key: cord-0706856-zml4o93t authors: Peck, Richard W; Weiner, Daniel; Cook, Jack; Powell, J Robert title: A Real‐World Evidence Framework for Optimising Dosing in All Patients with COVID‐19 date: 2020-05-23 journal: Clin Pharmacol Ther DOI: 10.1002/cpt.1922 sha: b1e4eee947b9734978617ed29c6adb070adf5c50 doc_id: 706856 cord_uid: zml4o93t The SARS‐CoV‐2 pandemic and associated COVID‐19 disease are straining healthcare systems around the world with large numbers of patients becoming ill in a very short period of time, overwhelming healthcare systems in many countries. Several drugs are being repurposed into clinical trials in COVID‐19 patients, ranging from drugs already well established in other diseases, such as chloroquine/hydroxychloroquine, lopinavir+ ritonavir, azithromycin and tocilizumab/sarilumab, to those such as remdesivir still in development for their initial indication (1). The opportunities for clinical pharmacology to contribute to the development of new treatments have already been described by others in Clinical Pharmacology & Therapeutics (2). The SARS-CoV-2 pandemic and associated COVID-19 disease are straining healthcare systems around the world with large numbers of patients becoming ill in a very short period of time, overwhelming healthcare systems in many countries. Several drugs are being repurposed into clinical trials in COVID-19 patients, ranging from drugs already well established in other diseases, such as chloroquine/hydroxychloroquine, lopinavir+ ritonavir, azithromycin and tocilizumab/sarilumab, to those such as remdesivir still in development for their initial indication (1) . The opportunities for clinical pharmacology to contribute to the development of new treatments have already been described by others in Clinical Pharmacology & Therapeutics (2) . It is clear that the first drugs demonstrated to be effective will rapidly gain widespread clinical use. This has already been seen with the FDA emergency use authorisation for chloroquine/hydroxychloroquine and reports of hospitals exhausting available supplies of tocilizumab even before the results of welldesigned RCTs are available. When the results of the ongoing RCTs are published the effective drugs will immediately start being used in large numbers of COVID-19 patients, many of whom will be outside the range of patients included in the trials. The gap between clinical trial participants and real-world use patients is well known, real-world patients are often older or younger, larger or smaller, pregnant, have worse organ dysfunction, are taking other drugs, have multiple co-morbidities, have more or less severe disease for longer or shorter periods of time or are otherwise different from those in the clinical trials. The speed at which this gap is closed for effective treatments for COVID-19 must be unprecedented. The risk of not doing so is that many patients or subgroups of patients may still die through not being treated with their optimal drug regimen. A general approach to adjusting the drug development and approval process to manage this for other diseases has been described by us in a companion paper in this issue of Clinical Pharmacology & Therapeutics (3). Here we consider the specific needs, challenges and opportunities presented by COVID-19. The specific needs for optimal drug use and dose selection in COVID-19 are four-fold. First, typically the repurposed drugs are studied at the same doses for which they currently have approval. This may not be the optimal dose for COVID-19. Comparisons of expected plasma exposures to in vitro EC50s for anti-viral activity may provide some dose justification but there is currently little clinical assessment of dose response for repurposed drugs. Furthermore, pharmacokinetics and exposure-response could be very different in COVID-19 patients, a population that may have differences in demographics and important covariates from those currently treated. Second, there is an obvious need to avoid under-dosing patients who will then be at risk of dying from avoidable lack of efficacy. Third, some of the drugs already under investigation and in clinical use have narrow therapeutic windows and potentially fatal adverse effects. For example, viral kinetic modelling suggests that hydroxychloroquine may need to be dosed above 800 mg daily in a typical patient to have much chance of efficacy whilst doses above 1200 mg daily may have an unacceptable risk of QTc prolongation, a surrogate for fatal arrhythmias (4) . Thus failing to adjust dosing for subjects at risk of higher than usual concentrations may carry a risk of significant adverse effects. Fourth, even for drugs with a wide therapeutic index, a policy of using a large dose in everyone, to mitigate the risk of treatment failure, may lead to drug shortages and an inability to treat all patients who might benefit. Additional challenges for COVID-19 patients include the impact of the disease on the therapy. COVID-19 patients often have obesity, diabetes, renal or hepatic impairment, and other co-morbidities (5) . Some have elevated levels of IL6, which can suppress hepatic cytochromes, including CYP3A4, with elevation of exposures for its many substrates (6) . The natural history of the disease may impact efficacy; direct antivirals may be more effective in the early stages of the disease (7) whereas treatment intended to modify the host immune response may need to be used only in late disease. The impact of disease appears to vary between populations, for example, men appear to be at greater risk of dying from COVID-19 than women (8); might there be differences in exposure-response to therapies due to gender or other factors? Disease progression and the effect of treatment will produce intra-patient variability with changes in clearance as the patient deteriorates or recovers. Inclusion criteria limit the impact of all this variation in clinical trials, therefore understanding and correcting for it in subsequent real world use will be essential for optimal treatment of many patients. We propose several actions to address these challenges and turn them into opportunities to enable optimal dosing of all COVID-19 patients (Figure 1 ). Include biomarkers of disease and drug activity in all trials to characterise baseline disease severity and response to treatment. Required biomarkers include serial measures of viral shedding and acute response markers such as