Development of a core minimum data set to advance real-world evidence generation for uterine fibroids treatment technologies

Introduction

Uterine fibroids (also known as leiomyoma) are growths that develop in the uterus. These benign growths can vary in size, number, and symptomatology. According to the Department of Health and Human Services,1 between 20% and 80% of women develop fibroids by age 50. In addition to existing pharmaceutical treatments, there are several interventions that are used to treat fibroids or their symptoms, including hysterectomy, myomectomy, radiofrequency ablation, uterine artery embolization, endometrial ablation, and magnetic resonance-guided focused ultrasound. Treatment decisions consider many factors, including experienced symptoms, size and location of the fibroids, patient’s age, patient preferences regarding uterine sparing procedures, and the provider’s clinical expertise and experience.2 Treatment decisions also consider the risk of an occult uterine sarcoma in a woman undergoing surgical intervention for presumed fibroids.3

Despite the large burden of disease, evidence on the relative safety and effectiveness of available uterine fibroid interventions remains sparse.4 Given the paucity of comparative studies, there is a clear need for the systematic collection of post-market real-world data for women undergoing treatments using medical devices, with careful consideration of which patient characteristics, procedural data, and health outcomes are most important to capture from a clinical perspective. Pre-market studies for uterine fibroid treatment technologies include a relatively small number of patients compared with the large number of women affected by fibroids. Systematic post-marketing collection of data provides an opportunity to understand device performance in the broader use population and to identify potentially rare but serious complications, such as undiagnosed leiomyosarcoma. Additionally, because many women affected by fibroids have an interest in maintaining their fertility,5 6 systematic methods for capturing reproductive outcomes data in future pregnancies may be possible with large numbers of subjects providing post-market data.

To enable this type of post-market surveillance, we identified the need to create a Coordinated Registry Network (CRN)7 8 that would be capable of generating real-world data to evaluate the safety and effectiveness of technologies used for uterine fibroids. Foreseeing the potential evolution of technologies used to treat uterine fibroids, stakeholders acknowledged the importance of creating a core minimum data set that would be applicable to multiple technologies for uterine fibroids, including new devices that enter the market in the future. As a first task within this CRN, we used the Delphi method to reach consensus on a core minimum data set for the study of current and future devices and surgical interventions for uterine fibroids.

Methods

On September 15, 2017, stakeholders from the US Food and Drug Administration (FDA), industry, non-profit organizations, patient advocacy groups, payers, professional society leaders, academia, and clinical experts met at the FDA White Oak Campus in Silver Spring, Maryland, to launch the CRN by discussing the current landscape of registries evaluating uterine fibroid treatment technologies and the perspectives of each major stakeholder.9 In the afternoon, a breakout session was held for stakeholders to propose data elements that should be included in the Delphi process to build the core minimum data set. Following the meeting, the uterine fibroids working group created an initial set of data elements based on the September 15, 2017, meeting, a review of the literature, regulatory expectations, and existing research efforts. The uterine fibroid working group consisted of 29 members, including practicing physicians, researchers, reviewers and medical officers from the FDA, industry representatives, and one patient partner who represented a large group of patients from the Fibroid Foundation.10 The full list of working group members is reported in online supplemental file 1. In the fall of 2017, the group streamlined their initial list from more than 350 data elements to about 200 data elements that could be used to begin the Delphi process.

The Delphi method is a group decision-making technique that was developed by Olaf Helmer and Norman Dalkey as part of an Air Force-sponsored Rand Corporation study in the early 1950s, for the purpose of addressing a specific military problem.11 The standard group decision-making technique, the consensus panel approach, brings experts together in a room to discuss an issue until a consensus emerges. The challenges with this traditional approach are that one person with a strong personality can have a large effect on the decision, and a lack of anonymity may introduce response bias. The Delphi method was developed to retain the strength of a joint consensus, while removing the potential bias from group dynamics and face-to-face responses. With the Delphi method, group input is received through a series of anonymous surveys, which are sent to a pre-selected group of experts. The questionnaires are answered anonymously and individually by each member of the group. Each survey also provides an opportunity for group members to introduce new options and suggestions in between rounds. Survey results of each round are collected, collated, and analyzed by a design team. Typically, responses with strong consensus (eg, >50%) are maintained for the next round, and responses that lack consensus are automatically dropped (eg, <50%). Subsequently, the results are summarized and discussed with the group. The questions for the next round are based on this analysis and discussion process. This process is repeated until a group consensus is reached. Usually, only two iterations are needed but sometimes as many as six rounds are needed before a consensus is reached.11–14 Most of these methodologies are standardized for CRN purposes and also used in maturity model framework development,15 and core minimum data set development for sterilization,16 pelvic organ prolapse,17 peripheral artery interventions,18 and prostrate ablation.19

