Tackling the Increasing Complexity of CF Care

Introduction

Over the past several decades, health outcomes for people with cystic fibrosis (CF) have dramatically improved. Recent estimates obtained by analyzing the U.S. CF Foundation Patient Registry note that if the rate of improved survival continues at the rate observed in the last decade, the median survival for a person with CF born in 2010 will be 50 years of age¹. In fact, the number of adults with CF now exceeds that of children with CF in most developed countries^2,3. These advancements occurred in parallel with better organization of clinical care systems, evolution of novel therapeutics, and improvements in diagnosis and screening for CF and CF-related complications. Evidence-based guidelines and systematic reviews for chronic CF therapies including management of complications have been published and recently revised^4–6. These reviews note the evolving therapeutic interventions now available to people with CF. These advances have come at a cost – an increasing complexity of care and challenges with adherence to CF treatment regimens. Additionally, novel therapeutics targeting the basic defect in CF have the potential to impact disease progression differently than existing therapies. The increased number and type of therapeutics therefore provides some clear opportunities to refine and personalize CF care. In this review, we will highlight both the challenges of the increasingly complex treatment regimens in CF and the opportunities to advance care by addressing adherence, implementation science, comparative effectiveness, and integration of novel technologies and therapeutics in CF care.

Increasing Complexity of Treatments in Cystic Fibrosis

Currently, the treatment regimen for CF involves respiratory, anti-microbial, and nutritional therapies, and may include therapies for other CF-related complications such as diabetes, liver disease, chronic pain, or depression. As new therapies for CF, particularly cystic fibrosis conductance transmembrane regulator (CFTR) modulators, are developed, the number and complexity of available therapies will continue to increase.

High treatment complexity is a major concern to people with CF and clinicians alike⁷. Complexity can be quantified by the number of medications and therapies prescribed, or by the time in which these therapies take to complete. Aerosolized therapies, in particular, require time for administration as well as time for cleaning of equipment. Airway clearance and chest physiotherapy, a necessary part of most CF therapeutic regimens, also is time-consuming. Numerous studies have identified long treatment times for recommended CF regimens, with average estimates for adults of up to two hours per day to complete stable baseline regimens⁸. Given advances in therapeutics, newer eradication protocols for Pseudomonas aeruginosa, and a paradigm of early, aggressive care, treatment complexity increases early in life such that for many children with CF their prescribed regimen is identical to that that of adolescents and adults⁹. In addition, the diagnosis of new CF-related complications such as diabetes increases with age, often resulting in additional therapies directed at these co-morbidities.

High Treatment Burden in CF: A Challenge for Adherence and Self-Management

Treatment complexity also leads to significant treatment burden; that is, the perceived impact of treatments on an individual’s ability to both complete therapies and remain engaged in other daily activities. Treatment burden is measured in validated CF-specific quality of life measures such as the CF Questionnaire-Revised (CFQ-R), and higher burden has been associated with increased treatment complexity^8,10,11.

The high treatment demands in CF result in significant challenges to adherence and chronic disease self-management. Numerous studies have documented low rates of adherence in CF utilizing multiple methods of assessment. Self-reported adherence has been found to be higher than objectively measured adherence for both pancreatic enzyme therapy and inhaled medications^12,13. Additionally, clinicians have over-estimated adherence in CF as well¹⁴. Prescription refills can serve as a measure of adherence, and several data sources have identified significant gaps in prescription refill rates for oral and inhaled medications¹⁵. Low refill rates of inhaled tobramycin were associated with higher odds of hospitalization¹⁶. Additionally, lower composite medication possession ratios were associated with more frequent exacerbations and lower lung function¹⁵, and a recent analysis identified a connection between poor prescription refill rates and increased cost¹⁷.

Achieving optimal adherence to chronic therapies is multi-factorial, and requires partnerships between individuals with CF, their caregivers, and clinicians. Those at highest risk for poor adherence appear to be adolescents and young adults, a time where developmental challenges intersect often with accelerated disease progression. Barriers to adherence include immediate time pressures and competing priorities, avoidance of therapies in favor of other activities due to a sense that life may be limited, a desire for normalcy in which an individual does not want to seem different from peers, and a lack of perceived consequences when no immediate benefit is perceived from a chronic daily therapy^18,19. Anxiety and depressive symptoms can also impact a patient’s perceived benefits of therapy. Recent studies have noted that both anxiety and depressive symptoms are common in persons with CF and their family members^20–22.

