The Changing Treatment Landscape

Over the past 3 decades, there has been a shift toward minimally invasive hysteroscopic, laparoscopic, and radiologic techniques to preserve the uterus and reduce the burden of recovery. Furthermore, to expand treatment options for nonprocedural alternatives, researchers have delved into finding novel nonpeptidic gonadotropin-releasing hormone receptor antagonists and selective progesterone receptor modulators since the early 2000s. The desire to avoid surgery altogether, to control symptoms after surgery, and/or preoperatively to treat fibroid tumors to reduce surgical complications has led to the discovery of multiple orally active therapeutics.

The ongoing transition toward uterine-sparing procedural and medical interventions has produced notable innovation. Treatments in development are focusing on longer term, etiologic care; research progresses into preventive strategies for those at highest risk for the development of fibroid tumors. Paired with a growing body of evidence on the long-term effects of hysterectomy, clinicians and guideline developers are increasingly cognizant of the importance of alternatives to hysterectomy in fibroid management. There is also evidence that shows that patients prefer to explore alternatives to hysterectomy when given a choice. Initial findings from COMPARE-UF, a nationwide patient registry that documents the outcomes of different UF treatment options, revealed that >50% of enrolled women chose a nonhysterectomy procedure.

The changing, expanding interventional landscape creates a compelling need for high-quality comparative effectiveness data. To date, a lack of evidence from randomized controlled trials to support the short- and long-term comparative risks and benefits of various interventions impinges on informed decision-making for patients, providers, and a range of health policymakers. This knowledge gap can affect conversations between a provider and patient about treatment decisions. As revealed by a population-based survey of 1443 women that characterized treatment decision-making for fibroid tumors, 58% of patients who had a hysterectomy cited provider recommendation as a primary reason. In fact, the Agency for Healthcare Research and Quality identified the knowledge gap surrounding the relative effectiveness of fibroid therapies as 1 of its 2 highest priority questions.

Past reviews conducted by Agency for Healthcare Research and Quality in 2001 and 2007 on the comparative effectiveness of various UF treatments reveal that studies had poor-quality evidence, reporting biases, and absence of long-term outcomes data. The number of studies that used patient-reported outcomes to reflect diminished QoL, lost work time, disruption of daily activities, and healthcare expenditures was also poor. A review published in 2017 painted a slightly more optimistic picture. However, the majority of studies that were reviewed were deemed poor quality for effectiveness outcomes, and strength of evidence for QoL outcomes was low to moderate.

The authors acknowledged that substantial knowledge gaps still exist because of heterogenous metrics and biased data collection methods, which is indicated by the low number of studies that addressed the primary outcomes chosen via their expert consensus panel. For example, the most commonly reported outcomes of fibroid characteristics and symptom status were captured in only 65% and 59% of studies, respectively. QoL and satisfaction outcomes were found in 39% of studies; future reproductive outcomes were reported in a mere 8%. Studies that reported the same outcomes often used different definitions and heterogenous instruments, some of which were unvalidated.

Cochrane systematic reviews have found similar results. Reviews cited very low -to-moderate quality evidence across UF studies. Unclear reporting of methods, lack of blinding, and variations in findings that resulted from heterogeneous metrics and imprecise measures were the most common reasons for evidence grading.

Difficulties synthesizing data across studies that resulted in a lack of high-quality comparative effectiveness evidence can be attributed to several factors. Per Stewart et al, the highly variable nature of UF creates a challenging backdrop. Considerable variation exists in fibroid biology, symptoms, and treatment type, which are affected by age of onset, race and ethnicity, and differing practice styles among providers. Moreover, few head-to-head trials exist, and there is significant heterogeneity in outcomes and measures among individual trials. ^, Without common denominators through which data can be analyzed, comparisons across multiple studies are exceedingly difficult.

Call to Action

Consensus on a “core set” of outcomes to be used across all therapeutic trials for UF will be a significant step toward improving the body of evidence that is available for decision-making. A core outcome set (COS) is an agreed on minimum set of outcomes that should be collected in all clinical trials for a given condition. ^, Development and dissemination of a COS ensures that a consistent, stakeholder-vetted set of outcomes will be accessible across different studies and promotes transparency for innovators who seek to anticipate the evidence needs of patients, providers, payers, regulators, and other stakeholders. The importance of core outcomes in benign gynecologic procedures is also emphasized by the CROWN Initiative, a consortium of >80 reputable women’s health journals that promotes COS development and dissemination. ^, Further efforts to harmonize data to assess device-based UF interventions are being addressed by MDEpiNet’s Women’s Health Coordinated Registry Network, a public-private collaborative that is developing a patient-centered medical device evaluation and surveillance system for a number of women’s health conditions.

