Health Evidence Review Commission

January 18, 2018 1:30 PM - 4:30 PM

Barbara Roberts Human Services Building Room 137A-D 500 Summer Street NE Salem OR 97301 Section 1.0 Call to Order AGENDA HEALTH EVIDENCE REVIEW COMMISSION Barbara Roberts Human Services Building 500 Summer Street, NE, Rooms 137A-D Salem, Oregon January 18, 2018 1:30-4:30 pm (All agenda items are subject to change and times listed are approximate)

Action # Time Item Presenter Item 1 1:30 PM Call to order Kevin Olson 2 1:35 PM Approval of minutes (1/5/18) Kevin Olson X 3 1:40 PM Director’s report Darren Coffman Ariel Smits 4 1:45 PM Value-based Benefits Subcommittee report X Cat Livingston Minimally invasive and non-corticosteroid percutaneous interventions for low back pain Adam Obley 5 2:15 PM X • Coverage guidance Cat Livingston • Prioritized List changes 3:00 PM Gene expression profiling for prostate cancer Adam Obley 6 • Coverage guidance X • Prioritized List changes Wally Shaffer 7 3:45 PM Conflict of interest forms Jason Gingerich X Next steps 8 4:20 PM  Schedule next meeting – March 8, 2018 Kevin Olson Wilsonville Training Center, rooms 111-112 9 4:30 PM Adjournment Kevin Olson

Note: Public comment will be taken on each topic per HERC policy at the time at which that topic is discussed.

MINUTES

HEALTH EVIDENCE REVIEW COMMISSION Lincoln Building Transformation Center Conference Room Teleconference Portland, Oregon January 5, 2018

Members Present (all by phone): Kevin Olson, MD, Chair; Mark Gibson; Leda Garside, RN, MBA; Angela Senders, ND; Holly Jo Hodges, MD; Devan Kansagara, MD; Lynnea Lindsey, PhD; Leslie Sutton; Adriane Irwin, PharmD.

Members Absent: Susan Williams, MD; Gary Allen, DMD.

Staff Present: Darren Coffman; Ariel Smits, MD, MPH (by phone); Denise Taray, RN (by phone); Jason Gingerich.

Also Attending: Jeremy Vandehey (Oregon Health Authority); Ted Falk (DOJ); Meganne Leach (OHSU); Rocky Dallum, (Tonken Torp/Sarepta); Alison Little, MD, MPH (Pacific Source); Courtney Iverson (Pac/West).

Call to order

Darren Coffman, Director of the Health Evidence Review Commission (HERC), called the meeting to order at 9:05 a.m.; roll was called. Coffman welcomed Adrian Irwin as it was her first meeting.

Chair election

Garside nominated Olson as Chair, who accepted the nomination. There were no other nominations.

MOTION: Elect Kevin Olson as Chair of the Health Evidence Review Commission. CARRIES 9-0.

A vice-chair will be elected at a later meeting.

Minutes approval

MOTION: To approve the minutes of the 11/9/20107 meeting as presented. CARRIES 8-0. (Irwin abstained)

HERC Minutes 1/5/2018 1

Prioritization of eteplirsen and deflazacort for treatment of Duchenne muscular dystrophy Meeting materials, pages 78-79

Coffman said the reason for the meeting is to revisit the Commission’s decision in September and November, 2017 to place deflazacor and eteplirsen on lines 500 and 660, respectively. The consideration for placing certain drugs on these lines of the Prioritized List is a new area of work for HERC. Drug manufacturers have raised questions about federal rebate law which requires states to cover certain FDA-approved drugs. From the time the decision was made by HERC regarding eteplirsen, those objecting to the November 9th decision have 60 days to file a lawsuit. As we are bumping against 60 days, OHA recommended that HERC remove the two drugs from their placement below the funding line on the Prioritized List for the time being. This will allow OHA and HERC more time to review the legal questions that were raised and determine the best path forward for addressing drugs with marginal or no established clinical benefit, harms that outweighs benefits, or have low cost-effectiveness. OHA is not questioning the evaluation of the evidence of these drugs. Rather, OHA will be reviewing the process and authority to place these drugs on the list.

Vandehey thanked the Commission for its service and expressed appreciation for the Commission’s work and its commitment to use the best evidence to prioritize benefit. The issue is about taking the time to hit pause and remove the drugs from the list while legal analysis related to this work proceeds. Leadership is watching other states processes as well.

Members asked if there is a time estimate for how long it will take to do the further review. Vandehey said there is not a time-frame but they will have a better sense by the March HERC meeting.

Members asked if this potential decision will allow patients to receive the medication temporarily. Coffman said by taking these drugs off lines 500 and 660, the drugs become an ancillary service and just like other drugs that are not called out; they would be covered if medically appropriate and meeting other criteria including prior authorization (PA) criteria already adopted by the P&T Committee. The PA criteria for eteplirsen mirrors the FDA criteria while the deflazacort PA states it as being second-line therapy, after a failure of prednisone. Roger Citron, staff to the P&T Committee, confirmed this information.

Vandehey confirmed that HERC would not take up any new drug topics during this process review period.

Public Comment

Written comment received from CCO medical director from Samaritan Health was forwarded to all members. The testimony was in support of the Commission’s original decision to place the drugs in question on lines 500 and 660.

Meganne Leach, nurse practitioner at OHSU and Doernbecher Children’s Hospital, who is in support of covering eteplirsen. She thanked Commission for potentially removing the low-prioritization of these drugs and allowing treatment. This is an exciting time as more information about the efficacy of the drug is forthcoming.

HERC Minutes 1/5/2018 2

HERC Staff Recommendations: 1. To remove deflazacort (Emflaza) from Guideline Note 172, and thereby line 500, due to procedural issues, while still affirming our finding that this drug has marginal benefit/low cost-effectiveness compared to equally effective but much less expensive alternative corticosteroids. 2. To remove eteplirsen (Exondys 51) from Guideline Note 173, and thereby line 660, due to procedural issues, while still affirming that we have not found this drug to have a clinically important benefit.

MOTION: To approve the staff recommendation to remove the drugs deflazacor and eteplirsen from lines 500 and 660 respectively. Carries 8-1. (Opposed: Gibson)

Next steps

Staff will publish a revised Prioritized List and Health Services Division will adopt a rule to incorporate the approved changes.

Olson asked about a communication plan. Vandehey said a letter was sent to the CCO CEOs and medical directors. There are questions about impact on rates and the Actuarial Services Unit is looking at some other actuarial issues.

Hodges expressed her discomfort about going forward without a timeline and wanted to set one by the next HERC meeting. Vendehey commented he would provide one by the January 18th HERC meeting.

Gibson explained his vote, expressing disappointment that members of the Commission are put in a situation where they cannot fully use evidence and clinical research to govern the Oregon Health Plan. He hoped that Oregon will be aggressive and work with other states so we can use evidence to make sound decisions in our health care programs. Others echoed this sentiment.

Hodges shared, for the record, there were 44 interested listeners on the call.

Adjournment

Meeting adjourned at 9:37 a.m. Next meeting will be from 1:30-4:30 pm on Thursday, 1/18/2018 at Barbara Robert’s Human Services Building, Rooms 137A-D, Salem, Oregon 97301.

HERC Minutes 1/5/2018 3 Section 2.0 VbBS Report Errata January 1, 2018

Errata to the 1/1/2018 Prioritized List 1. On 12/28/2017 the following corrections were posted to the pending prioritized list: a. HCPCS codes G0157-G0161 (Services performed by a qualified … therapist assistant in the home health or hospice setting) were added to line 81 FRACTURE OF HIPS. b. The placements of these new codes were corrected as follows:

Code Code Description Correct placement Previous Placement 31241 Nasal/sinus endoscopy, surgical; with ligation of sphenopalatine 463 CHRONIC SINUSITIS 469,509 artery 504 NASAL POLYPS, OTHER DISORDERS OF NASAL CAVITY AND SINUSES 1/18/2018

31253 Nasal/sinus endoscopy, surgical with ethmoidectomy; total (anterior 463 CHRONIC SINUSITIS 469,509 and posterior), including frontal sinus exploration, with removal of 504 NASAL POLYPS, OTHER DISORDERS tissue from frontal sinus, when performed OF NASAL CAVITY AND SINUSESfrom

31257 Nasal/sinus endoscopy, surgical with ethmoidectomy; total (anterior 463 CHRONIC SINUSITIS 469,509 and posterior), including sphenoidotomy 504 NASAL POLYPS, OTHER DISORDERS OF NASAL CAVITY AND SINUSES

31259 Nasal/sinus endoscopy, surgical with ethmoidectomy; total (anterior 463 CHRONIC SINUSITIS 469,509 and posterior), including sphenoidotomy, with removal of tissue 504 NASAL POLYPS, OTHER DISORDERS from the sphenoid sinus DocumentsOF NASAL CAVITY AND SINUSES

31298 Nasal/sinus endoscopy, surgical; with dilation of frontal and 463 CHRONIC SINUSITIS 469,509 sphenoid sinus ostia (eg, balloon dilation) 504 NASAL POLYPS, OTHER DISORDERS OF NASAL CAVITY AND SINUSES Summary

32994 Ablation therapy for reduction or eradication of 1 or more 263 CANCER OF LUNG, BRONCHUS, 267 pulmonary tumor(s) including pleura or chest wall when involved by PLEURA, TRACHEA, MEDIASTINUM AND tumor extension, percutaneous, including imaging guidance when OTHER RESPIRATORY ORGANS performed, unilateral; cryoablation Issue 34701 Endovascular repair of infrarenal aorta by deployment of an aorto- 284 DISSECTING OR RUPTURED AORTIC 289,330 aortic tube endograft including pre-procedure sizing and device ANEURYSM selection, all nonselective catheterization(s), all associated 325 NON-DISSECTING ANEURYSM radiological supervision and interpretation, all endograft ex WITHOUT RUPTURE VbBS

1/11/2018

Code Code Description Correct placement Previous Placement 34702 Endovascular repair of infrarenal aorta by deployment of an aorto- 284 DISSECTING OR RUPTURED AORTIC 289,330 aortic tube endograft including pre-procedure sizing and device ANEURYSM selection, all nonselective catheterization(s), all associated 325 NON-DISSECTING ANEURYSM radiological supervision and interpretation, all endograft ex WITHOUT RUPTURE

34703 Endovascular repair of infrarenal aorta and/or iliac artery(ies) by 284 DISSECTING OR RUPTURED AORTIC 289,330 deployment of an aorto-uni-iliac endograft including pre-procedure ANEURYSM sizing and device selection, all nonselective catheterization(s), all 325 NON-DISSECTING ANEURYSM associated radiological supervision and interpret WITHOUT RUPTURE 1/18/2018 34704 Endovascular repair of infrarenal aorta and/or iliac artery(ies) by 284 DISSECTING OR RUPTURED AORTIC 289,330 deployment of an aorto-uni-iliac endograft including pre-procedure ANEURYSM sizing and device selection, all nonselective catheterization(s), all 325 NON-DISSECTING ANEURYSM associated radiological supervision and interpret WITHOUT RUPTURE from

34705 Endovascular repair of infrarenal aorta and/or iliac artery(ies) by 284 DISSECTING OR RUPTURED AORTIC 289,330 deployment of an aorto-bi-iliac endograft including pre-procedure ANEURYSM sizing and device selection, all nonselective catheterization(s), all 325 NON-DISSECTING ANEURYSM associated radiological supervision and interpreta WITHOUT RUPTURE

34706 Endovascular repair of infrarenal aorta and/or iliac artery(ies) by 284 DISSECTING OR RUPTURED AORTIC 289,330 deployment of an aorto-bi-iliac endograft including pre-procedure ANEURYSM sizing and device selection, all nonselective catheterization(s), all 325 NON-DISSECTING ANEURYSM associated radiological supervision and interpreta DocumentsWITHOUT RUPTURE

34707 Endovascular repair of iliac artery by deployment of an ilio-iliac tube 325 NON-DISSECTING ANEURYSM 330 endograft including pre-procedure sizing and device selection, all WITHOUT RUPTURE nonselective catheterization(s), all associated radiological supervision and interpretation, and all endograft exte

34708 Endovascular repair Summaryof iliac artery by deployment of an ilio-iliac tube 325 NON-DISSECTING ANEURYSM 330 endograft including pre-procedure sizing and device selection, all WITHOUT RUPTURE nonselective catheterization(s), all associated radiological supervision and interpretation, and all endograft exte Issue 34709 Placement of extension prosthesis(es) distal to the common iliac 284 DISSECTING OR RUPTURED AORTIC 289,330 artery(ies) or proximal to the renal artery(ies) for endovascular ANEURYSM repair of infrarenal abdominal aortic or iliac aneurysm, false 325 NON-DISSECTING ANEURYSM aneurysm, dissection, penetrating ulcer, including pre-proce WITHOUT RUPTURE VbBS

H-2

Code Code Description Correct placement Previous Placement 34710 Delayed placement of distal or proximal extension prosthesis for 284 DISSECTING OR RUPTURED AORTIC 289,330 endovascular repair of infrarenal abdominal aortic or iliac aneurysm, ANEURYSM false aneurysm, dissection, endoleak, or endograft migration, 325 NON-DISSECTING ANEURYSM including pre-procedure sizing and device selection, all WITHOUT RUPTURE

34711 Delayed placement of distal or proximal extension prosthesis for 284 DISSECTING OR RUPTURED AORTIC 289,330 endovascular repair of infrarenal abdominal aortic or iliac aneurysm, ANEURYSM false aneurysm, dissection, endoleak, or endograft migration, 325 NON-DISSECTING ANEURYSM including pre-procedure sizing and device selection, all WITHOUT RUPTURE 1/18/2018 34713 Percutaneous access and closure of femoral artery for delivery of 325 NON-DISSECTING ANEURYSM 330 endograft through a large sheath (12 French or larger), including WITHOUT RUPTURE ultrasound guidance, when performed, unilateral (List separately in addition to code for primary procedure) from

34715 Open axillary/subclavian artery exposure for delivery of 325 NON-DISSECTING ANEURYSM 330 endovascular prosthesis by infraclavicular or supraclavicular incision, WITHOUT RUPTURE unilateral (List separately in addition to code for primary procedure)

36465 Injection of non-compounded foam sclerosant with ultrasound 379 CHRONIC ULCER OF SKIN compression maneuvers to guide dispersion of the injectate, 514 PHLEBITIS AND inclusive of all imaging guidance and monitoring; single incompetent THROMBOPHLEBITIS, SUPERFICIAL extremity truncal vein (eg, great saphenous vein, accessory 517 POSTTHROMBOTIC SYNDROME saphenous vein) 637 VARICOSE VEINS OF LOWER DocumentsEXTREMITIES WITHOUT ULCER OR OTHER MAJOR COMPLICATION

384,519,522,6 43 36466 Injection of non-compounded foam sclerosant with ultrasound 379 CHRONIC ULCER OF SKIN compression maneuvers to guide dispersion of the injectate, 514 PHLEBITIS AND inclusive of all imaging guidance and monitoring; multiple THROMBOPHLEBITIS, SUPERFICIAL incompetent truncal veins (eg, great saphenous vein, accessory 517 POSTTHROMBOTIC SYNDROME saphenous ve Summary 637 VARICOSE VEINS OF LOWER EXTREMITIES WITHOUT ULCER OR OTHER MAJOR COMPLICATION

384,519,522,6 Issue 43

VbBS

H-3

Code Code Description Correct placement Previous Placement 38573 Laparoscopy, surgical; with bilateral total pelvic lymphadenectomy 112 CANCER OF TESTIS and peri-aortic lymph node sampling, peritoneal washings, 133 CANCER OF CERVIX peritoneal biopsy(ies), omentectomy, and diaphragmatic washings, 209 CANCER OF UTERUS including diaphragmatic and other serosal biopsy(ies), when perf 239 CANCER OF OVARY 271 CANCER OF BLADDER AND URETER 286 CANCER OF VAGINA, VULVA, AND OTHER FEMALE GENITAL ORGANS 329 CANCER OF PROSTATE GLAND

116,137,213,2 1/18/201843,275,291,33 4 43286 Esophagectomy, total or near total, with laparoscopic mobilization 56 ULCERS, GASTRITIS, DUODENITIS, of the abdominal and mediastinal esophagus and proximal AND GI HEMORRHAGE gastrectomy, with laparoscopic pyloric drainage procedure if 64 CONGENITAL ANOMALIES OF UPPER performed, with open cervical pharyngogastrostomy or ALIMENTARY TRACT, EXCLUDINGfrom esophagogastrosto TONGUE 314 CANCER OF ESOPHAGUS; BARRETT'S ESOPHAGUS WITH DYSPLASIA

60,68,319 43287 Esophagectomy, distal two-thirds, with laparoscopic mobilization of 56 ULCERS, GASTRITIS, DUODENITIS, the abdominal and lower mediastinal esophagus and proximal AND GI HEMORRHAGE gastrectomy, with laparoscopic pyloric drainage procedure if 64 CONGENITAL ANOMALIES OF UPPER performed, with separate thoracoscopic mobilization ofDocuments the middle ALIMENTARY TRACT, EXCLUDING TONGUE 314 CANCER OF ESOPHAGUS; BARRETT'S ESOPHAGUS WITH DYSPLASIA

60,68,319 43288 Esophagectomy, total or near total, with thoracoscopic mobilization 56 ULCERS, GASTRITIS, DUODENITIS, of the upper, middle,Summary and lower mediastinal esophagus, with AND GI HEMORRHAGE separate laparoscopic proximal gastrectomy, with laparoscopic 64 CONGENITAL ANOMALIES OF UPPER pyloric drainage procedure if performed, with open cervical phar ALIMENTARY TRACT, EXCLUDING TONGUE 314 CANCER OF ESOPHAGUS; BARRETT'S ESOPHAGUS WITH DYSPLASIA Issue

60,68,319 VbBS

H-4

Code Code Description Correct placement Previous Placement 58575 Laparoscopy, surgical, total hysterectomy for resection of 133 CANCER OF CERVIX malignancy (tumor debulking), with omentectomy including 209 CANCER OF UTERUS salpingo-oophorectomy, unilateral or bilateral, when performed 239 CANCER OF OVARY 286 CANCER OF VAGINA, VULVA, AND OTHER FEMALE GENITAL ORGANS

137,213,243,2 91 97127 Therapeutic interventions that focus on cognitive function (eg, 92 SEVERE/MODERATE HEAD INJURY: 96,182,200,20 attention, memory, reasoning, executive function, problem solving, HEMATOMA/EDEMA WITH PERSISTENT 6,290,322,350 and/or pragmatic functioning) and compensatory strategies to SYMPTOMS ,382 manage the performance of an activity (eg, managing time or sc 178 INTRACEREBRAL HEMORRHAGE 196 SUBARACHNOID AND 1/18/2018 INTRACEREBRAL HEMORRHAGE/HEMATOMA; CEREBRAL ANEURYSM; COMPRESSION OF BRAIN 202 CHRONIC ORGANIC MENTAL DISORDERS INCLUDING DEMENTIAS 285 COMPLICATIONS OF Afrom PROCEDURE ALWAYS REQUIRING TREATMENT 317 STROKE 345 NEUROLOGICAL DYSFUNCTION IN COMMUNICATION CAUSED BY CHRONIC CONDITIONS 377 DYSFUNCTION RESULTING IN LOSS OF ABILITY TO MAXIMIZE LEVEL OF INDEPENDENCE IN SELF-DIRECTED CARE CAUSED BY CHRONIC CONDITIONS THAT CAUSE NEUROLOGICAL DYSFUNCTION Documents

Summary

2. On 12/1/2017 the following corrections were posted with the pending Prioritized List: a. The coding specification for line 393 was corrected to read as follows: Issue i. Chemodenervation with botulinum toxin injection (CPT 67345) is included on this line for the treatment of strabismus due to other neurological disorders (ICD-10 H50.89). CPT 92065 is included on Line 393 only for pairing with ICD-10 H50.31 intermittent monocular esotropia), H50.32 (Intermittent alternating esotropia), H50.33 (Intermittent monocular VbBS exotropia), and H50.34 (Intermittent alternating exotropia). b. Guideline note 76 was edited to include the following previously-omitted text:

H-5

The following tests are not included on this line (or any other line): 1. Real time tissue elastography 2. Hepascore (FibroScore) c. The following changes were made to evaluation and management codes: i. Add CPT code 99328 to line 332 CONDITIONS REQUIRING HYPERBARIC OXYGEN THERAPY. ii. Added standard inpatient codes 99339,99340,99341,99342,99343,99344, 99345, 99347, 99348,99349,99350,99358,99359,99360,99366,99367, 99368,99374,99375,99377,99378,99379,99380,99381,99382,99383,99384, 99385,99386,99387,99391,99392,99393,99394,99395,99396,99397,99415, 99416,99429,99487,99489,99495 and 99496 to lines 346 CONDITIONS OF THE BACK AND SPINE WITH URGENT SURGICAL INDICATIONS, 361 SCOLIOSIS, and 527 CONDITIONS OF THE BACK AND SPINE WITHOUT1/18/2018 URGENT SURGICAL INDICATIONS. iii. Add codes 99360,99415,99416,99429,99495,99496 to line 401 CONDITIONS OF THE BACK AND SPINE. iv. Added codes 99415 and 99416 to line 400 BENIGN fromCONDITIONS OF BONE AND JOINTS AT HIGH RISK FOR COMPLICATIONS. v. Added codes 99415 and 99416 to line 659 MISCELLANEOUS CONDITIONS WITH NO OR MINIMALLY EFFECTIVE TREATMENTS OR NO TREATMENT NECESSARY.

Documents

Summary

Issue

VbBS

H-6

Consent Agenda Issues—January, 2018

Code Code Description Line(s) Involved Issue Recommendation(s) 65435 Removal of corneal epithelium; 310 CORNEAL OPACITY AND HSD requested that 65435 pair Add 65435 to line 310 with or without OTHER DISORDERS OF CORNEA with corneal dystrophy on line chemocauterization (abrasion, 310. Currently, 65435 is on lines curettage) 113,435. Similar codes for other types of procedures for removal1/18/2018 of the cornea are on line 310. 66682 Suture of iris, ciliary body 404 APHAKIA AND OTHER HSD requested that 66682 be Add 66682 to line 404 (separate procedure) with DISORDERS OF LENS paired with dislocation of the lens retrieval of suture through online 404. Thefrom McCannel suture small incision (eg, McCannel is used to relocate a slipped lens suture) to the iris. 66682 is currently on lines 296, 336. 50590 Lithotripsy, extracorporeal 180 URETERAL STRICTURE OR HSD requested pairing of 50590 Add 50590 to line 180 shock wave OBSTRUCTION; with hydronephrosis diagnoses on HYDRONEPHROSIS; line 180. ICD10 N13.2 HYDROURETER (Hydronephrosis with renal and ureteral calculous obstruction) is on line 180. 50590 is currently on Documentsline 352 URINARY SYSTEM CALCULUS 50432 Placement of nephrostomy 275 UROLOGIC INFECTIONS HSD requested that 50432 and Add 50432 and 52332 to line 275 catheter, percutaneous, 52332 pair with pyonephrosis on including diagnostic line 275. 50432 is on lines nephrostogram and/or 180,231,352. 52332 is on lines ureterogram when performed, 47,80,180,271,352. Typical imaging guidance (eg, treatment of pyonephrosis is stent ultrasound and/or fluoroscopy) or nephrostomy tube placement. and all associated radiologicalSummary supervision and interpretation 52332 Cystourethroscopy, with insertion of indwelling ureteral stent (eg, Gibbons or double-J type) Issue

1 VbBS Consent Agenda Issues—January, 2018

Code Code Description Line(s) Involved Issue Recommendation(s) 11012 Debridement including removal 81 FRACTURE OF HIP HSD requested that 11012 pair Add 11012 and 27122 to line 81 of foreign material at the site with open hip fracture diagnoses. of an open fracture and/or an The closest code for open hip open dislocation (eg, excisional fracture is an unspecified hip debridement); skin, fracture code which is on line1/18/2018 81. subcutaneous tissue, muscle 11012 is on 17 lines. fascia, muscle, and bone 27122 Acetabuloplasty; resection, HSD requested that 27122 pair femoral head (eg, Girdlestone with hip fracturefrom diagnoses. The procedure) Girdlestone procedure is indicated for failed internal fixation of femoral neck fractures. 27122 is on lines 292,356,359,425,503,525 11740 Evacuation of subungual 208 DEEP OPEN WOUND, WITH HSD requested that 11740 pair Add 11740 to line 208 hematoma OR WITHOUT TENDON OR NERVE with laceration of the toe with nail INVOLVEMENT damage, which is on line 208. 11740 is on lines 131, 132, 206, 289, 355,583,632. 61020 Ventricular puncture through 285 COMPLICATIONS DocumentsOF A HSD requested that 61020 pair Add 61020 to line 285 previous burr hole, fontanelle, PROCEDURE ALWAYS REQUIRING with T85.730 (Infection and suture, or implanted TREATMENT inflammatory reaction due to ventricular catheter/reservoir; ventricular intracranial without injection (communicating) shunt). 61020 is currently on lines 19,68,371 90869 Therapeutic repetitive 7 MAJOR DEPRESSION, A provider requested that 90869 Add 90869 to line 7 transcranial magnetic RECURRENT; MAJOR DEPRESSION, be added to line 7. During the stimulation (TMS) treatment; SINGLE EPISODE, SEVERE coverage guidance review of TMS, subsequent motor threshold Summary 90867 and 90868 (similar TMS re-determination with delivery codes) were added to line 7. and management 90869 was not identified during that review and was not considered for addition to line 7 in Issue error.

2 VbBS Consent Agenda Issues—January, 2018

Code Code Description Line(s) Involved Issue Recommendation(s) 11005 Debridement of skin, 285 COMPLICATIONS OF A HSD requested that 11005, 44180, Add 11005, 44180, 62142, and subcutaneous tissue, muscle PROCEDURE ALWAYS REQUIRING 62142, and 69602 pair with 69602 to line 285 and fascia for necrotizing soft TREATMENT infection due to grafts or implants.1/18/2018 tissue infection; abdominal These codes are all on covered wall, with or without fascial lines closure 44180 Laparoscopy, surgical, enterolysis (freeing of intestinal from adhesion) 62142 Removal of bone flap or prosthetic plate of skull 69602 Revision mastoidectomy; resulting in modified radical mastoidectomy

Documents Various Inpatient CPT codes 118 NUTRITIONAL DEFICIENCIES There are currently no inpatient Add inpatient CPT codes to line CPT codes on line 118. There are 118 diagnoses that might require hospitalization on that line, such as kwashiorkor.

H0038 Self-help/peer services, per 15 62 SUBSTANCE-INDUCED MOOD, HSD requested that H0038 be Add H0038 to lines 62 and 312 minutes SummaryANXIETY, DELUSIONAL AND paired with stimulant-induced OBSESSIVE-COMPULSIVE anxiety disorder on line 62 and DISORDERS with gender dysphoria on line 312. 312 GENDER H0038 is currently on 35+ lines. DYSPHORIA/TRANSEXUALIS Issue

3 VbBS Consent Agenda Issues—January, 2018

Code Code Description Line(s) Involved Issue Recommendation(s) 10140 Incision and drainage of 1 Pregnancy HSD requested that 10140 be Add 10140 to line 1 hematoma, seroma or fluid paired with obstetrical wound collection disruption.10140 is currently on the complications lines; however, obstetrical wound complications1/18/2018 are coded with specific ICD-10 codes found only on line 1. 33750 Shunt; subclavian to pulmonary 77 PATENT DUCTUS ARTERIOSUS; HSD requested that 33750 be Add 33750 to line 77 artery (Blalock-Taussig type AORTIC PULMONARY paired with patentfrom ductus operation) FISTULA/WINDOW arteriosus. 33750 is currently on multiple congenital heart lines. 33606 Anastomosis of pulmonary 134 INTERRUPTED AORTIC ARCH HSD requested 33606 pair with Add 33606 to line 134 artery to aorta (Damus-Kaye- interrupted aortic arch. 33606 is Stansel procedure) currently on 105 TETRALOGY OF FALLOT (TOF); CONGENITAL VENOUS ABNORMALITIES, but literature search finds that it is being used for more types of Documentscongenital heart disease.

75573 Computed tomography, heart, 134 INTERRUPTED AORTIC ARCH HSD requested that 75573 be Add 75573 to line 134 with contrast material, for added to line 134. 75573 is on evaluation of cardiac structure 20+ other congenital heart disease and morphology in the setting lines. of congenital heart disease (including 3D image postprocessing, assessment of LV cardiac function, RV Summary structure and function and evaluation of venous structures, if performed) Issue

4 VbBS Consent Agenda Issues—January, 2018

Code Code Description Line(s) Involved Issue Recommendation(s) Q25.49 Other congenital 77 PATENT DUCTUS ARTERIOSUS; HSD requested that 33702 (Repair Add Q25.49 to line 77 malformations of aorta AORTIC PULMONARY sinus of Valsalva fistula, with FISTULA/WINDOW cardiopulmonary bypass) pair with Q25.49 (). Q25.49 is the correct code for sinus of Valsalva fistula.1/18/2018 It is currently on 3 other congenital heart disease lines as it may be used for a variety of diagnoses. from

52332 Cystourethroscopy, with 49 CONGENITAL HSD requested that 52332 pair Add 52332 to line 49 insertion of indwelling ureteral HYDRONEPHROSIS with several congenital stent (eg, Gibbons or double-J hydronephrosis diagnoses. 52332 type) is on lines 47,80,180,271,352.

64788 Excision of neurofibroma or 126 BENIGN NEOPLASM OF THE HSD requested that 64788 be Add 64788, 64790 and 64792 to neurolemmoma; cutaneous BRAIN AND SPINAL CORDDocuments added to the line with line 126 nerve neurofibromatosis. Two other 64790 Excision of neurofibroma or CPT codes are also specific to neurolemmoma; major neurofibroma removal and should peripheral nerve be added. These codes are on 64792 Excision of neurofibroma or lines 208, 294, 400, 415, 525, 534, neurolemmoma; extensive 556. (including malignant type)

Summary 27590 Amputation, thigh, through 605 SPRAINS AND STRAINS OF CPT 27590 appears on line 605 Remove 27590 from line 605 femur, any level ADJACENT MUSCLES AND JOINTS, with no appropriate ICD-10 code MINOR to pair. Issue

5 VbBS Consent Agenda Issues—January, 2018

Code Code Description Line(s) Involved Issue Recommendation(s) 92133 Scanning computerized 126 BENIGN NEOPLASM OF THE HSD requested that diagnostic Add 92133, 92134 and 92250 to ophthalmic diagnostic imaging, BRAIN AND SPINAL CORD imaging of eye structures be line 126 posterior segment, with paired with neurfibromatosis type interpretation and report, diagnoses. Most other unilateral or bilateral; optic ophthalmologic CPT codes appear1/18/2018 nerve on line 126. 92134 Retina 92250 Fundus photography with interpretation and report from 97802 Medical nutrition therapy; 71 Neurological dysfunction in HSD requested that medical Add 97802 and 97803 to line 71 initial assessment and breathing, eating, swallowing, nutrition therapy be paired with intervention, individual, face- bowel, or bladder control caused Down’s syndrome and with to-face with the patient, each by chronic conditions; attention dysphagia. People with Down’s 15 minutes to ostomies syndrome typically have issues 97803 Medical nutrition therapy; re- with obesity and constipation. assessment and intervention, Dysphagia can result in individual, face-to-face with the malnutrition. 97802-3 appear on patient, each 15 minutes multiple lines Documents 11640- Excision, malignant lesion 287 CANCER OF ORAL CAVITY, HSD requested that removal of Add 11640-11646 to line 287 11646 including margins, face, ears, PHARYNX, NOSE AND LARYNX malignant lesions of the lip (ICD- eyelids, nose, lips 10 C00) be paired these lesions, which appear on line 287. These CPT codes appear on line 230,243,276,589.

90675- Rabies vaccine 3 PREVENTION SERVICES WITH ICD-10 Z2.03 (Contact with and Add 90675-90676 to line 3 90676 SummaryEVIDENCE OF EFFECTIVENESS (suspected) exposure to rabies) is on line 3. The rabies vaccine CPT codes are currently only on the deep open wound line. Issue

6 VbBS Consent Agenda Issues—January, 2018

Code Code Description Line(s) Involved Issue Recommendation(s) 96150-5 Health and behavior 71 NEUROLOGICAL DYSFUNCTION HSD requested that the health and Add 96150-5 to lines 71, 103, 121, assessment/intervention IN BREATHING, EATING, behavior assessment codes be and 467 SWALLOWING, BOWEL, OR added to line 71 to pair with BLADDER CONTROL CAUSED BY several diagnoses, to line 103 to CHRONIC CONDITIONS; pair with adverse effects of 1/18/2018 ATTENTION TO OSTOMIES antipsychotics, to line 121 to pair 103 POISONING BY INGESTION, with sexual abuse, and to line 467 INJECTION, AND NON-MEDICINAL to pair with menopausal AGENTS symptoms. 96150from-5 appear on 121 ABUSE AND NEGLECT 180+ lines 467 GONADAL DYSFUNCTION, MENOPAUSAL MANAGEMENT 44202- Laparoscopy, surgical; 157 CANCER OF COLON, RECTUM, HSD requested that laparoscopic Add 44202-44203, 44950 and 44203 enterectomy, resection of small SMALL INTESTINE AND ANUS resection of the small bowel be 44955 to line 157 intestine paired with cancer of the small 44950 Appendectomy bowel. 44202-44203 currently 44955 Appendectomy; when done for appear on line 29,41,47,101,154. indicated purpose at time of Additionally, HSD requested that other major procedure Documentsappendectomy be added to line 157 to pair with malignant neoplasm of appendix. 44950 and 44955 is currently on lines 47,101 Z20.828 Contact with and (suspected) 1 PREGNANCY HSD requested that Z20.828 be Add Z20.828 to line 1 exposure to other viral paired with ultrasound codes for communicable diseases pregnancy. Women exposed to various viruses during pregnancy may need more frequent Summary monitoring for complications.

Issue

7 VbBS Corneal Transplant Rejection or Complication Treatments

Question: What procedures should pair with corneal transplant rejection or complications?

Question source: HSD claims reconsideration

Issue: Corneal transplant rejection (ICD-10 T86.840) and other complications of corneal transplant (T86.848) are on line 285 COMPLICATIONS OF A PROCEDURE ALWAYS REQUIRING TREATMENT. HSD has received requests for several procedures to pair with these diagnoses.

HERC staff has consulted with Winston Chamberlain MD, PhD, chief of the cornea division at Casey Eye Institute. Dr. Chamberlain recommends pairing corneal transplant rejection with CPT 68200 for use with dexamethasone or triamcinolone, 92025 to help with diagnostic evaluation,1/18/2018 66020 for treatment of endothelial keratoplasty failure, and 66250 for wound revision secondary to wound failure. Dr. Chamberlain did not recommend pairing another CPT code proposed for pairing by HSD (92286 Microscopic evaluation of deep cells of the eye). from In addition to the codes proposed by HSD, Dr. Chamberlain recommended coverage of topical Durezol and repeat transplant. He also wanted to ensure coverage of systemic medications for prevention of repeat transplant rejections, including oral prednisone, oral cyclosporine, oral tacrilimus, and CellCept. All corneal transplant codes already appear on line 285. The medications do not have CPT codes for placement.

CPT code Code description Current line(s) 68200 Subconjunctival injection Documents245,266,308,318,383,470 92025 Computerized mapping of corneal curvature 50+ lines 66020 Injection, anterior chamber of eye (separate 318,383 procedure); air or liquid 66250 Revision or repair of operative wound of 139,244,296,310,335 anterior segment, any type, early or late, major or minor procedure

Summary HERC staff recommendation: 1) Add CPT 66020, 66250, 68200, and 92025 to line 285 COMPLICATIONS OF A PROCEDURE ALWAYS REQUIRING TREATMENT Issue

VbBS

Code Clean Up for the Termination of Pregnancy Line

Issue: Multiple inappropriate ICD-10 codes were identified on line 35 TERMINATION OF PREGNANCY. More appropriate placements are shown in the table below.

