Using the Idea, Development, Exploration, Assessment, Long-Term Study Framework for Devices (IDEAL-D) to Better Understand the Evolution of Evidence Surrounding Fenestrated Abdominal Aortic Endovascular Grafts

Using the Idea, Development, Exploration, Assessment, Long-Term Study Framework for Devices (IDEAL-D) to Better Understand the Evolution of Evidence Surrounding Fenestrated Abdominal Aortic Endovascular Grafts Nikolaos Zacharias,1 Grace J. Wang,2 Art Sedrakyan,3 Jesse A. Columbo,1,4 Jonathan R. Boyle,5 and Philip P. Goodney,1,4 Lebanon, New Hampshire, Philadelphia, Pennsylvania, New York, New York, and Cambridge, United Kingdom

The use of fenestrated endovascular devices for repair of complex aortic aneurysms has increased to nearly 5,000 implantations annually among Medicare patients in the United States in recent years. Given that nearly all aspects of treatment for minimally invasive aortic intervention rely on medical devices to better care for patients with vascular disease, clearly understanding how new and innovative technology evolves over the life cycle of a medical device is an essential skill set for cardiovascular physicians. Despite the need for this understanding, there is no standard framework upon which cardiovascular physicians, regulators, and patients can rely on to better understand the evolution of evidence from product inception through adoption and long-term effectiveness evaluation. As the aforementioned devices are increasingly and broadly used, the need for a formal framework for regulation and device approval has emerged. The goal of this review is to describe the Idea, Development, Exploration, Assessment, Longterm Study Framework for Devices (IDEAL-D). This framework is a model developed recently by an international panel of experts dedicated to better understanding the data steps necessary to bring a device from idea to routine practice and further to marketing, approval, and monitoring. In this review, we use the example of fenestrated endovascular aortic devices to illustrate the IDEAL-D framework, how it can help cardiovascular physicians improve their understanding of new technology, and the evidence which surrounds it from inception to long-term use.

INTRODUCTION Implantable medical devices, such as those used in infrarenal endovascular abdominal aortic endovascular repair (EVAR), have become an essential

1 Section of Vascular Surgery, Dartmouth-Hitchcock Medical Center, Lebanon, NH. 2 Division of Vascular Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA. 3

Department of Surgery, Weill Cornell Medical College, New York,

NY. 4 The Dartmouth Institute for Health Policy and Clinical Practice, Lebanon, NH.

part of everyday cardiovascular care for patients with abdominal aortic aneurysms. The implantable devices that have enabled surgeons and interventionists to repair aortic aneurysms endoluminally have been studied for nearly 30 years1 using a Correspondence to: Philip P. Goodney, MD, MS, 1 Medical Center Drive, Lebanon, New Hampshire, 03756; E-mail: [email protected] Ann Vasc Surg 2019; 59: 293–299 https://doi.org/10.1016/j.avsg.2019.02.010 Ó 2019 Published by Elsevier Inc. Manuscript received: August 1, 2018; manuscript accepted: February 10, 2019; published online: 19 April 2019

5 Cambridge University Hospitals NHS Trust, Addenbrookes Hospital, Cambridge, UK.

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variety of observational, randomized, and registrybased data sources.2e9 Newer techniques in endovascular aortic surgery, such as fenestrated endovascular abdominal aortic aneurysm repair, have now become more common in vascular practice for patients with aortic aneurysms involving renal or mesenteric arteries. Increasingly complex endograft designs, with the incorporation of fenestrations and branches, have been used to treat juxtarenal, pararenal, and thoracoabdominal aneurysms.10 During the initial evolution of this technology, single-center and limited multicenter studies demonstrated to vascular physicians that fenestrated endografts can be used to treat complex aneurysms, potentially offering lower mortality and morbidity rates than traditional open repair.11e14 Results collected worldwide from the use of fenestrated endografts have resulted in an increase of patient-customized devices, and industry remains focused on developing the ideal endograft. However, little guidance exists for physicians, patients, and policymakers as to how this evidence should be studied and implemented when determining if this new technology is truly a step forward for patients facing high-risk treatments for cardiovascular disease.15 Marketing approval for devices, both in the European Union (EU) as well as the United States, has historically focused on proof of safety and short-term efficacy as a minimum requirement.15 In the United States, requirements for safety regulation are met with thirty-day outcome data, and requirements for efficacy with one-year outcomes. Once the aforementioned requirements have been attained, approval is then granted based on preclinical evidence alone, with no randomized control trials.16 Fenestrated endograft devices often develop complications such as migration, stenosis, occlusion of visceral fenestrations, and endoleaks beyond the one-year timepoint.11e14 Currently in the EU, the Conformit e Europ eenne mark requirements are being moved in a similar direction by the evolving medical device reform program.16 Similarly, in the United States, more invasive devices now generally require a rigorous ‘‘pivotal’’ clinical trial either through the Food and Drug Administration’s premarket approval pathway or within the 510k pathway. Nonetheless, the pathway by which approval occurs and by which evidence-based dissemination into practice is encouraged is opaque to many who treat patients with vascular disease. In this review, we discuss this pathway for evidence evaluation which emerged when a group of