Multistakeholder participation is crucial in determining a COS. Participants should include balanced representation from a number of stakeholder groups, including patients, clinicians, payers, health technology assessors, regulators, researchers, and industry. Building a diverse panel ensures robust representation during the voting process. This allows for the inclusion of viewpoints from those persons who are essential to the healthcare decision-making process, which will contribute to outcomes that will be helpful both downstream for clinical decisions and upstream for regulator and payer purposes. Because providing a forum for discussion by diverse stakeholders is necessary, groups who lead COS development efforts should be neutral facilitators and establish transparent processes for outcomes extraction as demonstrated by coreHEM, a COS project for hemophilia gene therapies led by the Center for Medical Technology Policy.

The Patient Perspective

A notable part of the COS development process involves incorporating the patient’s voice to articulate outcomes meaningful to them that may not be prioritized in studies. The significance of their perspective is recognized by the US Food and Drug Administration, which has drafted guidance for integrating the patient’s voice into product development and regulatory decision-making. In addition to providing firsthand knowledge about living with UF, patients can also contribute insights into the translatability of improvements in outcomes to real world functionality.

Over a span of 6 months in 2019, we held informal calls with patients who had UF and patient advocates about the outcomes currently being used in UF trials to vet the need for a COS from a patient’s perspective. The patients we spoke with unanimously expressed that, although information about changes in heavy menstrual bleeding is important to collect, several outcomes that significantly burden everyday experiences are either absent or inconsistently captured. Outcomes related to QoL and bulk symptoms, particularly bloating, urinary dysfunction, pain, and constipation, were mentioned most commonly. Interestingly, several patients disclosed concerns regarding the psychologic impact of reproductive and sexual issues that result from fibroid tumors and about feelings of fatigue and stress that linger after treatment. A handful of conversations also centered around financial burden, which covers the day-to-day costs of sanitary products to the long-term costs of missed productivity. As the US Food and Drug Administration moves toward patient-focused drug development, it is crucial to consider outcomes that are important to patients when trials are designed. Doing so will ensure that the research-generated evidence is relevant in decision-making contexts for not only providers, payers, and regulators but also the patients they all serve.

Applying the COS

After a defined, multistakeholder-driven COS that sufficiently reflects patient-important outcomes has been developed, the determination of the appropriate measurement instruments will allow for uniform implementation of the core set. Although the COS emphasizes what should be measured, standardizing how these concepts should be measured is equally necessary for cross-study interpretation and synthesis of data. ^, The use of heterogenous measures in UF trials is problematic and particularly apparent in the assessment of heavy menstrual bleeding, which is a primary endpoint in many UF trials. The most widely recognized measure of menorrhagia is the alkaline hematin method. However, studies have also used the pictorial blood loss assessment chart, menstrual pictogram, and Menorrhagia Impact Questionnaire, among others. Some of these measures contain multiple versions, which further attenuates comparisons. Similarly, QoL instruments range from the disease-specific Uterine Fibroid Symptom and Quality of Life Questionnaire (UFS-QOL), to broader measures like the 36-Item Short Form Health Survey (SF-36) and European Qol 5-Dimension 5-Level scale (EQ-5D-5L).

Establishing standard instruments for UF outcomes poses a unique challenge, given the wide array of symptoms that affect different facets of daily living. For example, women who experience menorrhagia are impacted not only physically but also socially and emotionally. However, these psychosocial outcomes are not captured in single blood loss measurement tools. The multifaceted impact of uterine fibroid tumors on QoL might explain the considerable variation in instruments that attempt to capture the multitude of outcomes. As such, it is essential to have a well-constructed, holistic picture of the UF experience to accurately define the main QoL outcomes that reflect patients interests and concerns.

The applicability of a UF COS with a defined set of measures that is patient-centric and multistakeholder vetted extends well beyond clinical trials to span the lifecycle of an intervention. It is practical in after-market registry and observational studies, which are implications for real world data collection and coverage with evidence development programs. Regulators and payers continuously seek after-market evidence that will inform an intervention’s safety and effectiveness, which they then translate into policy decisions that are both relevant to a broader population and clinically meaningful. However, it is important to acknowledge that the applicability of the COS may be limited in different healthcare systems and cultural settings. The COS should be used pragmatically and contextualized when necessary.

The complex nature of UF and its symptom-driven treatment modalities creates a complicated environment for the assessment of the true value of interventions in long-term outcome and cost comparison contexts. Considering the different disease states, varying impacts on QoL, and possibility of retreatment in a mobile and diverse population, strategizing effective after-marketing studies to fill evidence gaps appears overwhelming. As part of the underlying solution, we can use the COS process to extract outcome definitions and measures that resonate with multiple decision-makers. Having a common language is the cornerstone of comparing the clinical utility of different treatment approaches.

Comment

The development of a COS for UF is not only timely, given the innovation boom that is occurring, but also very much needed, as demonstrated by the severe lack of high-quality comparative effectiveness data and profound knowledge gaps. Adoption of the COS in clinical trials and after-marketing studies ultimately will result in research-generated evidence that is pertinent to multiple stakeholders and comparable for the assessment of the value of interventions. Although the complexity of the condition elicits technicalities that require careful thought and discussion, we must first address the larger issue of whether outcomes that are important to critical stakeholder groups are being considered and included in studies. After all, the utility of outcomes data lies in its relevance and meaning to those who need it most.