HERC staff recommendation: 1/18/2018 1) Move the ICD-10 codes as shown in the table below

ICD-10 Code Description Current Recommended Comment code Placement Placement from A34 Obstetrical tetanus 35 TERMINATION 237 TETANUS Obstetrical tetanus is tetanus caused by contamination of OF PREGNANCY wounds with Clostridium tetani spores during pregnancy, or the use of contaminated tools or practices during nonsterile deliveries or abortions. It is treated in the same manner as non-OB tetanus cases. The CDC reported 1 case in 2016 nationwide (first case in 30+ yrs). O03.87 Sepsis following complete or 35 63 SAB related, not TAB unspecified spontaneous SPONTANEOUS abortion ABORTION; MISSEDDocuments ABORTION O08.0 Genital tract and pelvic 35 37 ECTOPIC Not mentioned in hyperbaric oxygen guideline. Needs to be infection following ectopic 332 Conditions PREGNANCY; on ectopic/molar pregnancy line and molar pregnancy requiring HYDATIDIFORM hyperbaric MOLE; oxygen therapy CHORIOCARCINO MA O08.1- Complications following an 35 37 Ectopic and molar pregnancies belong on that specific line O08.9 ectopic and molar pregnancy Summary O36.812 Decreased fetal movements, 1,35 1 Remove from line 35 second trimester O36.813 Decreased fetal movements, 1,35 1 Remove from line 35 third trimesterIssue

VbBS O36.819 Decreased fetal movements, 1,35 1 Remove from line 35 unspecified trimester Z3A Weeks of gestation 1,35 Informational Informational only (cannot be used as a primary code) File

1/18/2018

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Summary

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VbBS Cataract Guideline

Question: How should the cataract guideline be updated given newer recommendations for indications for surgery?

Question source: Holly Jo Hodges, MD; HERC staff

Issue: The cataract guideline has a long history with the HSC/HERC with many previous discussions and edits. It has not been updated in 7 years.

Recently, Dr. Hodges requested a review of glare as a criteria for cataract surgery. Glare is reduced vision in bright light conditions, and can particularly affect the ability to drive. Glare as an indication for cataract removal has been considered multiple times: -In 2003, adding glare was considered and rejected as it does not affect ADLs. 1/18/2018 -Discussed again in 2004 -Discussed again in 2009 and inadequate evidence was found to add glare as a criteria, based on a 1995 AHRQ review that found no benefit to glare testing. from In review of this question, HERC staff became aware of significantly changed indications for cataract surgery with CMS and with NICE, as well as the American Academy of Ophthalmology. Newer guidelines have eliminated visual acuity as a criteria, as this has evidence of being a poor indicator of postoperative functional improvement. Instead, guidelines are now being driven by how much the patients ADL’s are affected by their vision loss from the cataract. The current cataract guideline is mainly focused on visual acuity.

The cataract guideline was last reviewed as part of the 2012 ICD-10 Ophthalmology review. At that time, medical indications were added for cataract surgery for patients in whom visual improvement was not the primary goal. The visual acuity criteria asDocuments a general indication for surgery were maintained.

Currently, cataract surgery is on line 296 CATARACT. GN32 is applied to this line.

GUIDELINE NOTE 32, CATARACT Line 296 Cataract extraction is covered for binocular visual acuity of 20/50 or worse OR monocular visual acuity of 20/50 or worse with the recent development of symptoms related to poor vision that affect activities of daily living (ADLs). Cataract removal must be likely to restore vision and allow the patient to resume activities of daily living.Summary There are rare instances where cataract removal is medically necessary even if visual improvement is not the primary goal: A) Hypermature cataract causing inflammation and glaucoma OR B) To see the back of the eye to treat posterior segment conditions that could not be monitored due to the poor view and very dense lens opacity (i.e. diabetic retinopathy, glaucoma) OR C) IssueSignificant anisometropia causing aniseikonia.

VbBS

Cataract Guideline

Evidence 1) NICE 2017 update to cataract guideline (https://www.nice.org.uk/guidance/ng77) a) Practice recommendation: i) Base the decision to refer a person with a cataract for surgery on a discussion with them (and their family members or carers [caregivers], as appropriate) that includes: (a) how the cataract affects the person's vision and quality of life (b) whether 1 or both eyes are affected (c) what cataract surgery involves, including possible risks and benefits (d) how the person's quality of life may be affected if they choose not to have cataract surgery (e) whether the person wants to have cataract surgery. ii) Do not restrict access to cataract surgery on the basis of visual acuity. 1/18/2018 a) Visual acuity evidence i) High-quality evidence from 1 prospective cohort study containing 4,356 participants found that people with worse preoperative visual acuity (worse than 6/60) had larger gains in postoperative visual acuity than those with betterfrom preoperative visual acuity (better than 6/12). ii) Very low-quality evidence from a meta-analysis of 3 cohort studies containing 368,644 participants could not differentiate proportions of people with improved postoperative visual acuity between those with better and worse preoperative visual acuity. iii) Low-quality evidence from 1 prospective cohort study containing 93 participants found that people satisfying a visual acuity criterion for surgery had clinically meaningfully higher odds of postoperative visual acuity improvement. i) Low-quality evidence from 1 prospective cohort study containing 453 participants could not differentiate self-reportedDocuments improvement indices between people with better and worse preoperative visual acuity. b) Visual function evidence i) Low-quality evidence from a meta-analysis of 2 studies containing 5,569 participants found there was no meaningful difference in the proportions of people with improved postoperative visual function between those with better and worse preoperative visual acuity. i) Moderate quality evidence from 1 prospective cohort study containing 93 participants found that people satisfying a visual function criterion for surgery had clinicallySummary meaningfully higher odds of postoperative visual function improvement. b) Cost utility analysis i) One partially applicable CUA with serious limitations suggests that cataract surgery may be cost effective even when there is low expectation of visual acuity gain. The degree of uncertainty in this finding is significant, and no incremental analysis was Issueperformed. One partially applicable CUA with serious limitations suggests that, based on a prospective assessment of possible health related quality of life (HRQoL) gain following surgery, cataract surgery may be cost effective if the patient has bilateral cataracts and the intention is to operate on both eyes, but uncertainty in these findings is significant. VbBS ii) One directly applicable original health economic analysis with potentially serious limitations suggests that: 1) Offering first-eye cataract surgery is cost effective compared with no surgery in almost all cases even if it confers no immediate HRQoL

Cataract Guideline

gain, because future costs of low vision and QALY losses are prevented. 2) When compared with delayed surgery (waiting until the first-eye acuity drops to 6/12), most people are predicted to benefit from immediate surgery even if it confers no immediate HRQoL gain, although there are more cases where a ‘very small’ gain of HRQoL is necessary to justify the slightly higher cost of immediate surgery. c) Committee discussion i) The committee agreed that, whilst visual acuity is still commonly used to decide whether cataract surgery is needed, it is a crude measure that will often fail to detect other vision problems that may justify surgery (for example, glare, loss of colour vision). The committee agreed that the best possible decision-making aids would be measures of pre- and postoperative vision-related quality of life, which could be used to quantify the impact of surgery for the person, and identify any groups of people who do not gain in quality of life after surgery. However,1/18/2018 it noted that most existing prioritisation criteria were based primarily on visual acuity and visual function (usually measured using the VF-14), which capture only part of the impact of a cataract on quality of life. ii) The committee also noted that, when undertaking watchfulfrom waiting of patients, complication rates increase with increasing severity of cataract. It noted that, whilst not everyone gets worse (as many are stable), for those who do, this effect can be substantial and increases the risks of surgery. iii) In the absence of the ideal data, the committee agreed that the emphasis should be placed on patient–healthcare professional discussions regarding the effect the cataract is having on the person’s quality of life. The committee agreed that such discussions should be used to inform people with cataracts of the risks as well as the benefits of surgery. A willingness on behalf of the person with cataracts to proceed with surgery following such a discussion provides evidence that the person’s visual problems are having a significantDocuments impact on their quality of life to the extent that they felt that the potential benefits of surgery outweigh the risks. iv) The committee was presented with an original economic analysis that estimates the magnitude of utility gain needed for cataract surgery to be cost effective given multiple risk-factors for visual loss. The model compared three strategies – no surgery, immediate surgery, and delayed surgery (to a 6/12 acuity threshold). In the majority of model simulations, cataract surgery for first- or second-eye surgery was cost effective compared with no or delayed surgery even if it does not generate immediate HRQoL benefit, as future costs and QALY losses were avoided by performingSummary surgery. v) The committee concluded that visual acuity thresholds, or limits on second-eye surgery, were likely to incur avoidable QALY losses in most cases, and could be shown to increase longer-term costs by raising the demand for low vision services. The committee therefore agreed it was appropriate to make a clear Issuerecommendation that visual acuity thresholds should not be used as a criterion to restrict access to cataract surgery. The committee agreed it was appropriate to distinguish between effects on overall vision (which are an important part of the decisions making process) and visual acuity, which was been shown not to be effective as a decision-making criteria. VbBS vi) The committee noted that the evidence presented was largely in line with current clinical opinion. It noted that no relevant studies were identified to inform a distinct tool or set of criteria that could be used to determine a threshold for cataract

Cataract Guideline

surgery. In particular, whilst many papers found that people rated less appropriate for surgery had smaller gains after surgery, even in the least appropriate group there were still statistically significant postoperative gains. i) It agreed that the evidence did not support the use of visual acuity measurements as a threshold indicator for surgery. No studies were able to identify a group of patients by visual acuity at baseline who did not improve after surgery.

Guidelines 1) CMS 2017 a. MEDICAL NECESSITY: Lens extraction is considered medically necessary and therefore covered by Medicare when one (or more) of the following conditions or circumstances are documented in the medical record (see Documentation Requirements): 1/18/2018 i. Cataract causing symptomatic (i.e., causing the patient to seek medical attention) impairment of visual function not correctable with a tolerable change in glasses or contact lenses resulting in the patient's inability to function satisfactorily while performing Activities of Daily Life including,from but not limited to reading, viewing television, driving, or meeting vocational or recreational needs. ii. Concomitant intraocular disease (e.g., diabetic retinopathy or intraocular tumor) requiring monitoring or treatment that is prevented by the presence of cataract. iii. Lens-induced disease threatening vision or ocular health (including, but not limited to, phacomorphic or phacolytic glaucoma). iv. High probability of accelerating cataract development as a result of a concomitant or subsequent procedure (e.g., pars plana vitrectomy, iridocyclectomy, procedure for ocular trauma) and treatments such as external beam irradiation. Documents v. Cataract interfering with the performance of vitreoretinal surgery. vi. Intolerable anisometropia or aniseikonia uncorrectable with glasses or contact lenses that exists as a result of lens extraction in the first eye (despite satisfactorily corrected monocular visual acuity. vii. Any circumstances not listed may be considered based on the standard of care and other factors related to medical necessity at redetermination. viii. Surgery is not deemed to be medically necessary purely on the basis of lens opacity in the absence of symptoms. b. Visual acuity:Summary While a single arbitrary objective measure might be desirable a specific Snellen visual acuity alone can neither rule in nor rule out the need for surgery. Visual acuity should be considered in the context of the patient’s visual impairment and other ocular findings. 2) AAO 2016 (https://www.aao.org/Assets/5215127e-87b8-4ddc-af88- Issue3d9d03c02fcb/636217263645470000/cataract- in-the-adult-eye-ppp-pdf) a. Evidence for visual function and QOL i. Visual impairment, such as poor depth perception and low contrast sensitivity, is an important risk factor for falls and hip fractures. In a randomized controlled trial, first-eye cataract surgery reduced the rate of falling and fracture by 34% VbBS over a 12-month period. Similar improvement following second-eye surgery has also been confirmed. Visual loss from cataracts and the increased risk of falls are both contributing factors for nursing home placement. A decrease in visual

Cataract Guideline

acuity and contrast sensitivity is associated with driving difficulties. Drivers with visually significant cataracts are 2.5 times more likely to have an at-fault motor vehicle crash over a 5-year period compared with drivers without cataracts. In a cohort of 277 patients with cataract, those who underwent surgery had half the rate of crash involvement compared with those who did not undergo surgery in a 4- to 6-year follow-up period. One large study that assessed patients’ visual function pre- and postoperatively found the largest improvements in “driving during the day,” “self-care activities,” and “driving during the night.” Studies also show a reduction in mortality after cataract surgery and evidence that waiting more than 4 months to perform cataract surgery after it is clearly indicated and scheduled can also result in increased vision-related complications, such as falls and accidents. ii. There is no single test or measure that adequately describes the effect1/18/2018 of a cataract on a patient’s visual status or functional ability. Similarly, no single test can properly define the threshold for performing cataract surgery. iii. Because preoperative distance visual acuity alone may be an unreliable predictor of postoperative functional improvement, thefrom decision to recommend cataract surgery should not be made solely on the basis of Snellen visual acuity. 3) Aetna 2017 (http://www.aetna.com/cpb/medical/data/500_599/0508.html) b. Criteria based on visual acuity, with various levels of acuity allowable depending on the functional impairment and other factors i. Visual acuity of 20/40 or greater when the member perceives that his or her ability to carry out needed or desired activities is impaired. ii. No loss of visual acuity in certain clinical situations

Documents HERC staff summary: NICE has removed visual acuity thresholds as a qualification for cataract surgery based on the fact that such limits were likely to incur avoidable QALY losses in most cases, may lead to increased costs from more complicated surgeries, and could be shown to increase longer-term costs by raising the demand for low vision services. Vision related quality of life measures were felt to be a more accurate way to identify patients who would benefit from surgery. Similarly, CMS no longer has a visual acuity threshold for surgery, but rather relies on non-correctable impairment of visual function. The American Academy of Ophthalmology has reviewed literature on the risks and costs associated with delayed surgery and recommends visual acuity thresholds not be used to determine surgical eligibility. The AAO guidelines citeSummary the increased risk of falls, motor vehicle accidents, and need for SNF care as costs of delaying surgery. Some major insurers are continuing to use visual acuity thresholds as criteria for approving surgery.

Of note, fitting of glasses CPT codes are on the cataract line. Issue CCO input: The CCO medical directors were queried about the effects of this guideline change on their CCOs. In general, the CCOs were supportive of the staff proposed guideline change, and indicated that they rarely VbBSPA cataracts due to the low number of denials.

Cataract Guideline

HERC staff recommendation: 1) Modify GN32 as shown below

GUIDELINE NOTE 32, CATARACT Line 296 Cataract extraction is covered for binocular visual acuity of 20/50 or worse OR monocular visual acuity of 20/50 or worse with the recent development of symptoms related to poor vision that affect activities of daily living (ADLs). Cataract causing symptomatic (i.e. causing the patient to seek medical attention) impairment of visual function not correctable with a tolerable change in glasses or contact lenses resulting in the patient's inability to function satisfactorily while performing activities of daily living (ADLs). Cataract removal must be likely to restore vision and allow the patient to resume activities of daily living. There are rare instances where cataract removal is medically necessary even if visual improvement is not the primary goal: 1/18/2018 A) Hypermature cataract causing inflammation and glaucoma OR B) To see the back of the eye to treat posterior segment conditions that could not be monitored due to the poor view and very dense lens opacity (i.e. diabetic retinopathy, glaucoma) OR C) Significant anisometropia causing aniseikonia. from

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Summary

Issue

VbBS

Implantable Cardiac Defibrillators for Congestive Heart Failure

Question: Should implantable cardiac defibrillators (ICDs) be paired as a treatment for congestive heart failure (CHF)?

Question source: HSD claims reconsideration

Issue: ICDs are currently on several lines on the Prioritized List, including those containing life threatening arrhythmias. However, ICDs are not currently on the CHF line. HSD has received multiple claims for ICDs for patients with CHF as the indication. Currently, heart failure ICD-10 codes (I50.1-I50.9) are on line 98 HEART FAILURE which does not contain any defibrillator insertion, maintenance or removal CPT codes. Cardiomyopathy is paired with ICDs on line 99 CARDIOMYOPATHY. 1/18/2018 The ICD-10 Cardiology review group looked at the cardiology lines, including the placement of ICDs in 2012 and did not recommend changes. In 2015, wearable cardiac defibrillators were reviewed, and added to a series of lines with implantable ICD procedure codes with a guideline restricting their use to patients who otherwise would qualify for an ICD but could not have one insertedfrom due to infection, current serious medical condition, etc.

HSD has received multiple claims for ICD insertion as well as maintenance and programming associated with CHF diagnoses. The maintenance and programming requests are likely for patients who had an ICD inserted for CHF prior to coming on OHP.

GUIDELINE NOTE 49, WEARABLE CARDIAC DEFIBRILLATORS Lines 69,99,111,189,281,347 Documents Wearable cardiac defibrillators (WCDs; CPT 93745, HCPCS K0606-K0609) are included on these lines for patients at high risk for sudden cardiac death who meet the medical necessity criteria for an implantable cardioverter defibrillator (ICD) as defined by the CMS 2005 National Coverage Determination but are unable to have an ICD implanted due to medical condition (e.g. ICD explanted due to infection with waiting period before ICD reinsertion or current medical condition contraindicates surgery). WCDs are not included on these lines for use during the waiting period for ICD implantation after myocardial infarction, coronary bypass surgery, or coronary artery stenting.

Summary

Issue

VbBS

Current Prioritized List status CPT Code Description Current Line(s) code 33215 Repositioning of previously implanted transvenous 69 ACUTE AND SUBACUTE ISCHEMIC pacemaker or implantable defibrillator (right atrial or HEART DISEASE, MYOCARDIAL right ventricular) electrode INFARCTION 99 CARDIOMYOPATHY 111 CONGENITAL HEART BLOCK; OTHER OBSTRUCTIVE ANOMALIES OF HEART 183 CHRONIC ISCHEMIC HEART DISEASE 281 LIFE-THREATENING1/18/2018 CARDIAC ARRHYTHMIAS 285 COMPLICATIONS OF A PROCEDURE ALWAYS REQUIRING TREATMENTfrom 347 CARDIAC ARRHYTHMIAS 33216 Insertion of a single transvenous electrode, permanent 69,99,111,189,281,347 pacemaker or implantable defibrillator 33217 Insertion of 2 transvenous electrodes, permanent 69,111,189,281,285,347 pacemaker or implantable defibrillator 33218 Repair of single transvenous electrode, permanent 69,99,111,189,281,285,347 pacemaker or implantable defibrillator 33220 Repair of 2 transvenous electrodes for permanent 69,99,111,189,281,285,347 pacemaker or implantable defibrillator 33223 Relocation of skin pocket for implantableDocuments defibrillator 69,99,111,189,281,285,347 33224 Insertion of pacing electrode, cardiac venous system, 69,99,111,189,281,347 for left ventricular pacing, with attachment to previously placed pacemaker or implantable defibrillator pulse generator (including revision of pocket, removal, insertion, and/or replacement of existing generator) 33225 Insertion of pacing electrode, cardiac venous system, 69,99,111,189,281,347 for left ventricular pacing, at time of insertion of implantableSummary defibrillator or pacemaker pulse generator (eg, for upgrade to dual chamber system) 33230 Insertion of implantable defibrillator pulse generator 99,111,281,285 only; with existing dual leads 33231 Insertion of implantable defibrillator pulse generator 99,111,281,285 Issueonly; with existing multiple leads 33240 Insertion of implantable defibrillator pulse generator 99,111,281,285 only; with existing single lead 33241 Removal of implantable defibrillator pulse generator 99,111,281,285 only VbBS33243 Removal of single or dual chamber implantable 99,111,281,285 defibrillator electrode(s); by thoracotomy

CPT Code Description Current Line(s) code 33244 Removal of single or dual chamber implantable 99,111,281,285 defibrillator electrode(s); by transvenous extraction 33249 Insertion or replacement of permanent implantable 99,111,281,285 defibrillator system, with transvenous lead(s), single or dual chamber 33262 Removal of implantable defibrillator pulse generator 99,111,281,285 with replacement of implantable defibrillator pulse generator; single lead system 33263 Dual lead system 99,111,281,285 33264 Multiple lead system 99,111,281,285 33270 Insertion or replacement of permanent subcutaneous 99,111,281,285 1/18/2018 implantable defibrillator system, with subcutaneous electrode, including defibrillation threshold evaluation, induction of arrhythmia, evaluation of sensing for arrhythmia termination, and programming or from reprogramming of sensing or therapeutic parameters, when performed 33271 Insertion of subcutaneous implantable defibrillator 99,111,281,285 electrode 33272 Removal of subcutaneous implantable defibrillator 99,111,281,285 electrode 33273 Repositioning of previously implanted subcutaneous 99,111,281,285 implantable defibrillator electrode 93260 Programming device evaluation (in person) with Ancillary iterative adjustment of the implantableDocuments device to test the function of the device and select optimal permanent programmed values with analysis, review and report by a physician or other qualified health care professional; implantable subcutaneous lead defibrillator system 93261 Interrogation device evaluation (in person) with Ancillary analysis, review and report by a physician or other qualified healthSummary care professional, includes connection, recording and disconnection per patient encounter; implantable subcutaneous lead defibrillator system 93282 Programming device evaluation (in person) with 69,99,111,189,281,347 iterative adjustment of the implantable device to test Issuethe function of the device and select optimal permanent programmed values with analysis, review and report by a physician or other qualified health care professional; single lead transvenous implantable defibrillator system 93283 dual lead transvenous implantable defibrillator system 69,99,111,189,281,347 VbBS93284 multiple lead transvenous implantable defibrillator 69,99,111,189,281,347 system

vii

CPT Code Description Current Line(s) code 93287 Peri-procedural device evaluation (in person) and 69,99,111,189,281,347 programming of device system parameters before or after a surgery, procedure, or test with analysis, review and report by a physician or other qualified health care professional; single, dual, or multiple lead implantable defibrillator system 93289 Interrogation device evaluation (in person) with 69,99,111,189,281,347 analysis, review and report by a physician or other qualified health care professional, includes connection, recording and disconnection per patient encounter; single, dual, or multiple lead transvenous implantable 1/18/2018 defibrillator system, including analysis of heart rhythm derived data elements 93292 Interrogation device evaluation (in person) with 69,99,111,189,281,347 analysis, review and report by a physician or other from qualified health care professional, includes connection, recording and disconnection per patient encounter; wearable defibrillator system 93295 Interrogation device evaluation(s) (remote), up to 90 69,99,111,189,281,347 days; single, dual, or multiple lead implantable defibrillator system with interim analysis, review(s) and report(s) by a physician or other qualified health care professional 93296 Interrogation device evaluation(s) (remote), up to 90 69,99,111,189,281,347 days; single, dual, or multiple lead pacemakerDocuments system or implantable defibrillator system, remote data acquisition(s), receipt of transmissions and technician review, technical support and distribution of results 93640 Electrophysiologic evaluation of single or dual chamber 281,347 pacing cardioverter-defibrillator leads including defibrillation threshold evaluation (induction of arrhythmia, evaluation of sensing and pacing for arrhythmia termination) at time of initial implantation or replacement;Summary 93641 Electrophysiologic evaluation of single or dual chamber 281,347 pacing cardioverter-defibrillator leads including defibrillation threshold evaluation (induction of arrhythmia, evaluation of sensing and pacing for Issuearrhythmia termination) at time of initial implantation or replacement; with testing of single or dual chamber pacing cardioverter-defibrillator pulse generator 93642 Electrophysiologic evaluation of single or dual chamber 281,347 transvenous pacing cardioverter-defibrillator (includes VbBS defibrillation threshold evaluation, induction of arrhythmia, evaluation of sensing and pacing for

viii

CPT Code Description Current Line(s) code arrhythmia termination, and programming or reprogramming of sensing or therapeutic parameters) 93644 Electrophysiologic evaluation of subcutaneous 99,111,281,285 implantable defibrillator (includes defibrillation threshold evaluation, induction of arrhythmia, evaluation of sensing for arrhythmia termination, and programming or reprogramming of sensing or therapeutic parameters) 93745 Initial set-up and programming by a physician or other 69,99,111,189,281,347 qualified health care professional of wearable cardioverter-defibrillator includes initial programming 1/18/2018 of system, establishing baseline electronic ECG, transmission of data to data repository, patient instruction in wearing system and patient reporting of problems or events from

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Summary

Issue

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Evidence 1) Kober 2016, DANISH trial a. N=1,116 (556 ICD, 560 usual care) patients with symptomatic systolic HF (left ventricular ejection fraction, ≤35%) not caused by CAD randomized to ICD or not, in addition to standard medical therapy. In both groups, 58% of the patients received cardiac resynchronization Therapy (CRT). The primary outcome of the trial was death from any cause. The secondary outcomes were sudden cardiac death and cardiovascular death. b. Median follow-up period of 67.6 months i. 54 patients (9.6%) in the control group received ICDs; analyzed as intent to treat (i.e. non ICD) c. The primary outcome (death from any cause) had occurred in 120 patients (21.6%) in the ICD group and in 131 patients (23.4%) in the control group (hazard ratio, 0.87; 95% confidence interval [CI], 0.68 to 1.12; P = 0.28). Sudden cardiac death occurred1/18/2018 in 24 patients (4.3%) in the ICD group and in 46 patients (8.2%) in the control group (hazard ratio, 0.50; 95% CI, 0.31 to 0.82; P = 0.005). d. Lack of significance with ICD thought by other authors to be due to the improved medical management of all patients compared to earlier trials from e. CONCLUSIONS In this trial, prophylactic ICD implantation in patients with symptomatic systolic heart failure not caused by coronary artery disease was not associated with a significantly lower long-term rate of death from any cause than was usual clinical care. f. Funded by Medtronic and others 2) Kołodziejczak 2016, meta-analysis of ICDs compared to conventional care for primary prevention of death in adults with ischemic or nonischemic cardiomyopathy a. N=11 RCTs (8716 patients) i. 4 RCTs (1781 patients) nonischemic cardiomyopathy (included the DANISH trial) ii. 6 RCT (4414 patients) ischemic cardiomyopathy iii. 1 RCT (2521 patients) bothDocuments types of cardiomyopathy. b. Mean ventricular ejection fraction of trial participants was 26.20%. Most patients had moderately symptomatic heart failure (NYHA class II or III). c. Mean follow-up was 3.2 years. d. An overall reduction in all-cause mortality, from 28.26% with conventional care to 21.37% with ICD therapy (hazard ratio [HR], 0.81 [95% CI, 0.70 to 0.94]; P = 0.043), was found. The magnitude of reduction was similar in the cohorts with nonischemic (HR, 0.81 [CI, 0.72 to 0.91]) and ischemic (HR, 0.82 [CI, 0.63 to 1.06]) disease, although the latter estimate did not reach statistical significance. The rate of sudden death fell from 12.15%Summary with conventional care to 4.39% with ICD therapy (HR, 0.41 [CI, 0.30 to 0.56]), with a similar magnitude of reduction in patients with ischemic (HR, 0.39 [CI, 0.23 to 0.68]) and those with nonischemic disease (HR, 0.44 [CI, 0.17 to 1.12]). Noncardiac and any cardiac deaths did not differ significantly by treatment. i. Note: the ischemic trials included 2 early post– myocardial infarction treatment Issue trials (DINAMIT and IRIS) and the immediate post–coronary bypass surgery treatment trial (CABG Patch) showing no survival benefit with ICD therapy. This is no longer standard of care. These trials likely influenced the outcome to appear to have non-significance in the meta-analysis e. Limitation: Heterogeneous timing of ICD placement; heterogeneous pharmacologic and VbBS resynchronization co-interventions; trials conducted in different eras; adverse events and complications not reviewed.

f. Conclusion: Overall, primary prevention with ICD therapy versus conventional care reduced the incidence of sudden and all cause death. 3) Stavrakis 2017, meta-analysis of RCTs of ICDs for nonischemic cardiomyopathy (NICM) a. N=6 RCTs (2,967 patients, ICD, n = 1,553; control, n = 1,414). i. Included the DANISH trial ii. Study subjects were mostly middle-aged men with mild-to-moderate heart failure (New York class association II–III). b. Based on the pooled estimate across the six studies, the use of ICD was associated with a significant reduction in total mortality (HR = 0.78, 95% CI 0.66–0.92; P = 0.003), as well as arrhythmic death (HR = 0.46, 95% CI 0.29–0.71; P = 0.0005) compared to control. ICD decreased total mortality in younger patients compared to control (HR = 0.63, 95% CI 0.46–0.86; P = 0.004), but not in older patients (HR = 0.97, 95% CI 0.56–1.68; P = 0.92). In patients with cardiac resynchronization therapy (CRT), ICD reduced total mortality1/18/2018 compared to control (HR = 0.78, 95% CI 0.65–0.95; P = 0.02), but not in patients with CRT (HR = 0.71, 95% CI 0.40–1.26). c. Conclusions: ICDs decrease total mortality and arrhythmic deaths in patients with NICM. The benefit of ICD appears to be dependent on age and concomitantfrom use of CRT.

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Other policies CMS/Medicare 2005 National Coverage Determination for ICD placement: 1. Documented episode of cardiac arrest due to ventricular fibrillation (VF), not due to a transient or reversible cause (effective July 1, 1991). 2. Documented sustained ventricular tachyarrhythmia (VT), either spontaneous or induced by an electrophysiology (EP) study, not associated with an acute myocardial infarction (MI) and not due to a transient or reversible cause (effective July 1, 1999). 3. Documented familial or inherited conditions with a high risk of life-threatening VT, such as long QT syndrome or hypertrophic cardiomyopathy (effective July 1, 1999). Additional indications effective for services performed on or after October 1, 2003: 4. Coronary artery disease with a documented prior MI, a measured left ventricular ejection1/18/2018 fraction (LVEF) ≤ 0.35, and inducible, sustained VT or VF at EP study. (The MI must have occurred more than 40 days prior to defibrillator insertion. The EP test must be performed more than 4 weeks after the qualifying MI.) 5. Documented prior MI and a measured LVEF ≤ 0.30 and a QRS duration of >120 milliseconds (the QRS restriction does not apply to services performed on or after January 27,from 2005) . Patients must not have: a. New York Heart Association (NYHC) classification IV; b. Cardiogenic shock or symptomatic hypotension while in a stable baseline rhythm; c. Had a coronary artery bypass graft (CABG) or percutaneous transluminal coronary angioplasty (PTCA) within past 3 months; d. Had an enzyme positive MI within past month (Effective for services on or after January 27, 2005, patients must not have an acute MI in the past 40 days); e. Clinical symptoms or findings that would make them a candidate for coronary revascularization; or Documents f. Any disease, other than cardiac disease (e.g., cancer, uremia, liver failure), associated with a likelihood of survival less than 1 year.

Additional indications effective for services performed on or after January 27, 2005:

6. Patients with ischemic dilated cardiomyopathy (IDCM), documented prior MI, NYHA Class II and III heart failure, and measured LVEF ≤ 35%; 7. Patients with non-ischemicSummary dilated cardiomyopathy (NIDCM) >9 months, NYHA Class II and III heart failure, and measured LVEF ≤ 35%; 8. Patients who meet all current Centers for Medicare & Medicaid Services (CMS) coverage requirements for a cardiac resynchronization therapy (CRT) device and have NYHA Class IV heart failure;Issue All indications must meet the following criteria:

a. Patients must not have irreversible brain damage from preexisting cerebral disease; b. MIs must be documented and defined according to the consensus document of the Joint VbBS European Society of Cardiology/American College of Cardiology Committee for the Redefinition of Myocardial Infarction;

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Indications 3 - 8 (primary prevention of sudden cardiac death) must also meet the following criteria:

a. Patients must be able to give informed consent; b. Patients must not have:  Cardiogenic shock or symptomatic hypotension while in a stable baseline rhythm;  Had a CABG or PTCA within the past 3 months;  Had an acute MI within the past 40 days;  Clinical symptoms or findings that would make them a candidate for coronary revascularization;  Any disease, other than cardiac disease (e.g., cancer, uremia, liver failure), associated with a likelihood of survival less than 1 year; 1/18/2018 c. Ejection fractions must be measured by angiography, radionuclide scanning, or echocardiography; d. The beneficiary receiving the defibrillator implantation for primary prevention is enrolled in either a Food and Drug Administration (FDA)-approved category B investigationalfrom device exemption (IDE) clinical trial (42 CFR §405.201), a trial under the CMS Clinical Trial Policy (National Coverage Determination (NCD) Manual §310.1) or a qualifying data collection system including approved clinical trials and registries. Initially, an implantable cardiac defibrillator (ICD) database will be maintained using a data submission mechanism that is already in use by Medicare participating hospitals to submit data to the Iowa Foundation for Medical Care (IFMC) a Quality Improvement Organization (QIO) contractor for determination of reasonable and necessary and quality improvement. Initial hypothesis and data elements are specified in this decision (Appendix VI) and are the minimum necessary to ensure that the device is reasonable and necessary. Data collection will be completed using the ICDA (ICD Abstraction Tool) and transmitted via QNet (Quality Network Exchange)Documents to the IFMC who will collect and maintain the database. Additional stakeholder-developed data collection systems to augment or replace the initial QNet system, addressing at a minimum the hypotheses specified in this decision, must meet the following basic criteria:  Written protocol on file;  Institutional review board review and approval;  Scientific review and approval by two or more qualified individuals who are not part of the research team;  CertificationSummary that investigators have not been disqualified.

For purposes of this coverage decision, CMS will determine whether specific registries or clinical trials meet these criteria.

e. IssueProviders must be able to justify the medical necessity of devices other than single lead devices. This justification should be available in the patient's medical record.

9. Patients with NIDCM >3 months, NYHA Class II or III heart failure, and measured LVEF ≤ 35%, only if VbBSthe following additional criteria are also met: a. Patients must be able to give informed consent;

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b. Patients must not have:

 Cardiogenic shock or symptomatic hypotension while in a stable baseline rhythm;  Had a CABG or PTCA within the past 3 months;  Had an acute MI within the past 40 days;  Clinical symptoms or findings that would make them a candidate for coronary revascularization;  Irreversible brain damage from preexisting cerebral disease;  Any disease, other than cardiac disease (e.g. cancer, uremia, liver failure), associated with a likelihood of survival less than 1 year; c. Ejection fractions must be measured by angiography, radionuclide scanning, or 1/18/2018 echocardiography; d. MIs must be documented and defined according to the consensus document of the Joint European Society of Cardiology/American College of Cardiology Committee for the Redefinition of Myocardial Infarction; from e. The beneficiary receiving the defibrillator implantation for this indication is enrolled in either an FDA-approved category B IDE clinical trial (42 CFR §405.201), a trial under the CMS Clinical Trial Policy (NCD Manual §310.1), or a prospective data collection system meeting the following basic criteria:

 Written protocol on file;  Institutional Review Board review and approval;  Scientific review and approval by two or more qualified individuals who are not part of the research team;  Certification that investigators have notDocuments been disqualified.

For purposes of this coverage decision, CMS will determine whether specific registries or clinical trials meet these criteria.

f. Providers must be able to justify the medical necessity of devices other than single lead devices. This justification should be available in the patient's medical record.

Other Indications Summary

All other indications for implantable automatic defibrillators not currently covered in accordance with this decision will continue to be covered under Category B IDE trials (42 CFR §405.201) and the CMSIssue routine clinical trials policy (NCD §310.1).

NICE 2014 (https://www.nice.org.uk/guidance/ta314) 1) Implantable cardioverter defibrillators (ICDs) are recommended as options for: a. treating people with previous serious ventricular arrhythmia, that is, people who, without a treatable cause: VbBS i. have survived a cardiac arrest caused by either ventricular tachycardia (VT) or ii. ventricular fibrillation or

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iii. have spontaneous sustained VT causing syncope or significant haemodynamic compromise or iv. have sustained VT without syncope or cardiac arrest, and also have an associated reduction in left ventricular ejection fraction (LVEF) of 35% or less but their symptoms are no worse than class III of the New York Heart Association (NYHA) functional classification of heart failure. b. treating people who: i. have a familial cardiac condition with a high risk of sudden death, such as long QT syndrome, hypertrophic cardiomyopathy, Brugada syndrome or arrhythmogenic right ventricular dysplasia or have undergone surgical repair of congenital heart disease. 2) Implantable cardioverter defibrillators (ICDs), cardiac resynchronization therapy (CRT) with defibrillator (CRT-D) or CRT with pacing (CRT-P) are recommended as treatment options1/18/2018 for people with heart failure who have left ventricular dysfunction with a left ventricular ejection fraction (LVEF) of 35% or less as specified in table 1.

