20 May 2020

Article by
Flic Gabbay, Managing Partner
Sarah Daniels, Head of Drug Safety, Pharmacovigilance & Risk Management
Dominic Bowers, Deputy Head of CNS & Pain

Background
COVID-19 is a novel respiratory viral disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that emerged in China in late 2019. It has since spread rapidly across the globe resulting in nearly 5 million cases and over 300,000 recorded deaths (Worldometer). This mortality is comparable to the total global seasonal influenza-associated respiratory deaths estimated annually at 291,243 to 645,832 (Iuliano et al., 2018).

Although many of those infected remain asymptomatic (estimates run between 40 and 80%), some will develop mild illness not requiring hospitalisation or moderate to severe respiratory illness requiring treatment within the hospital setting. Hospitalisation rates have varied over time and by country, and in some countries, 50% of the deaths have occurred outside of hospital (Comas-Herrera A, 2020). Severe COVID-19 requiring invasive mechanical ventilation is frequently complicated by acute respiratory distress syndrome (ARDS), sepsis, multiorgan failure, including acute kidney injury, and cardiac injury (Guan et al., 2020, Williamson et al., 2020). Hospital case fatality rates vary between 2.3% of patients (in China, where patients were admitted immediately after diagnosis) and 40% of patients (in the UK, where the initial admission policy was to delay hospitalisation).

The big difference between SARS-CoV-2 and influenza infection is that the former is highly transmissible. COVID-19 has a relatively long asymptomatic period (5-7 days) compared to influenza (2-3 days). Also, it is probable that a greater number of COVID-19 patients remain asymptomatic and shed virus for longer than patients with influenza. However, little is known about the number of asymptomatic influenza cases. Whilst milder forms of COVID-19 may last for approximately a week, moderate and severe disease have an average hospital stay of 7-24 days before discharge, depending on country policies for hospitalisation (Docherty et al., 2020, Guan et al., 2020, Williamson et al., 2020).

In addition, whilst COVID-19 death rates by age and comorbidity largely mirror other forms of community acquired pneumonia (Fine et al., 1997), there are characteristics relating to susceptibility of certain groups of individuals who are recognised as being at a higher risk of death. A multivariate analysis by Du et al (Du et al., 2020) identified only four risk factors, including age ≥65 years, pre existing concurrent cardiovascular or cerebrovascular diseases, CD3+CD8+ T cells ≤75 cell/μL, and cardiac troponin I ≥0.05 ng/mL. Subsequent studies have questioned any evidence that hypertension or use of angiotensin-converting enzyme (ACE) inhibitors is a risk factor (Mehra et al., 2020). A recent UK publication of 16,749 patients with COVID-19 after multivariate analysis reported age and male sex as associated variables. They also report obesity as an associated variable as it has been for H1N1 influenza (Docherty et al., 2020).

Current Medical Interventions 
Standard of care
Until the start of the pandemic in 2020, experience of severe infection with coronavirus was limited to SARS-CoV and MERS-CoV. COVID-19 disease has some unique characteristics compared to other viral infections and resulting pneumonias although ARDS, sepsis and multiorgan failure are frequent causes of mortality in both viral and bacterial pneumonia. Standard of care, especially in mild and moderate disease, has been constantly varied during the pandemic as more becomes known about the disease, meaning that new medical interventions are difficult to evaluate against a backdrop of changing routine treatment and resulting outcome. 

At the start of the pandemic there were no antivirals registered for treatment of COVID-19 but there was rapidly emerging evidence that some targeted antivirals, either licensed already for other conditions or in phase 3 trials (e.g. lopinavir/ritonavir and remdesivir) and some more broad spectrum antimicrobials (e.g. hydroxychloroquine [HCQ]) were active in vitro against SARS-CoV-2. In a pandemic there is no time to take anything from pre-clinical development to the clinic during the first wave of infections and this can still be a challenge if further waves occur due lack of consistent numbers of patients to study. Even vaccination (with the most rapid development path) can rarely be developed in less than a year.

There are COVID-19 treatment guidances for infection including upper respiratory symptomatology, fever, community acquired pneumonia, and subsequent treatment where the disease progresses to the inflammatory phase with the need for ventilation and other complications such as bacterial secondary infection, ARDS and multiple organ failure. All of these have well established clinical treatment algorithms within the health care system as illustrated on the UK’s National Institute for Health and Care Excellence (NICE) COVID 19 web site (NICE, 2020).  