high sensitivity CRP and treatment specific markers such as soluble IL6 receptor levels for studies of anti-IL6 therapies. Include sparse sampling for drug concentrations to support development of population PKPD models in COVID-19 patients with identification of potential therapeutic ranges for drug exposures and an understanding of the impact of COVID-19 related co-variates on drug exposures and efficacy. It is also be useful to have plasma concentration data from patients developing adverse events or significant changes in symptoms. The additional burden of collecting these samples is recognised but they are essential to ensuring safe and effective use in all patients. Publish or otherwise make available all population PKPD models, and, whenever possible, de-identified data, for the treatments under investigation to provide a basis for development of disease specific models. This would allow immediate exploration of the COVID-19 patient co-variates, singly or in combination, predicted to be associated with lower or higher than desired drug exposures, potential toxicity or lack of efficacy or that provide an opportunity to use lower doses and allow scarce drug supplies to be used for more patients. Develop and make available drug-disease models including viral kinetic time-course models; models linking viral time-course to inflammation, coagulation and other pathophysiological systems; and PBPK models to predict the impact of COVID-19 on pharmacokinetic parameters. Identify a trusted third-party repository and partner, possibly the WHO, Gates Foundation, NIH, BARDA, Critical Path Institute or FDA to facilitate integration between models and their ongoing updating and refinement as new data become available. This will help maximise the value from all the data being collected in the many trials now ongoing, will be more informative than many separate models each developed from smaller datasets and will allow faster achievement of a consensus for how to adjust dosing of effective drugs to optimise responses in all patients. Today it can still take years to develop dosing recommendations for children, pregnant women and other important patient groups, or it may never happen at all. This should not be acceptable for COVID-19. Establish a system for capturing data from the real-world patients treated with effective medicines or receiving novel treatments as emergency therapy prior to completion of randomised clinical trials. Such a system is required to characterise the efficacy-effectiveness gap and help identify where dosing adjustments are needed to maximise safety and efficacy across all patients. Critical patient co-variates, disease biomarkers and clinical response data should be collected for all patients and plasma drug concentration data should also be collected wherever possible. The minimum list of key data elements and data standards should be agreed as soon as possible. FDA or another independent third party could guide this in combination with the repository of population PKPD models and a procedure for updating them with the data collected from the real-world patients. Work with major regulators including FDA, EMA, NMPA and PMDA, to determine how dynamic prescribing information and labelling will be approved. As the real-world patient analyses, described above, identify patients groups who require dose modifications or identify changes to existing dosing guidelines, this information must be included rapidly in approved drug labels. What are the immediate next steps? Many pharmaceutical companies have already agreed to collaborate on meaningful ways to accelerate the discovery and development of new treatments. For example, NIH have launched a public-private partnership to accelerate discovery and development of new treatments for COVID-19 (9) and Transcelerate consortium members have agreed to share clinical trial control group data (10) . This should also now include working together to ensure optimal use of effective treatments in all real-world patients. 1. The Global Heads of Clinical Pharmacology from the pharmaceutical companies developing potential treatments should meet together with representatives from organisations interested in becoming trusted third parties and key regulatory and academic opinion leaders to agree the principles for model and de-identified data sharing and how to establish the necessary infrastructure. 2. Academic, industry and regulatory authority opinion leaders should meet with healthcare providers to agree the key real-world data that should be collected and how this can be implemented. 3. The above groups should agree how real-world data will be analysed, how models will be updated and how to reach alignment on and publish new insights from the data analyses. 4 . Regulatory authorities should agree on a mechanism for rapid, initial, temporary approval of a new COVID-19 treatment with a mandated, later, more detailed safety & efficacy review and reevaluation with potential updates to the label. The means to achieve this must be established now to reduce the risk of continued, off-label prescribing of suboptimal dosing regimens for future COVID-19 therapies. Even with effective treatments for COVID-19 there will be no second chances for patients who are treated incorrectly. Pharmacologic treatments for coronavirus Disease 2019 (COVID-19) Challenges in drug deve;opment posed by the COVID-19 pandemic: An opportunity for clinical pharmacology Drug dosing recommendations for all patients: A roadmap for change Optimizing hydroxychloroquine dosing for patients with COVID-19: An integrative modelling approach for effective drug repurposing Groups at high risk of severe illness CYP-mediated therapeutic protein-drug interactions Timing of antiviral treatment initiation is critical to reduce SARS-CoV-2 viral load The gendered dimensions of COVID-19 NIH to launch public-private partnership to speed COVID-19 vaccine and treatment options A model-and real world data-based framework for continuous updating of dosing recommendations and labelling of treatments for COVID-19 patients (hsCRP: high sensitivity C-reactive protein, Rx: treatment, PKPD: pharmacokinetic/pharmacodynamics, VK: viral kinetic. PBPK: physiologically based pharmacokinetic) This article is protected by copyright. All rights reserved Biomarkers (e.g. Viral load, hsCRP, Rx specific markers) Sparse sampling for plasma drug concentrations