Table 1 from NYHA Class QRS interval I II III IV <120 milliseconds ICD if there is a high risk of sudden ICD and CRT not clinically cardiac death indicated 120–149 milliseconds ICD ICD ICD CRT-P without LBBB 120–149 milliseconds with LBBB ICD CRT-D CRT-P or CRT-D CRT-P ≥150 milliseconds with or without CRT- CRT-D CRT-P or CRT-D CRT-P LBBB D LBBB, left bundle branch block; NYHA, New York DocumentsHeart Association

Other insurer policies: 1) ICDs are covered by all queried private insurers for CHF patients who qualify based on Medicare NCD criteria

Expert input: From Dr. Eric Stecker, OHSUSummary cardiology: For purposes of primary prevention ICDs, heart failure and cardiomyopathy go together clinically. This is purely a coding problem. DANISH, like other trials, was entitled “heart failure…” but required patients to have both cardiomyopathy and heart failure (EF<35% and with heart Issuefailure symptoms or elevated BNP). There are a few trials in which patients could be included for cardiomyopathy without heart failure (MADIT-CRT and MADIT-I). But vast majority of ICDs will be implanted in patients who have both.

That said, few clinicians code the cardiomyopathy part because the diagnosis “chronic systolic heart failure” also directly invokes systolic dysfunction, which means EF <40% which = VbBS cardiomyopathy. Then their note will define the actual EF that qualifies the patient for ICD.

HERC staff summary: The available evidence supports that ICDs can reduce all-cause mortality and sudden cardiac death in patients with ischemic and nonischemic symptomatic heart failure for patients with a LVEF of ≤ 35%. CMS, NICE and all major insurers cover ICDs for congestive heart failure. The current limitation of ICDs to cardiomyopathy does not reflect general coding in the cardiology community. The patients who qualify for ICDs generally have a degree of heart failure that qualifies as cardiomyopathy, but the cardiology community uses the heart failure diagnosis for coding/billing purposes.

HERC staff recommendations 1) Add ICD insertion, replacement and removal CPT codes [CPT codes for ICD from line 99] to line 98 HEART FAILURE to pair with heart failure ICD-10 codes (I50.1-I50.9) a. CPT 33215, 33216, 33218-33273, 93282-93296, 93644, 93745 1/18/2018 b. This actually represents no change from previous intended coverage as the guideline will define the degree of heart failure to be equivalent to cardiomyopathy 2) Add the following guideline to lines 98, 99,111,281,285 a. This guideline is based on CMS criteria from

GUIDELINE NOTE XXX IMPLANTABLE CARDIAC DEFIBRILLATORS Lines 98, 99,111,281,285 Implantable cardiac defibrillators are included on these lines for patients with 1) Documented episode of cardiac arrest due to ventricular fibrillation (VF), not due to a transient or reversible cause Life threatening arrhythmias not due to transient or reversible cause 2) Documented sustained ventricular tachyarrhythmia (VT), either spontaneous or induced by an electrophysiology (EP) study, not associated with an acute myocardial infarction (MI) and not due to a transient or reversible cause 3) Documented familial or inherited conditionsDocuments with a high risk of life-threatening VT, such as long QT syndrome or hypertrophic cardiomyopathy 4) Coronary artery disease with a documented prior MI, a measured left ventricular ejection fraction (LVEF) ≤ 0.35, and inducible, sustained VT or VF at EP study. (The MI must have occurred more than 40 days prior to defibrillator insertion. The EP test must be performed more than 4 weeks after the qualifying MI.) 5) Documented prior MI and a measured LVEF ≤ 0.30. Patients must not have: a) New York Heart Association (NYHC) classification IV; b) CardiogenicSummary shock or symptomatic hypotension while in a stable baseline rhythm; c) Had a coronary artery bypass graft (CABG) or percutaneous transluminal coronary angioplasty (PTCA) within past 3 months; d) Had an acute MI in the past 40 days; e) Clinical symptoms or findings that would make them a candidate for coronary Issuerevascularization; or f) Any disease, other than cardiac disease (e.g., cancer, uremia, liver failure), associated with a likelihood of survival less than 1 year. 6) Patients with ischemic dilated cardiomyopathy (IDCM), documented prior MI, NYHA Class II and III heart failure, and measured LVEF ≤ 35%; 7) Patients with non-ischemic dilated cardiomyopathy (NIDCM) >9 months, NYHA Class II and III VbBS heart failure, and measured LVEF ≤ 35%;

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8) Patients who meet all current Centers for Medicare & Medicaid Services (CMS) coverage requirements for a cardiac resynchronization therapy (CRT) device and have NYHA Class IV heart failure;

All indications must meet the following criteria: i. Patients must not have irreversible brain damage from preexisting cerebral disease; ii. MIs must be documented and defined according to the consensus document of the Joint European Society of Cardiology/American College of Cardiology Committee for the Redefinition of Myocardial Infarction

Indications 3 - 8 (primary prevention of sudden cardiac death) must also meet the following criteria: a. Patients must be able to give informed consent; b. Patients must not have: 1/18/2018  Cardiogenic shock or symptomatic hypotension while in a stable baseline rhythm;  Had a CABG or PTCA within the past 3 months;  Had an acute MI within the past 40 days; from  Clinical symptoms or findings that would make them a candidate for coronary revascularization;  Any disease, other than cardiac disease (e.g., cancer, uremia, liver failure), associated with a likelihood of survival less than 1 year; c. Ejection fractions must be measured by angiography, radionuclide scanning, or echocardiography;

9) Patients with NIDCM >3 months, NYHA ClassDocuments II or III heart failure, and measured LVEF ≤ 35%, only if the following additional criteria are also met: a) Patients must be able to give informed consent; b) Patients must not have: a) Cardiogenic shock or symptomatic hypotension while in a stable baseline rhythm; b) Had a CABG or PTCA within the past 3 months; c) Had an acute MI within the past 40 days; d) Clinical symptoms or findings that would make them a candidate for coronary Summaryrevascularization; e) Irreversible brain damage from preexisting cerebral disease; f) Any disease, other than cardiac disease (e.g. cancer, uremia, liver failure), associated with a likelihood of survival less than 1 year; c) Ejection fractions must be measured by angiography, radionuclide scanning, or Issueechocardiography; d) MIs must be documented and defined according to the consensus document of the Joint European Society of Cardiology/American College of Cardiology Committee for the Redefinition of Myocardial Infarction

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Neurostimlators for Parkinson’s Disease

Question: Should deep brain neurostimulators be paired with Parkinson’s disease? If so, for what degree of disease or with what restrictions?

Question source: HSD claims reconsideration

Issue: Currently neurostimulators are not paired with Parkinson’s disease (ICD-10 G20). Parkinson’s disease is on line 250 PARKINSON'S DISEASE as well as the four dysfunction lines.

Parkinson’s disease is typically treated with medications such as dopamine agonists, levodopa and MAO- B inhibitors. Specific symptoms such as depression or psychotic symptoms may be treated with medications for those conditions. Physical, occupational, speech/language, and nutrition therapy1/18/2018 may be needed. Medical devices such as wheelchairs or other supportive equipment may be required. These therapies and devices are currently covered for Parkinson’s disease on the Prioritized List if medically appropriate. from HSD recently had several claims for insertion or replacement of brain neurostimulators for Parkinson’s disease (CPT 61885, 61886) which are not on the Parkinson’s line. Neurostimulators for Parkinson’s disease was last discussed in 2005, at which time the HOSC felt there was “reasonable data” for use with Parkinson’s disease. However, there were few requests for this treatment and the HSC decided to not look into it further.

Neurostimulator CPT codes currently only appear on line 174 GENERALIZED CONVULSIVE OR PARTIAL EPILEPSY WITHOUT MENTION OF IMPAIRMENT OF CONSCIOUSNESS and 285 COMPLICATIONS OF A PROCEDURE ALWAYS REQUIRING TREATMENT. Documents

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Current code placement for deep brain stimulation CPT codes

CPT Code description Current lines code 61863 Twist drill, burr hole, craniotomy, or craniectomy with 174 GENERALIZED CONVULSIVE stereotactic implantation of neurostimulator electrode OR PARTIAL EPILEPSY WITHOUT array in subcortical site (eg, thalamus, globus pallidus, MENTION OF IMPAIRMENT OF subthalamic nucleus, periventricular, periaqueductal CONSCIOUSNESS gray), without use of intraoperative microelectrode recording; first array 61864 each additional array 174 61867 Twist drill, burr hole, craniotomy, or craniectomy with 174 stereotactic implantation of neurostimulator electrode 1/18/2018 array in subcortical site (eg, thalamus, globus pallidus, subthalamic nucleus, periventricular, periaqueductal gray), with use of intraoperative microelectrode recording; first array from 61868 each additional array 174 61880 Revision or removal of intracranial neurostimulator 174, 285 COMPLICATIONS OF A electrodes PROCEDURE ALWAYS REQUIRING TREATMENT 61885 Insertion or replacement of cranial neurostimulator pulse 174,285 generator or receiver, direct or inductive coupling; with connection to a single electrode array 61886 with connection to 2 or more electrode arrays 174,285 Documents

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Evidence 1) Okun 2012, systematic review of deep brain stimulation for Parkinson’s a. N=4 RCTs of deep brain stimulation for PD i. Deuschl 2006 1. N=156 patients under age 75 with severe motor complications from PD 2. Results: significant improvement in functionality (mobility, ADLs, emotional well-being, bodily discomfort) at 6 months with deep brain stimulation compared to medical therapy 3. Serious adverse events more common with neurostimulation compared to medication alone (13 percent vs. 4 percent, P<0.04) and included a fatal intracerebral hemorrhage. The overall frequency of adverse events (minor and serious) was higher in the medication group (64 percent vs. 50 percent, P = 0.08). 1/18/2018 ii. Weaver 2009 1. N=255 patients with Hoehn and Yahr stage ≥2 while not taking medications; 25% were aged 70 years or older. 2. Results: significant increase of 4.6 hours of “on”from time without troubling dyskinesia per day vs 0 hours in the medical therapy group. Motor function improved significantly (P<.001) with deep brain stimulation vs best medical therapy, such that 71% of deep brain stimulation patients and 32% of best medical therapy patients experienced clinically meaningful motor function improvements (≥5 points). Compared with the best medical therapy group, the deep brain stimulation group experienced significant improvements in the summary measure of quality of life and on 7 of 8 PD quality-of-life scores (P<.001). Neurocognitive testing revealed small decrements in some areas of information processingDocuments for patients receiving deep brain stimulation vs best medical therapy. At least 1 serious adverse event occurred in 49 deep brain stimulation patients and 15 best medical therapy patients (P<.001), including 39 adverse events related to the surgical procedure and 1 death secondary to cerebral hemorrhage. iii. Williams 2010 1. N=366 patients patients with Parkinson’s disease that was not adequately controlled by medical therapy 2. Results: functionality, mobility, ADLs and bodily discomfort were all Summarysignificantly increased at 1 yr compared to medical therapy 3. 36 (19%) patients had serious surgery-related adverse events; there were no suicides but there was one procedure-related death. 20 patients in the surgery group and 13 in the best medical therapy group had serious adverse events related to Parkinson’s disease and drug Issue treatment. iv. Okun 2009 1. N=45 patients, tested in 3 configurations (subthalamic nucleus (STN) vs. globus pallidus interna (GPi) and “off”) 2. Okun in his 2012 review stated that this study demonstrated “increased VbBS “on” time 11.2 hours per day with active electrode vs 8.9 hours per day with sham electrode at 3 months.” However, this statement could not be verified by review of the article

3. no significant difference in cognitive measures within the four stimulation settings (including “off”) at 7 months b. Adverse events i. In large series, rates of infection requiring further surgery have ranged from 1.2 to 15.2%. Infections most often require device removal and a period of antibiotic treatment before consideration of device replacement. ii. In an extensive literature review, the overall rate of intracranial hemorrhage was calculated to be 5.0%; symptomatic hemorrhage occurred in 2.1% of patients, and hemorrhage causing permanent deficit or death occurred in 1.1%. iii. Postprocedural seizures have also been reported, with an estimated incidence of 2.4% in one review of the literature. iv. Lead fractures and other hardware-related issues are not uncommon. v. A wide range of neurologic and neuropsychological adverse effects has1/18/2018 been reported with deep-brain stimulation. Some of these effects are related to device implantation and may require electrode relocation or, in some cases, may be permanent. Others are related to electrical stimulation and may be addressed by adjustment of device programming or discontinuationfrom of therapy. Neurologic side effects of deep-brain stimulation include cognitive impairment, memory deficits, difficulties with speech, disequilibrium, dysphagia, and motor and sensory disturbances. Emotional or psychological side effects have included mania, depression, apathy, laughter, crying, panic, fear, anxiety, and suicidal ideation 2) Pietzsch 2016, cost effectiveness analysis of deep brain stimulation (DBS) vs best medical treatment (BMT) for Parkinson’s disease a. Over ten years, DBS treatment led to discounted total costs of $130,510 compared to $91,026 for BMT and added 1.69 QALYs more than BMT, resulting in an ICER of $23,404 per QALY. This ICER was relativelyDocuments insensitive to variations in input parameters, with neurostimulator replacement, costs for DBS implantation, and costs for treatment of disease-related falls having the greatest effects. Across all investigated scenarios, including a five-year horizon, ICERs remained under $50,000 per QALY. Longer follow-up periods and younger treatment age were associated with greater cost-effectiveness. b. Conclusions: DBS is a cost-effective treatment strategy for advanced PD in the U.S. healthcare system across a wide range of assumptions. DBS yields substantial improvements in health-related quality of life at a value profile that compares favorably to other well-accepted therapies. Summary

Other policies 1) NICE 2017 Parkinson’s disease in adults (https://www.nice.org.uk/guidance/ng71/resources/parkinsons-disease-in-adults-pdf- Issue1837629189061 ) a. Do not offer deep brain stimulation to people with Parkinson's disease whose symptoms are adequately controlled by best medical therapy. [2017] b. Consider deep brain stimulation for people with advanced Parkinson's disease whose symptoms are not adequately controlled by best medical therapy. [2017] VbBS i. Efficacy:

1. The evidence suggested that deep brain stimulation results in improved motor skills, function and movement in patients with Parkinson's disease. 2. The Specialist Advisors considered the procedure to be established practice within specialised units. They did not question short-term efficacy, but commented that long-term efficacy was unknown. ii. Safety 1. The complications associated with deep brain stimulation include risk of stroke, confusion, speech disorders and visual problems. In the two largest studies, involving 102 and 111 patients, the incidence of stroke was approximately 3%. 2) CMS 2003, National Coverage Determination (https://www.cms.gov/medicare-coverage- database/details/nca-decision-memo.aspx?NCAId=21) 1/18/2018 a. Medicare will cover unilateral or bilateral thalamic VIM DBS for the treatment of essential tremor (ET) and/or Parkinsonian tremor and unilateral or bilateral STN or GPi DBS for the treatment of Parkinson’s disease only under the following conditions: i. Medicare will only consider DBS devices to be reasonablefrom and necessary if they are Food and Drug Administration (FDA) approved devices or devices used in accordance with FDA approved protocols governing Category B Investigational Device Exemption (IDE) DBS clinical trials. ii. For thalamic VIM DBS to be considered reasonable and necessary, patients must meet all of the following criteria: 1. Diagnosis of essential tremor (ET) based on postural or kinetic tremors of hand(s) without other neurologic signs, or diagnosis of idiopathic PD (presence of at least 2 cardinal PD features (tremor, rigidity or bradykinesia)) which is of a tremor- dominant form 2. Marked disablingDocuments tremor of at least level 3 or 4 on the Fahn-Tolosa- Marin Clinical Tremor Rating Scale (or equivalent scale) in the extremity intended for treatment, causing significant limitation in daily activities despite optimal medical therapy. 3. Willingness and ability to cooperate during conscious operative procedure, as well as during postsurgical evaluations, adjustments of medications and stimulator settings. iii. For STN or GPi DBS to be considered reasonable and necessary, patients must meet all of the following criteria: Summary1. Diagnosis of PD based on the presence of at least 2 cardinal PD features (tremor, rigidity or bradykinesia). 2. Advanced idiopathic PD as determined by the use of Hoehn and Yahr stage or Unified Parkinson’s Disease Rating Scale (UPDRS) part III motor subscale Issue 3. L-dopa responsive with clearly defined “on” periods. 4. Persistent disabling Parkinson’s symptoms or drug side effects (e.g., dyskinesias, motor fluctuations, or disabling “off” periods) despite optimal medical therapy. 5. Willingness and ability to cooperate during conscious operative VbBS procedure, as well as during postsurgical evaluations, adjustments of medications and stimulator settings.

b. DBS is not reasonable and necessary and is not covered for ET or PD patients with any of the following: i. Non-idiopathic Parkinson’s disease or “Parkinson’s Plus” syndromes. ii. Cognitive impairment, dementia or depression which would be worsened by or would interfere with the patient’s ability to benefit from DBS iii. Current psychosis, alcohol abuse or other drug abuse. iv. Structural lesions such as basal ganglionic stroke, tumor or vascular malformation as etiology of the movement disorder. v. Previous movement disorder surgery within the affected basal ganglion. vi. Significant medical, surgical, neurologic or orthopedic co-morbidities contraindicating DBS surgery or stimulation. c. Patients who undergo DBS implantation should not be exposed to diathermy (deep heat treatment including shortwave diathermy, microwave diathermy and ultrasound1/18/2018 diathermy) or any type of MRI which may adversely affect the DBS system or adversely affect the brain around the implanted electrodes. d. DBS should be performed with extreme caution in patients with cardiac pacemakers or other electronically controlled implants which may adversely affectfrom or be affected by the DBS system. e. For DBS lead implantation to be considered reasonable and necessary, providers and facilities must meet all of the following criteria: 1) Neurosurgeons must: (a) be properly trained in the procedure; (b) have experience with the surgical management of movement disorders, including DBS therapy; and (c) have experience performing stereotactic neurosurgical procedures. 2) Operative teams must have training and experience with DBS systems, including knowledge of anatomical and neurophysiological characteristics for localizing the targeted nucleus, surgical and/or implantation techniques for the DBS system, and operational and functional characteristicsDocuments of the device. 3) Physicians specializing in movement disorders must be involved in both patient selection and postprocedure care. 4) Hospital medical centers must have: (a) brain imaging equipment (MRI and/or CT) for pre-operative stereotactic localization and targeting of the surgical site(s); (b) operating rooms with all necessary equipment for stereotactic surgery; and (c) support services necessary for care of patients undergoing this procedure and any potential complications arising intraoperatively or postoperatively.

Since long-term safety,Summary effectiveness and optimal targeting for DBS have not been established, CMS will review the appropriateness of Medicare coverage as pertinent new evidence becomes available. This review will include clinical follow-up and targeting information from the ongoing, randomized VA/NINDS Cooperative Trial comparing best medical therapy with DBS of the STN and GPi for PD, as well as longer term clinical results from mandatory annual progress reports and final report to the FDA of Medtronic’s bilateralIssue DBS PMA postapproval study.

Private insurers Most private insurers are covering deep brain stimulation for Parkinson’s disease with criteria similar to VbBSCMS.

HERC staff summary: Based on 3 good quality randomized controlled trials, deep brain stimulation appears to be effective at improving motor symptoms and functionality in patients with advanced Parkinson’s disease whose symptoms are not adequately treated with optimal medical management. The estimated ICER was $23,404 per QALY for deep brain stimulation vs best medical management. The improvements in function are short term; there is no change in the long term outcome of the disease. There is a significant rate of significant complications from deep brain stimulation, including intracerebral hemorrhage, stroke and death.

HERC staff recommendations: 1) Add deep brain stimulation to line 250 PARKINSON'S DISEASE a. CPT 61863 Twist drill, burr hole, craniotomy, or craniectomy with stereotactic1/18/2018 implantation of neurostimulator electrode array in subcortical site (eg, thalamus, globus pallidus, subthalamic nucleus, periventricular, periaqueductal gray), without use of intraoperative microelectrode recording; first array b. CPT 61864 each additional array from c. CPT 61867 Twist drill, burr hole, craniotomy, or craniectomy with stereotactic implantation of neurostimulator electrode array in subcortical site (eg, thalamus, globus pallidus, subthalamic nucleus, periventricular, periaqueductal gray), with use of intraoperative microelectrode recording; first array d. CPT 61868 each additional array e. CPT 61880 Revision or removal of intracranial neurostimulator electrodes f. CPT 61885 Insertion or replacement of cranial neurostimulator pulse generator or receiver, direct or inductive coupling; with connection to a single electrode array g. CPT 61886 with connection to 2 or more electrode arrays h. Note: the following codes are DiagnosticDocuments or Ancillary and do not need to be added i. CPT 95970 Electronic analysis of implanted neurostimulator pulse generator system (eg, rate, pulse amplitude, pulse duration, configuration of wave form, battery status, electrode selectability, output modulation, cycling, impedance and patient compliance measurements); simple or complex brain, spinal cord, or peripheral (ie, cranial nerve, peripheral nerve, sacral nerve, neuromuscular) neurostimulator pulse generator/transmitter, without reprogramming ii. CPT 95978 Electronic analysis of implanted neurostimulator pulse generator system (eg, rate, pulse amplitude and duration, battery status, electrode Summaryselectability and polarity, impedance and patient compliance measurements), complex deep brain neurostimulator pulse generator/transmitter, with initial or subsequent programming; first hour 2) Adopt the following new guideline for line 250 a. Based on the CMS requirements Issue GUIDELINE NOTE XXX DEEP BRAIN STIMULATION FOR PARKINSON’S DISEASE Line 250 Unilateral or bilateral deep brain stimulation (DBS) is included on this line only for treatment of intractable tremors due to Parkinson’s disease (PD) when all of the following conditions are met: VbBS1) For thalamic VIM DBS, patients must meet all of the following criteria: a. A diagnosis of idiopathic PD (presence of at least 2 cardinal PD features (tremor, rigidity or bradykinesia)) which is of a tremor- dominant form

b. Marked disabling tremor of at least level 3 or 4 on the Fahn-Tolosa-Marin Clinical Tremor Rating Scale (or equivalent scale) in the extremity intended for treatment, causing significant limitation in daily activities despite optimal medical therapy. c. Willingness and ability to cooperate during conscious operative procedure, as well as during postsurgical evaluations, adjustments of medications and stimulator settings. 2) For STN or GPi DBS, patients must meet all of the following criteria: a. Diagnosis of PD based on the presence of at least 2 cardinal PD features (tremor, rigidity or bradykinesia). b. Advanced idiopathic PD as determined by the use of Hoehn and Yahr stage or Unified Parkinson’s Disease Rating Scale (UPDRS) part III motor subscale c. L-dopa responsive with clearly defined “on” periods. d. Persistent disabling Parkinson’s symptoms or drug side effects (e.g., dyskinesias, motor fluctuations, or disabling “off” periods) despite optimal medical therapy. 1/18/2018 e. Willingness and ability to cooperate during conscious operative procedure, as well as during postsurgical evaluations, adjustments of medications and stimulator settings. 3) DBS is not included on this line for PD patients with any of the following: a. Non-idiopathic Parkinson’s disease or “Parkinson’s Plus” syndromes.from b. Cognitive impairment, dementia or depression which would be worsened by or would interfere with the patient’s ability to benefit from DBS c. Current psychosis, alcohol abuse or other drug abuse. d. Structural lesions such as basal ganglionic stroke, tumor or vascular malformation as etiology of the movement disorder. e. Previous movement disorder surgery within the affected basal ganglion. f. Significant medical, surgical, neurologic or orthopedic co-morbidities contraindicating DBS surgery or stimulation.

Documents

Summary

Issue

VbBS

Neurostimlators for Epilepsy

Question: Should the use of deep brain neurostimulators for epilepsy be continued to be included on the Prioritized List?

Question source: HSD claims reconsideration

Issue: Epilepsy is mainly treated by anti-epileptic drugs to prevent seizure recurrence. However, some patients have epilepsy that is inadequately controlled by medical treatment. These patients experience frequent seizure activity and are at risk of status epilepticus and also sudden death. If medical therapy fails to achieve adequate control, surgery to resect or disconnect parts of the brain or vagus nerve stimulation may be considered. DBS is used for selected patients with medically refractory epilepsy for whom surgical resection is considered unsuitable. It involves electrical stimulation of specific sites within the brain (such as the anterior nucleus of the thalamus), which may suppress1/18/2018 abnormal electrical activity associated with seizures.

HSD recently received several claims for use of neurostimulators for certain types of seizures which are not currently paired with this technology. These diagnoses include ICD-10 G04.0401from (Other generalized epilepsy and epileptic syndromes, not intractable, with status epilepticus) and G04.0409 (Other generalized epilepsy and epileptic syndromes, intractable, without status epilepticus), both of which appear on line 30 EPILEPSY AND FEBRILE CONVULSIONS. Currently, neurostimulators only appear on line 174 GENERALIZED CONVULSIVE OR PARTIAL EPILEPSY WITHOUT MENTION OF IMPAIRMENT OF CONSCIOUSNESS which contains diagnoses for partial and generalized epilepsy. Line 174 is a surgical line with a treatment description of SINGLE FOCAL SURGERY. Line 30 is the medical therapy line. All diagnoses on line 174 appear on line 30; in addition, Line 30 contains other epilepsy type diagnoses.

HSC/HERC history Review of HOSC/HSC minutes finds that in 2003 CPTDocuments 61885 (Insertion or replacement of cranial neurostimulator pulse generator or receiver, direct or inductive coupling; with connection to a single electrode array) was added to the equivalent of line 174 for use in vagal nerve stimulation (not deep brain stimulation), along with CPT 64573 (was used for vagal nerve stimulation, no longer a valid code), with the following guideline (which no longer exists and is unclear whether was ever added to the PL): To be eligible for vagal nerve stimulation, patients must meet all of the following criteria: A. Diagnosis of refractory partial onset seizures (ICD-9 345.41/345.51) B. Patients are refractory to medical management of partial epilepsy. C. Not a candidate for, or unwilling to undergo, focal neurosurgery D. PatientSummary is ≥12 years of age E. Patient/family/caregivers and providers agree on treatment goals and are motivated to achieve treatment goals. Note: Vagus nerve simulators are currently coded with CPT 64568 (Incision for implantation of cranial nerve (eg, vagus nerve) neurostimulator electrode array and pulse generator) and 64569 (Revision or replacementIssue of cranial nerve (eg, vagus nerve) neurostimulator electrode array, including connection to existing pulse generator). These codes are both on line 174.

In January, 2005, deep brain neurostimulators for epilepsy was discussed, and found to have no evidence for use except for Parkinson’s. Vagal nerve stimulation for epilepsy was the other exception. VbBSThe Commissioners at that time declined to discuss adding deep brain neurostimulators for epilepsy.

Neurostimlators for Epilepsy

It appears that the current pairing of deep brain neurostimulators for epilepsy is an error and was never intended by the HSC/HERC.

Vagal nerve stimulation was discussed at several HOSC meetings and was intended for pairing with epilepsy. A NICE review in 2004 found evidence of effectiveness for treatment of refractory seizures in children despite optimal medical management.

Coding for vagal nerve stimulation CPT Code description Current Placement code 61885 Insertion or replacement of cranial neurostimulator 174 Generalized convulsive or pulse generator or receiver, direct or inductive partial epilepsy without mention of coupling; with connection to a single electrode array impairment of consciousness1/18/2018 285 Complications of a procedure Note: also used for deep brain stimulation always requiring treatment 64553 Percutaneous implantation of neurostimulator Ancillary electrode array; cranial nerve from 64568 Incision for implantation of cranial nerve (eg, vagus 174,440 Trigeminal and other nerve nerve) neurostimulator electrode array and pulse disorders generator 64569 Revision or replacement of cranial nerve (eg, vagus 174,285,440 nerve) neurostimulator electrode array, including connection to existing pulse generator 64570 Removal of cranial nerve (eg, vagus nerve) 174,285,440 neurostimulator electrode array and pulse generator

Current code placement for deep brain stimulationDocuments CPT codes CPT Code description Current lines code 61863 Twist drill, burr hole, craniotomy, or craniectomy with 174 GENERALIZED CONVULSIVE stereotactic implantation of neurostimulator electrode OR PARTIAL EPILEPSY WITHOUT array in subcortical site (eg, thalamus, globus pallidus, MENTION OF IMPAIRMENT OF subthalamic nucleus, periventricular, periaqueductal CONSCIOUSNESS gray), without use of intraoperative microelectrode recording; firstSummary array 61864 each additional array 174 61867 Twist drill, burr hole, craniotomy, or craniectomy with 174 stereotactic implantation of neurostimulator electrode array in subcortical site (eg, thalamus, globus pallidus, subthalamic nucleus, periventricular, periaqueductal Issuegray), with use of intraoperative microelectrode recording; first array 61868 each additional array 174 61880 Revision or removal of intracranial neurostimulator 174, 285 Complications of a electrodes procedure always requiring VbBS treatment 61886 with connection to 2 or more electrode arrays 174,285

Neurostimlators for Epilepsy

Evidence 1) Sprengers 2017, Cochrane review of deep brain stimulation for epilepsy (http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD008497.pub2/epdf) a. N=12 RCTs comparing intracranial neurostimulation with sham stimulation b. Moderate-quality evidence could not demonstrate statistically or clinically significant changes in the proportion of patients who were seizure-free or experienced a 50% or greater reduction in seizure frequency (primary outcome measures) after one to three months of anterior thalamic DBS in (multi)focal epilepsy, responsive ictal onset zone stimulation in (multi)focal epilepsy patients and hippocampal DBS in (medial) temporal lobe epilepsy. c. A statistically significant reduction in seizure frequency was found for anterior thalamic DBS (mean difference (MD), -17.4% compared to sham stimulation; 95% confidence interval (CI) -31.2 to -1.0; high quality evidence), responsive ictal onset zone 1/18/2018stimulation (MD -24.9%; 95%CI -40.1 to -6.0; high-quality evidence) and hippocampal DBS (MD - 28.1%; 95% CI -34.1 to -22.2; moderate-quality evidence). Both anterior thalamic DBS and responsive ictal onset zone stimulation do not have a clinically meaningful impact on quality life after three months of stimulation (high-quality evidence).from d. Electrode implantation resulted in postoperative asymptomatic intracranial haemorrhage in 1.6% to 3.7% of the patients included in the two largest trials and 2.0% to 4.5% had postoperative soft tissue infections (9.4% to 12.7% after five years); no patient reported permanent symptomatic sequelae. Anterior thalamic DBS was associated with fewer epilepsy-associated injuries (7.4 versus 25.5%; P = 0.01) but higher rates of self-reported depression (14.8 versus 1.8%; P = 0.02) and subjective memory impairment (13.8 versus 1.8%; P = 0.03); there were no significant differences in formal neuropsychological testing results between the groups. Responsive ictal-onset zone stimulation seemed to be well-tolerated with few side effects. The limited number of patients preclude firm statementsDocuments on safety and tolerability of hippocampal DBS. a. Authors’ conclusions Except for one very small RCT, only short-term RCTs on intracranial neurostimulation for epilepsy are available. Compared to sham stimulation, one to three months of anterior thalamic DBS ((multi)focal epilepsy), responsive ictal onset zone stimulation ((multi)focal epilepsy) and hippocampal DBS (temporal lobe epilepsy) moderately reduce seizure frequency in refractory epilepsy patients. Anterior thalamic DBS is associated with higher rates of self-reported depression and subjective memory impairment. There is insufficient evidence to make firm conclusive statements on the efficacy and safety of hippocampal DBS, centromedian thalamic DBS, nucleus accumbensSummary DBS and cerebellar stimulation. There is a need for more, large and well- designed RCTs to validate and optimize the efficacy and safety of invasive intracranial neurostimulation treatments. 2) NICE 2013, guidance for deep brain stimulation for epilepsy a. The evidence on the efficacy of deep brain stimulation (DBS) for refractory epilepsy is Issuelimited in both quantity and quality. The evidence on safety shows that there are serious but well-known side effects. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research.

VbBS

Neurostimlators for Epilepsy

HERC staff summary: Deep brain stimulation for epilepsy currently pairs on the Prioritized List, but no intent of the HSC/HERC for such a pairing could be found in review of minutes or meeting materials. This pairing appeared to have occurred by the misidentification of the CPT codes for vagal nerve stimulation and therefore is highly likely an error.

Current evidence does not support the effectiveness of deep brain stimulation at reducing seizures in most types of epilepsy. While the Cochrane review found a statistically significant reduction in seizure frequency was found for anterior thalamic DBS, responsive ictal onset zone stimulation and hippocampal DBS, these reductions did not have a clinically meaningful impact on quality life. Anterior thalamic DBS is associated with higher rates of self-reported depression and subjective memory impairment. Serious safety concerns for DBS for epilepsy exist. DBS for epilepsy is not covered by major insurers as experimental. 1/18/2018

Vagal nerve stimulation has evidence to support its use, and has been intended for pairing with epilepsy for many years. from

HERC staff recommendations: 1) Continue to include vagus nerve stimulation on the epilepsy line, as this is the prior intent of the HSC. a. Add CPT 64553 Percutaneous implantation of neurostimulator electrode array; cranial nerve to line 174 GENERALIZED CONVULSIVE OR PARTIAL EPILEPSY WITHOUT MENTION OF IMPAIRMENT OF CONSCIOUSNESS i. Advise HSD to remove CPT 64553 from the Ancillary List b. All other appropriate CPT codes already appear on line 174 or are diagnostic 2) Remove deep brain stimulation CPT codesDocuments from the epilepsy line a. No evidence of effectiveness, evidence of harm; added to this line in apparent error b. Remove the following CPT codes from line 174 GENERALIZED CONVULSIVE OR PARTIAL EPILEPSY WITHOUT MENTION OF IMPAIRMENT OF CONSCIOUSNESS i. CPT 61863 Twist drill, burr hole, craniotomy, or craniectomy with stereotactic implantation of neurostimulator electrode array in subcortical site (eg, thalamus, globus pallidus, subthalamic nucleus, periventricular, periaqueductal gray), without use of intraoperative microelectrode recording; first array ii. CPT 61864 each additional array iii. SummaryCPT 61867 Twist drill, burr hole, craniotomy, or craniectomy with stereotactic implantation of neurostimulator electrode array in subcortical site (eg, thalamus, globus pallidus, subthalamic nucleus, periventricular, periaqueductal gray), with use of intraoperative microelectrode recording; first array iv. CPT 61868 each additional array Issuev. CPT 61880 Revision or removal of intracranial neurostimulator electrodes vi. CPT 61886 with connection to 2 or more electrode arrays c. Add the following coding specification to line 174 GENERALIZED CONVULSIVE OR PARTIAL EPILEPSY WITHOUT MENTION OF IMPAIRMENT OF CONSCIOUSNESS i. “CPT 61885 is included on this line only for vagal nerve stimulation. It is not VbBS included on this line for deep brain stimulation.” 3) Add an entry to GN173 for deep brain stimulation as shown below a. No evidence of effectiveness, evidence of harm

Neurostimlators for Epilepsy

GUIDELINE NOTE 173, TREATMENTS THAT HAVE NO CLINICALLY IMPORTANT BENEFIT OR HAVE HARMS THAT OUTWEIGH BENEFITS FOR CERTAIN CONDITIONS; UNPROVEN TREATMENTS

The following treatments are prioritized on Line 660, CONDITIONS FOR WHICH CERTAIN TREATMENTS HAVE NO CLINICALLY IMPORTANT BENEFIT OR HAVE HARMS THAT OUTWEIGH BENEFITS; UNPROVEN TREATMENTS, for the conditions listed here:

CPT/HCPCS Code TREATMENT Rational Date of Last Review/Link to Meeting Minutes 61863, 61864, 61867, Deep brain stimulation No evidence of January, 2018 61868, 61880, for any type of effectiveness, 61886 epilepsy evidence of harm 1/18/2018

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VbBS

Diagnosis of sleep apnea - guideline update

Question: Should the guideline on the diagnosis of sleep apnea be modified?