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leaders in research, implantation science, clinical care, regulatory design, and evidence syntheses convened in 2009 to consider how devices evolve during the approval process. This framework, called the Idea, Development, Exploration, Assessment, Long-term study Framework for Devices (IDEALD), seeks to guide evidence evaluation at each step in a given technology’s life cycle. IDEAL-D’s potential to provide structure throughout a device life cycle offers a multitude of benefits for physicians, patients, and regulators alike, as they seek to best understand how to study and use new technology in the most efficient way possible. Why a Better Framework for Evidence Development is Necessary? Both EU and United States regulatory systems currently dichotomize device status as either premarket (not yet approved) or postmarket (approved). A system providing incentives for further evaluation and reporting at both early and later stages in the evolution of the device could create better evidence development and reporting and provide a more granular and descriptive pathway for evaluation at every ‘‘stage’’ of a given technology’s life cycle. If prospective registries were started from preclinical development used to monitor device performance through the outset of clinical use, late adverse events such as endoleak, endograft migration, or branch occlusion would be captured early and addressed accordingly. In the example of fenestrated aortic endografts, a framework such as this could potentially add value. It would help patients, physicians, and regulators better anticipate how this new technology will be studied over its life cycle and what quality of evidence to expect when making decisions about the use of these new tools and techniques. Data requirements for device approval and surveillance can be matched to the device’s stage of development, known as total product life cycle evaluation.17 This framework is described in this review to aid in dissemination for cardiovascular physicians, as was done with prior reviews published in Lancet,18 BMJ,16 and the Journal of Vascular Surgery.19 To add to this prior literature, this review uses the example of fenestrated endografts as an illustrative example for the framework. The IDEAL-D Framework The IDEAL-D framework, derived from the IDEAL framework which describes the development of new surgical procedures, was created by an expert consensus group at a series of conferences and

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meetings to describe what types of studies and reporting should be used for new surgical devices, from first use through adoption in practice.17 The IDEAL framework consists of five main stages (Fig. 1). Stage 0: Preclinical The first stage involves the preclinical development. For example, the application of the IDEAL-D framework to fenestrated endografts would entail the in vitro and bench testing involved in conceptualizing and testing devices before testing in vivo. Early reports of device concepts have had to balance intellectual property concerns, and this stage necessitates careful cooperation between investigators and registry personnel. Product design, materials, and functional components were developed and tested to prepare the device for first-in-human (stage 1) studies. In general, stage 0 could include animal studies to optimize the technique before human studies begin.17 Although reporting of preclinical research for fenestrated endograft devices is available, international minimum reporting standards for studies of therapeutic devices are lacking.20 Stage 1: Idea, First in Human The current IDEAL-D calls for an international registry of all first-in-human studies with a description made available to the public. The registry enables the surveillance and identification of the benefit and harm reported by first-in-human studies. Possible device-related adverse events can be detected at an early stage, ensuring that unsuccessful innovation is not repeated through ignorance. Physicians and device engineers would take the opportunity to review the registry before embarking on a first-in-human study to avoid repeating a harmful error reported by another investigator. For fenestrated endografts, an international registry was established in 2007 with the creation of the Global collaborators on advanced stent-graft techniques for aneurysm repair (GLOBALSTAR) project.21 The goals of this project included creating standardized follow-up protocols for patients undergoing EVAR of complex aortic aneurysms, developing reporting standards for the aforementioned techniques and providing an early warning system of complications specific to the techniques. The early results of the GLOBALSTAR registry were published in 2012 and included patients who underwent fenestrated EVAR of abdominal aortic aneurysms in the United Kingdom from 2007 to 2010.22 Three-year outcomes were reported as well. The GLOBALSTAR registry is in the process of recruiting and is a good paradigm of the importance of an international

