Editorial to the supplement entitled “assessments of pulmonary function in patients with amyotrophic lateral sclerosis: options and applicability in both the clinical care and clinical trial settings”

On 11 March 2020, the World Health Organization reported that SARS-CoV-2 infections were widespread worldwide and declared COVID-19 a pandemic. At that time, there were more than 118,000 cases in 114 countries, with over 4000 deaths attributed to the virus (1). As of May 2021, there were only 14 countries (including 12 island nations in the Atlantic and Pacific oceans) that had no reported cases of COVID-19 cases with a total worldwide case count of over 156 million and deaths totally more than 3 million (2). Many countries locked down for variable lengths of time; this included closing outpatient facilities or limiting access to outpatient clinics to reduce the risk of spreading the disease. This had swift and immediate impact on both providing routine clinical care to ALS patients as well as trial conduct. A survey of members of the Northeast ALS Consortium (NEALS) in late April 2020/early May 2020 revealed that only 16% of respondents reported the ability to provide the same care as they had done prior to the pandemic (3). In both North America and Europe, patient contact by video or telephone frequently replaced in person visits during the pandemic (3,4). ALS clinical research was also severely impacted by the limitations brought on by COVID-19, and the clear majority of NEALS sites (80%) were at least transiently unable to enroll new patients in trials and many were not able to conduct planned in person visits as per protocol due to regulations imposed because of the pandemic (3). In response to this unprecedented event in the era of clinical trials, both the European Medicines Agency (EMA) and the Federal Drug Administration (FDA) published guidance first in March 2020 with subsequent updates providing recommendations for clinical trial management during the pandemic. While some difference existed in the details of the two, the overall principles were the same. Guidance was provided not only for trial sponsors, but also sites, institutional review boards and ethics committees with the goals to assure patient safety, maintain good clinical practice, and to minimize risks to the integrity of the trial and the data collected. Suggestions included possibly delaying the start of new trials, pausing ongoing trials, closing sites, and using remote visits and alternative approaches to perform efficacy assessments (5,6).

Pulmonary function assessments, done for both clinical trials and for routine patient care in ALS, were substantially impacted by the pandemic. Both the American Thoracic Society and the European Respiratory Society recommended greatly limiting the use of pulmonary function testing to those patients in whom it was viewed as critical to medical decision making because of the concern of transmitting COVID-19 infections to the respiratory therapists or to other patients subsequently being evaluated in the room. Testing that could potentially be associated with aerosolization, including evaluations that could provoke a cough during performance of the maneuver, was considered high risk for spreading viral particles. Use of personal protective equipment (which may have been in short supply) and enhanced cleaning of the room used for the test (increasing the time the room could not be used further limiting the number of patients who could be evaluated) were recommended to reduce the risk of disease transmission (7,8). Nearly 70% of NEALS centers reported they were limited in their ability to get pulmonary measurements on their ALS patients, indicating the recommendations clearly impacted the availability of obtaining these evaluations (3).

Born out of the inability to easily perform pulmonary function assessments in ALS patients due to the COVID-19 pandemic, this supplement focuses on alternatives to evaluate ventilatory status and or predict prognosis in patients with ALS. For ALS care and clinical trials, perhaps no single assessment is more important than vital capacity testing. Evaluating vital capacity when the patient is seen for their initial evaluation provides prognostic information (9). Serial measurement of vital capacity obtained longitudinally help direct timing of noninvasive ventilation initiation, feeding tube placement independent of swallowing status or weight, and discussions on end of life care (10,11).

The various outcome measures described in this supplement are not mutually exclusive but rather the circumstances around the interaction with the patient may help drive which of the alternatives posed may be a practical and viable option. Is the patient able to attend the clinic or is the visit a virtual one? Are the results needed to drive medical decision about interventions? Is this for routine clinical care or is the patient participating in a clinical trial? If being used in a trial, is its purpose to assist in determining trial eligibility, is it an outcome measure, or will it be used to stratify the patient for prognostic purposes?