New Treatment Innovations
To obtain a marketing approval for a COVID-19 indication, any potential treatment must be shown to be both efficacious and safe. The regulatory gold standard route for defending the use of a new medicine in an indication in which there are adequate numbers of patients, is to demonstrate benefit-risk through phase 2 exploratory and dose ranging trials, followed by phase 3 confirmatory randomised double-blind controlled clinical trials (RCTs). For most therapeutic indications this is performed over at least a 5 year period. Numerous expedited routes for programmes aimed at licensing are now available where fewer or even uncontrolled studies may be conducted as part of the development programme, without the need for conventional phase 3 clinical trials. The US FDA has released a guidance for developing new drugs to treat aspects of the COVID-19 infection (COVID-19: Developing, Drugs and Biological Products for Treatment or Prevention (11 May 2020) (FDA, 2020b)). The new US FDA guidance strongly recommends that drugs to treat or prevent COVID-19 be evaluated in randomised, placebo-controlled, double-blind clinical trials using superiority designs for confirmatory studies.

Prevention, prophylaxis 
Active (vaccination), passive (delivery of antibodies) or natural immunity (by infection), is used to establish resistance in the community and reduce both infection rate and transmission. The intent is to develop ‘herd immunity’ preventing transmission through the community. 

Prophylactic antivirals may also be used in a similar way to antimalarials to prevent patients catching the disease. Due to HCQ’s in vitro activity against SARS-CoV-2 it has been widely used for prophylaxis under compassionate use protocols (EMA, 2020a) or in trials but to date there are no published trials.

Treatment stages 
There are many different types of treatments that may be used during the progression of COVID-19. Most will only be effective during certain stages of the disease. It is therefore essential to clearly define the different stages to provide prescribers with the appropriate information to identify the patient population in whom they will work.

The following stages of disease have been defined by the US FDA (FDA, 2020b) and may be used to categorize patients for inclusion into a study:

SARS-CoV-2 infection without symptoms

  • Defined as positive testing by standard reverse transcription polymerase chain reaction (RT-PCR) assay, or equivalent test, and no symptoms.

Mild COVID-19

  • Positive testing by standard RT-PCR assay or equivalent test
  • Symptoms of mild illness with COVID-19 that could include fever, cough, sore throat, malaise, headache, muscle pain, gastrointestinal symptoms, without shortness of breath or dyspnoea and 
  • No clinical signs indicative of moderate, severe, or critical severity.

Moderate COVID-19

  • Positive testing by standard RT-PCR assay or equivalent testing
  • Symptoms of moderate illness with COVID-19, which could include any symptom of mild illness or shortness of breath with exertion
  • Clinical signs suggestive of moderate illness with COVID-19, such as respiratory rate ≥20 breaths per minute, saturation of oxygen (SpO2) >93% on room air at sea level, heart rate ≥90 beats per minute
  • No clinical signs indicative of severe or critical illness severity.

Severe COVID-19

  • Positive testing by standard RT-PCR assay or an equivalent test
  • Symptoms suggestive of severe systemic illness with COVID-19, which could include any symptom of moderate illness or shortness of breath at rest, or respiratory distress 
  • Clinical signs indicative of severe systemic illness with COVID-19, such as respiratory rate ≥30 breaths per minute, heart rate ≥125 beats per minute, SpO2 ≤93% on room air at sea level or PaO2/FiO2 <300
  • No criteria for critical severity.

Critical COVID-19

  • Positive testing by standard RT-PCR assay or equivalent test
  • Evidence of critical illness, defined by at least one of the following:
  • Respiratory failure defined based on resource utilization requiring at least one of the following: 
  1. Endotracheal intubation and mechanical ventilation, oxygen delivered by high flow nasal cannula (heated, humidified, oxygen delivered via reinforced nasal cannula at flow rates >20 L/min with fraction of delivered oxygen ≥0.5), non-invasive positive pressure ventilation, extracorporeal membrane oxygenation (ECMO), or clinical diagnosis of respiratory failure (i.e., clinical need for one of the preceding therapies, but preceding therapies not able to be administered in setting of resource limitation)
  • Shock (defined by systolic blood pressure <90 mm Hg, or diastolic blood pressure <60 mm Hg or requiring vasopressors) 
  • Multiorgan dysfunction/failure.

