CME Offering:Treatment of In-Stent Restenosis for Saphenous Vein Grafts Using Intravascular Brachytherapy: Regulatory Challenges

Learning objectives. At the conclusion of this activity, the participant should be able to: 1) discern that SVG lumen diameters extend over a larger range than do native vessels, and this article provides justification for treating this increased range of vessel sizes with the 90Sr system; 2) observe that this article provides a framework for obtaining institutional approval for “off-label” use of the 90Sr system, in this case treatment within SVGs; and 3) readily determine the correct radiation dose and IVBT duration for a given lumen diameter and lesion length, regardless of whether it is a native vessel or SVG. Activity instructions. Successful completion of this activity entails reading the article, answering the test questions and obtaining a score of over 70%, and submitting the test and completed evaluation form to the address listed on the form. Tests will be accepted until the expiration date listed below. A certificate of completion will be mailed to you within 60 days. Estimated time to complete this activity: 1 hour Initial release date: February 6, 2004 Expiration date: February 6, 2005 Target audience. This educational activity is designed for cardiologists, nurses and cardiovascular technologists. Accreditation statements. Physicians: HMP Communications is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. HMP Communications designates this continuing medical education activity for a maximum 1 credit hour in category 1 credit toward the AMA Physician’s Recognition Award. Each physician should claim only those hours of credit that he/she actually spent in the educational activity. This activity has been planned and produced in accordance with the ACCME Essential Areas and Policies. Nurses: Provider approved by the California Board of Registered Nursing (Provider Number 13255) for 1.2 contact hours. ASRT. Radiologic Technologists: Activities approved by the American Medical Association (AMA category 1) are eligible for ARRT Category B credit as long as they are relevant to the radiologic sciences. Radiologic technologists, registered by the ARRT, may claim up to 12 Category B credits per biennium. This activity is approved for 1 AMA category 1 credit. SICP. This activity is approved for 1 contact hour by the Society of Invasive Cardiovascular Professionals. Commercial support disclosure. This educational activity has been supported by an educational grant from Novoste Corporation. Faculty disclosure information. All faculty participating in Continuing Medical Education programs sponsored by HMP Communications are expected to disclose to the activity audience any real or apparent conflict(s) of interest related to the content of their presentation. Drs. Rivard and Zinkin have received travel support from an educational grant from Novoste Corporation to Tufts-New England Medical Center. Drs. Mignano and Kimmelstiel have no real or apparent conflicts of interest. This article contains discussion of published and/or investigational uses of agents that are not indicated by the FDA. Neither HMP Communications nor Novoste Corporation recommends the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings.

---

ABSTRACT: Intravascular brachytherapy (IVBT) has been demonstrated to be successful and has become the standard of care for in-stent restenosis (ISR) in native coronary arteries. Due to unsatisfactory treatment options to address ISR in saphenous vein grafts (SVGs), an ever-increasing population in interventional practice as well as current FDA-approved indications for IVBT use, we sought institutional approval for off-label use of the 90Sr system (Beta-Cath™ System, Novoste Corporation, Norcross, Georgia) for the therapy of ISR in SVGs. Identification of institutional regulatory bodies and related procedures for obtaining off-label device use was performed. The IVBT written directive prescription and patient informed consent forms were revised to accurately administer radiation dose and to disclose the regulatory status of using IVBT for this anatomic site. While the specifics are outlined in this report, this process and the resources needed to obtain institutional approval for off-label IVBT will likely be similar at comparable institutions.