Question source: Douglas Carr, MD. Umqua Health Alliance CCO

Issue: From Dr. Carr

I would propose that OHP adopt a two tier coverage guideline that requires that home testing be performed first for suspected Obstructive Sleep Apnea in uncomplicated adult members. Facility based PSG could be performed subsequently if home testing was not adequate. 1/18/2018 Facility PSG is appropriately used first in children, adults with complicating comorbidities (eg COPD, CHF), inability to utilize a home study, suspected central sleep apnea, or sleep related conditions such as periodic leg movements, parasomnias, etc. Split session PSG should always be done withfrom trial of PAP once Dx obtained.

With the new Auto-PAP machines, titration need not be part of the diagnostic session.

I’d base this tiered recommendation to reduce unnecessary costs to OHP.

Background Documents The guideline note on diagnosis of sleep apnea was derived from a Health Technology Assessment Subcommittee (HTAS) Coverage Guidance adopted in 2013. The box language for this guidance is as follows:

The following diagnostic tests for Obstructive Sleep Apnea (OSA) should be covered for adults: 1. Type I PSG is covered when used to aid the diagnosis of OSA in patients whoSummary have clinical signs and symptoms indicative of OSA if performed attended in a sleep lab facility. 2. Type II or Type III sleep testing devices are covered when used to aid the diagnosis of OSA in patients who have clinical signs and symptoms indicative of OSA if performed unattended in or out of a sleep lab facility Issueor attended in a sleep lab facility. 3. Type IV sleep testing devices measuring three or more channels, one of which is airflow, are covered when used to aid the diagnosis of OSA in patients who have signs and symptoms indicative of OSA if performed unattended in or out of a sleep lab facility or attended in a sleep lab VbBS facility.

Diagnosis of sleep apnea - guideline update, Issue #1350 Page 1

Diagnosis of sleep apnea - guideline update

4. Sleep testing devices measuring three or more channels that include actigraphy, oximetry, and peripheral arterial tone, are covered when used to aid the diagnosis of OSA in patients who have signs and symptoms indicative of OSA if performed unattended in or out of a sleep lab facility or attended in a sleep lab facility.

HTAS completed an updated literature search in 2015 to see if the Coverage Guidance needed to be reopened.

Bottom Line: Most of the newly available evidence pertains to the comparability of portable level III testing with the gold standard level I testing that is done in a sleep lab. Portable level III testing appears to have favorable diagnostic 1/18/2018 performance in adults with a high pre-test probability of uncomplicated OSA and may be less expensive. While the additional evidence identified in this search would be unlikely to substantially alter the existing coverage guidance, HERC may wish to consider addressing clinical pathways to encouragefrom the most efficient use of less costly diagnostic tests or empiric therapeutic trials in selected patients with a high pre-test probability of uncomplicated sleep apnea.

Definition of sleep apnea (from AASM, 2017 Clinical Practice Guideline) (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5337595/pdf/jcsm.13.3.479.pdf) International Classification of Sleep Disorders (ICSD-3) defines OSA as a PSG-determined obstructive respiratory disturbance index (RDI) ≥ 5 events/h associated with the typical symptoms of OSA (e.g., unrefreshing sleep, daytime sleepiness, fatigue or insomnia, awakening with a gasping or choking sensation,Documents loud snoring, or witnessed apneas), or an obstructive RDI ≥ 15 events/h (even in the absence of symptoms).

Increased risk of moderate to severe OSA is indicated by the presence of excessive daytime sleepiness and at least two of the following three criteria: habitual loud snoring; witnessed apnea or gasping or choking; or diagnosed hypertension.

A technically adequate HSAT includes a minimum of 4 hours of technically adequate oximetry and flowSummary data, obtained during a recording attempt that encompasses the habitual sleep period.

Current Prioritized List Status Issue Line: 207 Condition: SLEEP APNEA, NARCOLEPSY AND REM BEHAVIORAL DISORDER (See Guideline Notes 27,64,65,118) Treatment: MEDICAL AND SURGICAL TREATMENT VbBS ICD-10: G47.30-G47.31,G47.33-G47.39,G47.411-G47.429,G47.52 CPT: 21193-21235,30117,30140,30520,31600,31601,31610,31820,31825, 42140-42160,42820-42836,94660,96150-96155,98966-98969,99051,

Diagnosis of sleep apnea - guideline update, Issue #1350 Page 2

Diagnosis of sleep apnea - guideline update

99060,99070,99078,99184,99201-99239,99281-99285,99291-99404, 99408-99449,99468-99480,99487-99498,99605-99607 HCPCS: G0396,G0397,G0406-G0408,G0425-G0427,G0463-G0467,G0490,G0508, G0509

Prioritized Fee Code Code Description List Schedule Placement 95800 Sleep study, unattended, simultaneous recording; Diagnostic Not on fee heart rate, oxygen saturation, respiratory analysis (eg, Procedures schedule by airflow or peripheral arterial tone), and sleep time File 1/18/2018 95801 Sleep study, unattended, simultaneous recording; Diagnostic Not on fee minimum of heart rate, oxygen saturation, and Procedures schedule respiratory analysis (eg, by airflow or peripheral File arterial tone) from 95806 Sleep study, unattended, simultaneous recording of, Diagnostic $119.36 heart rate, oxygen saturation, respiratory airflow, and Procedures respiratory effort (eg, thoracoabdominal movement) File 95807 Sleep study, simultaneous recording of ventilation, Diagnostic $326.19 respiratory effort, ECG or heart rate, and oxygen Procedures saturation, attended by a technologist File 95808 Polysomnography; any age, sleep staging with 1-3 Diagnostic $448.92 additional parameters of sleep, attended by a Procedures technologist DocumentsFile 95810 Polysomnography; age 6 years or older, sleep staging Diagnostic $437.03 with 4 or more additional parameters of sleep, Procedures attended by a technologist File 95811 Polysomnography; age 6 years or older, sleep staging Diagnostic $459.07 with 4 or more additional parameters of sleep, with Procedures initiation of continuous positive airway pressure File therapy orSummary bilevel ventilation, attended by a technologist

Prioritized Fee Schedule HCPCS Code Description List Code Issue Placement G0398 Home sleep study test (hst) with type ii portable Diagnostic $167.43 monitor, unattended; minimum of 7 channels: eeg, Procedures eog, emg, ecg/heart rate, airflow, respiratory effort File VbBS and oxygen saturation G0399 Home sleep test (hst) with type iii portable monitor, Diagnostic $167.43

Diagnosis of sleep apnea - guideline update, Issue #1350 Page 3

Diagnosis of sleep apnea - guideline update

Prioritized Fee Schedule HCPCS Code Description List Code Placement unattended; minimum of 4 channels: 2 respiratory Procedures movement/airflow, 1 ecg/heart rate and 1 oxygen File saturation G0400 Home sleep test (hst) with type iv portable monitor, Diagnostic $105.11 unattended; minimum of 3 channels Procedures File

1/18/2018 DIAGNOSTIC GUIDELINE D8, DIAGNOSTIC TESTING FOR OBSTRUCTIVE SLEEP APNEA (OSA) IN ADULTS Type I PSG is covered when used to aid the diagnosis of OSA in patients who have clinical signs and symptoms indicative of OSA if performed attended infrom a sleep lab facility.

OHP clients should have access to least one of the alternatives listed below: 1) Type II or Type III sleep testing devices when used to aid the diagnosis of OSA in patients who have clinical signs and symptoms indicative of OSA if performed unattended in or out of a sleep lab facility or attended in a sleep lab facility. 2) Type IV sleep testing devices measuring three or more channels, one of which is airflow, when used to aid the diagnosis of OSA in patients who have signs and symptoms indicative of OSA if performedDocuments unattended in or out of a sleep lab facility or attended in a sleep lab facility. 3) Sleep testing devices measuring three or more channels that include actigraphy, oximetry, and peripheral arterial tone, when used to aid the diagnosis of OSA in patients who have signs and symptoms indicative of OSA if performed unattended in or out of a sleep lab facility or attended in a sleep lab facility. CPAP titration should be performed as part of the diagnostic study, if possible.

The developmentSummary of this guideline note was informed by a HERC coverage guidance. See http://www.oregon.gov/oha/HPA/CSI-HERC/Pages/Evidence-based-Reports.aspx.

GUIDELINE NOTE 27, SLEEP APNEA IssueLine 203 CPAP is covered initially when all of the following conditions are met:  12 week ‘trial’ period to determine benefit. This period is covered if apnea- hypopnea index (AHI) or respiratory disturbance index (RDI) is greater than or equal to 15 events per hour; or if between 5 and 14 events with additional VbBS symptoms including one or more of the following:

Diagnosis of sleep apnea - guideline update, Issue #1350 Page 4

Diagnosis of sleep apnea - guideline update

o excessive daytime sleepiness defined as either an Epworth Sleepiness Scale score>10 or daytime sleepiness interfering with ADLs that is not attributable to another modifiable sedating condition (e.g. narcotic dependence), or o documented hypertension, or o ischemic heart disease, or o history of stroke;  Providers must provide education to patients and caregivers prior to use of CPAP machine to ensure proper use; and  Positive diagnosis through polysomnogram (PSG) or Home Sleep Test (HST).

CPAP coverage subsequent to the initial 12 weeks is based on documented patient1/18/2018 tolerance, compliance, and clinical benefit. Compliance (adherence to therapy) is defined as use of CPAP for at least four hours per night on 70% of the nights during a consecutive 30-day period. from Mandibular advancement devices (oral appliances) are covered for those for whom CPAP fails or is contraindicated.

Surgery for sleep apnea in adults is not included on this line (due to lack of evidence of efficacy). Surgical codes are included on this line only for children who meet criteria according to GUIDELINE NOTE 118 OBSTRUCTIVE SLEEP APNEA DIAGNOSIS AND TREATMENT FOR CHILDREN.

The development of this guideline note wasDocuments informed by a HERC coverage guidance. See http://www.oregon.gov/oha/HPA/CSI-HERC/Pages/Evidence-based-Reports.aspx.

GUIDELINE NOTE 118, OBSTRUCTIVE SLEEP APNEA DIAGNOSIS AND TREATMENT FOR CHILDREN Line 203 Obstructive sleep apnea (OSA) in children (18 or younger) must be diagnosed by Summary A) nocturnal polysomnography with an AHI >5 episodes/h or AHI>1 episodes/h with history and exam consistent with OSA, OR B) nocturnal pulse oximetry with 3 or more SpO2 drops <90% and 3 or more clusters of desaturation events, or alternatives desaturation (>3%) index >3.5 Issueepisodes/h, OR C) use of a validated questionnaire (such as the Pediatric Sleep Questionnaire or OSA 18), OR D) consultation with a sleep medicine specialist.

VbBSPolysomnography and/or consultation with a sleep medicine specialist to support the diagnosis of OSA and/or to identify perioperative risk is recommended for

Diagnosis of sleep apnea - guideline update, Issue #1350 Page 5

Diagnosis of sleep apnea - guideline update

A) high risk children (i.e. children with cranio-facial abnormalities, neuromuscular disorders, Down syndrome, etc.) B) children with equivocal indications for adenotonsillectomy (such as discordance between tonsillar size on physical examination and the reported severity of sleep-disordered breathing), C) children younger than three years of age

Adenotonsillectomy is an appropriate first line treatment for children with OSA. Weight loss is recommended in addition to other therapy in patients who are overweight or obese. Adenoidectomy without tonsillectomy is only covered when a child with OSA has previously had a tonsillectomy, when tonsillectomy is contraindicated, or when tonsillar1/18/2018 hypertrophy is not present. More complex surgical treatments are only included on this line for children with craniofacial anomalies.

Intranasal corticosteroids are an option for children with mild OSA in fromwhom adenotonsillectomy is contraindicated or for mild postoperative OSA.

CPAP is covered for a 3 month trial for children through age 18 who have

1. undergone surgery or are not candidates for surgery, AND 2. have documented residual sleep apnea symptoms (sleep disruption and/or significant desaturations) with residual daytime symptoms (daytime sleepiness or behavior problems) Documents CPAP will be covered for children through age 18 on an ongoing basis if:

 There is documentation of improvement in sleep disruption and daytime sleepiness and behavior problems with CPAP use  Annual re-evaluation for CPAP demonstrates ongoing clinical benefit and compliance with use, defined as use of CPAP for at least four hours per night on 70% of theSummary nights in a consecutive 30 day period

Evidence summary HTAS Coverage Guidance, 2013 Issue Overall Summary of evidence

Although PSG (type I monitor) is considered the gold standard for diagnosing sleep apnea, the strength of evidence that AHI is a strong and independent VbBS predictor of all‐cause mortality is limited to AHI > 30. The association between baseline AHI and the other long‐term clinical outcomes is less robust, no current

Diagnosis of sleep apnea - guideline update, Issue #1350 Page 6

Diagnosis of sleep apnea - guideline update

established threshold level for AHI exists that indicates the need for treatment. Type II, III and IV monitors can all accurately diagnosis OSA, although there is wide variation in estimating the actual AHI for type II monitors, and type III monitors perform better than type IV monitors. Some clinical prediction models and the Berlin questionnaire have evidence of efficacy as screening tools for OSA.

Box language

1/18/2018

from

Documents

Jonas, 2017 https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0091057/pdf/PubMedHealth_PMH0 091057.pdf

 AHRQ systematic review of screening for obstructive sleep apnea for the USPSTF.  110 studiesSummary  Studies reporting accuracy of PMs for diagnostic testing of persons with suspected OSA found wide ranges for sensitivity and specificity (Type II monitors: 85% to 94% and 77% to 95%; Type III monitors: 49% to 92% and 79% to 95%; Type IV monitors: 7% to 100% and 15% to 100%, respectively, for Issuepolysomnography AHI ≥15). Data were limited by imprecision and inconsistency for Type IV monitors. We found sparse data on reliability of PMs.  Authors Conclusions: There is uncertainty about the clinical utility of all potential screening tools. Although screening with Multivariable Apnea Prediction Score followed by home PM testing may have promise for distinguishing persons in the VbBS general population who are more or less likely to have OSA, current evidence is limited. Multiple treatments for OSA reduce AHI, ESS, and blood pressure.

Diagnosis of sleep apnea - guideline update, Issue #1350 Page 7

Diagnosis of sleep apnea - guideline update

Although good evidence has established that persons with severe OSA die at twice the rate of controls, trials of CPAP and other treatments have not established whether treatment reduces mortality or improves most other health outcomes, barring evidence of some possible benefit for sleep-related quality of life.

El Shayeb, 2014 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3883848/pdf/18600e25.pdf)

1. Systematic review and meta-analysis of the diagnostic accuracy of level 1 versus level 3 portable sleep tests for the diagnosis of sleep-disordered breathing 2. 59 studies involving 5026 patients (mostly patients suspected of having OSA).1/18/2018 19 studies included in meta-analysis 3. Results: a. The estimated area under the receiver operating characteristics curve (AUROC) was high, ranging between 0.85 and 0.99 acrossfrom different levels of disease severity. b. Summary sensitivity ranged between 0.79 and 0.97 c. Summary specificity ranged between 0.60 and 0.93 across different apnea–hypopnea cut-offs. d. No significant difference in the clinical management parameters between patients who underwent either test to receive their diagnosis. 4. Authors Interpretation: Level 3 portable devices showed good diagnostic performance compared with level 1 sleep tests in adult patients with a high pretest probability of moderate toDocuments severe obstructive sleep apnea and no unstable comorbidities.

Cooksey, 2016

1. Non-systematic review of portable sleep apnea testing 2. Summarized a number of studies a. Kuna, 2011 Summaryi. Randomized trial of 296 VA patients ii. PSG followed by in-laboratory CPAP titration or a home portable study followed by in-home autotitrating positive airway pressure (APAP). After 4 to 5 days of APAP, a fixed CPAP pressure was selected based on the 90th percentile APAP pressure (ie, the Issue pressure below which a study participant spent 90% of the time and which led to AHI # 10 events per hour). iii. home testing pathway was noninferior to the traditional in- laboratory pathway in terms of CPAP adherence at 3 months and functional outcomes of sleepiness (ESS, FOSQ), and depression. VbBS iv. 25% of patients required PSG due to either technical failure of the portable study (5.6%) or due to a negative portable study result

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Diagnosis of sleep apnea - guideline update

based on a diagnostic threshold of an AHI > 15 events per hour (18.9%). This false-negative rate, albeit at a different diagnostic threshold, supports the AASM recommendation that a negative portable study result should be followed up with in-laboratory PSG if the pretest probability of moderate to severe OSA is high. b. Berry, 2014 i. 156 symptomatic VA patients diagnosed with Level 3 study ii. Randomized to undergo in laboratory CPAP titration or outpatient APAP titration iii. Results: no difference in PAP adherence, residual AHI, or functional outcomes. But higher satisfaction in APAP group. c. Rosen 2012 HomePAP study 1/18/2018 i. Multicenter trial of 373 patients ii. Compared traditional in-laboratory PSG vs home testing followed by APAP titration followed by CPAP at the 90th percentile pressure. from iii. Results: ESS scores were similar between the two groups but that CPAP adherence was higher at 3 months in the home testing and titration group. 3. Concluded portable monitoring is a reasonable substitute for inlaboratory PSG in appropriately selected patients. 4. Close follow up to improve CPAP adherence is important 5. Importantly, there is a continuing role for in-laboratory PSG within home testing algorithms. In-laboratory testing is still indicated in the event of technical failure of the portable monitoring study, Documentsin the event of a negative portable study result with a high suspicion of OSA, or to rule out other concomitant sleep disorders in patients who remain symptomatic despite effective PAP therapy.

Corral, 2017 (http://dx.doi.org/10.1164/rccm.201612-2497OC)

1. Noninferiority, randomized controlled trial with two open parallel arms and a cost-effectiveness analysis 2. 12 tertiarySummary hospitals in Spain 3. 430 Patients with intermediate to high suspicion of sleep apnea, treated with or without CPAP 4. Randomized to respiratory polygraphy or polysomnography protocols a. Our HRP (Embla-Embletta; Natus, Pleasanton, CA) measurements Issueincluded oxygen saturation, airflow through nasal pressure, and thoracic and abdominal movements measured by piezoelectric bands. 5. Respiratory polygraphy protocol was noninferior to the polysomnography protocol based on the Epworth scale. Quality of life, blood pressure, and polysomnography were similar between protocols. VbBS 6. Respiratory polygraphy was the most cost-effective protocol, with a lower per- patient cost of 416.7€.

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Diagnosis of sleep apnea - guideline update

7. Considerations: The home testing resulted in CPAP in 15% fewer patients than the polysomnography group. However, this was not associated with important consequences because improvements in the primary and secondary outcomes were similar between the arms in the subgroup of patients not treated with CPAP (with the exception of a smaller deep-sleep percentage with the HRP protocol). 8. Author conclusions: Home respiratory polygraphy management is similarly effective to polysomnography, with a substantially lower cost. Therefore, polysomnography is not necessary for most patients with suspected sleep apnea. This finding could change established clinical practice, with a clear economic benefit. 9. HERC Staff Conclusions: This study supports that home testing has similar1/18/2018 outcomes to polysomnography, even though there is 15% less CPAP prescribed. from Chai-Coetzer 2017 http://dx.doi.org/10.7326/M16-1301

1. Multicenter randomized non-inferiority trial 2. 7 academic sleep centers in Australia 3. Patients (n = 406) aged 25 to 80 years with suspected OSA. 4. 3 way comparison between Level 1 polysomnography data, Level 3 which included airflow, thoracoabdominal bands, body position, electrocardiography, and oxygen saturation; or level 4 which included oxygen saturation and heart rate (n = 135). Documents 5. Results: Change in Functional Outcomes of Sleep Questionnaire (FOSQ) score at 4 months was not inferior for L3 (mean difference [MD], 0.01 [95% CI, -0.47 to 0.49; P = 0.96]) or L4 (MD, -0.46 [CI, -0.94 to 0.02; P = 0.058]) versus L1 (noninferiority margin [NIM], -1.0). Compared with L1, change in Epworth Sleepiness Scale (ESS) score was not inferior for L3 (MD, 0.08 [CI, -0.98 to 1.13; P = 0.89]) but was inconclusive for L4 (MD, 1.30 [CI, 0.26 to 2.35; P = 0.015]) (NIM, 2.0). For L4 versus L1, there was less improvement in Sleep Apnea Symptoms QuestionnaireSummary (SASQ) score (-17.8 vs. -24.7; P = 0.018), less CPAP use (4.5 vs. 5.3 hours per night; P = 0.04), and lower physician diagnostic confidence (P = 0.003). 6. Major limitation – the limited channel studies were not actually done at home. They were simulated by laboratory PSG data. 7. Authors Conclusion: The results support manually scored L3 testing in routine Issuepractice. Poorer outcomes with L4 testing may relate, in part, to reduced physician confidence. 8. HERC Staff Conclusions: This study reaffirms the utility of level 3 testing with patient oriented RCT outcomes, but doesn’t take into account additional factors VbBS related to home-based testing. Level 4 studies may be inferior.

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Diagnosis of sleep apnea - guideline update

Goldstein, 2017

1. Retrospective cohort study 196 patients 2. First home sleep apnea testing performed. Those with negative tests had in lab polysomnography. Patients were also characterizied by a modified STOP Score (2 symptoms of STOP plus either BMI > 35 or male gender. Negative sleep apnea tests were followed up by polysomnography (except for 27% which did not have a f/u polysomnography) 3. Results: Among 196 individuals, pre-test probability was low in 74 (38%) and high in 122 (62%). A lower percentage of individuals with a low versus high pre-test probability for moderate to severe OSA had HSAT results that confirmed OSA (61versus 84%, p = 0.0002) resulting in an odds ratio (OR) of 0.29 for 1/18/2018 confirmatory HSAT in the low pre-test probability group (95% CI [0.146, 0.563]). Multivariate logistic regression demonstrated that age ≤ 50 (OR 3.10 [1.24– 7.73]), female gender (OR 3.58[1.50–8.66]), non-enlarged neck circumference (OR 11.50 [2.50–52.93]), and the absence of loud snoring (ORfrom 3.47 [1.30 –9.25]) best predicted non-diagnostic HSAT. OSA was diagnosed by PSG in 54%of individuals with negative HSAT which was similar in both pre-test probability groups. 4. Authors conclusions: HSATs should be reserved for individuals with high pre-test probability for moderate to severe disease as opposed to any individual with suspected OSA. 5. HERC Staff Consideration – Authors have strong opinions on insurer mandates to require home apnea testing first Documents Guidelines Kapur, 2017 - American Academy of Sleep Medicine (AASM) guidelines http://jcsm.aasm.org/ViewAbstract.aspx?pid=30972

AASM Good Practice Statements:  Diagnostic testing for OSA should be performed in conjunction with a comprehensive sleep evaluation and adequate follow-up.  PolysomnographySummary is the standard diagnostic test for the diagnosis of OSA in adult patients in whom there is a concern for OSA based on a comprehensive sleep evaluation.

AASMIssue Recommendations: 1. We recommend that clinical tools, questionnaires and prediction algorithms not be used to diagnose OSA in adults, in the absence of polysomnography or home sleep apnea testing. (STRONG) 2. We recommend that polysomnography, or home sleep apnea testing with a VbBS technically adequate device, be used for the diagnosis of OSA in uncomplicated adult patients presenting with signs and symptoms that indicate an increased risk of moderate to severe OSA. (STRONG)

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Diagnosis of sleep apnea - guideline update

3. We recommend that if a single home sleep apnea test is negative, inconclusive, or technically inadequate, polysomnography be performed for the diagnosis of OSA. (STRONG) 4. We recommend that polysomnography, rather than home sleep apnea testing, be used for the diagnosis of OSA in patients with significant cardiorespiratory disease, potential respiratory muscle weakness due to neuromuscular condition, awake hypoventilation or suspicion of sleep related hypoventilation, chronic opioid medication use, history of stroke or severe insomnia. (STRONG) 5. We suggest that, if clinically appropriate, a split-night diagnostic protocol, rather than a full-night diagnostic protocol for polysomnography be used for the diagnosis of OSA. (WEAK) 1/18/2018 6. We suggest that when the initial polysomnogram is negative and clinical suspicion for OSA remains, a second polysomnogram be considered for the diagnosis of OSA. (WEAK) from

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Diagnosis of sleep apnea - guideline update

Other payers: Cigna, 2016 http://help.carecentrix.com/ProviderResources/Cigna%20Medical%20Coverage%20Polic y.pdf

Home/Portable Study: Cigna covers a home/portable sleep study* as medically necessary for the diagnosis of obstructive sleep apnea (OSA) in an adult (age 18 or older) when ALL of the following criteria are met: study/test equipment meets the minimum definition described in at least one of the following Current Procedural Terminology (CPT) or Health Care Procedure Coding System (HCPCS) codes: 95800: Sleep study, unattended, simultaneous recording:1/18/2018 heart rate, oxygen saturation, respiratory analysis (eg, by airflow or peripheral arterial tone) and sleep time 95801: Sleep study, unattended, simultaneous recording: minimum of heart rate, oxygen saturation, and respiratory analysis (eg, by airflow or peripheralfrom arterial tone) 95806: Sleep study, unattended, simultaneous recording of heart rate, oxygen saturation, respiratory airflow, and respiratory effort (eg, thoracoabdominal movement) G0398: Home sleep study test (HST) with type II portable monitor, unattended; minimum of 7 channels: EEG, EOG, EMG, ECG/heart rate, airflow, respiratory effort and oxygen saturation G0399: Home sleep test (HST) with type III portable monitor, unattended; minimum of 4 channels: 2 respiratory movement/airflow, 1 ECG/heart rate and 1 oxygen saturation

• medical necessity criteria for a sleep studyDocuments for suspected OSA as outlined above have been met • absence of significant comorbid condition that would be expected to degrade the accuracy of a home/portable study, such as any of the following: moderate to severe pulmonary disease, such as chronic obstructive pulmonary disease (COPD), documented on pulmonary function studies (PFTs) moderate to severe neuromuscular/neurodegenerative disorder causing restrictive lung diseases (e.g., kyphoscoliosis, myasthenia gravis, amyotropic lateral sclerosis (ALS), post-polio, syndrome,Summary polymyositis, Guillian Barre syndrome) congestive heart failure New York Heart Association (NYHA) Class III or IV (LVEF ≤ 45%) obesity hypoventilation syndrome, previously documented (defined as pCO2 > 45 mmHg and pO2 < 60 mmHg on arterial blood gas) pulmonaryIssue hypertension (defined as mean pulmonary artery pressure (mPAP) ≥ 25 mmHg) • no sleep disorder other than OSA is suspected (e.g., central sleep apnea, periodic limb movement disorder, complex; potentially injurious or violent parasomnias, narcolepsy, REM behavior sleep disorder, nocturnal seizures) VbBS*Note: A home/portable study is considered to be one study, whether performed during a single night or during two or more consecutive nights.

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Diagnosis of sleep apnea - guideline update

Cigna covers a follow-up home/portable sleep study when the diagnosis of OSA has been established in an adult (age 18 or older) when ALL of the following criteria are met: • testing is to be performed for ANY of the following: confirmation of therapeutic benefit following final adjustment of a mandibular repositioning appliance (MRA) assessment of results following surgical treatment for OSA clinical response is insufficient or symptoms return despite a good initial response to oral appliance therapy

• no significant oxygen desaturation* during diagnostic sleep study • absence of comorbid sleep disorder or significant comorbid medical condition, 1/18/2018as described above, that would be expected to degrade the accuracy of a home/portable study Cigna covers full night in-facility polysomnography (PSG) (CPT codes 95808, 95810) as medically necessary in an adult (age 18 or older) when BOTH of the fromfollowing criteria are met: • medical necessity criteria for a sleep study for suspected obstructive sleep apnea (OSA) as outlined above have been met • ANY of the following: significant comorbid condition that would be expected to degrade the accuracy of a home/portable study such as any of the following: o moderate to severe pulmonary disease, such as chronic obstructive pulmonary disease (COPD) o moderate to severe neuromuscular/neurodegenerativeDocuments disorder causing restrictive lung diseases (e.g., kyphoscoliosis, myasthenia gravis, amyotropic lateral sclerosis (ALS), post-polio syndrome, polymyositis, Guillian Barre syndrome) o congestive heart failure (moderate to severe) NYHA Class III or IV (LVEF ≤ 45%) o obesity hypoventilation syndrome, previously documented (defined as pCO2 > 45 mmHg and pO2 < 60 mmHg on arterial blood gas) o pulmonary hypertension (defined as mPAP ≥ 25 mmHg) sleep disorder other than OSA is suspected (e.g., central sleep apnea, periodic limb movement disorder,Summary complex; potentially injurious of violent parasomnias, narcolepsy, REM behavior sleep disorder, nocturnal seizures) that is corroborated by the clinical documentation recent home/portable testing proved to be technically inadequate or failed to establishIssue the diagnosis of OSA in an individual with high pretest likelihood of OSA individual and caregiver/companion incapable of operating home testing equipment

Cigna covers full night in-facility polysomnography (PSG) (CPT codes 95808, 95810) as medically necessary prior to a planned multiple sleep latency test (MSLT) in an adult VbBS(age 18 or older) with suspected narcolepsy.

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Diagnosis of sleep apnea - guideline update

Aetna, 2017 http://www.aetna.com/cpb/medical/data/1_99/0004.html

Aetna considers the diagnosis and treatment of obstructive sleep apnea (OSA) in adults aged 18 and older medically necessary according to the criteria outlined below.

I. Diagnosis

Aetna considers attended full-channel nocturnal polysomnography (NPSG) (Type1/18/2018 I device) performed in a healthcare facility medically necessary for diagnosis in members with symptoms suggestive of obstructive sleep apnea (see appendix), when attended NPSG is used as part of a comprehensive sleep evaluation, and member has one or more of the following indications for attended NPSG: from

A. Member has at least one of the following comorbid medical conditions that degrade the accuracy of portable monitoring:

1. moderate to severe pulmonary disease (for example, COPD or ashma) (with nocturnal oxygen use or daytime hypercapnea with documented arterial blood gasses showing pO2 less than 60 or pCO2 greater than 45), 2. neuromuscular disease (e.g., Parkinson’s disease, spina bifida, myotonic dystrophy, amyotrophic lateralDocuments sclerosis), 3. stroke with residual respiratory effects, 4. epilepsy, 5. congestive heart failure (NYHA class III or IV or LVEF less than 45%), 6. super obesity (BMI greater than 45, or pulmonary function studies show obesity hypoventilation syndrome (BMI greater than 35 plus arterial blood gas with PCO2 greater than 45, or BMI greater than 35 plus inability to lie flat in bed));Summary or

B. Member has one or more of the following comorbid sleep disorders:

1. periodic limb movement disorder (involuntary, jerking movements of the legs Issueduring sleep causing excessive daytime sleepiness (EDS) due to sleep fragmentation), 2. parasomnias that are unusual or atypical because of the individual’s age at onset, the time, duration or frequency of occurrence of the behavior including, but not limited to: nocturnal seizures, psychogenic dissociative VbBS states, REM sleep behavior disorder, sleep talking and/or confusional arousals,

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Diagnosis of sleep apnea - guideline update

3. narcolepsy, 4. central sleep apnea or complex sleep apnea; or

C. Member has negative or technically inadequate portable monitoring results; or D. Member has low pretest probability of obstructive sleep apnea (normal BMI (less than 30), normal airway (Mallampati score 1 or 2), no snoring, and normal neck circumference (less than 17 inches in men, and less than 16 inches in women)); or E. Member lacks the mobility or dexterity to use portable monitoring equipment safely at home.

Note: Where attended NPSG is indicated, a split-night study NPSG is considered medically necessary, in which the final portion of the NPSG is used to titrate 1/18/2018 continuous positive airway pressure (CPAP), if the Apnea Hypopnea Index (AHI) is greater than 15 in first 2 hours of a diagnostic sleep study. An additional full-night CPAP titration NPSG is considered medically necessary only if the AHI is less than or equal to 15 during the first 2 hours of a diagnostic sleep study, or iffrom the split-night study did not allow for the abolishment of the vast majority of obstructive respiratory events (see section III below).

II. Unattended (Home) Sleep Studies

Aetna considers unattended (home) sleep studies using any of the following diagnostic techniques (see appendix for definition ofDocuments device types) medically necessary for members with symptoms suggestive of OSA (see appendix) when the home sleep study is used as part of a comprehensive sleep evaluation:

. Sleep monitoring using a Type II device; or A. Sleep monitoring using a Type III device, or B. Sleep monitoring using a Type IV(A) device, measuring airflow and at least 2 other channels and providing measurement of apnea-hypopnea index (AHI); or C. Sleep monitoringSummary using a device that measures 3 or more channels that include pulse oximetry, actigraphy, and peripheral arterial tone (e.g., Watch-PAT device).

Note: Sleep studies using devices that do not provide a measurement of apnea- hypopnea index (AHI) and oxygen saturation are considered not medically necessary becauseIssue they do not provide sufficient information to prescribe treatment. Examples include the Biancamed SleepMinder, SNAP testing with fewer than three channels, and the SleepImage Sleep Quality Screener. Note that the ApneaLink does not meet criteria as a covered type IV device because it does not measure VbBS airflow; however, the ApneaLink Plus records 5 channels, including airflow, and meets criteria for a covered sleep study device.

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Diagnosis of sleep apnea - guideline update

Repeat home sleep testing on multiple consecutive nights has no proven value.

III. Attended Nocturnal Polysomnography (NPSG)

Attended full-channel nocturnal polysomnography (NPSG) (Type I device) performed in a healthcare facility is considered medically necessary for persons diagnosed with obstructive sleep apnea who have any of the following indications for attended NPSG:

. To titrate CPAP in persons diagnosed with clinically significant OSA for whom in- laboratory NPSG was medically necessary, but who were unable to undergo a split-1/18/2018 night study because they had an insufficient AHI (less than 15) during the first two hours of an attended NPSG; or A. To titrate CPAP in persons with clinically significant OSA for whom in-laboratory NPSG was medically necessary, and who underwent a split-night study thatfrom did not abolish the vast majority of obstructive respiratory events; or B. To monitor results from CPAP in persons with OSA who have persistent significant symptoms (disturbed sleep with significant arousals) despite documented AHI less than 5 on CPAP and documented compliance with CPAP (CPAP used for 70 percent of nights for four or more hours per night, for two or more months); or C. To confirm diagnosis of obstructive sleep apnea prior to surgical modifications of the upper airway. Documents MODA, 2017 https://www.modahealth.com/pdfs/med_criteria/ObstructiveSleepApnea_NonSurgical Mgmt.pdf

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Diagnosis of sleep apnea - guideline update

1/18/2018

from

HERC Staff Summary Insufficient evidence supports screening for obstructive sleep apnea with clinical tools. Home sleep studies appear to be of reasonableDocuments efficacy compared to laboratory polysomnography. There will be a number of patients (approximately 15-25%) with a negative home sleep study who would test positive with laboratory polysomnography, but the clinical value of identifying this “false negative” group is unclear. Home sleep studies are much less costly than laboratory polysomnography. Other insurers generally require home sleep studies over attended polysomnography unless there are specific clinical indications which would decrease the potential accuracy of home testing.

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Diagnosis of sleep apnea - guideline update, Issue #1350 Page 18

Diagnosis of sleep apnea - guideline update

HERC Staff Recommendations: 1. Modify Diagnostic Guideline D8 as follows: DIAGNOSTIC GUIDELINE D8, DIAGNOSTIC TESTING FOR OBSTRUCTIVE SLEEP APNEA (OSA) IN ADULTS Type I PSG is covered when used to aid the diagnosis of OSA in patients who have clinical signs and symptoms indicative of OSA if performed attended in a sleep lab facility.

OHP clients should have access to least one of the alternatives listed below: 1) Type II or Type III sleep testing devices when used to aid the diagnosis of OSA in patients who have clinical signs and symptoms indicative of OSA if performed1/18/2018 unattended in or out of a sleep lab facility or attended in a sleep lab facility. 2) Type IV sleep testing devices measuring three or more channels, one of which is airflow, when used to aid the diagnosis of OSA in patients who have signs and symptoms indicative of OSA if performed unattended in or outfrom of a sleep lab facility or attended in a sleep lab facility. 3) Sleep testing devices measuring three or more channels that include actigraphy, oximetry, and peripheral arterial tone, when used to aid the diagnosis of OSA in patients who have signs and symptoms indicative of OSA if performed unattended in or out of a sleep lab facility or attended in a sleep lab facility. CPAP titration should be performed as part of the diagnostic study, if possible.