The Delphi process for the uterine fibroids working group was initiated and completed over a 3-month period from June 2018 to August 2018. Two rounds of surveys were designed and administered by the analysis team at Weill Cornell Medicine and sent to the expert panelists through a secure anonymous online questionnaire (https://www.surveymonkey.com). The data collection forms from the COMPARE-UF registry20 were used as an initial basis for candidate data elements. The panelists were instructed to vote on which variables, from a clinical perspective, are the most important variables to study the safety and effectiveness of medical devices and procedures used to treat uterine fibroids. The first-round Delphi survey results were analyzed by the analysis team and discussed in a series of conference calls with the working group co-chairs. Any variable with less than 50% consensus was removed from the list of data elements and any variable with greater than 50% consensus was retained for the second-round survey. These results and open response suggestions were presented and discussed with the full working group until consensus was achieved on how to proceed for each variable and open response comment. For example, if a working group member saw value in one of the variables that received less than 50% consensus, the working group member would have the opportunity to bring this up for discussion in the working group conference calls and argue the case to retain this variable. The analysis team incorporated the results of these discussions into the design of the second-round survey and subsequently distributed the survey to the working group. The same process was repeated until the consensus was achieved on the final core minimum data set in August 2018. Although the Delphi process was completed in August 2018, the final core minimum data set was not fully approved until after a formal review process by the FDA was completed in 2019. On completion of this process, the coauthors drafted the manuscript from 2019 to 2020, and this manuscript also went through a formal review and approval process which was completed by the FDA in early 2021.

Results

Informatics work

To create a CRN that is capable of conducting patient-centered outcomes research for multiple women’s health conditions (WHT-CRN), the FDA partnered with the Office of the National Coordinator for Health Information Technology (ONC), the National Library of Medicine (NLM), and a multistakeholder community coordinated by MDEpiNet in a large project funded by the Patient-Centered Outcomes Research Trust Fund (PCORTF) administered by the Office of the Assistant Secretary for Planning and Evaluation of the US Department of Health and Human Services.22 Through this project, core minimum data sets were concurrently being developed for stress urinary incontinence, pelvic organ prolapse, sterilization, and long-acting and reversible contraception. In order to create a CRN capable of evaluating medical devices used for all of these conditions, it was imperative to harmonize common data elements among all of the clinical areas to ensure interoperability of data sets stemming from future registries. After the core minimum data sets were developed for each of these clinical conditions, the project team formed an informatics team consisting of representatives from the National Institutes of Health (NIH), FDA, NLM, and ONC to lead the harmonization of each of the core data sets.

This group identified, compared, and aggregated data elements for each of the clinical areas prior to modeling. Any data elements that were common in at least two of the clinical areas were reviewed and refined through an iterative and collaborative process with both the informatics team and the clinical working groups, resulting in an initial set of harmonized common data elements. Modeling of data elements entails creating a form for each of the clinical registries in the NIH Common Data Elements (CDE) repository. Each form contained the full harmonized set of data elements with their associated permissible values linked to standardized codes and the data elements required in the Health Level Seven International (HL7) profiles. Code sets were included from standard clinical vocabularies, including the Value Set Authority Center,23 the Current Procedural Terminology, the Healthcare Common Procedure Coding System, and the International Classification of Diseases. The clinical working group reviewed these forms and provided feedback before the data elements were added to the HL7 Women’s Health Technologies (WHT) CRN Implementation Guide (IG).24

ONC will use the harmonized list of data elements in the WHT-CRN IG to define the data collection instruments and collect data for testing during pilot activities. The WHT-CRN IG is built to be an interoperable data exchange standard that consists of the resources, profiles, value sets, capability statements and specific implementation guidance for organizations (eg, hospitals, provider groups, researchers) to receive system data that meet current WHT-CRN use cases. Please see figure 1A,B for illustrations of how the WHT-CRN data will be collected and accessed by organizations. The WHT-CRN IG will also provide a platform for new use cases. The goal of this project is to make women’s health data available for exchange among providers and authorized researchers. Because this is also a goal of the Patient-Centered Outcome Research Network (PCORNet) and this project has been funded by the PCORTF, the WHT-CRN IG requirements have been drawn from the PCORNet use cases and implementations.25 Additional implementations that support this IG include the US-Core IG (mapped to the ONC 2015 Edition Common Clinical Data Set; Structured Data Capture Fast Health Interoperability Resources (FHIR) IG (the framework for questionnaire and questionnaire response resources); and the Patient-Reported Outcomes (PRO) FHIR IG (the framework for the Questionnaire Resource for capturing Patient Reported Outcome data). ONC will create new profiles and extensions for data elements that are not mapped to existing profiles. Registries will pilot the WHT-CRN FHIR IG in a test production environment (eg, clinical or provider setting), and/or manufacturing setting for CRN specific capabilities.26 Please see online supplemental file 2 for further clarification on these concepts and a full list of acronyms used in this manuscript.