Fig. 1. Stages in the IDEAL-D framework.

registry that will monitor, report, and compare outcomes and complications of fenestrated endografts, providing guidelines and indications for use to vascular surgeons all over the world. The ideal international registry will follow up the recruited patients for a long-period of time, identifying late complications such as endoleaks, migration, stenosis, and occlusion of visceral fenestrations. Stage 2: the Development and Exploration of New Treatment Paradigms The second stage involves the development and exploration stages. The development stage is characterized by rapid iterative changes in the device and is reflective of learning curves and lessons experienced by the operator. In the exploration stage, the device is usually more widely used, and observational studies collect prospective data to facilitate learning and familiarity with the device. In fenestrated endografts, this stage occurred in the first case reports which demonstrated safety and potentially early efficacy of these new devices (Table I). Further application of the IDEAL-D framework should describe the single-center series as well as small, multicenter reports that demonstrate the effectiveness of the device in preventing aneurysm rupture and bolster the argument that these devices can be used in everyday practice. Stage 3: Assessing the New Treatment in Rigorous Ways In the assessment stage, definitive observational studies should use a quasiexperimental study design with protocol-driven controlled studies, standardized eligibility, and prospective data collection. The

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Table I. IDEAL framework Stage 0

Stage 1

Stage 2

Stage 3

Stage 4

The idea

Development of evidence in registries

Exploration of new treatment paradigms

Assessing the new treatment in rigorous ways

Evaluating longterm outcomes

Question Can the fenestrated device safely and effectively repair complex aortic aneurysms?

Which type of aneurysm anatomy would benefit the most? Any adverse events?

Is the device safe and effective in treating ruptured aneurysms?

Would a valid experimental study be required to further evaluate the device?

How well is the device doing compared with the previously established devices after long-term follow-up?

Aim Proof of concept

Indications

Safety, efficacy

Efficacy

Comparative effectiveness

10s

100s

100s+

1000s

First-in-human studies

Single-center series or small multicenter reports

Randomized controlled trials, tracker trials, or adaptive designs

Creation of prospective registries for safety surveillance

Patient base Few Optimal study design In vitro and bench testing of the device

question raised in this stage of the IDEAL-D framework is whether randomized controlled trials are necessary for novel devices that are similar to existing postmarket devices. Even small modifications can potentially harm patients, suggesting that a clinical trial should be required for an implantable device.20,23 IDEAL-D allows for valid experimental designs, including randomized controlled trials, tracker trials, and adaptive designs. Studies based on economic modeling and reporting of health economic data for new devices are important additions to this stage.24e26 Stage 3 reports related to fenestrated endograft would begin to compare this new technology with established treatment mechanisms. Specifically, this would involve observational or randomized studies comparing fenestrated treatments with traditional surgery. Many would argue that at present, fenestrated endograft is in stage III of this framework. A good example representing stage 3 of the IDEAL framework is the UK COMPlex AneurySm Study, which is a risk-adjusted and anatomically stratified cohort comparison of open surgery, endovascular techniques, and medical management for juxtarenal aortic aneurysms (ISRCTN85731188). This study is planned to recruit patients from the spring of 2018 through June 2022 and is funded by the National Institute for Health Research and Health Technology Assessment Programme in England.

Stage 4: Evaluating Long-Term Outcomes In this stage, established procedures are assessed for rare and long-term outcomes and for variations in outcome. IDEAL-D recommends the design of registries for long-term follow-up. Prospective registries can be used for safety surveillance.27,28 Individual surgeons can access the registries, share experiences and adverse events, and identify device adverse events and structural inadequacies early on in the use of the new device. Finally, for fenestrated endografts, long-term outcomes within registries would represent an invaluable source of information about the longterm clinical effectiveness of these devices in preventing rupture. The more granular the evidence collected in the registry, the better the resolution would be in discerning the factors associated with good and bad outcomes. For example, unusual presentation of endoleaks could be identified over time, and reporting of these events can prevent further complications such as a delayed rupture.