Study designs and endpoints
General guidance
Each intervention will also need different endpoints depending on the stage of disease and the objective of the interventions. The US FDA have not been prescriptive about endpoints but have given examples both of clinical outcome measures and choice of the time frame. Interpretation of endpoints may differ depending on the population evaluated. All-cause mortality remains a critical endpoint but time to resolution of symptoms (the standard respiratory antiviral endpoint) has been acknowledged. Detailed guidance and precedence are available both from the EMA and US FDA on other similar indications such as influenza (FDA, 2011) and sepsis (EMA, 2006) and it is anticipated that most of the principles espoused in these guidance documents will be upheld in COVID-19 development programmes where appropriate. 

Specific guidance for antivirals
The US FDA have given specific guidance for antivirals in COVID-19. In phase 2 treatment trials, a virologic measure may be acceptable as a primary endpoint to support development of a phase 3 clinical endpoint study. However, virologic endpoints are not appropriate as primary endpoints in phase 3 trials. The optimal sample size, timing, methods for collection procedures, and assays for clinically relevant virologic measurements have not been established. Collection of virologic data and valuation of antiviral resistance are important components of drug development for COVID-19.

Challenges in running Clinical Trials in COVID-19
Numbers of patients
One of the biggest challenges in conducting a clinical trial in the midst of an epidemic/pandemic, as counter intuitive as it might seem, is patient numbers. This was illustrated by the recent remdesivir study, sponsored by Gilead, conducted in China which was prematurely terminated due to lack of patients as the number of infections declined almost to zero once the peak of the pandemic was passed (Wang et al., 2020).  

Patient population 
The COVID-19 patients at highest risk of mortality have many comorbidities and the US FDA suggests that a broad study population should be chosen to obtain a safety database to best inform the safe use of the drug. Hence patients from racial and ethnic minority groups, older individuals (e.g. patients in care homes), patients with a high risk of complications due to comorbidities, and patients who are pregnant or lactating should be included if possible. These requirements should be considered when selecting sites to ensure that sufficient patients from these groups are included. It is cautioned, however, that many treatments being considered for evaluation in COVID-19 may not have adequate reproductive pre-clinical drug safety to allow treatment of pregnant and lactating women.

Operational issues
There are many operational challenges in setting up RCTs in the midst of a pandemic, when healthcare workers are overstretched managing their clinical load. Patient consent processes, data collection, and monitoring during the pandemic may be problematic due to the requirements to limit staff exposure. The US FDA, MHRA and EMA have provided guidance on how to overcome Good Clinical Practice (GCP) challenges for these activities (EMA, 2020b, FDA, 2020a, MHRA, 2020).

Interpretation of data and safety/efficacy
Clinical trials in severe COVID-19 patients are highly confounded e.g. by underlying co-existing health conditions and concurrent medications, which will make both efficacy and safety interpretation very difficult. 

The US FDA encourages sponsors to use an independent data monitoring committee (DMC) to ensure subject safety and trial integrity and such a committee might also review the multiple amendments which are inevitable with the constant changes in standard of care.  

Summary
Current trials of antivirals mix patient categories (mild, moderate and/or severe) and endpoints (including both resolution of symptoms and/or all-cause mortality), regardless of types of treatments. This makes interpretation challenging when comparing trials and especially those which have largely been conducted in a single country. For example, studies of HCQ in moderate to severe hospitalised patients, based on all cause mortality in patients in whom the viral disease is well established and less susceptible to antivirals, may struggle to demonstrate success, even though the product may have utility earlier in the course of the disease. However, such studies may demonstrate success in other countries where ‘moderate’ is defined as a milder disease. The situation is further compounded by large non- randomised observational trials where, in spite of multiple regression analyses, it is hard to interpret the data collected (Magagnoli et al., 2020, Rosenberg et al., 2020).

In spite of the number of available patients and the challenge of endpoints for antivirals, some double blind randomised remdesivir trials (Adaptive COVID-19 Treatment Trial (NIAD, 2020), (Wang et al., 2020), have completed or terminated early with endpoints indicating benefit of markedly improved time to resolution of symptoms. The drug has been licensed for use in Japan and review is underway by the US FDA and EMA.

Conducting clinical trials in a pandemic is extremely challenging. It requires rapid start up and at the time of planning there will be much speculation as to how the pandemic will develop and the best optimisation of standard of care. New clinical guidance for standard of care will appear repeatedly, sometimes conflicting between countries and sometimes within countries. Regulatory guidance from the US FDA has recently appeared for COVID-19 specific treatments and is a welcome start to providing definitions of disease stages and study designs, but it still allows for considerable flexibility in the use of primary endpoints. Critically, endpoints must establish inhibition of infection, or reduction in disease course and/or severity as well as attempting to ascertain effects on mortality. 

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