In patients with clinical signs and symptoms consistent with obstructive sleep apnea (OSA), a home sleep study is the first-line diagnostic test for most patients, when available. Documents

Polysomnography in a sleep lab is indicated as a first-line test for patients with significant cardiorespiratory disease, potential respiratory muscle weakness due to a neuromuscular condition, awake hypoventilation or suspicion of sleep related hypoventilation, chronic opioid medication use, history of stroke or severe insomnia. If a patient has had an inconclusive (or negative) home sleep apnea test and a clinical suspicion for OSA remains, then attended polysomnography is included on this line. Summary For portable devices, Type II-III are included on this line. Type IV sleep testing devices must measure three or more channels, one of which is airflow, to be included on this line. Sleep testing devices that are not Type1-IV and measure three or more channels thatIssue include actigraphy, oximetry, and peripheral arterial tone, are included on this line.

Split night diagnostic protocols are required when a diagnosis of OSA is confirmed in the first portion of the night.

VbBSThe development of this guideline note was informed by a HERC coverage guidance. See http://www.oregon.gov/oha/HPA/CSI-HERC/Pages/Evidence-based-Reports.aspx.

Diagnosis of sleep apnea - guideline update, Issue #1350 Page 19

Statement of Intent for Public Health Emergencies

Question: Should a new statement of intent (SOI) be adopted that indicates that the HERC intends to cover the necessary treatments/prophylactic care for public health outbreaks?

Question source: Legislative council, HSD leadership

Issue: During the last Legislative session, House Bill (HB) 3276 was passed mandating that private insurers cover the “necessary antitoxins, serums, vaccines, immunizing agents, antibiotics, antidotes and other pharmaceutical agents, medical supplies or other prophylactic measures approved by the United States Food and Drug Administration deemed necessary to prevent the spread of the disease, epidemic or other condition of public health importance.” HSD would like a similar policy for OHP.

From HB3276 1/18/2018 If the director determines that there exists a disease outbreak, epidemic or other condition of public health importance in a geographic area of this state or statewide, an insurer shall, for enrollees in a health benefit plan offered by the insurer, reimburse the cost of necessary antitoxins, serums, vaccines, immunizing agents, antibiotics, antidotes and other pharmaceutical agents, medicalfrom supplies or other prophylactic measures approved by the United States Food and Drug Administration that the director deems necessary to prevent the spread of the disease, epidemic or other condition of public health importance.

A similar guideline was adopted in 2011 during the avian flu epidemic which specifically deals with treatment/prophylaxis of influenza.

GUIDELINE NOTE 87, INFLUENZA Line 404 Treatment and post-exposure prophylaxisDocuments of influenza should comply with state and national public health recommendations.

A taskforce met in August of 2017 and published recommendations related to public health emergencies in October, 2017. They developed 8 recommendations; the 2 recommendations relevant to the Prioritized List were:

Task Force recommendations with the greatest support  OHA shouldSummary explore Medicaid options (for instance, state plan amendment or waiver and presumptive eligibility) with respect to an epidemic or other condition of public health importance for measures included in HB 3276.  OHA should establish rules and guidelines that assure Oregon Health Plan member access to services as a result of a disease outbreak, epidemic or other condition of public health Issueimportance regardless of in-network status, with payment assured to any Medicaid provider including pharmacies, local health departments and student health centers.

HERC staff recommendations: VbBS1) Adopt a new statement of intent as shown below 2) Delete GN87 INFLUENZA

Statement of Intent for Public Health Emergencies

a. Now redundant

STATEMENT OF INTENT XX, PUBLIC HEALTH EMERGENCIES It is the intent of the Commission that treatment and post-exposure prophylaxis of any communicable disease of public health importance should comply with state and national public health recommendations. Such treatment and prophylaxis includes all necessary antitoxins, serums, vaccines, immunizing agents, antibiotics, antidotes and other pharmaceutical agents, medical supplies or other prophylactic measures approved by the United States Food and Drug Administration.

GUIDELINE NOTE 87, INFLUENZA Line 404 Treatment and post-exposure prophylaxis of influenza should comply with state and national1/18/2018 public health recommendations. from

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Catheter-directed thrombolysis for DVT

Question: Should catheter-directed thrombolysis for deep vein thrombosis (DVT) continue to be included on the Prioritized List?

Question source: HERC staff

Issue: Catheter directed thrombolysis for DVT is currently on several lines on the Prioritized List. A large study was just published indicating that this therapy is no better than oral anticoagulation and may cause increased bleeding.

DVT is treated with either oral anticoagulation (warfarin or newer agents). DVT can also be removed or locally treated with catheter directed use of anticoagulant medications. Post- thrombotic syndrome develops within 2 years in approximately half of patients with proximal deep-vein thrombosis. The post-thrombotic syndrome commonly causes chronic limb pain1/18/2018 and swelling and can progress to cause major disability, leg ulcers, and impaired quality of life. Small trials have indicated that local treatment of the DVT can reduce the risk of post-thrombotic syndrome compared to oral anticoagulation alone. A new large, high quality trial was just published that found that this hypothesis is not true. from

On review, HERC staff found catheter directed thrombolysis procedure codes on several lines with no appropriate diagnoses (no thrombosis diagnoses or the stroke line when the procedure specifies non-intracranial). The catheter directed thrombolysis codes are suggested for removal from these lines as a code clean up.

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Catheter-directed thrombolysis for DVT, Issue #1360 Page 1

Catheter-directed thrombolysis for DVT

Current Prioritized List status CPT Code description Current Lines code 37211 Transcatheter therapy, arterial infusion for 254 ARTERIAL EMBOLISM/THROMBOSIS: thrombolysis other than coronary or ABDOMINAL AORTA, THORACIC AORTA intracranial, any method, including 285 COMPLICATIONS OF A PROCEDURE radiological supervision and ALWAYS REQUIRING TREATMENT interpretation, initial treatment day 317 STROKE 349 NON-LIMB THREATENING PERIPHERAL VASCULAR DISEASE 446 ATHEROSCLEROSIS, AORTIC AND RENAL 37212 Transcatheter therapy, venous infusion for 47 DEEP ABSCESSES, INCLUDING1/18/2018 thrombolysis, any method, including APPENDICITIS AND PERIORBITAL radiological supervision and ABSCESS interpretation, initial treatment day 79 PHLEBITIS AND THROMBOPHLEBITIS, DEEP from 280 BUDD-CHIARI SYNDROME, AND OTHER VENOUS EMBOLISM AND THROMBOSIS 285 37213 Transcatheter therapy, arterial or venous 79,254,280,317,349,446 infusion for thrombolysis other than coronary, any method, including radiological supervision and interpretation, continued treatment on subsequent day during course of Documents thrombolytic therapy, including follow-up catheter contrast injection, position change, or exchange, when performed; 37214 Transcatheter therapy, arterial or venous 79,254,280,317,349,446 infusion for thrombolysis other than coronary, any method, including radiological supervision and interpretation, continued treatment on subsequentSummary day during course of thrombolytic therapy, including follow-up catheter contrast injection, position change, or exchange, when performed; cessation of thrombolysis including Issueremoval of catheter and vessel closure by any method

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Catheter-directed thrombolysis for DVT

Evidence 1) Vedantham 2017, RCT of oral anticoagulation vs anticoagulation plus catheter-mediated pharmacomechanical thrombolysis with or without stenting a. N=692 patients with acute proximal deep-vein thrombosis b. Between 6 and 24 months, there was no significant between-group difference in the percentage of patients with the post-thrombotic syndrome (47% in the pharmacomechanical-thrombolysis group and 48% in the control group; risk ratio, 0.96; 95% confidence interval [CI], 0.82 to 1.11; P = 0.56). c. Pharmacomechanical thrombolysis led to more major bleeding events within 10 days (1.7% vs. 0.3% of patients, P = 0.049) d. No significant difference in recurrent venous thromboembolism was seen over the 24-month follow-up period (12% in the pharmacomechanical-thrombolysis group and 8% in the control group, P = 0.09). 1/18/2018 e. Moderate-to-severe post-thrombotic syndrome occurred in 18% of patients in the pharmacomechanical-thrombolysis group versus 24% of those in the control group (risk ratio, 0.73; 95% CI, 0.54 to 0.98; P = 0.04). Severity scores for the post-thrombotic syndrome were lower in the pharmacomechanicalfrom thrombolysis group than in the control group at 6, 12, 18, and 24 months of follow-up (P<0.01 for the comparison of the Villalta scores at each time point), but the improvement in quality of life from baseline to 24 months did not differ significantly between the treatment groups. f. CONCLUSIONS Among patients with acute proximal deep-vein thrombosis, the addition of pharmacomechanical catheter-directed thrombolysis to anticoagulation did not result in a lower risk of the post-thrombotic syndrome but did result in a higher risk of major bleeding. 2) Wang 2017, meta-analysis of complications of catheter directed thrombolysis for acute lower extremity DVT Documents a. N=6 studies comparing CDT with anticoagulation (N=303 patients) i. 3 RCTs (150 patients), 2 retrospective cohort studies (106 patients), 1 prospective cohort study (47 patients) b. meta-analysis of 6 studies comparing the risk of complications and PE related to CDT with those related to anticoagulation showed that CDT was associated with an increased risk of complications (OR=4.36; 95% CI: 2.94–6.47) and PE (OR=1.57; 95% CI: 1.37–1.79). c. Conclusion: In acute lower extremity DVT patients, CDT is associated with a higherSummary risk of complications and PE compared with anticoagulation 3) Watson 2016, Cochrane review of thrombolysis for DVT (http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD002783.pub4/epdf) a. N=17 Randomised controlled trials (RCTs) examining thrombolysis and anticoagulation versus anticoagulation for acute DVT (1103 patients). Issue i. Fourteen studies were rated as low risk of bias and three studies were rated as high risk of bias. b. Complete clot lysis occurred significantly more often in the treatment group at early follow-up (RR 4.91; 95%CI 1.66 to 14.53, P = 0.004) and at intermediate follow-up (RR 2.44; 95% CI 1.40 to 4.27, P = 0.002; moderate quality evidence). VbBS c. N=3 RCTs (306 patients) examined post thrombotic syndrome risk i. Up to five years after treatment significantly less PTS occurred in those receiving thrombolysis (RR 0.66, 95% CI 0.53 to 0.81; P < 0.0001;

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Catheter-directed thrombolysis for DVT

moderate quality evidence). This reduction in PTS was still observed at late follow-up (beyond five years), in two studies (RR 0.58, 95% CI 0.45 to 0.77; P < 0.0001; moderate quality evidence). d. Leg ulceration was reduced although the data were limited by small numbers (RR 0.87; 95%CI 0.16 to 4.73, P = 0.87). e. Those receiving thrombolysis had increased bleeding complications (RR 2.23; 95% CI 1.41 to 3.52, P = 0.0006; moderate quality evidence). f. There was no significant effect on mortality detected at either early or intermediate follow-up. g. Data on the occurrence of pulmonary embolism (PE) and recurrent DVT were inconclusive h. Systemic thrombolysis and CDT had similar levels of effectiveness. i. Authors’ conclusions Thrombolysis increases the patency of veins and reduces1/18/2018 the incidence of PTS following proximal DVT by a third. Evidence suggests that systemic administration and CDT have similar effectiveness. Strict eligibility criteria appears to improve safety in recent studies and may be necessary to reduce the risk of bleeding complications. This may limit thefrom applicability of this treatment. In those who are treated there is a small increased risk of bleeding. Using GRADE assessment, the evidence was judged to be of moderate quality due to many trials having low numbers of participants. However, the results across studies were consistent and we have reasonable confidence in these results.

Expert guidelines 1) American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, 2016 (http://journal.chestnet.org/article/S0012-3692(15)00335-9/pdf) a. In patients with acute proximalDocuments DVT of the leg, we suggest anticoagulant therapy alone over CDT (Grade 2C).

Cost comparison 1) Bashir 2014, cohort study of CDT vs usual care for DVT a. N=90,618 patients in national database i. 3649 (4.1%) underwent CDT b. The rates of blood transfusion (11.1% vs 6.5%) (OR, 1.85 [95%CI, 1.57-2.20]) (P < .001), pulmonary embolism (17.9% vs 11.4%) (OR, 1.69 [95%CI, 1.49-1.94]) (P < .001),Summary intracranial hemorrhage (0.9% vs 0.3%) (OR, 2.72 [95%CI, 1.40-5.30]) (P = .03), and vena cava filter placement (34.8% vs 15.6%) (OR, 2.89 [95%CI, 2.58- 3.23]) (P < .001) were significantly higher in the CDT group. c. The CDT group had longer mean (SD) length of stay (7.2 [5.8] vs 5.0 [4.7] days) (OR, 2.27 [95%CI, 1.49-1.94]) (P < .001) and higher hospital charges ($85,094 vs Issue$28,164) (P < .001) compared with the anticoagulation group. .

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Catheter-directed thrombolysis for DVT

HERC staff summary Catheter directed thrombolysis with systemic anticoagulation appears to offer little or no additional benefit for prevention of post-thrombotic syndrome or PE compared to systemic anticoagulation alone. This is based on one meta-analysis and one large, high quality randomized controlled trial. Cochrane found that catheter directed thrombolysis did decrease the risk of post-thrombotic syndrome, but based this finding on 3 small RCTs. The Cochrane review authors noted that strict eligibility requirements are needed to reduce the bleeding risk of the procedure. Meta-analysis and high quality RCT data find that catheter directed thrombolysis increases the risk of bleeding; it is also significantly more costly than oral anticoagulation. Oral anticoagulation is recommended over catheter directed thrombolysis by expert groups.

Based on a cost comparison analysis which included hospitalization for DVT (rapidly changing1/18/2018 to outpatient management as standard care in the US system), CDT costs approximately triple the cost of standard therapy, or approximately $57,000 more than usual care. There is also a significantly higher complication rate of CDT, which would further be expected to raise costs. If standard care for DVTs is outpatient management, the relative cost of CDT fromwould be expected to be significantly more than 3 times standard therapy.

Based on the evidence of lack of benefit and increased harms from catheter-directed thrombolysis and significantly higher cost, HERC staff recommend removal of this procedure from pairing with DVT on the Prioritized List.

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Catheter-directed thrombolysis for DVT

HERC staff recommendations: 1) Remove catheter directed thrombolysis for non-intracranial and non-coronary thrombosis (CPT 37211-37214) from lines with no appropriate diagnoses: A. 47 DEEP ABSCESSES, INCLUDING APPENDICITIS AND PERIORBITAL ABSCESS B. 317 STROKE C. 349 NON-LIMB THREATENING PERIPHERAL VASCULAR DISEASE D. 446 ATHEROSCLEROSIS, AORTIC AND RENAL 2) Remove catheter directed thrombolysis from lines 79 PHLEBITIS AND THROMBOPHLEBITIS, DEEP A. CPT 37212 Transcatheter therapy, venous infusion for thrombolysis, any method…initial treatment day B. CPT 37213 Transcatheter therapy, arterial or venous infusion for thrombolysis other than coronary, any method…continued treatment on subsequent 1/18/2018day C. CPT 37214 Transcatheter therapy, arterial or venous infusion for thrombolysis other than coronary, any method…continued treatment on subsequent day during course of thrombolytic therapy, including follow-up catheter contrast injection, position change, or exchange, when performed; cessationfrom of thrombolysis including removal of catheter and vessel closure by any method 3) Add the following coding specification to line 280 BUDD-CHIARI SYNDROME, AND OTHER VENOUS EMBOLISM AND THROMBOSIS A. “Catheter directed thrombolysis (CPT 37212-37214) is not paired on this line with peripheral DVT (CPT I82.6, I82.7, I82.A, I82.B, I82.8, I82.9).” B. Use for Budd-Chiari syndrome and other central vein clots not reviewed 4) Add the following entry to GN173

GUIDELINE NOTE 173, INTERVENTIONS THAT ARE UNPROVEN, HAVE NO CLINICALLY IMPORTANT BENEFIT OR HAVE HARMS THATDocuments OUTWEIGH BENEFITS FOR CERTAIN CONDITIONS Line 660 The following Interventions are prioritized on Line 660 CONDITIONS FOR WHICH CERTAIN INTERVENTIONS ARE UNPROVEN, HAVE NO CLINICALLY IMPORTANT BENEFIT OR HAVE HARMS THAT OUTWEIGH BENEFITS:

Procedure Intervention Description Rationale Last Review Code 37212-37214 Transcatheter therapy, venous Increased risk of January, 2018 infusionSummary for thrombolysis for harm compared to treatment of peripheral deep equally effective vein thrombosis alternative therapy; significantly less cost effective Issue

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Yttrium Internal Radiation Therapy for Liver Cancer January, 2018

Question: Should yttrium internal radiation therapy (CPT 79445) be covered for primary liver cancers or isolated colon cancer metastases to the liver?

Question source: Holly Jo Hodges, MD, OHP medical director; multiple providers

Issue: Yttrium-90 is a radioactive element that can be injected into the arterial system of the liver to treat non-surgically resectable primary liver cancer or liver metastases from colon cancer. This treatment was removed from the Prioritized List in 2006. It was reviewed again in May 2015, with a HERC staff recommendation for coverage due to a NICE 2013 review recommending coverage for primary hepatocellular carcinoma and NCCN recommendations for use in certain clinical situations. However, VBBS was concerned about the relative cost-effectiveness of this therapy, as Y-90 1/18/2018therapy is more expensive than chemoembolization. There was also concern for the low level of evidence, and the subcommittee noted that 3 RCTs were currently in process. The decision was made to not cover this therapy until these RCTs were published and found to have positive results. The evidence reviewed in 2015 consisted of case series and uncontrolled trials and was considered poor quality.from

Dr. Hodges has seen increasing requests for this procedure. She has consulted with OHSU, and determined that they perform approximately 100 Y-90 procedures a year (all payers). The CPT code for this procedure 79445 (Radiopharmaceutical therapy, by intra-arterial particulate administration) is on multiple lines on the Prioritized List other than the liver cancer line.

From the April, 2006 HOSC minutes (line 489 was liver cancer): Treatment of Liver Cancer: Little explained that the Commission previously considered embolization for tumor destruction using yttrium and elected not to place it on the list; however, the code for embolization remains. A case atDocuments OMAP resulted in her questioning whether appropriate treatments were listed on this line. Olson explained the different treatments, as follows: Radiofrequency ablation is insertion of a an ultrasound catheter with use of heat to kill tissue, cryotherapy is the same thing except using a liquid nitrogen probe, chemoembolization is when a catheter is inserted into an artery that feeds the tumor, chemotherapy is infused then the artery is embolized with gel foam. The yttrium procedure does not involve embolization. All of these are used to treat both primary liver cancer and metastatic colon cancer. Saha asked if any of these treatments were controversial except the yttrium. Olson stated that for colon cancer metastatic only to the liver, resection can result in 25% long-term survival. Hepatic artery infusion with 5-FU improvedSummary outcomes as well. The data on RFA and cryotherapy is weaker. Chemoembolization results in shrinkage of tumor, but causes severe side-effects. RFA and yttrium have fewer side effects. Hepatic artery infusion is also effective, but systemic chemotherapy has improved to the point that it is rarely done anymore. Saha clarified that the task today is to determine if any of these treatments should be removed from the List. Olson stated that there are someIssue cases where an isolated metastasis is too close to the bile duct to operate, and in those cases it makes sense to use RFA or cryotherapy. He also said that yttrium treatment costs approximately $70,000. Decision: Line 489: Delete 79445 – Radiopharmaceutical therapy, by intra-arterial particulate

From the May, 2015 VBBS minutes: VbBS Discussion: Smits reviewed the summary document. There was significant concern about the low level of evidence supporting the use of yttrium. The cost of this therapy was also

Yttrium Internal Radiation Therapy for Liver Cancer January, 2018

concerning—cost was more than $20,000 per treatment. There was also discussion that the evidence best supported treatment of hepatocellular carcinoma (HCC), although this evidence is poor. Evidence for metastatic cancer to the liver is of even a lower level. It was also noted that there are three ongoing RCTs of yttrium as treatment for liver tumors or metastatic disease to the liver (SARAH, SIRT, and FOXFIRE studies). The subcommittee decided to not add yttrium therapy to the Prioritized List. HERC staff will bring this topic back for re-review once the ongoing RCTs are published and this new data can be reviewed. Note: yttrium 90 therapy for cancers other than liver cancer or metastatic cancer in the liver were not included in this discussion. Recommended Actions: Do not add yttrium 90 therapy to line 320 for liver tumors 1/18/2018

Current Prioritized List status: 79445 (Radiopharmaceutical therapy, by intra-arterial particulate administration) is on lines 129,130,160,161,162,165,195,204,214,238,242,262,265,274,279,291,292,299,319,321,333,346,376,439,from 465,533,600,611

Line 320 CANCER OF LIVER

HCPCS C2616 (Brachytherapy source, non-stranded, yttrium-90, per source) is Ancillary

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Yttrium Internal Radiation Therapy for Liver Cancer January, 2018

Evidence SARAH 1) Vilgrain 2017, Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial a. Methods: i. multicenter, open label RCT phase 3 trial done in France ii. Patients were eligible if they were aged at least 18 years with a life expectancy greater than 3 months, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, Child-Pugh liver function class A or B score of 7 or lower, and locally advanced hepatocellular carcinoma (Barcelona Clinic Liver Cancer [BCLC] stage C), or new hepatocellular carcinoma not eligible1/18/2018 for surgical resection, liver transplantation, or thermal ablation after a previously cured hepatocellular carcinoma (cured by surgery or thermoablative therapy), or hepatocellular carcinoma with two unsuccessful rounds of transarterial chemoembolisation. from iii. Patients were randomly assigned (1:1) to receive continuous oral sorafenib (400 mg twice daily) or SIRT with 90Y-loaded resin microspheres 2–5 weeks after randomisation. iv. The primary endpoint was overall survival. Analyses were done on the intention- to-treat population b. Results: i. N=467 patients (237 were assigned to SIRT and 222 to sorafenib) 1. In the SIRT group, 53 (22%) of 237 patients did not receive SIRT; 26 (49%) of these 53 patients were treated with sorafenib. ii. Median follow-up was 27.9Documents months (IQR 21·9–33·6) in the SIRT group and 28.1 months (20·0–35·3) in the sorafenib group. iii. Median overall survival was 8.0 months (95% CI 6.7–9.9) in the SIRT group versus 9.9 months (8.7–11.4) in the sorafenib group (hazard ratio 1.15 [95% CI 0.94–1.41] for SIRT vs sorafenib; p=0.18). iv. In the safety population, at least one serious adverse event was reported in 174 (77%) of 226 patients in the SIRT group and in 176 (82%) of 216 in the sorafenib group. 19 deaths in the SIRT group and 12 in the sorafenib group were deemed to be treatment related. c. Conclusion:Summary In patients with locally advanced or intermediate-stage hepatocellular carcinoma after unsuccessful transarterial chemoembolisation, overall survival did not significantly differ between the two groups. Quality of life and tolerance might help when choosing between the two treatments.

Issue FOXFIRE, SIRFLOX, and FOXFIRE-Global 1) Wasan 2017 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593813/pdf/main.pdf) a. Combined analysis of FOXFIRE, SIRFLOX, and FOXFIRE-Global RCTs for yttrium-90 with chemotherapy compared to chemotherapy alone for colorectal liver metastases to the VbBS liver

Yttrium Internal Radiation Therapy for Liver Cancer January, 2018

b. Combined analysis of 3 trials done in 14 countries for chemotherapy-naive patients with metastatic colorectal cancer (WHO performance status 0 or 1) with liver metastases not suitable for curative resection or ablation c. Methods: i. Treatment groups: oxaliplatin-based chemotherapy (FOLFOX: leucovorin, fluorouracil, and oxaliplatin) or FOLFOX plus single treatment SIRT concurrent with cycle 1 or 2 of chemotherapy. ii. Participants and investigators were not masked to treatment. iii. The primary endpoint was overall survival, analysed in the intention-to-treat population, using a two-stage meta-analysis of pooled individual patient data. All three trials have completed 2 years of follow-up. d. Findings: 1/18/2018 i. N=549 FOLFOX alone, 554 FOLFOX plus SIRT ii. Median follow-up was 43.3 months (IQR 31.6–58.4). iii. There were 411 (75%) deaths in 549 patients in the FOLFOX alone group and 433 (78%) deaths in 554 patients in the FOLFOX plus SIRT group.from There was no difference in overall survival (hazard ratio [HR] 1.04, 95% CI 0.90–1.19; p=0.61). The median survival time in the FOLFOX plus SIRT group was 22.6 months (95% CI 21.0–24.5) compared with 23.3 months (21.8–24.7) in the FOLFOX alone group. iv. Serious adverse events of any grade occurred in 244 (43%) of 571 patients receiving FOLFOX alone and 274 (54%) of 507 patients receiving FOLFOX plus SIRT. 10 patients in the FOLFOX plus SIRT group and 11 patients in the FOLFOX alone group died due to an adverse event; eight treatment-related deaths occurred in the FOLFOX plus SIRT group and three treatment-related deaths occurred in the FOLFOX alone group. e. Interpretation Addition of SIRT toDocuments first-line FOLFOX chemotherapy for patients with liver-only and liver-dominant metastatic colorectal cancer did not improve overall survival compared with that for FOLFOX alone. Therefore, early use of SIRT in combination with chemotherapy in unselected patients with metastatic colorectal cancer cannot be recommended. To further define the role of SIRT in metastatic colorectal cancer, careful patient selection and studies investigating the role of SIRT as consolidation therapy after chemotherapy are needed.

Summary 1) NICE 2013, guidance on SIRT for primary intrahepatic cholangiocarcinoma a. Current evidence on the safety and efficacy of selective internal radiation therapy (SIRT) for primary intrahepatic cholangiocarcinoma is limited in both quantity and quality. Therefore this procedure should only be used with special arrangements for clinical Issuegovernance, consent and audit or research.

Other guidelines 1) NCCN 2015, hepatocellular carcinoma a. Locoregional therapy should be considered in patients who are not candidates for VbBS surgical curative treatments, or as part of a strategy to bridge patients to other curative therapies.

Yttrium Internal Radiation Therapy for Liver Cancer January, 2018

b. Radioembolization (RE) with yttrium-90 is listed as a locoregional therapy c. Listed as category 2B d. Sorefenib is recommended as first line, with locoregional therapy second line in the majority of these cases e. Evidence reviewed that yttrium-90 RE has been found to be safe and effective in the treatment of non-resectable cholangiocarcinoma f. For HCC, ablation therapy should be first line, and locoregional therapy, including yttrium RE, should only be considered when ablation is not feasible

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Yttrium Internal Radiation Therapy for Liver Cancer January, 2018

HERC staff summary: New randomized controlled trial data of yttrium 90 compared to standard chemotherapy for either primary hepatocellular carcinoma or metastatic colorectal cancer in the liver find that this therapy is at best no better than standard chemotherapy. There is a concerning trend in the data that yttrium 90 actually reduces survival and increases serious complications, although this was not statistically significant. Yttrium 90 is a much higher cost therapy than traditional chemotherapy.

HERC staff recommendation: 1) Do not add yttrium-90 radioembolization (CPT 79445) as a treatment to Line 320 CANCER OF LIVER 2) Add a new entry to GN172/line 500 CONDITIONS FOR WHICH CERTAIN INTERVENTIONS RESULT IN MARGINAL CLINICAL BENEFIT OR LOW COST-EFFECTIVENESS as shown below for yttrium-901/18/2018 for treatment of primary hepatocellular carcinoma, or colorectal cancer metastatic to the liver a. Less cost-effective than conventional chemotherapy

b. May be harmful from GUIDELINE NOTE 172, INTERVENTIONS WITH MARGINAL CLINICAL BENEFIT OR LOW COST- EFFECTIVENESS FOR CERTAIN CONDITIONS Line 500 The following interventions are prioritized on Line 500 CONDITIONS FOR WHICH CERTAIN INTERVENTIONS RESULT IN MARGINAL CLINICAL BENEFIT OR LOW COST-EFFECTIVENESS:

Procedure Intervention Description Rationale Last Review Code 79445 Radiopharmaceutical therapy, by Low cost- January, 2018 intra-arterial particulate effectiveness administration for use in treatingDocuments compared to equally primary hepatocellular carcinoma effective but less or colorectal cancer metastatic to expensive standard the liver chemotherapies; concern for possible C2616 Brachytherapy source, non- harms compared to stranded, yttrium-90, per source, standard for use in treating primary liver chemotherapy cancerSummary or metastatic cancer to the liver

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Iliotibial Band Syndrome January 2018

Question: Where should iliotibial band syndrome be prioritized and what treatments should be paired with it?

Question source: VBBS

Issue: Iliotibial band syndrome (ICD10 M76.3 Iliotibial band syndrome) was discussed at the September, 2017 VBBS meeting. At that time, VBBS indicated that they desired iliotibial band syndrome to be placed on a line with PT, chiropractic, and medical services, but not surgical services. The subcommittee did not want GN98 SIGNIFICANT INJURIES TO LIGAMENTS AND TENDONS to apply.

Iliotibial band syndrome is inflammation and pain of the iliotibial band, a thick band of fascia1/18/2018 on the lateral aspect of the knee, extending from the outside of the pelvis, over the hip and knee, and inserting just below the knee. The band is crucial to stabilizing the knee during running, as it moves from behind the femur to the front of the femur during activity. The continual rubbing of the band over the lateral femoral epicondyle, combined with the repeated flexion and extension of the kneefrom during running may cause the area to become inflamed. The main treatment for IT band syndrome is rest, ice, compression, and NSAIDs. Stretching, massage and physical therapy can also be helpful.

Currently, IT band syndrome is only on line 376 DISRUPTIONS OF THE LIGAMENTS AND TENDONS OF THE ARMS AND LEGS, EXCLUDING THE KNEE, RESULTING IN SIGNIFICANT INJURY/IMPAIRMENT. Other possible lines include 430 INTERNAL DERANGEMENT OF KNEE AND LIGAMENTOUS DISRUPTIONS OF THE KNEE, RESULTING IN SIGNIFICANT INJURY/IMPAIRMENT, but this line has surgical codes and IT band syndrome is not actually a knee condition. Line 605 SPRAINS AND STRAINS OF ADJACENT MUSCLES AND JOINTS, MINOR could apply, but would result in non-covered status. Staying on line 376 continues to have the issue of having GN98 possibly apply. Documents

The only medical lines that contain both chiropractic and PT CPT codes that are above the current funding line and involve diagnoses of the lower extremities are lines 292 NEUROLOGICAL DYSFUNCTION IN POSTURE AND MOVEMENT CAUSED BY CHRONIC CONDITIONS and 461 OSTEOARTHRITIS AND ALLIED DISORDERS. Neither of these codes appear to be appropriate for IT band syndrome. Line 605 SPRAINS AND STRAINS OF ADJACENT MUSCLES AND JOINTS, MINOR has both sets of codes and involves similar diagnoses, but is below the funding line.

Line 605 contains manySummary sprains and strains which could benefit from limited PT, but which are generally self-limited. These conditions are similar to IT band syndrome. Currently, these diagnoses receive only office visits for diagnosis, and primary care instruction on home care. Medications such as NSAIDs may be covered if not prior authorized.

HERC staffIssue were directed to investigate the intent of GN98—was this to apply to surgical treatment only or also to PT and other medical treatment? Staff were not able to identify specific discussion about this in minutes or meeting materials. However, if a sprain or strain is considered minor, it should self-resolve and therefore the guideline intuitively makes sense that only significant injuries are meant to be covered for any type of treatment. VbBS After internal discussions with HSD and HERC staff, it was determined that the best course of action would be to specify the coverage for IT band syndrome in the current GN98. HSC and HERC staff found

Iliotibial Band Syndrome January 2018

that only PT is indicated for the treatment of IT band syndrome, and a total of 2 PT visits should be sufficient for treatment.

HERC staff recommendations: 1) Add Iliotibial (IT) band syndrome (ICD10 M76.3) to line 605 SPRAINS AND STRAINS OF ADJACENT MUSCLES AND JOINTS, MINOR 2) Modify GN98 as shown below a. Specifies coverage intended for IT band syndrome b. Clarifies that GN98 applies to both medical and surgical treatment of the conditions on the included lines 3) Change the treatment description on line 376: REPAIR, MEDICAL THERAPY 1/18/2018

GUIDELINE NOTE 98, SIGNIFICANT INJURIES TO LIGAMENTS AND TENDONSfrom Lines 376,430,605 Significant injuries to ligaments and/or tendons are those that result in clinically demonstrable joint instability or mechanical interference with motion. Significant injuries are covered on Line 376 or Line 430 for both medical and surgical interventions; non-significant injuries are included on Line 605.

Iliotibial (IT) band syndrome (ICD10 M76.3) is included on line 376 only for pairing with 2 physical therapy visits, anti-inflammatory medications, and primary care office visits. Otherwise, it is included on line 605.

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Fractional Exhaled Nitric Oxide Testing for Asthma Diagnosis and Management January 2018

Question: Should fractional exhaled nitric oxide (FeNO) determination be a covered service?

Question source: Circassia (manufacturer)

Issue: Nitric oxide expired gas determination (CPT 95012) is a test for airway inflammation which is used in the diagnosis and management of asthma. It can be used to help determine whether a patient will respond well to steroid medications, and to help monitor airway inflammation in asthmatic patients.

Various tests, including spirometry pre and post bronchodilator, and bronchoprovocation challenge, may be used by clinicians to aide in the diagnosis of asthma in the appropriate clinical context. However, the diagnosis remains clinical, based on compatible symptoms and evidence of reversible airway1/18/2018 obstruction; no single criterion standard diagnostic test exists. More recently, fractional exhaled nitric oxide (FeNO) concentration has been added to the list of tests that clinicians may use to diagnose asthma, select treatment options, and monitor the response to therapy. from Nitric oxide (NO) is a gas normally found in each exhaled breath in all humans. Patients with asthma often have increased levels of inducible nitric oxide synthase (iNOS2), the enzyme that produces NO in their airway epithelium. FeNO can be measured by exhalation into an analyzer. It has been found to be elevated in patients with atopic asthma (i.e., asthma associated with either positive skin test or specific IgE to aeroallergens) and was shown to correlate modestly with eosinophilia in sputum and endobronchial biopsy in steroid-naïve patients. It has also been found to be elevated in both children and adults with atopy without a diagnosis of asthma (eg, atopic rhinitis).

Multiple factors may confound the interpretation of FeNO data. These include asthma phenotype, atopy, use of inhaled or oral corticosteroids, patient’sDocuments weight, and age. In addition, FeNO measurements can be affected by acute changes proximal to the time of testing, such as exposure to tobacco smoke, use of bronchodilators, fasting state or food intake, or use of mouthwash. Moreover, the criteria for the “normal” range of FeNO (and the level considered diagnostic of a disease state, such as asthma) and the level of change in FeNO that is clinically significant remain uncertain.

FeNO was reviewed by the HSC in 2007 and determined to be experimental and placed on the Excluded/Never Covered List based on a 2005 TEC report. It was re-reviewed in 2010 and again found to be experimental. Its last review was in August, 2015, and again, FeNO was found to be experimental. Currently, FeNO is foundSummary on line 660 CONDITIONS FOR WHICH CERTAIN INTERVENTIONS ARE UNPROVEN, HAVE NO CLINICALLY IMPORTANT BENEFIT OR HAVE HARMS THAT OUTWEIGH BENEFITS. Circassia is requesting that the HERC re-review exhaled nitric oxide testing, based on a just published AHRQ systematic review and updated NICE guidelines, and place it on line 9 ASTHMA.

