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I'm Drowning

— A researcher-patient's plea for broader inclusion in cystic fibrosis trials

MedpageToday

I've always known cystic fibrosis (CF) is a progressive disease; it destroys lung cells, tightens the small airways in the bottom of my chest, and each day takes me closer to the time when it will have ravaged my lungs. I had never really questioned if there was some way this process could be altered. I accepted that it couldn't.

Recently, however, this has changed. The epicenter of new CF research is the development of medications that will slow, stop, and hopefully even reverse the effects and damage that CF inflicts on the body. The possibility of the cells in my lungs functioning to their full potential -- with CF transmembrane conductance regulator protein function restored and working correctly, expelling chloride out of my cells, hydrating the surface of my lungs, and halting the thick sticky mucus that has caused my airways to be enveloped in a suffocating cloak for all these years -- is like a feeling of being rescued when you are drowning.

Unfortunately, I am still drowning.

"I'm very sorry, Ms. Balasa, but you will not be able to be a participant in this clinical trial." This was the response I received during one of my searches for these drug trials. Excited by the possibility of participating, finding one recruiting at my local adult clinic, I reached out to study coordinators and was informed that I met all but one criterion to participate in the studies. This specific criterion has prevented me from prior trial participation involving other investigational medications treating the symptoms of CF, including anti-infectives and anti-inflammatories.

Most CF studies, including phase I, II, and III trials, require a lung function minimum of at least 40% FEV1 (forced expiratory volume in one second). My FEV1 is 25%, so I am excluded from these trials. Many patients face a similar situation. The 40% threshold biases samples toward a young patient population, as this degenerative condition causes steadily decreasing lung function with time. Furthermore, as CF treatment has rapidly progressed and increased patients' life expectancies, there are now more adults with CF in the U.S. than children, according to the CF Foundation Patient Registry.

As a patient who works in the science field, I started to ask myself: Where does that number come from? Should this one variable be such a deciding factor? Are we getting comprehensive results from these studies if a subset of patients is omitted? Are investigators using eligibility criteria from a prior study without determining whether the exclusions are scientifically justifiable?

There are safety concerns to consider when thinking about including patients with a lung function below 40%. Those with lower lung function have a higher chance of illness during the trial period because of disease progression or possible adverse effects from the drug. Additionally, patients who are more ill most likely will not have the same level of symptom relief and disease reversal as someone with less scar tissue and damage to the lungs. These patients may not have a significant change in lung function, and for the drug company, this means fewer positive data results to present to the FDA.

CF affects each patient differently. There are patients who have lung function above the inclusion criteria minimum who require the use of supplemental oxygen, who have a hard time completing daily tasks, who are unable to work due to symptoms of lung bleeding, and who are on disability, and yet might qualify for a trial. On the other hand, there are patients like me, who use oxygen only during sleep or laborious physical activity, who have 30% lung function, who still work jobs, travel, and have good quality of life, and yet are excluded.

Drug companies should consider that although lung function percentage is a relative indicator of a person's overall health, there are a variety of factors, not just the volume of air that can be expelled from a patient's lungs in the first second of exhalation – i.e., FEV1. Giving individual consideration to patients for inclusion based on their quality of life and overall health is a reasonable adjustment to current inclusion and exclusion practice throughout studies.

It is not a good idea, however, to simply lower the inclusion criteria to 30% or 20%, as there are patients in this range who are severely sick. Rather, a separate cohort of patients could be included within this lung function range who could provide other parameters that are a measure of lung health such as blood oxygen saturation percentage, carbon dioxide blood test, and physical endurance as measured by a 6-minute walk test. These are parameters that can be recorded over the span of the study and are viable indicators of improving or deteriorating lung health.

Additionally of value is the inclusion of information from patient-reported outcome measurements, which are currently underutilized in clinical practice. The inclusion of a broader patient population in the trial phases, specifically lower FEV1 scoring patients, is important for understanding the effects of a drug on this population, and without it, there is a lack of knowledge on these patients' responses. Many studies also have a small sample size, as few as half a dozen patients, and increasing the number of participants potentially increases the quality of the results.

Trial periods usually last a few years for a drug to gain FDA approval, and patients ineligible for trials are unable to access medications even after successful phase III efficacy trial results. In addition, studies could be devised with adaptive features where the eligibility criteria may be expanded during the course of a trial, based on accumulating data. The question is, will drug companies be willing to contribute the necessary resources to examine data from this additional population?

A few weeks ago I found myself in an interview with a drug company explaining these ideas in response to what they can do to better serve the CF patient population as a whole and what key factors they are missing. This essay is my response, which I hope can be taken into consideration for designing current and future clinical trials for CF, as well as serve as an example of what patients with all types of diseases face.

Ella Balasa was diagnosed with CF at the age of 1. She works as a microbiology lab manager at Virginia Commonwealth University and is the director of the United States Adult Cystic Fibrosis Association. She has a column at and contributes to the blog.