Flic Gabbay, Managing Partner
Marcin Mankowski, Deputy Managing Partner
Sarah Daniels, Head of Drug Safety, Pharmacovigilance & Risk Management
Dominic Bowers, Head of Rare Diseases & Advanced Therapeutics
This short paper outlines the currently available guidance on clinical outcomes for COVID-19 therapeutic clinical trials and summarises how these can be used effectively to facilitate progression towards standardised clinical study designs.
At the end of 2019, the world became aware of a new and potentially deadly infection caused by a novel virus SARS-CoV-2, later known as COVID-19.
As the world struggled to comprehend and manage this new pandemic, a plethora of clinical studies were designed and executed, assessing the efficacy and safety of a myriad of drugs, both old and new. These clinical study designs deployed a large variety of clinical endpoints, rendering the comparison, interpretation and comprehension of results difficult.
With time, a better understanding of the novel virus and the spectrum of disease it causes evolved, bringing with it guidance on appropriate clinical outcomes for assessment of COVID-19 in clinical trials. Key guidance’s have been issued by major regulatory authorities and the World Health Organisation (WHO).
The guidance produced by the US Food and Drugs Authority (FDA), the European Medicines Agency (EMA) and the World Health Organisation (WHO) stress the importance of the clinically meaningful aspects of clinical study endpoints. Placed under parameters surrounding mortality, patient function and clinical recovery; the similarities and differences amongst these guidelines highlighted in this paper provide an important insight into the need for and the use of consistent clinical outcome measures.
US Food and Drugs Administration Guidance (FDA) –May & September 2020
In May 2020, the US FDA provided guidance on developing drugs and biological products for the treatment of COVID-19 (1).
Efficacy Endpoints: The appropriateness of endpoints (primary and secondary) should be evaluated based on the effect of the investigational drug relative to placebo on clinically meaningful aspects of the disease. Sponsors should consider that the relevance and appropriateness of outcome measures may depend on the population studied, the clinical setting, and/or baseline disease severity (mild/moderate/severe/critical).
Examples of important clinical outcome measures in clinical trials include:
- All-cause mortality
- Respiratory failure (i.e., need for mechanical ventilation, extracorporeal membrane oxygenation (ECMO), non-invasive ventilation, or high-flow nasal cannula oxygen delivery)
- Need for invasive mechanical ventilation
- Need for intensive care unit (ICU) level care based on clear definitions and specific clinical criteria
- Need for hospitalization based on clear definitions and specific clinical criteria
- Objective measures of sustained improvement (e.g., return to room air or baseline oxygen requirement)
- Sustained clinical recovery (e.g., resolution of symptoms)
The choice, time frame, and interpretation of endpoints may differ, depending on the population evaluated in the trial. The FDA Guidance provides 5 detailed examples of how to assess baseline disease severity: SARS-CoV-2 infection without symptoms, mild, moderate, severe and critical COVID-19.
For example, appropriate endpoints for severe and/or critical patients include:
- All-cause mortality at an appropriate time point (e.g., at least 28 days)
- Proportion of patients alive and free of respiratory failure at an appropriate time point (e.g., at least 28 days)
- Clinical status at an appropriate time point assessed using an ordinal scale that incorporates multiple clinical outcomes of interest (e.g., death, mechanical ventilation) ordered by their clinical importance
- Time to sustained recovery assessed over an appropriate duration
The May 2020 FDA guidance lists appropriate endpoints for outpatient treatment trials as:
- Proportion of patients hospitalized by an appropriate time point (e.g., at least 28 days)
- Time to sustained clinical recovery assessed over an appropriate duration
In September 2020, the FDA released further guidance titled “Assessing COVID-19-Related Symptoms in Outpatient Adult and Adolescent Subjects in Clinical Trials of Drugs and Biological Products for COVID-19 Prevention or Treatment Guidance for Industry” (2). This document recommends the use of patient-reported outcome (PRO) instruments to assess COVID-19-related symptoms in outpatient clinical trials and provides an example of an assessment of key COVID-19-related symptoms.