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Fractional Exhaled Nitric Oxide Testing for Asthma Diagnosis and Management January 2018

Evidence 1) AHRQ 2017, Systematic review of the Clinical Utility of Fractional Exhaled Nitric Oxide in Asthma Management (https://effectivehealthcare.ahrq.gov/sites/default/files/pdf/cer-197-fractional- exhaled-nitric-oxide_0.pdf) a. Included studies: N=175 studies in adults and children over the age of 5 b. Diagnostic accuracy/use in diagnosis of asthma i. N= 43 studies with a total of 13,747 patients 1. 19 studies were nonrandomized longitudinal studies, 23 cross sectional studies, and 1 case-control study. ii. FeNO results increased the odds of correctly diagnosing asthma between 5.85 and 16.95 fold. iii. Using FeNO cutoffs of <20, 20-30, 30-40, ≥40 part per billion (ppb); respectively,1/18/2018 FeNO testing had sensitivities of 0.79, 0.64, 0.53 and 0.41; and specificities of 0.72, 0.81, 0.84, 0.94 (Strength of Evidence (SOE): Moderate). 1. Depending on the FeNO cutoff, the posttest odds of having asthma given a positive FeNO test result increased by 2.80from to 7.00 fold. 2. Diagnostic accuracy was modestly better in steroid-naïve asthmatics, children and nonsmokers than the overall population. iv. Notes: 1. Low FeNO does not exclude asthma 2. The prevalence of asthma in the population being tested also impacts the expected positive and negative predictive values. c. Clinical utility in monitoring disease activity i. N= 58 studies with a total of 8,999 patients ii. In adults (ages >18) and children (ages 5 -18), FeNO level is weakly associated with asthma control (as measuredDocuments by the ACQ and ACT). This association can be further attenuated in those who smoke, pregnant or are on inhaled corticosteroids (ICS). (SOE: Low). In adults (ages >18) and children (ages 5 -18), FeNO levels have a weak association with the risk of subsequent and prior exacerbations. (SOE: Low) The association between FeNO levels and exacerbation risk is likely stronger in individuals (ages>5 years) with atopy. (SOE: Low) 1. In adults with asthma, numerous observational studies showed that FeNO levels have weak associations both with asthma control (as Summarymeasured by ACQ and ACT) and that FeNO can modestly predict exacerbations. The overall strength of this evidence is low because of the observational nature of the majority of evidence. 2. In children with asthma, evidence from numerous studies suggests Issue that FeNO levels have weak association with ACT, and risk of exacerbation. There is some evidence to suggest that the association may be attenuated in patients on ICS but increased in those with atopy. The overall strength of this evidence is low because of the observational nature of the majority of evidence. VbBS 3. Based on 43 observational studies with 8072 patients

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4. “Exacerbation” was defined as systemic corticosteroids use, hospitalizations, ED visits, ICU admission/intubations, death iii. In adults (ages >18) and children (ages 5 -18) with acute asthma exacerbations, FeNO levels do not correlate with exacerbation severity and were poorly reproducible. (SOE: Low) iv. In children (ages 5 - 12) and adolescents (ages 13 - 18), FeNO levels were inversely associated with adherence to asthma medications (mainly inhaled corticosteroids (ICS)). (SOE: Low). Evidence supporting a FeNO-based adherence monitoring program are unavailable (in terms of cost effectiveness, acceptability, feasibility and outcomes, of such program). 1. SOE low based on observation studies 1/18/2018 2. Adherence of children and adolescents to asthma medications based on 3 observational studies of 1,035 patients d. Clinical utility for selecting medication options i. N= 24 studies with a total of 2,820 patients 1. 14 randomized controlled trials from ii. In adults (ages of >18 years) and children (ages of 5-18 years), using asthma management algorithms that incorporate FeNO testing reduced the risk of exacerbations (SOE: High), and possibly the risk of exacerbations requiring oral steroids (SOE: Moderate), but did not affect other outcomes such as hospitalization, quality of life, asthma control, or FEV1% predicted. 1. For the outcome of exacerbations requiring oral steroids, exploratory analysis that combines data from adults and children, demonstrated that the reduction was statistically significant (I2=0%), suggesting that this analysis in each subgroup analysis (adults or children) was underpowered becauseDocuments of small sample sizes. iii. The number of patients needed to treat using FeNO-based algorithms to prevent one person with exacerbation is 9 (for both, adults and children). iv. Management algorithms that incorporate FeNO testing may be associated with a modest reduction in medical expenses, compared to management approaches that do not include FeNO testing. 1. 5 studies; 3 found cost savings to strategies incorporating FeNO into an asthma control algorithm, 1 study found no savings, 1 found higher Summarycosts with mild asthma and cost savings with more severe asthma v. FeNO testing can identify patients who are more likely to respond to inhaled corticosteroids (SOE: Low). e. Clinical utility for assessing response to treatment i. N= 41 studies with a total of 1,728 patients Issueii. FeNO levels are reduced when patients with asthma take inhaled corticosteroids, leukotriene receptor antagonists or omalizumab. FeNO levels are not reduced when patients with asthma take long acting beta agonists. iii. FeNO predicts exacerbations in patients undergoing ICS reduction or withdrawal, but FeNO alone is likely insufficient and its ability to predict exacerbations can be substantially enhanced by clinical measures (e.g. ACT). VbBS f. Ability to predict the development of asthma in children 0-4 with wheezing 3

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i. N=9 studies with a total of 1,735 patients ii. It is unclear whether FeNO testing in children at ages 0-4 years with symptoms suggestive of asthma can predict a future asthma diagnosis (SOE: insufficient). g. Limitations i. Need to consider atopic predisposition in patients with asthma, because FeNO may be elevated owing to atopy alone h. Conclusions. This systematic review provides the diagnostic accuracy measures of FeNO in people ages 5 years and older. Test performance is modestly better in steroid-naïve asthmatics, children, and nonsmokers than the general population with suspected asthma. Algorithms that include FeNO measurements can help in monitoring response to anti-inflammatory, or long-term control medications, including dose titration, weaning, and treatment adherence. At this time, evidence is insufficient to support1/18/2018 the measurement of FeNO in children under the age of 5 as a means for predicting a future diagnosis of asthma. 2) Karrasch 2017, systematic review of FeNO in the diagnosis of asthma a. N=26 studies (4518 patients) from b. The overall sensitivity in the meta-analysis was 0.65 (95% CI 0.58 to 0.72), the overall specificity 0.82 (0.76 to 0.86), the diagnostic OR 9.23 (6.55 to 13.01) and the area under the curve 0.80 (0.77 to 0.85). c. In meta-regression analyses, higher cut-off values were associated with increasing specificity (OR 1.46 per 10 ppb increase in cut-off) while there was no association with sensitivity. Sensitivities varied significantly within the different FENO devices, but not specificities. Neither prevalence, age, use of bronchoprovocation in >90% of participants or as exclusive reference standard test, nor risk of bias were significantly associated with diagnostic accuracy. d. Conclusions There appears to beDocuments a fair accuracy of FENO for making the diagnosis of asthma. The overall specificity was higher than sensitivity, which indicates a higher diagnostic potential for ruling in than for ruling out the diagnosis of asthma. 3) Gomersal 2016, systematic review of FeNO in the management of asthma in children a. N=7 RCTs b. There was some evidence that FeNO-guided monitoring results in improved asthma control during the first year of management, although few results attained statistical significance. The impact on severe exacerbations was unclear. Similarly, the impact on use of anti-asthmatic drugs was unclear, and appears to depend on the step up/down protocols,Summary and the clinical characteristics of patients. c. Conclusions: The potential benefit of FeNO monitoring is equivocal. Trends toward reduced exacerbation and increased medication use were seen, but typically failed to reach statistical significance. There are a number of issues that complicate data interpretation, including differences in the likely severity of included cohorts and Issuevariations in treatment algorithms. Further work is needed to systematically explore the impact of these parameters. 4) Essat 2016, systematic review of FeNO on the management of asthma in adults (https://pdfs.semanticscholar.org/64b4/2c3e405f111ceee372e36e782e34fbbc0d71.pdf) VbBS a. N=6 studies

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b. Four studies reported a wider definition of exacerbation rates (major or severe exacerbation) with a pooled rate ratio of 0.80 (95% CI 0.63–1.02). Two studies reported rates of severe exacerbations (requiring oral corticosteroid use) with a pooled rate ratio of 0.89 (95% CI 0.43–1.72). Inhaled corticosteroid use was reported by four studies, with a pooled standardised mean difference of −0.24 (95% CI −0.56–0.07). No statistically significant differences for health-related quality of life or asthma control were found. c. FeNO guided management showed no statistically significant benefit in terms of severe exacerbations or inhaled corticosteroid use, but showed a statistically significant reduction in exacerbations of any severity. However, further research is warranted to clearly define which management protocols (including cut-off points) offer best efficacy and which patient groups would benefit the most. 5) Petsky 2016, Cochrane review of FeNO to guide treatment of asthma in adults 1/18/2018 (http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD011440.pub2/pdf) a. N=7 trials (1546 patients), b. Results: i. In the meta-analysis, there was a significant difference fromin the primary outcome of asthma exacerbations between the groups, favouring the FeNO group. The number of people having one or more asthma exacerbations was significantly lower in the FeNO group compared to the control group (odds ratio (OR) 0.60, 95% confidence interval (CI) 0.43 to 0.84). The number needed to treat to benefit (NNTB) over 52 weeks was 12 (95% CI 8 to 32). Those in the FeNO group were also significantly more likely to have a lower exacerbation rate than the controls (rate ratio 0.59, 95% CI 0.45 to 0.77). However, we did not find a difference between the groups for exacerbations requiring hospitalisation (OR 0.14, 95% CI 0.01 to 2.67) or rescue oral corticosteroids (OR 0.86, 95% CI 0.50 to 1.48). There was also no Documentssignificant difference between groups for any of the secondary outcomes (FEV1, FeNO levels, symptoms scores, or inhaled corticosteroid doses at final visit). ii. The GRADE quality of the evidence ranged from moderate (for the outcome ’exacerbations’) to very low (for the outcome inhaled corticosteroid dose at final visit’) based on the lack of blinding and statistical heterogeneity. iii. Authors’ conclusions With new studies included since the last version of this review, which included adults and children, this updated meta-analysis in adults with asthma showed that tailoring asthma medications based on FeNO levels Summary(compared with primarily on clinical symptoms) decreased the frequency of asthma exacerbations but did not impact day-to-day clinical symptoms, end-of- study FeNO levels, or inhaled corticosteroid dose. Thus, the universal use of FeNO to help guide therapy in adults with asthma cannot be advocated. c. Petsky 2016, Cochrane review of FeNO to guide treatment of asthma in children Issue(http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD011439.pub2/epdf ) i. N=9 studies ii. There was a significant difference in the number of children having one or more asthma exacerbations over the study period, they were significantly lower in the FeNO group in comparison to the control group (odds ratio (OR) 0.58, 95% VbBS confidence interval (CI) 0.45 to 0.75; 1279 participants; 8 studies). The number

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needed to treat for an additional beneficial outcome (NNTB) over 52 weeks was 9 (95% CI 6 to 15). There was no difference between the groups when comparing exacerbation rates (mean difference (MD) -0.37, 95% CI -0.8 to 0.06; 736 participants; 4 studies; I2 = 67%). The number of children in the FeNO group requiring oral corticosteroid courses was lower in comparison to the children in the control group (OR 0.63, 95% CI 0.48 to 0.83; 1169 participants; 7 studies; I2 = 0%). There was no statistically significant difference between the groups for exacerbations requiring hospitalisation (OR 0.75, 95% CI 0.41 to 1.36; 1110 participants; 6 studies; I2 = 0%). There were no significant differences between the groups for any of the secondary outcomes (forced expiratory volume in one second (FEV1), FeNO levels, symptom scores or inhaled corticosteroid doses at final visit). The included studies recorded no adverse events. 1/18/2018 iii. The GRADE quality of the evidence ranged from moderate (for the outcome ’Number of participants who had one or more exacerbations over the study period’) to very low (for the outcome ’Exacerbation rates’), based on lack of blinding, statistical heterogeneity and imprecision. from d. Authors’ conclusions In this updated review with five new included studies, tailoring asthma medications based on FeNO levels (in comparison with primarily guideline management) significantly decreased the number of children who had one or more exacerbations over the study period but did not impact the day-to-day clinical symptoms or inhaled corticosteroid doses. Therefore, the use of FeNO to guide asthma therapy in children may be beneficial in a subset of children, it cannot be universally recommended for all children with asthma.

Practice guideline Documents 1) NICE 2017, diagnosis, monitoring and management of chronic asthma (https://www.nice.org.uk/guidance/ng80/resources/asthma-diagnosis-monitoring-and-chronic- asthma-management-pdf-1837687975621) a. Diagnosing asthma i. For children under 5 with suspected asthma, treat symptoms based on observation and clinical judgement, and review the child on a regular basis (see section 1.8). If they still have symptoms when they reach 5 years, carry out objective tests (see section 1.3 and algorithm B). b. ObjectiveSummary tests for diagnosing asthma in adults, young people and children aged 5 and over i. Airway inflammation measures 1. Fractional exhaled nitric oxide 2. 1.3.2 Offer a FeNO test to adults (aged 17 and over) if a diagnosis of Issue asthma is being considered. Regard a FeNO level of 40 parts per billion (ppb) or more as a positive test. 3. 1.3.3 Consider a FeNO test in children and young people (aged 5 to 16) if there is diagnostic uncertainty after initial assessment and they have VbBS either: normal spirometry or obstructive spirometry with a negative

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bronchodilator reversibility (BDR) test. Regard a FeNO level of 35 ppb or more as a positive test. 4. 1.3.4 Be aware that a person's current smoking status can lower FeNO levels both acutely and cumulatively. However, a high level remains useful in supporting a diagnosis of asthma. ii. Lung function tests 1. Spirometry 2. 1.3.5 Offer spirometry to adults, young people and children aged 5 and over if a diagnosis of asthma is being considered. Regard a forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) ratio of less than 70% (or below the lower limit of normal if this value is available) as a positive test for obstructive airway disease (obstructive1/18/2018 spirometry). 3. Bronchodilator reversibility 4. 1.3.6 Offer a BDR test to adults (aged 17 and over) with obstructive spirometry (FEV1/FVC ratio less than 70%). Regardfrom an improvement in FEV1 of 12% or more, together with an increase in volume of 200 ml or more, as a positive test. 5. 1.3.7 Consider a BDR test in children and young people (aged 5 to 16) with obstructive spirometry (FEV1/FVC ratio less than 70%). Regard an improvement in FEV1 of 12% or more as a positive test. 6. Peak expiratory flow variability 7. 1.3.8 Monitor peak flow variability for 2 to 4 weeks in adults (aged 17 and over) if there is diagnostic uncertainty after initial assessment and a FeNO test and they have either: 1. normal spirometryDocuments or 2. obstructive spirometry, reversible airways obstruction (positive BDR) but a FeNO level of 39 ppb or less. 8. Regard a value of more than 20% variability as a positive test. 9. 1.3.9 Consider monitoring peak flow variability for 2 to 4 weeks in adults (aged 17 and over) if there is diagnostic uncertainty after initial assessment and they have: a. obstructive spirometry and b. irreversible airways obstruction (negative BDR) and a FeNO level Summarybetween 25 and 39 ppb. c. Regard a value of more than 20% variability as a positive test. 10. 1.3.10 Monitor peak flow variability for 2 to 4 weeks in children and young people (aged 5 to 16) if there is diagnostic uncertainty after initial assessment and a FeNO test and they have either: Issue a. normal spirometry or b. obstructive spirometry, irreversible airways obstruction (negative BDR) and a FeNO level of 35 ppb or more. 11. Regard a value of more than 20% variability as a positive test. iii. Airway hyperreactivity measures VbBS 1. Direct bronchial challenge test with histamine or methacholine

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2. 1.3.11 Offer a direct bronchial challenge test with histamine or methacholine to adults (aged 17 and over) if there is diagnostic uncertainty after a normal spirometry and either a: a. FeNO level of 40 ppb or more and no variability in peak flow readings or b. FeNO level of 39 ppb or less with variability in peak flow readings. 3. Regard a PC20 value of 8 mg/ml or less as a positive test. 4. 1.3.12 Consider a direct bronchial challenge test with histamine or methacholine in adults (aged 17 and over) with: a. obstructive spirometry without bronchodilator reversibility and b. a FeNO level between 25 and 39 ppb and no variability1/18/2018 in peak flow readings (less than 20% variability over 2 to 4 weeks). c. Regard a PC20 value of 8 mg/ml or less as a positive test. 5. 1.3.13 If a direct bronchial challenge test with histamine or methacholine is unavailable, suspect asthma andfrom review the diagnosis after treatment, or refer to a centre with access to a histamine or methacholine challenge test. c. 1.14 Monitoring asthma control i. 1.14.4 Do not routinely use FeNO to monitor asthma control. ii. 1.14.5 Consider FeNO measurement as an option to support asthma management in people who are symptomatic despite using inhaled corticosteroids.

Expert guidelines Documents 1) Dinakar 2017, AAP asthma control tools a. Peak flow, spirometry, PFTs, standardized questionnaires listed as the main tools for asthma diagnosis and monitoring b. FeNO listed as an option, with concerns about false positive tests in patients with atopy c. “The value of additional FENO monitoring in children whose asthma is appropriately managed using guideline-based strategies is unproven” d. “some asthma specialists have adopted the use of FENO as an adjunct ambulatory clinical tool for measuring airway inflammation and serial monitoring asthma control in individualSummary patients with difficult- to-control asthma” 2) Chung 2013, ATS guideline for diagnosis and management of severe asthma a. We suggest that clinicians do not use FeNO to guide therapy in adults or children with severe asthma.

Issue Other coverage policies 1) Aetna 2017 and Cigna 2015 consider the measurement of exhaled nitric oxide or exhaled breath to be experimental. 2) Most BCBS cover FeNO testing VbBS a. Oregon Regence BCBS considers FeNO experimental

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3) Currently, Medicaid payers in 37 states cover FeNO (Mummadi et al 2016)

Cost: The national average Medicare reimbursement for 2015 is $19.69 with 0.55 relative value unit assigned (no physician work relative value units). The average commercial reimbursement for FENO testing is between $25 and $35. (Mummadi et al 2016)

From Circassia: From the payer perspective; FeNO testing is regarded as a point of care service; providers test patients in their offices and submit their billing to payers (Commercial, Medicare, Medicaid) under CPT code 95012. Regarding CPT code 95012, the current average national reimbursement rate for Fee For Service Medicaid is $13.00. The new national CMS Medicare Fee Schedule was just released – the national1/18/2018 average is $20.52. More specifically, the CMS Medicare rates for FeNO testing in Portland is $21.53; and $19.78 outside the metropolitan area

Regarding the NIOX VERO device, physician offices or systems (ie - Kaiser) purchasefrom a device(s) outright at a cost of $1,500.00 each. The device uses a disposable sensor that measures FeNO level and is pre- loaded with 100, 300, 500 or 1,000 tests. Each FeNO test works out to be less than $10.00 each for providers / systems. Note, there can be some variability on sensor price based on volume with the range being from $7.50 on the low end and still less than $10.00 on the upper end. Each year the NIOX VERO device will require a new breathing handle at a cost of $135.00. There are a few additional accessory options, but this covers the main components. NIOX VERO devices are good for 5 years or 15,000 tests, whichever comes first. Circassia works with the offices to see which sensor (100, 300, 500, 1000) is most appropriate for their needs. The sensors have a shelf life of 1 year. Depending on utilization, some offices will use all the FeNO tests on a sensor prior to a years’ time – hence, they would simply reorder a new sensor. Documents

Clinical utilization in Oregon: 1) Kaiser reports using FeNO to determine whether or not a chest xray should be ordered for patients with asthma exacerbations

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HERC staff summary: The AHRQ meta-analysis concluded that FeNO has moderate diagnostic accuracy for asthma in persons over the age of 5, with sensitivities and specificities that vary with the test cut-off value chosen and the prevalence in the population, with caveats about not being able to rule out asthma with a negative test and the strong influence of atopy on test results. NICE includes FeNO as an accepted objective test for the diagnosis of asthma and is a major decision point in its algorithm for diagnosing asthma in children over age 5 and adults.

The AHRQ report finds that FeNO used as part of a treatment algorithm can reduce asthma exacerbations and need for systemic steroids, but not quality of life, hospitalizations, or other outcomes. There is a weak association between FeNO testing and determination of whether a patient could benefit from inhaled corticosteroid use. FeNO is not helpful during acute exacerbations. FeNO may 1/18/2018be useful for monitoring adherence to therapy, based on observational data. Cochrane concludes that the evidence for use of FeNO for the management of asthma does not support its use for adults or children. NICE guidelines do not recommend routine use for the management of asthma. The AAP currently does not recommend use for routine management of asthma. from

There is weak evidence that algorithms using FeNO may be cost saving, particularly for patients with severe asthma.

Currently, FeNO does not appear to be widely used in clinical practice in Oregon. The test is inexpensive.

HERC staff recommendation: 1) Add fractional exhaled nitric oxide (FeNO; CPT 95012) to the Diagnostic Procedures File, but not on line 9 ASTHMA Documents a. Moderate strength evidence that FeNO can assist in the diagnosis of asthma in persons over the age of 5 b. Low strength of evidence that FeNO assists in the management of asthma in persons already diagnosed 2) Add a new diagnostic guideline as shown below

DIAGNOSTIC GUIDELINE DX Fractional exhaled nitric oxide (FeNO) is covered only for the initial diagnosis of asthma in patients over the age of 5. It is not includedSummary for the monitoring of asthma, selection of medications, or diagnosis of acute asthma exacerbations.

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Fractional Exhaled Nitric Oxide Testing for Asthma Diagnosis and Management January 2018

Material submitted by Circassia

1) Circassia. Letter to the HERC summarizing their testimony on FeNO 2) Circassia, 2017. Summary of Evidence Supporting the Clinical and Economic Value of Monitoring Exhaled Nitric Oxide in the Management of Asthma 3) 2017 Fee for service Medicaid coverage map for FeNO

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Section 3.0 Coverage Guidances

HEALTH EVIDENCE REVIEW COMMISSION (HERC) COVERAGE GUIDANCE: LOW BACK PAIN: MINIMALLY INVASIVE AND NON-CORTICOSTEROID PERCUTANEOUS INTERVENTIONS DRAFT for 1/18/2018 VbBS/HERC meeting materials

HERC COVERAGE GUIDANCE Minimally invasive discectomy is recommended for coverage as an alternative to microdiscectomy or open discectomy, when discectomy is indicated (weak recommendation). The following are not recommended for coverage for low back pain:  Percutaneous laser disc decompression (strong recommendation)  Ozone therapy injections (strong recommendation)  Radiofrequency denervation (weak recommendation)

Note: Definitions for strength of recommendation are provided in Appendix A GRADE Informed Framework Element Description.

RATIONALE FOR DEVELOPMENT OF COVERAGE GUIDANCES AND MULTISECTOR INTERVENTION REPORTS Coverage guidances are developed to inform coverage recommendations for public and private health plans in Oregon as they seek to improve patient experience of care, population health and the cost- effectiveness of health care. In the era of the Affordable Care Act and health system transformation, reaching these goals may require a focus on population-based health interventions from a variety of sectors as well as individually focused clinical care. Multisector intervention reports will be developed to address these population-based health interventions or other types of interventions that happen outside of the typical clinical setting. HERC selects topics for its reports to guide public and private payers based on the following principles:  Represents a significant burden of disease or health problem  Represents important uncertainty with regard to effectiveness or harms  Represents important variation or controversy in implementation or practice  Represents high costs or significant economic impact  Topic is of high public interest Our reports are based on a review of the relevant research applicable to the intervention(s) in question. For coverage guidances, which focus on clinical interventions and modes of care, evidence is evaluated using an adaptation of the GRADE methodology. For more information on coverage guidance methodology, see Appendix A. Multisector interventions can be effective ways to prevent, treat, or manage disease at a population level. For some conditions, the HERC has reviewed evidence and identified effective interventions, but has not made coverage recommendations because many of these policies are implemented in settings beyond traditional healthcare delivery systems.

2 Low Back Pain: Minimally Invasive and Non-Corticosteroid Percutaneous Interventions DRAFT for 1/18/2018 VbBS/HERC meeting materials

GRADE-INFORMED FRAMEWORK HERC develops recommendations by using the concepts of the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. GRADE is a transparent and structured process for developing and presenting evidence and for carrying out the steps involved in developing recommendations. There are several elements that determine the strength of a recommendation, as listed in the table below. HERC reviews the evidence and makes an assessment of each element, which in turn is used to develop the recommendations presented in the coverage guidance box. Estimates of effect are derived from the evidence presented in this document. Assessments of confidence are from the published systematic reviews and meta-analyses, where available. Otherwise, the level of confidence in the estimate is determined by HERC based on assessment of two independent reviewers from the Center for Evidence-based Policy. Unless otherwise noted, estimated resource allocation, values and preferences, and other considerations are assessments of the Commission. Coverage question: Should minimally invasive discectomy be recommended for the treatment of low back pain? Outcomes Estimate of Effect for Outcome/ Resource Allocation Values and Other Confidence in Estimate Preferences Considerations Short-term No statistically significant difference in Oswestry This is a relatively Patients would likely Compared to open function Disability Index (ODI) at >6 months compared to expensive procedure prefer a treatment discectomy, (Critical outcome) microdiscectomy or open discectomy (mean compared to that offers rapid and minimally invasive difference 0.84 on a 100 point scale, 95% CI -0.21 noninvasive treatments sustained relief, but discectomy is to 1.88) of low back pain. It is would prefer to associated with ●●◌◌ (Low confidence, based on 3 RCTs, N=312) associated with some avoid treatments slightly higher mean harms (increased risk that are more leg pain intensity at Lower SF-36 physical functioning subscore at >6 of worse pain and invasive or one year (0.13, 95% months compared to microdiscectomy or open functional outcomes associated with CI 0.09-0.16) and discectomy (mean difference -4.7 on a 100-point and rehospitalization) adverse effects. mean low back pain scale, 95% CI -5.05 to -4.35) but also with lower Patients would like intensity at 6 ●●◌◌ (Low confidence, based on 2 RCTs, N=385) rates of surgical site to avoid both months (0.35, 95% Long-term Insufficient data infection. The impact hospitalizations for CI 0.19-0.51). At 1 function on other factors that recurrent disk year, low back pain (Critical outcome) would impact the herniation and intensity was similar

3 Low Back Pain: Minimally Invasive and Non-Corticosteroid Percutaneous Interventions DRAFT for 1/18/2018 VbBS/HERC meeting materials

Coverage question: Should minimally invasive discectomy be recommended for the treatment of low back pain? Outcomes Estimate of Effect for Outcome/ Resource Allocation Values and Other Confidence in Estimate Preferences Considerations Long-term risk of Insufficient data resources allocation surgical site (0.19, 95% CI -0.22- surgery (e.g. hospital length of infections. We 0.59). (Critical outcome) stay and utilization of would expect

other therapies) was moderate variability Change in Insufficient data utilization of not identified. based on patient other therapies comorbidities and (Important how individually they would weigh outcome) treatment failure Adverse events Fewer surgical site and other infections compared and infection risk. (Important to microdiscectomy or open discectomy (RR 0.23, Less invasive outcome) 95% CI 0.07 to 0.79) techniques would ●●●◌ (Moderate confidence, based on 9 RCTs, likely be much more N=931) appealing to

patients at higher Greater re-hospitalization for recurrent disc risk of complications herniation compared to microdiscectomy or open such as surgical site discectomy (RR 1.74, 95% CI 1.03 to 2.94) infections. ●●◌◌ (Low confidence, based on 6 RCTs, N=949) Balance of benefits and harms: Minimally invasive discectomy appears generally non-inferior to open discectomy or microdiscectomy. It has slightly lower improvements in pain and functional outcomes, but these do not rise to the level of clinical significance. It decreases the risk of surgical site infections, but is associated with a greater number of re-hospitalizations. Rationale: We recommend coverage of minimally invasive discectomy as an alternative to open discectomy, when indicated. This recommendation is based on roughly equivalent benefits and a similar risk of an adverse event (although the adverse events are different compared to open discectomy). Patient preferences would be moderately variable depending on patients’ comorbidities and how they would value the tradeoff between a higher surgical failure rate and an improved surgical infection rate. This is a weak recommendation because

4 Low Back Pain: Minimally Invasive and Non-Corticosteroid Percutaneous Interventions DRAFT for 1/18/2018 VbBS/HERC meeting materials

Coverage question: Should minimally invasive discectomy be recommended for the treatment of low back pain? Outcomes Estimate of Effect for Outcome/ Resource Allocation Values and Other Confidence in Estimate Preferences Considerations further evidence could change the recommendation, there is moderate variability in values and preferences, and this is a comparison between subtypes of surgery, rather than against placebo or nonsurgical interventions. Recommendation: Minimally invasive discectomy is recommended for coverage as an alternative to microdiscectomy or open discectomy, when discectomy is indicated (weak recommendation).

Coverage question: Should percutaneous laser disc decompression be recommended for the treatment of low back pain? Outcomes Estimate of Effect for Outcome/ Resource Allocation Values and Other Confidence in Estimate Preferences Considerations Short-term No statistically significant difference in Roland- Patients would In terms of pain, function Morris Disability Questionnaire or SF-36 physical likely prefer a there were no (Critical outcome) function subscore at eight weeks compared to treatment that significant microdiscectomy offers rapid relief differences in pain ●◌◌◌ (Very low confidence, based on 1 RCT, and helps them to between N=115) avoid additional percutaneous laser Long-term No difference in overall recovery at 12 months procedures, but discectomy and This is a relatively function compared to microdiscectomy (odds ratio 0.81, would prefer to microdiscectomy at expensive intervention (Critical outcome) 95% CI 0.4 to 1.9) avoid treatments 4-, 8-, or 52-week compared to many ●◌◌◌ (Very low confidence, based on 1 RCT, that are more follow-up. At 26 other treatments for N=115) invasive or weeks, there was a low back pain. Long-term risk of More patients required repeat surgery within 1 associated with small benefit in favor surgery year compared to microdiscectomy (44% vs. 16%) adverse effects. of microdiscectomy (Critical outcome) ●◌◌◌ (Very low confidence, based on 1 RCT, There would likely for VAS back pain N=115) be low variability in score. Overall, VAS Change in Insufficient data patients’ interest in leg pain score was utilization of undergoing this better in patients other therapies procedure, given with

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Coverage question: Should percutaneous laser disc decompression be recommended for the treatment of low back pain? Outcomes Estimate of Effect for Outcome/ Resource Allocation Values and Other Confidence in Estimate Preferences Considerations (Important the need for microdiscectomy outcome) additional surgical (mean difference - Adverse events Fewer patient experienced adverse events procedures. 6.9, 95% CI 12.6 to (Important compared to microdiscectomy (5% vs. 11%) -1.3). outcome) ●◌◌◌ (Very low confidence, based on 1 RCT, N=115) Time to perceived recovery was slower for laser discectomy.

Balance of benefits and harms: We have very low confidence that percutaneous laser discectomy is non-inferior to microdiscectomy with regard to function and may be associated with slightly worse leg pain. The possible benefit of fewer adverse events does not outweigh the much higher harm associated with a need for repeat surgery compared to microdiscectomy. Rationale: We recommend against coverage based on the lack of clear benefit, the cost, and uncertainty about harms; it is a strong recommendation because the cost is higher, alternatives are available, and the rehospitalization rate is higher. Recommendation: Percutaneous laser decompression is not recommended for coverage (strong recommendation).

Coverage question: Should ozone therapy be recommended for the treatment of low back pain? Outcomes Estimate of Effect for Outcome/ Resource Allocation Values and Other Confidence in Estimate Preferences Considerations Short-term Greater percentage of patients with ODI<20 at six Intramuscular ozone Patients would likely A separate May, function months compared to patients undergoing injection would likely prefer a treatment 2017 coverage (Critical outcome) intradiscal or intraforaminal steroid with local be moderate cost; that offers rapid and guidance did not anesthetic injections without ozone (74% vs. 47%) intradiscal or sustained relief, but find that epidural ●◌◌◌ (Very low confidence, based on 1 RCT, intraforaminal injection would prefer to steroid injections N=159) would be significantly avoid treatments (the comparator)

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Coverage question: Should ozone therapy be recommended for the treatment of low back pain? Outcomes Estimate of Effect for Outcome/ Resource Allocation Values and Other Confidence in Estimate Preferences Considerations Long-term Insufficient data higher cost compared that are more offered clear clinical function with alternative invasive or benefit. (Critical outcome) treatments for low associated with back pain. adverse effects. We For pain, ozone Long-term risk of Insufficient data would expect low treatments surgery variability in these provided at the (Critical outcome) preferences. level of the Change in No change in the use of analgesic medications herniated disc utilization of compared to sham injections improved short-and other therapies ●◌◌◌ (Very low confidence, based on 1 RCT, N=60) long-term pain (Important relief (OR 2.66, 95% outcome) CI 1.94 to 3.63). Adverse events Sparsely reported, but include case reports of However, the sham- (Important serious adverse effects including vitreoretinal controlled trial outcome) hemorrhage, pneumocephalus, and found no vertebrobasilar stroke statistically significant difference in pain. Balance of benefits and harms: The benefits of improvement in pain and function over epidural steroid injections might outweigh the harms of rare but serious adverse events. However, the evidence is too limited to confidently support this balance in favor of ozone. Rationale: We recommend against coverage of ozone therapy based on our very low level of confidence of effectiveness, the cost of the intervention, and risk of rare but serious adverse events. It is a strong recommendation because of very limited evidence of benefit and some serious harms. Recommendation: Ozone therapy injections are not recommended for coverage for low back pain (strong recommendation).

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Coverage question: Should radiofrequency denervation be recommended for the treatment of low back pain due to facet joint arthropathy? Outcomes Estimate of Effect for Outcome/ Resource Allocation Values and Other Confidence in Estimate Preferences Considerations Short-term Improved ODI at one month compared to placebo function (mean difference -5.5, 95% CI -8.7 to -2.4) (Critical outcome) ●◌◌◌ (Very low confidence, based on 1 RCT, N=60) Patients would likely For pain outcomes, Note: An additional RCT published after the prefer a treatment there is mixed systematic review found no significant differences that offers rapid and evidence: one study in ODI prior to six months; given the inconsistency sustained relief, but showed benefit at in these findings, the confidence in the estimate of would prefer to one month and the effects has been downgraded to very low. This is a relatively avoid treatments another showed no Long-term Improved ODI beyond six months compared to expensive intervention that are more benefit; these function placebo (mean difference -3.7, 95% CI -6.9 to -0.5) compared to other invasive or studies had (Critical outcome) ●◌◌◌ (Very low confidence, based on 1 RCT, N=60) treatments for low associated with opposite results at Note: An additional RCT published after the back pain. Two adverse effects. longer-term follow- systematic review found considerably greater separate diagnostic However, patients up. improvements in ODI beyond one year; given the medical branch blocks with chronic inconsistency in these findings, the confidence in may be required prior debilitating pain Expert and public the estimate of the effect has been downgraded to to the procedure which may be more willing commenters very low. increases the to accept invasive suggested that the Long-term risk of Insufficient data associated cost. treatments. We subcommittee focus surgery would expect their examination (Critical outcome) moderate variability on studies using Change in Insufficient data in these more stringent utilization of preferences. criteria for patient other therapies selection. (Important outcome)

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Balance of benefits and harms: There is limited evidence of benefit on short- and long-term pain, and limited evidence of improved short and long term-function. There are mixed results on whether the functional benefits are clinically important or unimportant. Given that there is insufficient evidence about harms, the balance is neutral to positive. Rationale: We recommend against coverage of radiofrequency denervation for facet joint arthropathy because of very low confidence in its effectiveness for improving pain and function. Given the lack of proven benefit, the relatively high resource allocation, and the availability of alternatives, it is a recommendation against coverage. It is a weak recommendation due the reported discrepancy between the study inclusion criteria and locally-defined optimal patient characteristics which may affect external validity, and the possibility that further studies examining this subgroup may reach different conclusions. Recommendation: Radiofrequency denervation is not recommended for coverage for the treatment of low back pain (weak recommendation).