Improving adherence and self-management among individuals with CF is an important goal. A recent survey of U.S. CF Care Centers found that only 8% used an objective measure of adherence in routine clinical care, with little reported use of behavioral strategies to improve adherence among their populations.²³ Clinicians and researchers need to refine methods to identify who is non-adherent, develop and study approaches to reduce burden and facilitate chronic disease self-management, improve communication between people with CF and their care teams, and identify individual barriers to adherence amenable to intervention. Mobile health devices have potential for improving adherence rates in CF, but further study is needed²⁴. Interventions to improve adherence need to be tailored to developmental trajectories, and facilitate goals for adherence behaviors that incorporate caregivers, peers, and multi-disciplinary clinician input.

Tackling the Solutions: Integration of Technologies to CF Therapies

Improving drug delivery, particularly for aerosolized medications, could help decrease treatment burden and improve adherence. One of the first major technological advances in CF care was the introduction of the e-Flow nebulizer. This rapid nebulizer utilizes a vibrating mesh technology to generate a fine consistent aerosol appropriate for conducting airways delivery²⁵, and has been demonstrated to deliver a specific dose of drug in roughly half the time of the traditional nebulizer. E-flow technology was introduced as a combination drug device delivery system to administer inhaled aztreonam^26,27. This device is battery powered (thus is a mobile device) and delivers drug much faster than traditional nebulizers potentially leading to the high rate of adherence noted in an 18 month open label extension study^28,29. Recently, a similar device (e-Rapid) has been studied for delivery of medications such as dornase alfa³⁰. Dry-powder drug formulation may also decrease the patient burden for certain aerosolized medications. A dry powder formulation for tobramycin has been formulated specifically to improve the ease of delivery and decrease treatment burden³¹. A number of studies have been conducted to demonstrate clinical efficacy and showed significant decreases in administration time in conjunction with increased treatment satisfaction^32,33. While advancing technologies to decrease administration time may lead to improved adherence and improved quality of life, at this time, evidence is lacking regarding whether any of these devices have indeed improved adherence. Further studies to address this issue are needed.

Novel technologies not only include changing methods of drug delivery but new approaches to remote monitoring to provide feedback to both the provider and the person with CF. Early feasibility of such an approach was documented in the late 1980s and early 1990s^35,36. For a two-year period, individuals maintained daily diaries recording vital capacity, weight, respiratory rate, pulse, and symptoms, with a daily participation rate of approximately 80%. Subsequently, a small study compared individuals using home monitoring with those that were not and showed that over 4 years, the home monitoring group had a slower decline in lung function³⁵. Later extensions of this work demonstrated the ability of patients to transmit the results of their home spirometry to the CF clinic via computer modem³⁶. Other forms of telemedicine have also been evaluated but efficacy data are lacking to support its use in CF^37–39. Currently, an ongoing multicenter study [the early Intervention in CF Exacerbation study (eICE Study)] is assessing the role of home spirometry and symptom monitoring to identify and manage pulmonary exacerbations in adolescents and adults with CF³⁴. We will soon have the results of the eICE study to help understand whether such home monitoring is effective and in which CF populations it may be beneficial.

Tackling the Solutions: The Role of Comparative Effectiveness Research (CER) and Implementation Science

One of the challenges with current treatment approaches in CF is that evidence for treatment regimens is based in formal efficacy studies required for drug approval and registration. Many CF therapies have been studied in isolation without an active comparator in studies appropriate to determine efficacy, but these studies may be limited in their ability to determine effectiveness. Additionally, most clinical trials of CF therapeutics have also been of relatively short duration (6–12 months), yet clinicians extrapolate this data to recommend therapies that are often used for life.

Research designs aimed at evaluating effectiveness of therapies in the “real world” setting are needed to help fill gap in evidence for how to appropriately structure a chronic CF care regimen. The first step in understanding which of our many therapies to use in any given population starts with a careful and systematic approach to weighing the evidence. With the support of the CF Foundation, a number of key systematic reviews have been conducted^4–6. These reviews have been able to shed light first on those therapies with good supporting evidence and more importantly, those areas where we have clear gaps in evidence to guide clinical care, including questions on how to prioritize different treatments for an individual.

Comparative effectiveness research (CER), may also provide an approach to address clinical questions posed by systematic reviews. The U.S. Department of Health and Human Services (DHHS) and the Patient Protection and Affordable Care Act of 2010 established the Patient Centered Outcomes Research Institute (PCORI) to define methodological standards for CER and to establish policies regarding research funding. DHHS has defined CER as the “conduct and synthesis of research comparing the benefits and harms of different interventions and strategies to prevent, diagnose, treat and monitor health conditions in ‘real world’ settings. The purpose of this research is to improve health outcomes by developing and disseminating evidence-based information to patients, clinicians, and other decision-makers, responding to their expressed needs, about which interventions are most effective for which patients under specific circumstances⁴⁰.” CER clearly supports the broad use of evidence to evaluate effectiveness including observational data such as the use of large scale registries like the CF Foundation Patient Registry (CFFPR)^41,42.