Key words: intravascular brachytherapy, saphenous vein grafts, off-label use

Introduction Intravascular brachytherapy (IVBT) is a well-established, approved therapy for in-stent restenosis (ISR) of native coronary arteries.^1–4 While the failure rate of repeat coronary interventions, such as balloon angioplasty, atherectomy, laser ablation and re-stenting, ranges from 50–85%, the IVBT failure rate using photon- or electron-emitting brachytherapy sources is generally less than 25%.⁵ While this failure rate is promising, the FDA-approved indications for IVBT use are limited, generally restricted to ISR of native coronary arteries over a fixed range of lumen diameters. Furthermore, the availability of drug-eluting stents (DES) and their related conveniences, such as less regulatory oversight and independence from the involvement of radiation oncologists and medical physicists, portends a shift of patients away from IVBT.⁶ However, the long-term safety and efficacy of DES under widespread use has not yet been demonstrated,^6,7 and some investigators have explored expanding the utility of IVBT treatment devices, such as for repeat irradiation^8,9 and for saphenous vein grafts (SVGs).^10–13 While IVBT for ISR in SVGs may be considered standard of care, there is no established method for implementing off-label use of radiation therapy devices.¹⁴ Furthermore, off-label use of IVBT is frowned upon by some members of the medical community;¹⁵ we consequently sought to obtain necessary institutional approvals for the off-label use of our current IVBT treatment device, the 90Sr system (Beta-Cath™ System, Novoste Corporation, Norcross, Georgia). This report documents the institutional approvals required to legitimately perform off-label IVBT in SVGs and complements related work defining the written directive prescription needed to administer the same treatment doses to the clinical point of interest.^16–18 Methods The 90Sr system is FDA approved for treatment of native coronary arteries having ISR and lumen diameters ranging from with 2.7 to 4.0 mm. A dose of 18.4 Gy is applied at a distance of r = 2 mm on the transverse-plane. This position corresponds to a depth of 0.5 mm and is the reference depth for all vessel lumen diameters. As relates to treating SVGs, we assumed the same physical dose and treatment position in comparison to native coronary arteries. However, the vessel lumen diameter range for SVGs is larger in comparison to native coronary arteries. We consequently calculated the written directive treatment doses using approved methodologies^19–23 to apply 18.4 Gy to a depth of 0.5 mm for SVGs having an inner lumen range of 2.0 to 5.0 mm.¹⁸ Once these doses were calculated, our written directive prescription was revised to include SVGs for the aforementioned lumen diameter range. Furthermore, the wording of our IVBT Patient Consent Form required clarification to describe the accepted use of IVBT for SVGs as performed in the medical community yet to particularly state that IVBT for SVGs is not FDA approved. Finally, we performed a literature search of salient publications and related work supporting justification to use IVBT for SVGs. Thoroughness of this literature search was enhanced by communications and guidance from clinical liaisons at the Novoste Corporation. The revised written directive and consent forms were then reviewed to determine if further additions were required based on knowledge gained from the literature review. Preparation of these materials benefited from a multidisciplinary approach, involving the radiation oncology medical disciplines as well as partners from industry. Results and Discussion With the revised written directive prescription (Figure 1), patient consent form (Figure 2) and supporting publications in hand, we contacted the Tufts-New England Medical Center Risk Management (legal) division to request guidance on how to proceed. Risk Management suggested that we first clear the project with our Institutional Review Board (IRB) to determine the investigational status of IVBT for SVGs. As there was existing literature that described use of IVBT for SVGs in a non-investigational environment with prescribed doses within the range accepted as standard of care, our IRB informed us that a clinical protocol was not required. The proposal for IVBT of SVGs was then reviewed by the Radiation Safety Committee (RSC) and its subcommittee on human use. The subcommittee confirmed the findings of our IRB that proposed treatments could happen outside of an IRB-approved investigational protocol and that the peer-review scientific literature presented clinical results of IVBT for SVGs in a non-investigational environment and with reasonable follow-up times. Full RSC approval soon followed the subcommittee approval. With review of the IRB and RSC findings, Risk Management suggested minor changes to the consent form and advised that only an attending physician, fellow or senior member of the resident staff (e.g., Chief Resident) obtain patient consent. To streamline pre-treatment process, patient consent for possible IVBT is now obtained by the cardiology staff instead of the radiation oncology staff. All approvals were obtained by February 28, 2003. Since IVBT for SVGs is performed in an identical manner to the procedure in native vessels, our practice (like that of colleagues that we surveyed) is to utilize the same billing methodology for IVBT regardless of vessel type. Conclusion Intravascular brachytherapy for the treatment of in-stent restenosis in native coronary arteries is a proven technology. Additional data is available for the treatment of in-stent restenosis of saphenous vein grafts with IVBT, even though it is not an approved indication by the FDA. We have obtained institutional approval to use IVBT to treat in-stent restenosis of SVGs according to the revised written directive prescription. We are now routinely using IVBT to treat these patients and we plan to present our clinical follow-up data later this year.