Coverage question: Should radiofrequency denervation of lumbar discs be recommended for the treatment of discogenic low back pain? Outcomes Estimate of Effect for Outcome/ Resource Allocation Values and Other Confidence in Estimate Preferences Considerations Short-term No difference in ODI at one month compared to Patients would For pain outcomes, This is relatively function placebo (mean difference 1.0, 95% CI -6.9 to 8.9) prefer interventions low-quality expensive compared to (Critical outcome) based on one trial with 57 patients that result in rapid evidence of no alternate therapies for ●●◌◌ (Low confidence, based on 1 RCT, N=57) and sustained differences in VAS low back pain. Long-term Improved ODI beyond 6 months compared to improvement in pain scores at up to Improved long-term function placebo (mean difference -6.8, 95% CI -13.4 to symptoms and less six months. Beyond function may be cost- (Critical outcome) -0.1) ●●●◌ (Moderate confidence, based on 2 invasive procedures six months, there effective. RCTs, N=76) associated with few was moderate

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Balance of benefits and harms: We have moderate confidence these interventions result in long-term improvements in function and pain, but improvements for both outcomes fail to meet commonly-accepted thresholds for clinically meaningful differences. There is insufficient evidence to understand harms. Rationale: We recommend against coverage based on the moderate confidence that the benefits of this therapy do not meet commonly- accepted thresholds of clinically meaningful differences, and the cost. It is a weak recommendation because further evidence could change the recommendation. Recommendation: Radiofrequency denervation of lumbar discs is not recommended for coverage for the treatment of discogenic low back pain (weak recommendation).

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Coverage question: Should radiofrequency denervation be recommended for the treatment of sacroiliac joint pain? Outcomes Estimate of Effect for Outcome/ Resource Allocation Values and Other Confidence in Estimate Preferences Considerations Short-term No difference in ODI at one month compared to function placebo (mean difference -14.1, 95% CI -30.4 to (Critical outcome) 2.3) ●◌◌◌ (Very low confidence, based on 2 RCTs, For pain outcomes, N=75) there was very low- quality evidence of Improved ODI between 1 and 6 months compared no differences in Patients would to placebo (mean difference -11.0, 95% CI -17.9 to VAS pain scores at prefer interventions -4.1) one month. that result in rapid ●●◌◌ (Low confidence, based on 1 RCT, N=49) This treatment is Between one and and sustained Long-term Insufficient data relatively expensive six months, there improvement in function compared to alternate was low-quality symptoms and less (Critical outcome) therapies for low back evidence of a invasive procedures pain. Improved long- statistically Long-term risk of Insufficient data associated with few term function may be significant surgery adverse events. We cost-effective. improvement in (Critical outcome) would expect low VAS pain scores for Change in Insufficient data variability in these RF treatment over utilization of preferences. placebo (mean other therapies difference -1.3, 95% (Important CI -2.1 to -0.5). outcome)

Adverse events Insufficient data (Important outcome) Balance of benefits and harms: We have very low confidence that short-term function (between one and six months) may be improved. There is insufficient data about adverse effects. Our very low confidence in the evidence makes the balance of benefits and harms uncertain.

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Coverage question: Should radiofrequency denervation be recommended for the treatment of sacroiliac joint pain? Outcomes Estimate of Effect for Outcome/ Resource Allocation Values and Other Confidence in Estimate Preferences Considerations Rationale: We recommend against coverage due to the uncertainty about the benefits, unknown harms, and high associated costs. It is a weak recommendation because further evidence could change the recommendation. Recommendation: Radiofrequency denervation for sacroiliac joint pain is not recommended for coverage (weak recommendation).

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EVIDENCE OVERVIEW Clinical Background Low back pain is the leading cause of disability in individuals under 45 years of age in the United States and globally (The American Academy of Pain Medicine, n.d.). Approximately 80% of adults experience low back pain at some point in their lifetimes. In one large survey, more than 25% of adults reported low back pain during the past three months (National Institute of Neurological Disorders and Stroke [NINDS], 2014). The impact of low back pain on health in the U.S. has increased in recent years. A 1990 study ranked low back pain as the sixth most burdensome condition in the U.S. in terms of morbidity or poor health (NINDS, 2014). In a 2010 reproduction of the study, back pain was ranked as the third most burdensome condition, following ischemic heart disease and chronic obstructive pulmonary disease (NINDS, 2014). Low back pain is also associated with high economic costs: annual cost estimates are upward of $100 billion in the United States (Bicket et al., 2013).

A majority of low back pain is defined as acute, lasting a few days to a few weeks, and resolves on its own with self-care. However, about 20% of people affected by low back pain develop chronic low back pain and have persistent symptoms at one year. Even with a thorough examination, it is often challenging to determine a specific cause of a patient’s back pain (NINDS, 2014). Many cases of low back pain are attributed to a mechanical disruption influencing the way in which components of the back fit together and move. Low back pain is often associated with spondylosis, which refers to general spinal wear and tear that typically occurs as people age. In rare cases, low back pain is related to more serious underlying conditions requiring immediate medical attention, such as infections, tumors, cauda equina syndrome, and abdominal aortic aneurysms (NINDS, 2014).

A variety of treatment options are used to address low back pain, and treatment plans often reflect individual values and preferences (Chou, 2009). Conservative treatments for low back pain include pharmacological treatment such as nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids, acupuncture, physical therapy, exercise therapy, spinal manipulation, psychological therapies, superficial heat or cold, and back supports (Chou, 2016). Surgical options for treating low back pain include decompression, total disc arthroplasty, total facet arthroplasty, and fusion (Balgia et al., 2015). For some cases of low back pain, surgery may not be indicated and/or the pain may not be adequately relieved by conservative treatment. Multiple percutaneous or minimally invasive interventions are performed for low back pain. This report discusses the following interventions: ozone injections, minimally-invasive percutaneous and laser discectomy, and radiofrequency denervation procedures. Several other interventions had originally been included in the scope, and were excluded either because no or very limited evidence was found using the search criteria or because most major payers do not cover the interventions because of experimental status or insufficient evidence. See Appendix C for details about interventions originally included in scope but not discussed in the remainder of the Coverage Guidance.

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Indications Low back pain is the fifth most common reason for all physician visits in the United States (American Academy of Family Physicians, 2016). Despite use of recommended conservative treatments, management of low back pain remains a challenge (Chou, 2009). Utilization of surgical and nonsurgical interventions for back pain has increased. Yet, disability rates have continued to rise as well (Bicket et al., 2013). As the prevalence of low back pain continues to increase, interventional pain management as a specialty is also growing (Manchikanti et al., 2013). Table 1 describes some of the more common scales used to measure pain levels and the levels of disability or impairment that might be caused by pain. Table 1. Scales that Measure Pain and Associated Disability Scale Range Direction Numeric Rating Scale (NRS) 0 to 10 Higher scores represent greater pain levels Visual Analog Scale (VAS) 0 to 10 Higher scores represent greater pain levels Oswestry Disability Index (ODI) 0 to 100 Higher scores represent greater disability/impairment Roland-Morris Disability 0 to 24 Higher scores represent greater Questionnaire (RMDQ) disability/impairment Short Form 36 (SF-36) 0 to 100 for Lower scores represent greater each subscale disability/impairment

Technology Description Percutaneous Discectomy/Minimally Invasive Discectomy In endoscopic percutaneous discectomy, an endoscope with fluoroscopic guidance is used as an indirect visualization technique while disc material is removed with micro-instruments or a laser. In automated percutaneous discectomy, a cannula is inserted into the intervertebral disc space and nuclear material is removed using nucleotome, laser, or radiofrequency heat. This technique also involves the use of an endoscope and typically fluoroscopic guidance for indirect visualization. Percutaneous discectomy does not require open dissection of the thoracolumbar fascia (Kreiner, 2014). Ozone Injections and Chemonucleolysis Chemonucleolysis broadly refers to procedures involving the injection of a substance into a herniated spinal disc to reduce its size. Ozone injections are one form of chemonucleolysis and involve releasing an ozone-oxygen mixture at a nontoxic concentration near a spinal disc to reduce the size of the disc. Disc shrinkage may in turn reduce nerve root compression. Additionally, medical ozone is used for its analgesic and anti-inflammatory effects (Andreula, 2003) and can be injected into lumbar paraspinal muscles.

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Radiofrequency Denervation Radiofrequency denervation is a procedure performed under local anesthesia or light intravenous sedation in which radiofrequency energy is delivered along an insulated needle to target nerves, which heats and denatures the nerves. Repeated radiofrequency denervation is intended to facilitate the regeneration of axons over time (NICE, 2016). Key Questions and Outcomes The following key questions (KQ) guided the evidence search and review described below. For additional details about the review scope and methods, please see Appendix C. 1. What is the comparative effectiveness of non-corticosteroid percutaneous or minimally invasive interventions for low back pain? 2. Does the comparative effectiveness of the interventions vary by: a. Duration of back pain b. Etiology of back or radicular pain (e.g., stenosis, disc herniation) c. Frequency of the intervention d. Presence or absence of neurological deficit e. Anatomic approach f. Use of imaging guidance g. Previous back interventions h. Response to previous percutaneous interventions (diagnostic or therapeutic) i. Risk level for poor functional prognosis j. Comorbidities (physical or behavioral) 3. What are the harms of non-corticosteroid percutaneous or minimally invasive interventions for low back pain? Critical outcomes selected for inclusion in the GRADE table are short-term function, long-term function, and long-term risk of undergoing surgery. Important outcomes selected for inclusion in the GRADE table are adverse events and change in utilization of comparators. Evidence Review Minimally Invasive Discectomy Rasouli et al., 2014 This is a good-quality Cochrane systematic review of 11 randomized or quasi-randomized trials comparing minimally invasive (percutaneous) discectomy procedures to microdiscectomy or open discectomy for patients with sciatica or low back pain who had not responded to conservative treatment (total N=1,172). Seven of the 11 trials were deemed to be at high risk of bias. In the meta-analysis, there were no statistically significant differences between the two groups with respect to the ODI at six months and beyond (mean difference 0.84, 95% CI -0.21 to 1.88) or in the likelihood of returning to work (odds ratio 2.07, 95% CI 0.18 to 24.15). However, in the minimally

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invasive discectomy group, the SF-36 physical function subscore was lower (mean difference -4.7, 95% CI -5.05 to -4.35). In the meta-analysis of pain outcomes, there were small but statistically significant differences between the two groups with respect to mean leg pain intensity at one year (0.13 higher in the minimally invasive group, 95% CI 0.09 to 0.16), mean low back pain intensity at six months (0.35 higher in the minimally invasive discectomy group, 95% CI 0.19 to 0.51), and mean low back pain intensity at two years (0.54 higher in the minimally invasive discectomy group, 95% CI 0.29 to 0.79). The mean low back pain score was also higher for minimally invasive discectomy at one year follow-up, although that result did not reach statistical significance (0.19 higher, 95% CI -0.22 to 0.59). The rate of surgical site infections was lower in the minimally invasive group (2.3 per 1,000 vs. 32 per 1,000, risk ratio 0.23, 95% CI 0.07 to 0.79), but the rate of re-hospitalization for recurrent disc herniation was higher in the minimally invasive group (75 per 1,000 vs. 43 per 1,000, risk ratio 1.74, 95% CI 1.03 to 2.94). There were no statistically significant differences in the rate of procedural complications, surgical re-intervention, dural tears, or length of hospital stay. In the subgroup of trials comparing minimally invasive discectomy to microdiscectomy, the primary functional outcomes were similar, although the physical functioning subscore of the SF-36 was lower for patients who underwent minimally invasive discectomy (mean difference -4.7, 95% CI -5.05 to -4.35). In the sensitivity analysis, when the trials at high risk of bias were excluded, the results were similar except that minimally invasive discectomy no longer showed a statistically significant reduction in the rate of infection at the surgical site or elsewhere. In a separate good-quality systematic review and meta-analysis of 42 studies reporting microdiscectomy complication rates, the rate of any complication was 12.5% for open microdiscectomy, 13.3% for microendoscopic discectomy, and 10.8% for percutaneous microdiscectomy (Shriver et al., 2015). The rate of wound complications for open, microendoscopic, and percutaneous discectomy was 2.1%, 1.2%, and 0.5% respectively. The rate of reoperation for open, microendoscopic, and percutaneous discectomy was 7.1%, 3.7%, and 10.2% respectively. Additional RCTs The extended search identified one additional RCT (Nie et al., 2016) that compared interlaminar to transforaminal approaches for percutaneous endoscopic lumbar discectomy. The improvement in ODI was similar in both groups at the last follow-up. The interlaminar approach did result in significantly shorter operative and fluoroscopy times. Percutaneous Laser Discectomy Singh et al., 2013 This is a poor-quality systematic review of percutaneous lumbar laser disc decompression. The authors identified no randomized trials and 17 non-randomized studies (mostly non-comparative case series) for inclusion. Meta-analysis was not performed, and the manuscript is not structured in such a way that it is possible to extract relevant outcomes from the studies. In general, most of the trials reported good or excellent outcomes, including “significant pain relief” beyond 12 months for 60–85% of patients who

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underwent laser disc decompression. The authors concluded that the evidence for lumbar laser discectomy is “limited.” Additional RCTs The extended search identified one randomized controlled non-inferiority trial comparing percutaneous laser disc decompression to microdiscectomy in patients with sciatica (Brouwer et al., 2015). The trial randomized 115 consecutive adults with at least six to eight weeks of sciatica despite conservative measures to undergo percutaneous laser disc decompression (N = 57) or microdiscectomy (N = 58). Patients were eligible if an MRI confirmed disc herniation at the level to which their symptoms could be attributed. The groups were similar at baseline, and the trial was unblinded. The primary outcome measure was improvement in the Roland-Morris Disability Questionnaire (RMDQ) at 8 weeks and 52 weeks. At both time points, there were no statistically significant differences between the two groups for the primary outcome of RMDQ score. Pain was assessed using the VAS leg pain and VAS back pain scores. There were no significant differences between the two groups on either pain measure at 4-, 8-, or 52-week follow-up. At 26 week follow-up, there was a small but statistically significant benefit in favor of microdiscectomy for the VAS back pain score (mean difference -9.4, 95% CI -18.6 to -0.1), but not for the VAS leg pain score. In a repeated measurement analysis spanning the length of the trial, there was a small but statistically significant benefit in favor of microdiscectomy with respect to the VAS leg pain score (mean difference -6.9, 95% CI -12.6 to -1.3). There were no statistically significant differences between the two groups with respect to the SF-36 physical functioning score at any time point during the 12 months of follow-up. There were no statistically significant differences between the groups with respect to the SF-36 pain scale at 4, 8, or 52 weeks; at 26 weeks there was a statistically significant difference in favor of microdiscectomy (mean difference 11.3, 95% CI 2.4 to 20.1). Overall recovery at one year was reported by 69% of the patients undergoing laser discectomy compared to 75% of patients undergoing microdiscectomy (odds ratio 0.81, 95% CI 0.4 to 1.9). However, the median time to perceived recovery was statistically significantly longer for laser discectomy (8 weeks) than for microdiscectomy (6 weeks) (hazard ratio 0.64. 95% CI 0.42 to 0.97). It should be noted that 44% of patients who had a technically successful laser discectomy underwent another surgical procedure within one year compared to 16% in the microdiscectomy arm. The complication rate was 5% in the laser discectomy arm (all transient nerve root injuries) compared to 11% in the microdiscectomy group (including dural tears, urinary retention, transient nerve root injury, and wrong level of surgery). Overall, the authors concluded that laser discectomy is non-inferior to microdiscectomy for the primary outcomes, but acknowledged concerns related to the high rate of reoperation in the laser discectomy group. Ozone Therapy Magalhaes et al., 2012 This is a fair-quality systematic review and meta-analysis of four randomized controlled trials (RCTs) and eight observational studies of ozone therapy for discogenic low back pain. The primary purpose of the review was to summarize the results of ozone therapy for pain relief, and outcomes related to functional improvement were not separately summarized or discussed. In the single RCT that reported on a

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functional outcome (ODI), 159 patients with lumbar disc herniation and radicular pain for at least eight weeks despite conservative management were randomized to undergo intradiscal and intraforaminal injection of steroid and local anesthetic with (N=77) or without (N=82) ozone. The injection was deemed successful if the ODI was no greater than 20. At six-month follow-up, 47% of patients who received steroid and local anesthetic injections had an ODI <20 compared to 74% of patients who received steroid, local anesthetic, and ozone. One randomized trial reported on SF-36 and reduction in use of analgesics. In this trial, 60 patients with acute low back pain and MRI evidence of disc protrusion were randomized to thrice weekly intramuscular paravertebral infiltration of ozone (N=36) or to a placebo injection with a false needle (N=24) for five weeks. At six-month follow-up, patients receiving the ozone treatment were more likely to be pain-free (61% vs. 33% compared to those receiving placebo), but there were no statistically significant differences in the total SF-36 score or the use of analgesic medications. The authors performed a fixed effects meta-analysis of the four randomized trials with respect to “short- and long-term pain relief.” Three of the four trials compared ozone injections to steroid injections; the fourth trial used a sham control. The authors concluded that there is a benefit to ozone treatments provided at the paravertebral muscle and juxtaforaminal area at the level of the herniated disc (OR 2.66, 95% CI 1.94 to 3.63). It should be noted that the sham-controlled trial found no statistically significant differences in pain. The authors of the review noted that complications of ozone therapy are sparsely reported in the literature, but include one case of vitreoretinal hemorrhage, one thunderclap headache that was attributed to an intrathecal puncture and pneumoencephalus, three cases of paresthesias or impaired sensation in the lower extremities, one case of hematoma at the puncture site, and one case of vertebrobasilar stroke. Additional RCTs The extended search did not identify any additional RCTs that met inclusion criteria. Radiofrequency Denervation Maas et al., 2015 This is a good-quality systematic review and meta-analysis of 23 RCTs of radiofrequency (RF) denervation procedures for chronic low back pain arising from lumbar discs, facet joints, or sacroiliac joints. The 23 studies included 1,309 participants. The authors judged 13 of the included studies to be at low risk of bias. Most of the studies (N=12) examined RF treatments for chronic facet joint pain; the remaining trials examined RF treatments for disc pain, sacroiliac joint pain, or low back pain with or without features of radiculopathy. For RF treatment of facet joints, the authors found low-quality evidence of improved ODI at one month compared to placebo (mean difference -5.5, 95% CI -8.7 to -2.4) based on one trial with 60 patients. Beyond six months, there was low-quality evidence of improved ODI for RF treatment of facet joints compared to placebo (mean difference -3.7, 95% CI -6.9 to -0.5) based on one trial of 60 patients. For pain outcomes, the authors found moderate-quality evidence of a statistically significant improvement in VAS pain scores at one month with RF treatment compared to placebo (mean difference -1.5, 95% CI - 2.3 to -0.7). There were no statistically significant differences in the VAS pain score at one to six months or beyond. For trials comparing RF treatment with steroid injections, the authors found low-quality

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evidence of a statistically significant benefit in VAS pain scores at one month with RF treatment (mean difference -2.2, 95% CI -2.4 to -2.1). There was very low-quality evidence of a statistically significant benefit in VAS pain scores at six months (mean difference -2.1, 95% CI -3.5 to -0.8) and 12 months (mean difference -2.7, 95% CI -3.4 to -1.9) with RF treatment.

For RF treatment of discs, the authors found low-quality evidence of no difference in ODI at one month compared to placebo (mean difference 1.0, 95% CI -6.9 to 8.9) based on one trial with 57 patients. Beyond six months, there was moderate-quality evidence of improved ODI for RF treatment of discs compared to placebo (mean difference -6.8, 95% CI-13.4 to -0.1) based on two trials with 76 patients. For pain outcomes, the authors found low-quality evidence of no statistically significant differences in VAS pain scores at up to six months. Beyond six months, there was moderate-quality evidence of a statistically significant improvement in VAS pain scores for RF treatment over placebo (mean difference - 0.8, 95% CI -1.2 to -0.3). For RF treatment of sacroiliac joints, the authors found very low-quality evidence of no difference in ODI at one month compared to placebo (mean difference, -14.1, 95% CI -30.4 to 2.3) based on two trials with 75 patients. Between one and six months, there was low-quality evidence of improved ODI for RF treatment of sacroiliac joints compared to placebo (mean difference -11.0, 95% CI -17.9 to -4.1) based on one trial with 49 patients. For pain outcomes, the authors found very low-quality evidence of no statistically significant differences in VAS pain scores at one month. Between one and six months, there was low-quality evidence of a statistically significant improvement in VAS pain scores for RF treatment over placebo (mean difference -1.3, 95% CI -2.1 to -0.5). Adverse effects were sparsely reported in the trials: 10 studies reported no adverse effects. Two studies found no differences between RF and control groups with respect to adverse events. The adverse events in the remaining studies included increased pain, transient lower limb weakness, transient paresthesias, and superficial burns. The authors of the review cautioned that no clear conclusions can be drawn about the risks of RF denervation based on the results of small RCTs. Additional RCTs Five additional RCTs meeting inclusion criteria were identified in the extended search. The first study (Kapural et al., 2015) reported 12-month follow-up of an RCT of intradiscal biacuplasty (a form of RF treatment) compared to sham treatment for patients with discogenic low back pain. However, at six months patients were unblinded and patients in the sham arm were allowed to crossover to biacuplasty (24 of 30 subjects did so). Thus, the authors only reported results in comparison to baseline values, not in comparison to the patients remaining in the sham treatment group. The second trial (Koh et al., 2015) randomly assigned 62 patients with lumbar spinal stenosis in a single interventional pain management practice to undergo pulsed RF treatment to the lumbar dorsal root ganglion (N=31) or to sham lesioning (N=31). All patients received transforaminal injection of local anesthetic and steroid at the end of the procedure. The trial was double-blinded. The groups were similar at baseline. The rates of functional improvement (as measured by a >10 point or >30% decrease in the ODI score) at one and three months were reported. At one month, 45% of patients in the RF

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group and 32% in the sham group demonstrated functional improvement (p=0.43); at three months, 26% of patients in the RF group and 19% in the sham group demonstrated functional improvement (p=0.76). At three months, the estimated mean difference in ODI between the RF and sham groups was 2.13 (95% CI -4.3 to 8.5). There were no statistically significant between-group differences with respect to the NRS pain score during three months of follow-up. The third trial (Lee, Ahn, & Lee, 2016) randomly assigned 38 patients with radicular pain caused by disc herniation to undergo pulsed RF treatment of a targeted dorsal root ganglion or to transforaminal epidural steroid injection with dexamethasone and bupivacaine. There is no description of randomization method, efforts to ensure allocation concealment, or blinding. Among the 20 patients who underwent lumbar procedures (the remaining patients had treatments to the cervical spine), there were no between-group differences at 2-, 4-, 8-, or 12-week follow-up, although both groups demonstrated improvement compared to baseline ODI. There were no statistically significant between- group differences with respect to the mean VAS pain scores through 12 weeks of follow-up. The fourth trial (Moussa & Khedr, 2016) randomly assigned 120 patients with chronic low back pain caused by a facet joint (confirmed by diagnostic block) to receive RF ablation of the facet joint capsule, RF ablation of the medial dorsal branch nerve, or sham RF treatment. All patients received an injection of methylprednisolone and bupivacaine with the procedure. Methods to ensure proper randomization and allocation concealment were not described. Patients were blinded to the treatment group. The groups were similar at baseline, and the participants were mostly women (72%). Mean change in ODI was measured for each group at 3, 6, 12, 24, and 36 months. At three months, there were no statistically significant differences between the groups with respect to change in ODI. At six months and one year, RF capsule ablation and medial dorsal branch denervation performed similarly and significantly better than the control group for mean change in ODI (mean changes in ODI at 6 months were 38.1, 40.3, and 10.3 for capsule ablation, medial dorsal branch denervation, and sham control respectively, p=0.042). RF capsule ablation performed better than medial dorsal branch ablation at two-year follow-up (mean changes in ODI 29.5, 12.3, and 3.2 for capsule ablation, medial dorsal branch denervation, and sham control respectively, p=0.018) and three-year follow-up (mean changes in ODI at 29.2, 8.2, and 2.9 for capsule ablation, medial dorsal branch denervation, and sham control respectively, p=0.007); both groups showed greater ODI improvement compared to control subjects. For pain outcomes assessed by mean change in the VAS leg pain and VAS back pain scores, there were no statistically significant differences at one and six months, but statistically significant improvement in both measures at one to three years in the patients who received RF joint capsule denervation. By three-year follow-up, 20% of patients were lost to follow-up. The fifth study (Patel, 2016) reported 12-month follow-up of a trial that randomly assigned 51 patients with sacroiliac region pain to undergo RF denervation of lumbosacral dorsal nerve roots (N=34) or control treatment (N=17). Because 16 of 17 patients in the control group crossed over to RF denervation at three months, between-group comparisons were not performed in this study. Additionally, only 25 “study completers” were included in the analysis. Compared to baseline, patients who originally underwent RF treatment had statistically significant improvements in ODI (mean difference -13.9, P=0.0003) and the SF-36 physical functioning subscore (mean difference 17.4, p<0.0001). Similarly,

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when compared to baseline, patients who originally underwent RF treatment had statistically significant improvements in the NRS pain score at 12 months (mean difference -2.7, p<0.0001). EVIDENCE SUMMARY A variety of minimally invasive and percutaneous treatments for low back pain have been studied. In general, there is a paucity of RCT data to support these interventions, and most of the trials that do exist are small and methodologically limited. For the interventions for which we can assess outcomes with moderate or low confidence, the benefits may not be clinically important. Minimally invasive discectomy appears to have comparable results to open discectomy. Few trials have examined long-term outcomes beyond 12 months. Adverse events associated with these interventions are inconsistently and sparsely reported in the studies. OTHER DECISION FACTORS Other Considerations For radiofrequency ablation for facet joint pain, public commenters submitted an analysis of the evidence that differed from what was initially gleaned from the evidence review. They provided clinical context showing that many studies are not conducted with what are considered optimal techniques nor on appropriately selected subjects, and they acknowledged overuse of this procedure. They identified for the subcommittee a limited number of studies that approximated the optimal techniques and patient selection criteria, and those studies demonstrated some positive results (i.e., Nath, 2008; Lakemeier, 2013; Tekin, 2007; Dreyfuss, 2000). The subcommittee reviewed specific studies that more closely aligned with the Oregon expert-defined optimal technique to determine if sufficient evidence existed to support a subgroup of patients benefitting from the procedure. The subcommittee did not feel the evidence supported benefit in a selected or nonselected population. POLICY LANDSCAPE Quality Measures A search of the National Quality Measures Clearinghouse did not identify any measures directly related the interventions discussed in this coverage guidance. The National Quality Measures Clearinghouse includes measures that address assessment and collaborative decision-making regarding low back pain. For example, one quality measure is the “percentage of patients with non-specific low back pain diagnosis who have had collaborative decision-making with regards to referral to a specialist” (Institute for Clinical Systems Improvement, 2012). Payer coverage policies Private Payers Coverage policies were assessed for Aetna, Cigna, Moda, and Regence for the interventions outlined below to treat low back pain.

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Coverage Policies for Percutaneous Discectomy Cigna, Moda, and Regence do not cover percutaneous discectomy because the technique is considered investigational. Aetna covers manual or automated percutaneous lumbar discectomy for the treatment of a contained herniated lumbar disc for patients who are otherwise candidates for open laminectomy, have failed six months of conservative management, have no previous surgery or chemonucleolysis of the disc to be treated, and have clinical symptoms of radicular pain. Coverage Policies for Ozone Injections and Chemonucleolysis Aetna and Cigna consider ozone injection therapy experimental and do not cover the procedure. No coverage policy addressing ozone injections was identified for Moda or Regence, but both companies have policies stating that chemonucleolysis in general is not covered. Although Aetna and Cigna do not cover ozone injections, they do provide coverage for other forms of chemonucleolysis when medically necessary. Specifically, Aetna covers chymopapain chemonucleolysis for the treatment of sciatica caused by a single-level herniated disc for patients with leg pain worse than their lower back pain, radicular symptoms, a confirmed neurological deficit, and pain that is not relieved by at least six weeks of conservative therapy. Coverage Policies for Radiofrequency Denervation Aetna, Cigna, and Regence cover non-pulsed radiofrequency facet denervation, or facet neurotomy, for certain patients with back pain that has failed to respond adequately to a reasonable trial of conservative treatment. Moda lists facet neurotomy as a procedure requiring prior authorization. Both Aetna and Cigna list additional criteria for treatment including a requirement that patients first have a positive clinical response to facet joint injections. Medicaid Washington Medicaid provides coverage for percutaneous discectomy and facet neurotomy radiofrequency for low back pain. For treatment with facet neurotomy, Washington Medicaid requires a medical necessity review by Qualis Health, and the patient must fail to respond to a three-month trial of conservative treatment. No coverage policy was identified for ozone injections. Medicare A Medicare National Coverage Determination (NCD), effective September 29, 2008, outlines the decision to not cover thermal intradiscal procedures, which include intradiscal electrothermal therapy (IDET), intradiscal thermal annuloplasty (IDTA), percutaneous intradiscal radiofrequency thermocoagulation (PIRFT), radiofrequency annuloplasty (RA), intradiscal biacuplasty (IDB), percutaneous (or plasma) disc decompression (PDD) or coblation, or targeted disc decompression (TDD). No NCDs addressing the other interventions discussed in this coverage guidance were identified. Six LCDs were identified for radiofrequency neurotomy for low back pain. All six LCDs cover certain patients who have experienced at least three months of moderate to severe pain that has failed to respond adequately to conservative treatment and has contributed to functional impairment. The treated pain must be predominantly axial, not associated with radiculopathy or neurogenic claudication,

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and of facet joint origin. Before receiving treatment, a patient must first experience at least 80% pain relief after receiving medial branch block facet joint injections. The procedure should be performed under fluoroscopic or computed tomographic guidance and should only be repeated if the patient has experienced at least five to six months of significant pain relief. No LCDs addressing the other interventions discussed in this coverage guidance were identified. Professional society guidelines Recommendations related to any of the interventions discussed in this Coverage Guidance are outlined below from four guidelines that addressed percutaneous or minimally invasive interventions for low back pain. The National Institute for Health and Care Excellence (NICE) 2016 guideline on Low Back Pain and Sciatica makes the following recommendations regarding the use of percutaneous or minimally invasive interventions for the treatment of low back pain (NICE, 2016):  Do not offer spinal injections for patients with low back pain.  Consider referring patients with chronic low back pain for the assessment of radiofrequency when non-surgical treatment has not been effective, the medial branch nerve is thought to be the source of pain (as confirmed by a diagnostic medial branch block), and the patient has moderate or severe levels of localized back pain.  Do not offer imaging as a prerequisite for the use of radiofrequency denervation to treat low back pain with specific facet joint pain. The North American Spine Society’s (NASS) 2014 guideline, An Evidence-Based Clinical Guideline for the Diagnosis and Treatment of Lumbar Disc Herniation with Radiculopathy, makes the following recommendations regarding the use of percutaneous or minimally invasive interventions for the treatment of low back pain (Kreiner et al., 2014):  Endoscopic percutaneous discectomy and automated percutaneous discectomy may be considered for the treatment of lumbar disc herniation with radiculopathy based on poor- quality evidence for endoscopic percutaneous discectomy and fair-quality evidence for automated percutaneous discectomy.  There is insufficient evidence to recommend for or against intradiscal ozone injections for the treatment of lumbar disc herniation with radiculopathy.  There is insufficient evidence to recommend for or against percutaneous electrothermal disc decompression for the treatment of lumbar disc herniation with radiculopathy. The American Society of Interventional Pain Physicians’ 2013 guideline, An Update of Comprehensive Evidence-Based Guidelines for Interventional Techniques in Chronic Spinal Pain, makes the following recommendations regarding the use of percutaneous or minimally invasive interventions for the treatment of low back pain (Manchikanti et al., 2013):  Evidence for automated percutaneous lumbar discectomy, percutaneous disc decompression, and decompressor use is limited. These procedures are recommended in select cases.