DISCUSSION Highly innovative devices should normally be subjected to the entire integrated pathway of IDEAL-D stage studies, including prospective development and prospective exploration studies, randomized controlled trials, and registry studies. The extent to

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Table II. Outcomes of juxtarenal (JRAA) and thoracoabdominal (TAAA) aneurysm repair with fenestrated endografts Year

Patients

Aneurysm type

Perioperative mortality (%)

Mean follow-up (months)

2015 2017

166 127

TAAA JRAA, TAAA

7.8 0

29.2 9.2

Mastracci et al.31

2015

610

1

92

Ramanan et al.32 Sveinsson et al.33 Eagleton et al.34 Budtz-Lilly et al.35

2016 2015 2016 2017

134 288 354 71

JRAA and type IV TAAA JRAA JRAA TAAA (II and III) JRAA

94 (5 years) 96 primary and 98 secondary (1 year) Not reported

4 2 4.8 2.8

31 11 36 36

94 Not reported 97 (3 years) 92.7 (3 years)

Publication

Verhoeven et al. Oderich et al.30

29

which these stages are operationalized in everyday practice has varied to date, and a better framework to guide physicians in undertaking these steps, and in evaluating new devices, may help improve this process. Fenestrated endovascular grafts illustrate many of these challenges. The early evidence has largely evolved from single-center studies, and large multicenter trials are lacking at present. There are several large, single-center databases demonstrating the benefits of fenestrated endografts for juxtarenal and thoracoabdominal aneurysm repair (Table II). These nascent efforts in large-scale reporting of results3,29e32,34,35 can serve as a starting point for future efforts. Furthermore, while these devices have been studied in registries for short-term outcomes, few long-term, widely disseminated efforts at longitudinal surveillance in registries have been accomplished. Therefore, there are both short- and long-term gaps in the outcome assessment of these new devices, a challenge the IDEAL-D framework may help address. Finally, randomized comparisons, either between device types or in comparison to open surgery, have not been accomplished. IDEAL-D may help to frame these challenges in important ways. For example, in new devices with incremental changes to a basic design, not seeking to substantially change the mechanisms of action but to compete on other grounds, the role of a randomized controlled trial would be controversial. If novel (first in kind) devices initiated a registry when they reach IDEAL-D stage 4, subsequent similar devices could be required to join. This might provide the infrastructure to conduct subsequent randomized trials comparing the new competitors with the first device, using the ‘‘trials within cohorts’’ or ‘‘nested within registry’’ design approach. This framework has been used in some instances already. Since

Branch patency

2011, when this collaboration started, the principles of IDEAL-D have been evident in the Food and Drug Administration guidance documents.36,37 Vallabhanemi et al.21 published the nationwide early results of fenestrated EVAR in the United Kingdom. In this study, data on 318 patients were collected from 14 centers through the GLOBALSTAR database. Perioperative mortality was 4.1%, and intraoperative target vessel loss was 0.6%. Survival at three years was 89%, and freedom from secondary intervention was 70%. Finally, investigators in the UK COMPlex AneurySm Study trial have begun to enter patients in their registry, and these efforts will continue over the seven-year enrollment period of the study. In summary, an IDEAL-D framework may help to guide generation and collection of evidence for evolving innovations in aortic care. The case of fenestrated endografts represents a potential paradigm shift in regulatory evidence and may help improve the methods cardiovascular physicians use to develop, study, and implement new medical devices and technologies. We envision the creation of a prospective device database accessible to all hospitals, health-care facilities, and health-care providers, independent from industry or third-party commercial groups. The IDEAL-D database will be self-funded by hospitals or federal and scientific funds. Data entry and maintenance of the database will require dedicated personnel with clinical experience in the field of vascular surgery. Through a continuous evaluation process, more efficient ways to bring evidence to bear may ‘‘ideally’’ become achievable.

P.P.G. and A.S. were supported by a grant from the FDA (U01FD005478e01 [Sedrakyan ¼ PI]) as part of The Vascular Implant Surveillance and Interventional Outcomes Network (VISION).

