regulatory authorities, can greatly accelerate early clinical development of promising drug therapies under extraordinary circumstances, such as the SARS-CoV-2 pandemic [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Accelerated first-in-human clinical trial of EIDD-2801/MK-4482 (molnupiravir), a ribonucleoside analog with potent antiviral activity against SARS-CoV-2

Holman

McIntosh

et al. 2021

Trials

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A recently published article described the safety, tolerability, and pharmacokinetic profile of molnupiravir (Painter et al. 2021), a novel antiviral agent with potent activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19). Here, we report an unprecedented collaboration between sponsor, contract research organization (CRO), and regulatory authorities that enabled accelerated generation of these phase I data, including administration of the first-in-human (FIH) dose of molnupiravir within 5 days of receiving regulatory approval in the United Kingdom (UK). Single and multiple ascending dose (SAD and MAD, respectively) cohorts were dosed in randomized, double-blind, and placebo-controlled fashion, with a 6:2 active-to-placebo ratio in each cohort. A food-effect (FE) cohort included 10 subjects who were randomized to receive drug in the fasted or fed state followed by the fed or fasted state to complete a fed and fasted sequence for each subject. Dose escalation decisions were accelerated and MAD cohorts were initiated prior to completion of all SAD cohorts with the provision that the total daily dose in a MAD cohort would not exceed a dose proven to be safe and well-tolerated in a SAD cohort. Dosing in healthy volunteers was completed for eight single ascending dose (SAD) cohorts, seven multiple ascending dose (MAD) cohorts, and one food-effect (FE) cohort within approximately 16 weeks of initial protocol submission to the Research Ethics Committee (REC) and Medicines and Healthcare products Regulatory Agency (MHRA). Working to standard industry timelines, the FIH study would have taken approximately 46 weeks to complete and 33 weeks to enable phase 2 dosing. Data from this study supported submission of a phase 2/3 clinical trial protocol to the US Food and Drug Administration (FDA) within 8 weeks of initial protocol submission, with FDA comments permitting phase 2 study initiation within two additional weeks. In the setting of a global pandemic, this model of collaboration allows for accelerated generation of clinical data compared to standard processes, without compromising safety.

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“…It could be considered that the Covid-19 pandemic has changed some of the contours of the regulatory landscape including clinical data sharing expectations. There have been calls for company sponsors to commit to a new interpretation of what is regarded as competitive data and share more than has been done in the past ( 36 ). Indeed, if company sponsors wish to access publicly held data sources such as real world data via electronic health records they may be called upon to reciprocally release more of their in-house data whilst also upholding intellectual property considerations.…”

Section: Discussionmentioning

confidence: 99%

Digital Innovation in Medicinal Product Regulatory Submission, Review, and Approvals to Create a Dynamic Regulatory Ecosystem—Are We Ready for a Revolution?

et al. 2021

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The pace of scientific progress over the past several decades within the biological, drug development, and the digital realm has been remarkable. The’omics revolution has enabled a better understanding of the biological basis of disease, unlocking the possibility of new products such as gene and cell therapies which offer novel patient centric solutions. Innovative approaches to clinical trial designs promise greater efficiency, and in recent years, scientific collaborations, and consortia have been developing novel approaches to leverage new sources of evidence such as real-world data, patient experience data, and biomarker data. Alongside this there have been great strides in digital innovation. Cloud computing has become mainstream and the internet of things and blockchain technology have become a reality. These examples of transformation stand in sharp contrast to the current inefficient approach for regulatory submission, review, and approval of medicinal products. This process has not fundamentally changed since the beginning of medicine regulation in the late 1960s. Fortunately, progressive initiatives are emerging that will enrich and streamline regulatory decision making and deliver patient centric therapies, if they are successful in transforming the current transactional construct and harnessing scientific and technological advances. Such a radical transformation will not be simple for both regulatory authorities and company sponsors, nor will progress be linear. We examine the shortcomings of the current system with its entrenched and variable business processes, offer examples of progress as catalysts for change, and make the case for a new cloud based model. To optimize navigation toward this reality we identify implications and regulatory design questions which must be addressed. We conclude that a new model is possible and is slowly emerging through cumulative change initiatives that question, challenge, and redesign best practices, roles, and responsibilities, and that this must be combined with adaptation of behaviors and acquisition of new skills.

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COVID-19 must catalyse changes to clinical development

Cited by 15 publications

References 2 publications

Accelerated First-in-Human Clinical Trial of EIDD-2801/MK-4482 (molnupiravir), a Ribonucleoside Analogue with Potent Antiviral Activity Against SARS-CoV-2

Accelerated First-in-Human Clinical Trial of EIDD-2801/MK-4482 (molnupiravir), a Ribonucleoside Analogue with Potent Antiviral Activity Against SARS-CoV-2

Accelerated first-in-human clinical trial of EIDD-2801/MK-4482 (molnupiravir), a ribonucleoside analog with potent antiviral activity against SARS-CoV-2

Digital Innovation in Medicinal Product Regulatory Submission, Review, and Approvals to Create a Dynamic Regulatory Ecosystem—Are We Ready for a Revolution?

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