Given the heterogenous nature of COVID-19 related symptoms in outpatients, the guidance suggests that symptoms be assessed systematically to provide an accurate evaluation of benefit. Through the provision of symptom rating and scoring, the guidance highlights the importance of utilising binary response scales, but also left sufficient room for sponsors to utilise alternative items and response options to cover the range of symptoms.
In selecting appropriate endpoints for prevention or treatment of outpatient adult and adolescent clinical trials, the guidance suggests that endpoints are selected based on the knowledge of the time course of COVID-19 related symptom onset or resolution, which is still evolving (for example, clinical findings show that certain symptoms (e.g., cough, fatigue, decreased sense of taste and sense of smell) may take longer to resolve in comparison to other symptoms, and take into account relevant information from literature sources and any relevant clinical trials to support the rationale for proposed endpoints.
The guidance further states that sponsors can use early phase trials to examine the effect of an investigational drug on the time course of symptoms to inform endpoint development for confirmatory trials. Sponsors can consider a variety of endpoint definitions to evaluate the effect of a drug on common COVID-19-related symptoms.
Virological Endpoints: While in phase 2 treatment trials, a virologic measure may be acceptable as a primary endpoint (to support a phase 3 clinical endpoint study), virologic endpoints are not appropriate as primary endpoints in a phase 3 trial. This is because there is no established predictive relationship between magnitude and timing of viral reductions and the extent of clinical benefit of how a patient feels, functions, or survives. Additionally, the optimal sample size, timing, methods for collection procedures, and assays for clinically relevant virologic measurements have not been established. Therefore, virologic endpoints may be better assessed as secondary endpoints in phase 3 trials.
Finally, for any endpoints defined by events through or at a prespecified time point, the time point should be defined as number of days after randomization. The time window should be sufficiently long to ensure capture of important events related to patient status, treatment, and COVID-19 progression.
European Medicines Agency (EMA) – July 2020
Efficacy Endpoints: The EMA guidance (agreed upon by the International Coalition of Medicines Regulatory Authorities [ICMRA]) (3), stated that the primary endpoint should be clinically meaningful, measurable, and sufficiently sensitive to allow realistic sample sizes. A sensible and suitable way of handling missing data/ intercurrent events and mortality should be pre-defined.
Unlike the FDA guidance, the EMA guidance did not define pre-established primary and secondary endpoints, but instead stated that the nature of the COVID-19 symptoms provided a range of options that can be considered as primary endpoints. Utilising ordinal scales and proportional odds models, the guidance highlighted 7 primary endpoints to be considered to inform on the clinical benefit of investigational therapeutics including:
Hospitalized patients with moderate/severe COVID-19:
- Time to recovery through Day 28/29
- Clinical status as improvement of 2 points on an ordinal scale (see below)
- Mortality within 28 days after randomization (especially for severe COVID-19)
Note: Though mortality is not the only acceptable primary endpoint, it should be collected as a key secondary endpoint in all studies
- Time to sustained recovery up to day 90 (defined as alive and no relapse)
- Progression of disease
- Number of days not on ventilator from randomization to a specified timepoint
- Recovery rates
Outpatients with mild COVID-19:
Mortality as the primary endpoint may not be suitable. However, objective criteria for disease progression should be included in the endpoint definition. Suggested alternative endpoints include:
- Rate of progression to severe disease (this could also be assessed using an ordinal scale)
- Proportion of patients not hospitalized at a prespecified time point, depending on the primary objective of the study
Note: Endpoints such as rate of hospitalization are not objective enough.