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18. McCulloch P, Altman DG, Campbell WB, et al. No surgical innovation without evaluation: the IDEAL recommendations. Lancet 2009;374:1105e12. 19. Wang GJ, Goodney PP, Sedrakyan A. Conceptualizing treatment of uncomplicated type B dissection using the IDEAL framework. J Vasc Surg 2018;67:662e8. 20. Scheinert D, Pratesi C, Chiesa R, et al. First-in-human study of the INCRAFT endograft in patients with infrarenal abdominal aortic aneurysms in the INNOVATION trial. J Vasc Surg 2013;57:906e14. 21. Rao Vallabhaneni S, Brennan J, Buth J, et al. Global collaborators on advanced stent-graft techniques for aneurysm repair (GLOBALSTAR) project. J Endovasc Ther 2007;14: 352e6. 22. British Society for Endovascular T, the Global Collaborators on Advanced Stent-Graft Techniques for Aneurysm Repair R. Early results of fenestrated endovascular repair of juxtarenal aortic aneurysms in the United Kingdom. Circulation 2012;125:2707e15. 23. Smith AJ, Dieppe P, Vernon K, et al. Failure rates of stemmed metal-on-metal hip replacements: analysis of data from the National Joint Registry of England and Wales. Lancet 2012;379:1199e204. 24. Lilford RJ, Braunholtz DA, Greenhalgh R, et al. Trials and fast changing technologies: the case for tracker studies. BMJ 2000;320:43e6. 25. Chick S, Forster M, Pertile P. A Bayesian decision theoretic model of sequential experimentation with delayed response. J R Stat Soc Ser B 2017;79:1439e62. 26. Pennell CP, Hirst A, Sedrakyan A, et al. Adapting the IDEAL Framework and Recommendations for medical device evaluation: a modified Delphi survey. Int J Surg 2016;28:141e8. 27. Campion TR Jr, Johnson SB, Paxton EW, et al. Implementing unique device identification in electronic health record systems: organizational, workflow, and technological challenges. Med Care 2014;52:26e31. 28. Krucoff MW, Sedrakyan A, Normand SL. Bridging unmet medical device ecosystem needs with strategically coordinated registries networks. JAMA 2015;314:1691e2. 29. Verhoeven EL, Katsargyris A, Bekkema F, et al. Editor’s choice - ten-year experience with endovascular repair of thoracoabdominal aortic aneurysms: results from 166 consecutive patients. Eur J Vasc Endovasc Surg 2015;49: 524e31. 30. Oderich GRM, Hofer J, Wigham J, et al. Prospective, nonrandomized study to evaluate endovascular repair of pararenal and thoracoabdominal aortic aneurysms using fenestrated-branched endografts based on supraceliac sealing zones. J Vasc Surg 2017;65:1249e59. 31. Mastracci TM, Eagleton MJ, Kuramochi Y, et al. Twelveyear results of fenestrated endografts for juxtarenal and group IV thoracoabdominal aneurysms. J Vasc Surg 2015;61:355e64. 32. Ramanan BFC, Sobel JD, Gasper WJ, et al. Low-profile versus standard-profile multibranched thoracoabdominal aortic stent grafts. J Vasc Surg 2016;64:39e45. 33. Sveinsson M, Sobocinski J, Resch T, et al. Early versus late experience in fenestrated endovascular repair for abdominal aortic aneurysm. J Vasc Surg 2015;61: 895e901. 34. Eagleton MJ, Follansbee M, Wolski K, et al. Fenestrated and branched endovascular aneurysm repair outcomes for type

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II and III thoracoabdominal aortic aneurysms. J Vasc Surg 2016;63:930e42. 35. Budtz-Lilly J, Wanhainen A, Eriksson J, et al. Adapting to a total endovascular approach for complex aortic aneurysm repair: outcomes after fenestrated and branched endovascular aortic repair. J Vasc Surg 2017;66:1349e56. 36. Administration UFaD. Transcript for public workshopbridging the IDEAL and TPLC approaches for evidence

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development for surgical medical devices and procedures 2011. 37. Administration UFaD. Investigational device exemptions (IDEs) for early feasibility medical device clinical studies, including certain first in human (FIH) studies. Guidance for Industry and Food and Drug Administration Staff. Online 2013. Available at: https://www.fda.gov/downloads/ medicaldevices/deviceregulationandguidance/guidancedocu ments/ucm279103.