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Figure 1

The abstract model, actors, and the data flow for WHT-CRN data collection. (A,B) Detail the capabilities required to implement a WHT-CRN workflow from the point of data collection to access of that data for research. The abstract model for collecting WHT-CRN data focuses on collection from patients undergoing various treatments of interest using a combination of clinical care delivery systems like EHRs and independent applications. The abstract model for accessing collected data from women’s health registries focuses on the ability of researchers to access the data currently collected and persisted in the registries. CRN, coordinated registry network; EHRs, electronic health records; IT, information technology; WHT, Women’s Health Technologies.

During the project, registry participants and CRN partners will continuously update the core common data elements within the IG and the sets of individual registry core data elements that are not represented in the IG. NLM will continue modifying the Pilot Harmonization form in the NIH CDE repository to supply the most recent vocabulary in the IG. NLM plans to update the CDE repository to support hosting, editing, harmonization, and export of the WHT-CRN data elements and other future CRN data elements. The data will be in machine readable format for use by data collection software applications for easier harmonization and reuse by stakeholders, specifically registries capturing device-related information on conditions affecting women. Technical assistance from NLM to support these efforts will include video tutorials and guides. In addition, throughout the pilot, the FDA and other stakeholders will continue monitoring and evaluating the implementation of the IG and the harmonized data set within clinical registries to support the refinement process. Patient data will be protected by institutional firewalls at each of the CRN’s clinical sites, and authorized researchers will only be able to access CRN data after going through a data sharing agreement process that will be managed by the MDEpiNet Coordinating Center.

Discussion

Single-purpose registries face many challenges in addressing questions involving multiple therapies and conditions. By leveraging fewer resources to collect predefined data for a greater number of conditions and therapies, this CRN will improve real-world evidence generation while saving time and reducing cost. We envision that this CRN will demonstrate that data from the different sources (eg, electronic health records, registries) can be used to: (1) evaluate the effectiveness (ie, quality of life) and safety associated with differing treatment options for uterine fibroids; (2) provide a framework for clinical studies to be conducted within the infrastructure, including industry-sponsored studies conducted for pre-market and/or post-market regulatory purposes; and (3) allow healthcare providers to track surgeon volume, patient outcomes, and quality measures for quality improvement activities and to fulfill upcoming requirements for the Centers for Medicare & Medicaid Services Merit-based Incentive Payment System and maintenance of certification requirements.

By using a Delphi process that engaged multiple stakeholders with varying perspectives on uterine fibroid treatment devices, we were able to achieve consensus on a minimum data set of variables capable of evaluating the performance of uterine fibroid treatment devices and technologies. One of the key steps in creating the CRN for uterine fibroids was identifying a core data set that would require minimal data entry by clinicians but would also be comprehensive enough to conduct safety and effectiveness studies. It was also important that the core data set would be well-suited for new technologies that enter the market in the future. The included stakeholders foresee many applications for new uterine fibroid treatment devices and technologies in the coming years and believe that the data elements captured in this registry are generalizable to both existing devices and novel technologies that may enter the market in the future.

Because the correlation between fibroid anatomy and symptoms is poor, ‘objective’ measures of success such as residual fibroid volume are not particularly helpful for evaluating effectiveness and do not allow for comparisons between procedures which affect fibroid size and those which physically remove the fibroids or the uterus itself. In addition, the lack of standards for reporting fibroid imaging further limits the utility of anatomic measurements as a relevant outcome. The participants focused on patient-reported outcomes related to symptoms but recognized that there is also a lack of clinical consensus on how best to measure and report fibroid-related symptoms. If validated patient-reported instruments such as the Uterine Fibroid Symptom Health-Related Quality of Life (UFS-QoL)27 can be easily incorporated into clinical practice (perhaps through patient-facing electronic portals or applications), adding them to this core dataset would be important.

There are both general and specific limitations to our methodology. Although multiple stakeholders were represented, the final consensus obviously includes trade-offs and may not represent the priorities of individual stakeholders or those who did not participate. In addition, the desire to capture data that are currently routinely captured as part of clinical care means that other important outcomes are not included. In particular, because validated quality-of-life instruments are not regularly collected as part of routine practice, treatment effectiveness within the current data elements can only be estimated through identification of additional procedures after the index treatment. Nonetheless, our results are strengthened by the fact that all participants shared an equal influence on the outcomes and potential bias from group dynamics and face-to-face responses was avoided through the Delphi method.

In conclusion, the data elements identified through the consensus process meet several criteria. They represent items that are currently routinely captured as part of the clinical record, they include factors that influence patient and provider decisions about treatment options which may influence outcomes (eg, past treatments, pregnancy history, uterine anatomy), and include important outcomes related to safety. In addition, the final common data elements were developed with input from multiple stakeholders, including patients, clinicians, researchers, manufacturers, and the FDA. Ultimately, the establishment of a national infrastructure for collecting these data elements will enable the accrual of high-quality data on devices and technologies used for uterine fibroids in the context of a multipurpose CRN. Additionally, the WHT-CRN will address FDA strategic priorities by increasing the use of real-world evidence, engaging patient partners, and promoting collaborative communities.28

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