One of the more critical components of study design in CER is the emphasis on pragmatic or practical clinical trials that emphasize effectiveness of therapies compared to traditional efficacy trials^43,44. Pragmatic trials are considered assessments of effectiveness, with investigators comparing treatments in a setting close to real life with very few exclusion criteria and much less controlled study conduct⁴⁵. One of the principal goals of pragmatic clinical trials is to generate evidence that is generalizable to a broad population. Randomized withdrawal trials⁴⁶ and registry-based randomized controlled trials⁴⁷ are potential pragmatic study designs. One recent example of such a trial is the Early Pseudomonas Infection Control (EPIC) trial in children with CF^48,49. In this trial, researchers responded to an express desire from the CF community (practitioners, family members and funded agencies) to design a randomized clinical trial to assess four different approaches of eradicated Pseudomonas aeruginosa from the airways of CF children who had recently acquired the organism. The inclusion criteria were quite broad only excluding those subjects in which the treatment medications were deemed to be potentially harmful. The results noted that less antibiotics could be used to achieve the same result⁴⁸. One could envision a number of research questions in CF that could be addressed by future retrospective and prospective observational studies and pragmatic clinical trials.

The increasing therapeutic choices in CF also generate important CER questions. There are now multiple different inhaled antibiotics available ^26,27,28,50; optimal combination and real world use of these therapies is unclear. Should they be used in alternate months as is commonly done clinically leaving no time interval off inhaled antibiotic? The numbers of one to one comparison trials in inhaled antibiotics have been limited ^51,52.. There also are three different aerosolized mucolytic treatments: inhaled rhDNase, inhaled hypertonic saline, and in Europe and Australasia, inhaled mannitol. Should individuals be on one, two or all three therapies? Are certain combinations of these therapies beneficial? A challenge with formal pragmatic clinical trials in an orphan population like CF is the relatively limited size of the potential pool of research participants; many of these studies would need to be designed as non-inferiority clinical trials which often require large sample sizes. Such CER questions, therefore, may be better addressed through analyses of registry data. Any study using observational data for CER is fraught with potential indication bias (patients who receive specific therapies are systematically different than those who do not in ways that cannot be accounted for using analytical methods). Propensity score adjustment or matching and use of instrumental variables have been advocated to address indication bias⁵³. Very few observational studies in CF have used these methodologies to date^54,55.

Evolving therapeutics in CF include the recently approved CFTR potentiator ivacaftor.⁵⁶ Several other CFTR modulators are in late phase clinical studies.⁵⁷ The introduction of CFTR modulators will add to the need for developing a clear framework to conduct CER studies in CF. With the introduction of CFTR modulators, a number of key questions arise: Should other chronic therapies be discontinued in the presence of CFTR modulators? How might CFTR modulators impact CF-related co-morbidities? Are there longer-term side effects of CFTR modulators? Are individuals stopping other treatments after starting CFTR modulators, and might such discontinuations result in lower longer term effectiveness of these therapies? Comparative effectiveness research will serve as one means to help address these clinical questions⁵⁸.

In addition to CER, there is a need for implementation science to reduce treatment barriers in CF. Broadly defined, implementation science encompasses the dissemination of new evidence and innovation into a broader clinical setting. The RE-AIM (reach, effectiveness, adoption, implementation, and maintenance) framework can be used to evaluate the widespread impact of interventions within a population⁵⁹. The Consolidated Framework for Implementation Research (CFIR) offers an additional framework for designing interventions for real-world settings, focusing on constructs that could guide effective implementation of strategies to improve population health outcomes⁶⁰. In CF, these frameworks can be employed in part through robust quality improvement collaboratives with incredible population level results⁶¹. Care centers have successfully used comprehensive QI-driven approaches to improve care processes, transform care delivery systems, and ultimately improve health outcomes among their patient populations⁶². These approaches can be adapted to tackle key barriers to CF care by evaluating approaches to reduce treatment burden, improve access to care, and augment behavioral strategies for disease self-management.

Conclusions

CF care has gone through a remarkable evolution in the last twenty years. For patients, families and care providers, the evolution of care has led to a transformation of the disease. In comparison to the 1980s and 1990s when few therapeutics were available to people with CF, we now have an increasingly complex and time intensive treatment approach. This is a welcome advance compared to historical management of the disease; however, the increasingly complex treatment regimens now have created their own challenges. The challenges include how best to implement new therapies and how best to ensure high levels of adherence to effective therapeutic regimens. Novel technologies may both improve adherence and also decrease the burden of treatment. Some of the most significant challenges may be in understanding the role of existing standard CF therapies in the era of new CFTR modulators. This new era in CF care has also raised a number of clinical questions regarding how best to use our existing therapies. Comparative effectiveness research has a clear role in CF now that a significant number of efficacious therapies are available.