Infectious concerns are not the only reason vital capacity testing may not be feasible; patients with frontotemporal dysfunction may not be able to follow the instruction to perform the procedure, facial weakness may limit the ability to form a good seal, and bulbar spasticity may cause abrupt cutoff as the patient exhales. For these circumstances, performing an assessment that is non-volitional (such as an electrophysiologic test) (Pinto) or has easy to follow instructions (those that involve single breath counting [Quinn] or sustained phonation [Stegman]) are appealing. The pandemic has drawn attention to the digital divide, and it is recognized that lack of access to the internet may make it impossible for all patients to perform video or app assisted assessments, so having outcomes that can be done without access to such technology, such as a patient reported outcome respiratory questionnaire (Heiman Patterson), will expand the ability to obtain additional information and provide care to patients in a remote setting who may only have a land line for contact. For measures that drive decisions about medical interventions including initiating noninvasive ventilation or obtaining a feeding tube prior to a vital capacity dropping to the extent of there is unacceptable risk to undergo the procedure, there will need to be buy-in from payers regarding the merits of the assessment given that coverage may be historically based on results of vital capacity but also on maximum inspiratory pressure (MIP) results. There was variability between institutions regarding whether MIP testing could be done during the height of SAR-CoV2 infections. Patients with ALS typically met the MIP cirteria for Medicare coverage for noninvasive ventilation earlier than the vital capacity criteria (Heiman Patterson pulmonary function decline), so in situations where MIP can be performed, this provides a good alternative. Machine learning and arterial blood gas analysis may provide assistance in survival prognostication and detecting response to therapy (Beaulieu, Manera).

Compared to using a new outcome in a purely clinical setting, regulators set the bar higher when the desire is to utilize a new clinical outcome assessment or a biomarker as an endpoint in an interventional clinical trial. In addition to performance outcome assessments, clinical outcome assessments include patient, clinician, and observer reported outcome assessments. Biomarkers may fit into one of several categories, including those that serve roles that are prognostic, diagnostic, or as a surrogate for a clinical efficacy endpoint. As part of the FDA’s Drug Development Tool process, there is a competitive qualification program for clinical outcome assessments which is encouraged but not required for new outcome measures; the expectation is that it would take several years to pass through the evaluation process. Prioritization for accepting proposals is given to outcome measures that fill a critical need, represents a significant improvement over what is already available, and is patient centric. As part of this process, the clinical outcome measure needs to demonstrate it has content and construct validity, reliability, and the ability to detect change. In addition, the development process should also identify what the patient perceives as the minimal clinically important difference, or the MCID (12–14). Placing more focus on drug development from the patient perspective is a concept gaining traction; the EMA is also developing guidelines that are directed at taking into greater account the patient’s perspective in drug development (15). While a biomarker may be used in a single new drug program and accepted through the drug approval process, the biomarker qualification process permits use of the biomarker across multiple programs. The FDA, EMA and Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) have been working together to advance programs for biomarker qualification and to make the process more seamless across the regulatory agencies (16,17).

It is noteworthy that the data from the manuscripts included in this supplement was primarily if not exclusively collected pre-COVID-19, reinforcing that alternative outcome measures of ventilatory function have been viewed as worthy of development by those who care for patients with ALS even prior to the pandemic. Gaining clinically relevant ventilatory information on patients who cannot easily perform vital capacity would be useful in improving clinical care. Monitoring disease progression remotely would ease patient burden and could permit addressing decompensation in a timelier fashion. New outcomes measures that may decrease the number of patients enrolled in a trial by improving power, better identifying patients to participate in a trial, or shortening trial duration has the potential of shortening time to identify promising therapies. COVID-19 resulted in the designers of protocols to re-think trial design, with more emphasis placed on remote monitoring and reducing in-clinic visits and it is likely post COVID-19, trials will continue to strive to be more patient centric. Those who have developed and promoted these alternative methods of assessing ventilatory function may want to engage regulators to discuss the approval process for qualification as a biomarker or a clinical outcome assessment. This could help pave the way for them to be widely accepted by regulatory agencies as outcome measures in ALS interventional trials.

Declaration of interest

Stacy Rudnicki is employed by and owns stock in Cytokinetics, Inc.