World Health Organisation (WHO) – August 2020
Recognising the difficulties in establishing a coordinated approach to clinical research and the pooling of data, the WHO Working Group on the Clinical Characterisation and Management of COVID-19 Infection published a minimum set of common outcome measures for studies of COVID-19 (4). This set includes three elements:
- Viral burden: Semiquantitative viral RNA of SARS-CoV-2 infection as measured by quantitative PCR or cycle threshold; nasopharyngeal swabs are associated with the highest viral load
Note: Quantification of viral burden provides no insight into the clinical status of the patient but does provide strong evidence of the presence of the pathogen, and it can be used to measure pathogen burden in response to treatment.
- Survival: All-cause mortality at hospital discharge or at 60 days
- Clinical progression: WHO Clinical Progression Scale measured daily over the course of the study
WHO Clinical Progression Scale
To facilitate data pooling across cohort studies and clinical trials, the WHO has developed an 11 point Clinical Progression Scale that can be measured daily over the course of a study (4). The 11 point scale replaces earlier versions of the scale that utilised a smaller number of clinical severity points. Therapeutic clinical COVID-19 trials conducted since December 2019 have deployed a variety of different ordinal point Clinical Progression Scales which has made direct comparison between these trials, insofar as assessments of recovery and/or progression assessments, challenging. Further testing and validation of the measure are needed which may lead to further modifications of the scale.
ECMO=extracorporeal membrane oxygenation. FiO2=fraction of inspired oxygen. NIV=non-invasive ventilation. pO2=partial pressure of oxygen. SpO2=oxygen saturation. *If hospitalised for isolation only, record status as for ambulatory patient.
Standardising Clinical Study Designs
The use of consistent clinical outcome measures in COVID-19 therapeutic trials is critical to enable the consistent implementation of future COVID-19 clinical trials as well as to enhance an accurate interpretation and cross comparison of results. The importance of establishing appropriate primary and secondary endpoints, representative of the trial population (outpatients vs hospitalised patients) and utilising an appropriate ordinal scale to measure and assess the symptom presentations and clinical course in clinical trial patients was a recurring theme throughout the FDA, EMA and WHO guidance. It is worth noting, that the ordinal scale example provided by the WHO is now being incorporated into therapeutic clinical study designs.
It is also worth nothing that both the FDA and EMA highlight that a virological endpoint is more appropriate as a secondary outcome measure in phase 3 trials, in contrast the WHO guidance does not make the distinction between phases of development.
The assessment of sustained clinical recovery in moderate to severe/critical disease is an important therapeutic outcome measure and EMA and FDA recommend its consideration as a primary endpoint. Its incorporation as either a primary or secondary outcome measure has important clinical and socioeconomic considerations as emerging clinical data demonstrates that recovery from COVID-19 can have a protracted course. Although the FDA does not stipulate a time period to evaluate sustained recovery without relapse, it recommends it should be over ‘an appropriate duration’ whereas the EMA has gone a step further to recommend assessment of sustained recovery, without relapse, up to day 90. While there is no specific regulatory guideline on the assessment of long-COVID, a sufficiently long period of follow-up is becoming more important in view of the emerging evidence of persistent symptoms present in a large proportion of patients with COVID-19 (5, 6).
Any assessment of mortality/survival should be made at a more appropriate time point than 7 days. It must be able to capture delayed deaths and sustained recovery. Critical care studies frequently assess all-cause mortality at day 28 from randomisation into clinical study designs and the incorporation, at least, of this time period is appropriate.
As both the FDA and EMA concur that outcome measures must be clinically meaningful it seems likely that clinical trials will incorporate robust longer-term clinical recovery outcome measures.
- WHO Working Group on the Clinical Characterisation and Management of COVID-19 Infection. A minimal common outcome measure set for COVID-19 clinical research. Lancet Infect Dis. 2020:DOI: https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30483-7/fulltext
- Arnold DT et al. Patient outcomes after hospitalisation with COVID-19 and implications for follow-up; results from a prospective UK cohort. https://doi.org/10.1101/2020.08.12.20173526
- Carfi A et al. Persistent symptoms in patients after acute COVID-19. JAMA. 2020;324(6):603-605