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 Conventional radiofrequency neurotomy is recommended as a therapeutic lumbar/cervical facet joint intervention for treating low back pain after an appropriate diagnosis with diagnostic facet joint blocks. However, evidence is limited for conventional radiofrequency neurotomy as a therapeutic sacroiliac joint intervention, and instead cooled radiofrequency is recommended after positive diagnostic sacroiliac joint injections. Evidence is limited for the use of radiofrequency neurotomy for therapeutic thoracic facet and zygapophysial joint nerve blocks, but it may be performed based on emerging evidence. The British Pain Society 2013 guideline, Low Back and Radicular Pain: A Pathway for Care Developed by the British Pain Society, makes the following recommendations (Lee et al., 2013):  Radiofrequency denervation is recommended for certain patients with persistent or severe pain in the context of a multidisciplinary treatment approach after the use of medial branch blocks to diagnose pain of facet joint origin.  The use of an MRI is not recommended at the primary care level for spinal pain. However, the use of other types of imaging guidance (e.g., X-ray, ultrasound, and fluoroscopy) is often indicated to facilitate spinal interventions to ensure patient safety. REFERENCES Evidence Sources

Brouwer, P. A., Brand, R., van den Akker-van Marle, M. E., Jacobs, W. C., Schenk, B., van den Berg- Huijsmans, A. A., ... Peul, W. C. (2015). Percutaneous laser disc decompression versus conventional microdiscectomy in sciatica: A randomized controlled trial. Spine Journal, 15(5), 857-865. DOI: 10.1016/j.spinee.2015.01.020. Kapural, L., Vrooman, B., Sarwar, S., Krizanac-Bengez, L., Rauck, R., Gilmore, C., ... Mekhail, N. (2015). Radiofrequency intradiscal biacuplasty for treatment of discogenic lower back pain: A 12-month follow-up. Pain Medicine, 16(3), 425-431. DOI: 10.1111/pme.12595. Koh, W., Choi, S. S., Karm, M. H., Suh, J. H., Leem, J. G., Lee, J. D., ... Shin, J. (2015). Treatment of chronic lumbosacral radicular pain using adjuvant pulsed radiofrequency: A randomized controlled study. Pain Medicine, 16(3), 432-441. DOI: 10.1111/pme.12624. Lee, D. G., Ahn, S. H., & Lee, J. (2016). Comparative effectivenesses of pulsed radiofrequency and transforaminal steroid injection for radicular pain due to disc herniation: A prospective randomized trial. Journal of Korean Medical Science, 31(8), 1324-1330. DOI: 10.3346/jkms.2016.31.8.1324. Maas, E. T., Ostelo, R. W., Niemisto, L., Jousimaa, J., Hurri, H., Malmivaara, A., & van Tulder, M. W. (2015). Radiofrequency denervation for chronic low back pain. Cochrane Database of Systematic Reviews (10), Cd008572. DOI: 10.1002/14651858.CD008572.pub2. Magalhaes, F. N., Dotta, L., Sasse, A., Teixera, M. J., & Fonoff, E. T. (2012). Ozone therapy as a treatment for low back pain secondary to herniated disc: A systematic review and meta-analysis of

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randomized controlled trials. Pain Physician, 15(2), E115-129. Retrieved from http://www.painphysicianjournal.com/current/pdf?article=MTU5Mg%3D%3D&journal=66 Moussa, W. M., & Khedr, W. (2016). Percutaneous radiofrequency facet capsule denervation as an alternative target in lumbar facet syndrome. Clinical Neurology and Neurosurgery, 150, 96-104. DOI: 10.1016/j.clineuro.2016.09.004. Nie, H., Zeng, J., Song, Y., Chen, G., Wang, X., Li, Z., ... Kong, Q. (2016). Percutaneous endoscopic lumbar discectomy for L5-S1 disc herniation via an interlaminar approach versus a transforaminal approach: A prospective randomized controlled study with 2-year follow up. Spine (Phila Pa 1976), 41 Suppl 19, B30-b37. DOI: 10.1097/brs.0000000000001810. Patel, N. (2016). Twelve-month follow-up of a randomized trial assessing cooled radiofrequency denervation as a treatment for sacroiliac region pain. Pain Practice, 16(2), 154-167. DOI: 10.1111/papr.12269. Rasouli, M. R., Rahimi-Movaghar, V., Shokraneh, F., Moradi-Lakeh, M., & Chou, R. (2014). Minimally invasive discectomy versus microdiscectomy/open discectomy for symptomatic lumbar disc herniation. Cochrane Database of Systematic Reviews(9), Cd010328. DOI: 10.1002/14651858.CD010328.pub2. Shriver, M. F., Xie, J. J., Tye, E. Y., Rosenbaum, B. P., Kshettry, V. R., Benzel, E. C., & Mroz, T. E. (2015). Lumbar microdiscectomy complication rates: A systematic review and meta-analysis. Neurosurgical Focus, 39(4), E6. DOI: 10.3171/2015.7.focus15281. Singh, V., Manchikanti, L., Calodney, A. K., Staats, P. S., Falco, F. J., Caraway, D. L., ... Cohen, S. P. (2013). Percutaneous lumbar laser disc decompression: An update of current evidence. Pain Physician, 16(2 Suppl), Se229-260. Retrieved from http://www.painphysicianjournal.com/current/pdf?article=MTg4Mg%3D%3D&journal=74 Other Citations

American Academy of Family Physicians. (2016). Imaging for low back pain. Retrieved from http://www.aafp.org/patient-care/clinical-recommendations/all/cw-back-pain.html American Academy of Pain Medicine. (n.d.). AAPM facts and figures on pain. Retrieved from http://www.painmed.org/patientcenter/facts_on_pain.aspx Andreula, C. F., Simonetti, L., De Santis, F., Agati, R., Ricci, R., & Leonardi, M. (2003). Minimally invasive oxygen-ozone therapy for lumbar disk herniation. AJNR American Journal of Neuroradiology, 24(5), 996-1000. Baliga, S., Treon, K., & Craig, N. J. (2015). Low back pain: Current surgical approaches. Asian Spine Journal, 9(4), 645-657. doi: 10.4184/asj.2015.9.4.645 Bicket, M. C., Gupta, A., Brown, C. H. t., & Cohen, S. P. (2013). Epidural injections for spinal pain: A systematic review and meta-analysis evaluating the "control" injections in randomized controlled trials. Anesthesiology, 119(4), 907-931. doi: 10.1097/ALN.0b013e31829c2ddd

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Chou, R., Deyo, R., Friedly, J., Skelly, A., Hashimoto, R., Weimer, M., ... Brodt, E. (2016). Noninvasive treatments for low back pain. Rockville (MD): Agency for Healthcare Research and Quality. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK350276/ Chou, R., Loeser, J. D., Owens, D. K., Rosenquist, R. W., Atlas, S. J., Baisden, J., ... Wall, E. M. (2009). Interventional therapies, surgery, and interdisciplinary rehabilitation for low back pain: An evidence-based clinical practice guideline from the American Pain Society. Spine, 34(10), 1066- 1077. doi: 10.1097/BRS.0b013e3181a1390d Dreyfuss, P., Halbrook, B., Pauza, K., Joshi, A., McLarty, J., & Bogduk, N. (2000). Efficacy and validity of radiofrequency neurotomy for chronic lumbar zygapophysial joint pain. Spine, 25(10), 1270-1277. Kreiner, D. S., Hwang, S. W., Easa, J. E., Resnick, D. K., Baisden, J. L., Bess, S., ... Toton, J. F. (2014). An evidence-based clinical guideline for the diagnosis and treatment of lumbar disc herniation with radiculopathy. Spine Journal, 14(1), 180-191. doi: 10.1016/j.spinee.2013.08.003 Lakemeier, S., Lind, M., Schultz, W., Fuchs-Winkelmann, S., Timmesfeld, N., Foelsch, C., & Peterlein, C. D. (2013). A comparison of intraarticular lumbar facet joint steroid injections and lumbar facet joint radiofrequency denervation in the treatment of low back pain: A randomized, controlled, double- blind trial. Anesthesia & Analgesia, 117(1), 228-235. doi: 10.1213/ANE.0b013e3182910c4d Lee, J., Gupta, S., Price, C., & Baranowski, A. P. (2013). Low back and radicular pain: A pathway for care developed by the British Pain Society. British Journal of Anaesthesia, 111(1), 112-120. doi: 10.1093/bja/aet172 Manchikanti, L., Abdi, S., Atluri, S., Benyamin, R. M., Boswell, M. V., Buenaventura, R. M., ... Hirsch, J. A. (2013). An update of comprehensive evidence-based guidelines for interventional techniques in chronic spinal pain. Part II: guidance and recommendations. Pain Physician, 16(2 Suppl), S49-283. Nath, S., Nath, C. A., & Pettersson, K. (2008). Percutaneous lumbar zygapophysial (facet) joint neurotomy using radiofrequency current, in the management of chronic low back pain: A randomized double-blind trial. Spine, 33(12), 1291-1297; discussion 1298. doi: 10.1097/BRS.0b013e31817329f0 National Institute for Health and Care Excellence. (2016). Clinical guidelines low back pain and sciatica in over 16s: Assessment and management. London: National Institute for Health and Care Excellence (UK). Retrieved from https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0090162/pdf/PubMedHealth_PMH0090162.p df National Institute of Neurological Disorders and Stroke (2014). Low back pain fact sheet. Retrieved from https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Low-Back-Pain- Fact-Sheet Tekin, I., Mirzai, H., Ok, G., Erbuyun, K., & Vatansever, D. (2007). A comparison of conventional and pulsed radiofrequency denervation in the treatment of chronic facet joint pain. Clinical Journal of Pain, 23(6), 524-529. doi: 10.1097/AJP.0b013e318074c99c

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The Center is not engaged in rendering any clinical, legal, business or other professional advice. The statements in this document do not represent official policy positions of the Center. Researchers involved in preparing this document have no affiliations or financial involvement that conflict with material presented in this document.

Suggested citation: Obley, A., Hackett, R., Mosbaek, C., & Livingston, C. (2017). Coverage guidance: Low back pain: Minimally invasive and non-corticosteroid percutaneous interventions. Portland, OR: Center for Evidence-based Policy, Oregon Health & Science University.

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APPENDIX A. GRADE INFORMED FRAMEWORK – ELEMENT DESCRIPTIONS

Element Description Balance of benefits The larger the difference between the desirable and undesirable effects, the higher the and harms likelihood that a strong recommendation is warranted. An estimate that is not statistically significant or has a confidence interval crossing a predetermined clinical decision threshold will be downgraded. Quality of evidence The higher the quality of evidence, the higher the likelihood that a strong recommendation is warranted Resource allocation The higher the costs of an intervention—that is, the greater the resources consumed in the absence of likely cost offsets—the lower the likelihood that a strong recommendation is warranted Values and The more values and preferences vary, or the greater the uncertainty in values and preferences preferences, the higher the likelihood that a weak recommendation is warranted Other considerations Other considerations include issues about the implementation and operationalization of the technology or intervention in health systems and practices within Oregon.

Strong recommendation In Favor: The subcommittee concludes that the desirable effects of adherence to a recommendation outweigh the undesirable effects, considering the balance of benefits and harms, resource allocation, values and preferences and other factors. Against: The subcommittee concludes that the undesirable effects of adherence to a recommendation outweigh the desirable effects, considering the balance of benefits and harms, resource allocation, values and preferences and other factors. Weak recommendation In Favor: The subcommittee concludes that the desirable effects of adherence to a recommendation probably outweigh the undesirable effects, considering the balance of benefits and harms, resource allocation, values and preferences and other factors., but further research or additional information could lead to a different conclusion. Against: The subcommittee concludes that the undesirable effects of adherence to a recommendation probably outweigh the desirable effects, considering the balance of benefits and harms, cost and resource allocation, and values and preferences, but further research or additional information could lead to a different conclusion. Confidence in estimate rating across studies for the intervention/outcome1 High: The subcommittee is very confident that the true effect lies close to that of the estimate of the effect. Typical sets of studies are RCTs with few or no limitations and the estimate of effect is likely stable. Moderate: The subcommittee is moderately confident in the estimate of effect: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Typical sets of

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studies are RCTs with some limitations or well-performed nonrandomized studies with additional strengths that guard against potential bias and have large estimates of effects. Low: The subcommittee’s confidence in the estimate of effect is limited: The true effect may be substantially different from the estimate of the effect. Typical sets of studies are RCTs with serious limitations or nonrandomized studies without special strengths. Very low: The subcommittee has very little confidence in the estimate of effect: The true effect is likely to be substantially different from the estimate of effect. Typical sets of studies are nonrandomized studies with serious limitations or inconsistent results across studies.

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APPENDIX B. GRADE EVIDENCE PROFILE

Quality Assessment (Confidence in Estimate of Effect) Minimally Invasive Discectomy No. of Study Risk of Other Studies Design(s) Bias Inconsistency Indirectness Imprecision Factors Quality Short-term function 2 to 3 RCTs Moderate Serious None Serious Low confidence in estimate of the effect ●●◌◌ Long-term function Insufficient data Long-term risk of undergoing surgery Insufficient data Change in utilization of comparators Insufficient data Adverse events 6 to 9 RCTs Moderate Serious None Serious Low to moderate confidence in estimate of the effect ●●◌◌ to ●●●◌

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Quality Assessment (Confidence in Estimate of Effect) Ozone Therapy No. of Study Risk of Other Studies Design(s) Bias Inconsistency Indirectness Imprecision Factors Quality Short-term function 1 RCT Moderate N/A None N/A Sparse Very low data confidence in estimate of the effect ●◌◌◌ Long-term function Insufficient data Long-term risk of undergoing surgery Insufficient data Change in utilization of comparators 1 RCT Moderate N/A None N/A Sparse Very low data confidence in estimate of the effect ●◌◌◌ Adverse events Insufficient data

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Quality Assessment (Confidence in Estimate of Effect) Radiofrequency denervation low back pain due to facet joint arthropathy? No. of Study Risk of Other Studies Design(s) Bias Inconsistency Indirectness Imprecision Factors Quality Short-term function 1 RCT Moderate N/A None None Inconsistent Very low findings in confidence subsequent in estimate RCT of the effect ●◌◌◌ Long-term function 1 RCT Moderate N/A None None Very low Inconsistent confidence findings in in estimate subsequent of the RCT effect ●◌◌◌ Long-term risk of undergoing surgery Insufficient data Change in utilization of comparators Insufficient data Adverse events Insufficient data

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Quality Assessment (Confidence in Estimate of Effect) Radiofrequency Denervation for Discogenic Low Back Pain No. of Study Risk of Other Studies Design(s) Bias Inconsistency Indirectness Imprecision Factors Quality Short-term function 1 RCT Moderate N/A None None Sparse Low data confidence in estimate of the effect ●●◌◌ Long-term function 2 RCTs Moderate None None Serious Moderate confidence in estimate of the effect ●●●◌ Long-term risk of undergoing surgery Insufficient data Change in utilization of comparators Insufficient data Adverse events Insufficient data

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Quality Assessment (Confidence in Estimate of Effect) Radiofrequency Denervation for Sacroiliac Joint Pain No. of Study Risk of Other Studies Design(s) Bias Inconsistency Indirectness Imprecision Factors Quality Short-term function 1 to 2 RCTs Moderate Serious None Serious Very low confidence in estimate of the effect ●◌◌◌ Long-term function 1 RCT Moderate N/A None None Low confidence in estimate of the effect ●●◌◌ Long-term risk of undergoing surgery Insufficient data Change in utilization of comparators Insufficient data Adverse events Insufficient data

35 Low Back Pain: Minimally Invasive and Non-Corticosteroid Percutaneous Interventions DRAFT for 1/18/2018 VbBS/HERC meeting materials

APPENDIX C. METHODS

Scope Statement Populations Adults with acute, subacute, or chronic low back pain with or without radiculopathy Population scoping notes: None Interventions* Local injections (including trigger point injections), botulinum toxin injection, coblation nucleoplasty, radiofrequency denervation, prolotherapy, intradiscal electrothermal therapy (IDET), medial branch block, percutaneous intradiscal radiofrequency thermocoagulation, lumbar radiofrequency neurotomy, spinal cord (dorsal column) stimulators, sacroiliac joint injections Intervention exclusions: Corticosteroid injections are considered separately; these interventions, when used for diagnostic purposes, are beyond the scope of this review. Anesthetic injections are excluded. Comparators Other interventions for low back pain (including others listed above, alone or in combination), no treatment Outcomes Critical: Short-term function, long-term function, long-term risk of undergoing surgery Important: Adverse events, change in utilization of comparators Considered but not selected for the GRADE table: Short-term pain, long-term pain Key Questions KQ1: What is the comparative effectiveness of non-corticosteroid percutaneous or minimally invasive interventions for low back pain? KQ2: Does the comparative effectiveness of the interventions vary by: a. Duration of back pain b. Etiology of back or radicular pain (e.g., stenosis, disc herniation) c. Frequency of the intervention d. Presence or absence of neurological deficit e. Anatomic approach f. Use of imaging guidance g. Previous back interventions h. Response to previous percutaneous interventions (diagnostic or therapeutic) i. Risk level for poor functional prognosis j. Comorbidities (physical or behavioral)

36 Low Back Pain: Minimally Invasive and Non-Corticosteroid Percutaneous Interventions DRAFT for 1/18/2018 VbBS/HERC meeting materials

KQ3: What are the harms of non-corticosteroid percutaneous or minimally invasive interventions for low back pain? Contextual Questions 1: Does the use of these therapies affect subsequent use of health care resources? 2: How would availability of these therapies affect the need for imaging to determine appropriate candidates for these interventions? Search Strategy A full search of the core sources was conducted to identify systematic reviews, meta-analyses, technology assessments, and clinical practice guidelines using terms for the interventions. Searches of core sources were limited to citations published after 2012. The core sources searched included: Agency for Healthcare Research and Quality (AHRQ) Blue Cross/Blue Shield Health Technology Assessment (HTA) program BMJ Clinical Evidence Canadian Agency for Drugs and Technologies in Health (CADTH) Cochrane Library (Wiley Interscience) Hayes, Inc. Institute for Clinical and Economic Review (ICER) Medicaid Evidence-based Decisions Project (MED) National Institute for Health and Care Excellence (NICE) Tufts Cost-effectiveness Analysis Registry Veterans Administration Evidence-based Synthesis Program (ESP) Washington State Health Technology Assessment Program

A MEDLINE® search was also conducted to identify systematic reviews, meta-analyses, and technology assessments. The search was limited to publications in English published since 2012. In addition, a MEDLINE® search was conducted for randomized controlled trials published after the search dates of the most recent systematic review selected for each intervention. Searches for clinical practice guidelines were limited to those published since 2012. A search for relevant clinical practice guidelines was also conducted, using the following sources: Australian Government National Health and Medical Research Council (NHMRC) Centers for Disease Control and Prevention (CDC) – Community Preventive Services Choosing Wisely Institute for Clinical Systems Improvement (ICSI) National Guidelines Clearinghouse New Zealand Guidelines Group NICE Scottish Intercollegiate Guidelines Network (SIGN) United States Preventive Services Task Force (USPSTF) Veterans Administration/Department of Defense (VA/DOD)

37 Low Back Pain: Minimally Invasive and Non-Corticosteroid Percutaneous Interventions DRAFT for 1/18/2018 VbBS/HERC meeting materials

Inclusion/Exclusion Criteria Studies were excluded if they were not published in English, did not address the scope statement, or were study designs other than systematic reviews, meta-analyses, technology assessments, or clinical practice guidelines.

Interventions Not Reviewed Several interventions were originally included in the scope, but later excluded to best utilize resources because most other payers do not cover the procedures for reasons of experimental status or insufficient evidence. These procedures are botulinum toxin injection, coblation nucleoplasty, prolotherapy, intradiscal electrothermal therapy, and percutaneous intradiscal radiofrequency thermocoagulation. In addition, other interventions were included in the search, but no systematic reviews were found. These procedures are trigger point injections, spinal cord stimulators, medial branch blocks, and sacroiliac joint injections.

38 Low Back Pain: Minimally Invasive and Non-Corticosteroid Percutaneous Interventions DRAFT for 1/18/2018 VbBS/HERC meeting materials

APPENDIX D. APPLICABLE CODES CODES DESCRIPTION CPT Codes Percutaneous laminotomy/laminectomy (interlaminar approach) for decompression of neural elements, (with or without ligamentous resection, discectomy, facetectomy 0275T and/or foraminotomy), any method, under indirect image guidance (e.g., fluoroscopic, CT), single or multiple levels, unilateral or bilateral; lumbar 22899 Unlisted procedure, spine Percutaneous aspiration within the nucleus pulosus, intervertebral disc, or 62267 paravertebral tissue for diagnostic purposes Decompression procedure, percutaneous, of nucleus pulposus of intervertebral disc, 62287 any method, single or multiple levels, lumbar (e.g., manual or automated percutaneous discectomy, percutaneous laser discectomy) Injection procedure for chemonucleolysis, including discography, intervertebral disc, 62292 single or multiple levels, lumbar Endoscopic decompression of spinal cord, nerve root(s), including laminotomy, partial 62380 facetectomy, foraminotomy, discectomy and/or excision of herniated intervertebral disc, 1 interspace, lumbar Destruction by neurolytic agent, paravertebral facet joint nerve(s), with imaging 64635 guidance (fluoroscopy or CT); lumbar or sacral, single facet joint … each additional facet joint (List separately in addition to code for primary 64636 procedure) Unlisted procedure, nervous system (applies to the nerve root and not the 64999 musculoskeletal system) HCPCS Level II Codes Decompression procedure, percutaneous, of nucleus pulposus of intervertebral disc, S2348 using radiofrequency energy, single or multiple levels, lumbar

39 Low Back Pain: Minimally Invasive and Non-Corticosteroid Percutaneous Interventions DRAFT for 1/18/2018 VbBS/HERC meeting materials

CG-Low Back Pain-Minimally Invasive and Non-Corticosteroid Percutaneous Interventions Question: How should the Coverage Guidance - Minimally Invasive and Non-Corticosteroid Percutaneous Interventions for Low Back Pain – be applied to the Prioritized List?

Question source: Evidence-based Guidelines Subcommittee (EbGS)

Issue: EbGS has developed a draft Coverage Guidance on Minimally invasive and non- corticosteroid percutaneous interventions.

This is one of a series of back pain Coverage Guidances HERC has completed:  Advanced Imaging for Low Back Pain (2012)  Non-pharmacologic, non-invasive interventions (2014)  Pharmacologic and Herbal Therapies (2014)  Lumbar Discography (2014)  Artificial Disk Replacement (2014)  Percutaneous Interventions for Low Back Pain (2014)  Vertebroplasty, Kyphoplasty, and Sacroplasty (2016)  Corticosteroid injections (2017)

The Coverage Guidance reviewed minimally invasive discectomy, percutaneous laser decompression, ozone therapy injections, and radiofrequency denervation. The draft box language is as follows:

HERC Coverage Guidance Minimally invasive discectomy is recommended for coverage as an alternative to microdiscectomy or open discectomy, when discectomy is indicated (weak recommendation). The following are not recommended for coverage for low back pain:  Percutaneous laser disc decompression (strong recommendation)  Ozone therapy injections (strong recommendation)  Radiofrequency denervation (weak recommendation)

The greatest debate was around radiofrequency denervation. A deeper evidence dive was performed following testimony from OHSU pain physicians about the need to identify a subgroup of patients for which this was felt to be effective. Additional evidence was reviewed and EbGS deliberated about consideration of coverage for a highly selected subgroup, but the final EbGS decision was to make a weak recommendation against coverage.

Current Prioritized List Status

CG-Low Back Pain-Minimally Invasive and Non-Corticosteroid Percutaneous Interventions, Issue #1207 Page 1 CG-Low Back Pain-Minimally Invasive and Non-Corticosteroid Percutaneous Interventions Line: 346 Condition: CONDITIONS OF THE BACK AND SPINE WITH URGENT SURGICAL INDICATIONS (See Guideline Notes 37,60,64,65,100,101) Treatment: SURGICAL THERAPY ICD-10: G83.4,M43.10-M43.19,M47.011-M47.27,M48.00-M48.05,M48.061-M48.08,M50.00-M50.01,M50.020-M50.11, M51.04-M51.17,M53.2X1-M53.2X9,M54.10-M54.18,Q06.8,Q76.2 CPT: 20660-20665,20930-20938,21720,21725,22206-22226,22532-22865,29000-29046,29710,29720,62287,63001- 63091,63170,63180-63200,63270-63273,63295-63610,63650,63655,63685,93792,93793,96150-96155,97110- 97124,97140-97168,97530,97535,98966-98969,99051,99060,99070,99078,99184,99201-99239,99281-99285, 99291-99404,99408-99449,99468-99480,99487,99489,99495,99496,99605-99607 HCPCS: G0157-G0160,G0248-G0250,G0396,G0397,G0406-G0408,G0425-G0427,G0463-G0467,G0508-G0511,G0513, G0514,S2350,S2351

Line: 527 Condition: CONDITIONS OF THE BACK AND SPINE WITHOUT URGENT SURGICAL INDICATIONS (See Guideline Notes 37,60,64,65,100,101,161) Treatment: SURGICAL THERAPY ICD-10: G95.0,M40.00-M40.15,M40.202-M40.57,M42.00-M42.9,M43.00-M43.28,M43.8X1-M43.8X9,M45.0-M45.9, M46.1,M46.40-M46.99,M47.20-M47.28,M47.811-M47.9,M48.00-M48.05,M48.061-M48.19,M48.30-M48.38, M48.8X1-M48.9,M49.80-M49.89,M50.10-M50.11,M50.120-M50.93,M51.14-M51.9,M53.80-M53.9,M54.10- M54.18,M96.1-M96.4,M99.20-M99.79,Q06.0-Q06.3,Q06.8-Q06.9,Q76.0-Q76.2,Q76.411-Q76.49,S13.0XXA- S13.0XXD,S23.0XXA-S23.0XXD,S23.100A-S23.100D,S23.110A-S23.110D,S23.120A-S23.120D,S23.122A-S23.122D, S23.130A-S23.130D,S23.132A-S23.132D,S23.140A-S23.140D,S23.142A-S23.142D,S23.150A-S23.150D,S23.152A- S23.152D,S23.160A-S23.160D,S23.162A-S23.162D,S23.170A-S23.170D,S33.0XXA-S33.0XXD,S33.100A-S33.100D, S33.110A-S33.110D,S33.120A-S33.120D,S33.130A-S33.130D,S33.140A-S33.140D,S34.3XXA-S34.3XXD CPT: 20610,20660-20665,20930-20938,21720,21725,22206-22226,22532-22865,27035,27096,27279,29000-29046, 29710,29720,62287,62322,62323,63001-63091,63170,63173-63200,63270-63273,63295-63610,63650,63655, 63685,64483,64484,64493-64495,93792,93793,96150-96155,97110-97124,97140-97168,97530,97535,98966- 98969,99051,99060,99070,99078,99184,99201-99239,99281-99285,99291-99404,99408-99449,99468-99480, 99487,99489,99495,99496,99605-99607 HCPCS: G0157-G0160,G0248-G0250,G0260,G0396,G0397,G0406-G0408,G0425-G0427,G0463-G0467,G0508-G0511, G0513,G0514,S2350,S2351

GUIDELINE NOTE 37, SURGICAL INTERVENTIONS FOR CONDITIONS OF THE BACK AND SPINE OTHER THAN SCOLIOSIS Lines 346,527 Spine surgery is included on Line 346 only in the following circumstances: A) Decompressive surgery is included on Line 346 to treat debilitating symptoms due to central or foraminal spinal stenosis, and only when the patient meets the following criteria: 1) Has MRI evidence of moderate or severe central or foraminal spinal stenosis AND 2) Has neurogenic claudication OR 3) Has objective neurologic impairment consistent with the MRI findings. Neurologic impairment is defined as objective evidence of one or more of the following: a) Markedly abnormal reflexes b) Segmental muscle weakness c) Segmental sensory loss d) EMG or NCV evidence of nerve root impingement e) Cauda equina syndrome f) Neurogenic bowel or bladder g) Long tract abnormalities Foraminal or central spinal stenosis causing only radiating pain (e.g. radiculopathic pain) is included only on Line 527.

B) Spinal fusion procedures are included on Line 346 for patients with MRI evidence of moderate or severe central spinal stenosis only when one of the following conditions are met: 1) spinal stenosis in the cervical spine (with or without spondylolisthesis) which results in objective neurologic impairment as defined above OR 2) spinal stenosis in the thoracic or lumbar spine caused by spondylolisthesis resulting in signs and symptoms of neurogenic claudication and which correlate with xray flexion/extension films showing at least a 5 mm translation OR 3) pre-existing or expected post-surgical spinal instability (e.g. degenerative scoliosis >10 deg, >50% of facet joints per level expected to be resected)

For all other indications, spine surgery is included on Line 527. CG-Low Back Pain-Minimally Invasive and Non-Corticosteroid Percutaneous Interventions, Issue #1207 Page 2

CG-Low Back Pain-Minimally Invasive and Non-Corticosteroid Percutaneous Interventions

The following interventions are not included on these lines due to lack of evidence of effectiveness for the treatment of conditions on these lines, including cervical, thoracic, lumbar, and sacral conditions:  prolotherapy  local injections  botulinum toxin injection  intradiscal electrothermal therapy  therapeutic medial branch block  coblation nucleoplasty  percutaneous intradiscal radiofrequency thermocoagulation  radiofrequency denervation  corticosteroid injections for cervical pain

Corticosteroid injections for low back pain with or without radiculopathy are only included on Line 527.

The development of this guideline note was informed by HERC coverage guidances on Percutaneous Interventions for Low Back Pain, Percutaneous Interventions for Cervical Spine Pain and Low Back Pain: Corticosteroid Injections. See http://www.oregon.gov/oha/HPA/CSI-HERC/Pages/Evidence-based-Reports.aspx.

CODES DESCRIPTION CPT Codes Placement on the Prioritized List Percutaneous laminotomy/laminectomy Not on Prioritized List (interlaminar approach) for decompression of neural elements, (with or without ligamentous 0275T resection, discectomy, facetectomy and/or foraminotomy), any method, under indirect image guidance (e.g., fluoroscopic, CT), single or multiple levels, unilateral or bilateral; lumbar 22899 Unlisted procedure, spine Ancillary Percutaneous aspiration within the nucleus Diagnostic 62267 pulosus, intervertebral disc, or paravertebral tissue for diagnostic purposes 346 Conditions of back and spine Decompression procedure, percutaneous, of with urgent surgical indications nucleus pulposus of intervertebral disc, any 361 Scoliosis 62287 method, single or multiple levels, lumbar (e.g., 527 Conditions of the back and manual or automated percutaneous discectomy, spine without urgent surgical percutaneous laser discectomy) indications 660 CONDITIONS FOR WHICH CERTAIN INTERVENTIONS ARE Injection procedure for chemonucleolysis, UNPROVEN, HAVE NO 62292 including discography, intervertebral disc, single CLINICALLY IMPORTANT BENEFIT or multiple levels, lumbar OR HAVE HARMS THAT OUTWEIGH BENEFITS Endoscopic decompression of spinal cord, nerve 660 root(s), including laminotomy, partial 62380 facetectomy, foraminotomy, discectomy and/or excision of herniated intervertebral disc, 1 interspace, lumbar Destruction by neurolytic agent, paravertebral 660 64635 facet joint nerve(s), with imaging guidance

CG-Low Back Pain-Minimally Invasive and Non-Corticosteroid Percutaneous Interventions, Issue #1207 Page 3

CG-Low Back Pain-Minimally Invasive and Non-Corticosteroid Percutaneous Interventions CODES DESCRIPTION (fluoroscopy or CT); lumbar or sacral, single facet joint … each additional facet joint (List separately 660 64636 in addition to code for primary procedure) Unlisted procedure, nervous system (applies to Ancillary 64999 the nerve root and not the musculoskeletal system) HCPCS Level II Codes Decompression procedure, percutaneous, of SRNC nucleus pulposus of intervertebral disc, using S2348 radiofrequency energy, single or multiple levels, lumbar

HERC Staff Assessment:  Minimally invasive discectomy – CPT code 62287 is already included on 346, 361, and 527. No change needed.  Ozone therapy injections are not explicitly called out in the guideline. There is no specific CPT code for this. Clarification of intent is indicated.  Radiofrequency denervation is currently non covered, place S2348 on Line 660 (currently listed as SRNC).  Percutaneous laser disc decompression 62287 is currently on 2 funded and 1 unfunded line. These need to be removed and an entry in GN 37 to indicate its non-inclusion.

HERC Staff Recommendations: 1) ADD S2348 Decompression procedure, percutaneous, of nucleus pulposus of intervertebral disc, using radiofrequency energy, single or multiple levels, lumbar to Line 660 (currently on SRNC) 2) REMOVE 62287 Decompression procedure, percutaneous, of nucleus pulposus of intervertebral disc, any method, single or multiple levels, lumbar (e.g., manual or automated percutaneous discectomy, percutaneous laser discectomy) from lines 346, 361, and 527. Place on line 660. 3) Modify Guideline Note 37 as follows:

CG-Low Back Pain-Minimally Invasive and Non-Corticosteroid Percutaneous Interventions, Issue #1207 Page 4

CG-Low Back Pain-Minimally Invasive and Non-Corticosteroid Percutaneous Interventions a) Markedly abnormal reflexes b) Segmental muscle weakness c) Segmental sensory loss d) EMG or NCV evidence of nerve root impingement e) Cauda equina syndrome f) Neurogenic bowel or bladder g) Long tract abnormalities Foraminal or central spinal stenosis causing only radiating pain (e.g. radiculopathic pain) is included only on Line 527.

D) Spinal fusion procedures are included on Line 346 for patients with MRI evidence of moderate or severe central spinal stenosis only when one of the following conditions are met: 1) spinal stenosis in the cervical spine (with or without spondylolisthesis) which results in objective neurologic impairment as defined above OR 2) spinal stenosis in the thoracic or lumbar spine caused by spondylolisthesis resulting in signs and symptoms of neurogenic claudication and which correlate with xray flexion/extension films showing at least a 5 mm translation OR 3) pre-existing or expected post-surgical spinal instability (e.g. degenerative scoliosis >10 deg, >50% of facet joints per level expected to be resected)

For all other indications, spine surgery is included on Line 527.

The following interventions are not included on these lines due to lack of evidence of effectiveness for the treatment of conditions on these lines, including cervical, thoracic, lumbar, and sacral conditions:  prolotherapy  local injections (including ozone therapy injections)  botulinum toxin injection  intradiscal electrothermal therapy  therapeutic medial branch block  coblation nucleoplasty  percutaneous intradiscal radiofrequency thermocoagulation  percutaneous laser disc decompression  radiofrequency denervation  corticosteroid injections for cervical pain

Corticosteroid injections for low back pain with or without radiculopathy are only included on Line 527.

The development of this guideline note was informed by HERC coverage guidances on Percutaneous Interventions for Low Back Pain, Percutaneous Interventions for Cervical Spine Pain, Low Back Pain: Corticosteroid Injections, and Low Back Pain: Minimally Invasive and Non- Corticosteroid Percutaneous Interventions. See http://www.oregon.gov/oha/HPA/CSI- HERC/Pages/Evidence-based-Reports.aspx.

CG-Low Back Pain-Minimally Invasive and Non-Corticosteroid Percutaneous Interventions, Issue #1207 Page 5

Low Back Pain: Minimally Invasive and Non-Corticosteroid Percutaneous Interventions Draft Coverage Guidance for HERC Consideration January 18, 2018

Center For Evidence-based Policy Scope Statement

• Populations – Adults with acute, subacute, or chronic low back pain with or without radiculopathy • Interventions included in evidence review – Minimally invasive discectomy – Percutaneous laser disc decompression – Ozone therapy injections – Radiofrequency denervation

2 Center For Evidence-based Policy Evidence Summary

• We excluded some interventions because of universal non-coverage or lack of systematic reviews • In general, there is a paucity of RCT data to support these interventions • Most trials are small and methodologically limited • Few trials have examined long-term outcomes beyond 12 months • For the interventions for which we can assess outcomes with moderate or low confidence, the benefits may not achieve commonly accepted thresholds of minimal clinically important differences • Adverse events associated with these interventions are inconsistently and sparsely reported in the studies

3 Center For Evidence-based Policy Minimally invasive discectomy

Intervention Description • Disc material is removed with micro-instruments • Can use an endoscope with fluoroscopic guidance as an indirect visualization technique • Automated percutaneous lumbar discectomy: a cannula is inserted into the intervertebral disc space and material is removed • Used as an alternative to microdiscectomy or open discectomy because it is less invasive and less likely to involve cutting/tearing of muscles

4 Center For Evidence-based Policy Minimally invasive discectomy

Benefits and Harms Balance of benefits and harms: Minimally invasive discectomy appears generally non-inferior to open discectomy or microdiscectomy. It has slightly lower improvements in pain and functional outcomes but these do not rise to the level of clinical significance. It decreases the risk of surgical site infections but is associated with a greater number of re-hospitalizations.

5 Center For Evidence-based Policy Minimally invasive discectomy

Guidelines North American Spine Society’s 2014 guideline, An Evidence-Based Clinical Guideline for the Diagnosis and Treatment of Lumbar Disc Herniation with Radiculopathy • Endoscopic percutaneous discectomy and automated percutaneous discectomy may be considered for treatment of lumbar disc herniation with radiculopathy American Society of Interventional Pain Physicians 2013 guideline, An Update of Comprehensive Evidence-Based Guidelines for Interventional Techniques in Chronic Spinal Pain • Evidence for automated percutaneous lumbar discectomy, percutaneous disc decompression, and decompressor use is limited; these procedures are recommended in select cases

6 Center For Evidence-based Policy Minimally invasive discectomy

Payer Policies • Private Payers – Cigna, Moda, and Regence do not cover percutaneous discectomy because the technique is considered investigational – Aetna covers manual or automated percutaneous lumbar discectomy for the treatment of a contained herniated lumbar disc with these conditions: • Have clinical symptoms of radicular pain • Failed six months of conservative management • No previous surgery or chemonucleolysis of the disc • Otherwise candidates for open laminectomy

7 Center For Evidence-based Policy Minimally invasive discectomy

Payer Policies • Washington Medicaid – Covers percutaneous discectomy • Medicare – One Medicare National Coverage Determination to not cover percutaneous disc decompression

8 Center For Evidence-based Policy Minimally invasive discectomy

Resource Allocation: This is a relatively expensive procedure compared to noninvasive treatments of low back pain. It is associated with some harms (increased risk of worse pain and functional outcomes and rehospitalization) but also with lower rates of surgical site infection. The impact on other factors that would affect resource allocation (e.g., hospital length of stay and utilization of other therapies) was not identified.

Values and Preferences: Patients would likely prefer a treatment that offers rapid and sustained relief, but would prefer to avoid treatments that are more invasive or associated with adverse effects. Patients would like to avoid hospitalizations for recurrent disk herniation and surgical site infections. We would expect moderate variability based on patients’ comorbidities and how they weigh treatment failure and infection risk. Less invasive techniques would likely be much more appealing to patients at higher risk of complications such as surgical site infections.

9 Center For Evidence-based Policy Minimally invasive discectomy

Other Considerations: Compared to open discectomy, minimally invasive discectomy is associated with slightly higher mean leg pain intensity at one year (0.13, 95% CI 0.09-0.16) and mean low back pain intensity at 6 months (0.35, 95% CI 0.19-0.51). At 1 year, low back pain intensity was similar (0.19, 95% CI -0.22-0.59).

10 Center For Evidence-based Policy Minimally invasive discectomy

Rationale: We recommend coverage of minimally invasive discectomy as an alternative to open discectomy, when indicated. This recommendation is based on roughly equivalent benefits and a similar risk of an adverse event (although the adverse events are different compared to open discectomy). Patient preferences would be moderately variable depending on patients’ comorbidities and how they would value the tradeoff between a higher surgical failure rate and an improved surgical infection rate. This is a weak recommendation because further evidence could change the recommendation, there is moderate variability in values and preferences, and this is a comparison between subtypes of surgery, rather than against placebo or nonsurgical interventions. DRAFT Coverage Guidance Minimally invasive discectomy is recommended for coverage as an alternative to microdiscectomy or open discectomy, when discectomy is indicated (weak recommendation).

11 Center For Evidence-based Policy Percutaneous laser disc decompression

Intervention Description • A laser fiber is inserted through a needle under local anesthesia • The laser energy is delivered to the herniated nucleus pulposus, which leads to vaporization of the water content of the nucleus pulposus and a change in its protein structure • This causes a disproportionate decrease in intradiscal pressure

12 Center For Evidence-based Policy Percutaneous laser disc decompression

Balance of benefits and harms

• Balance of benefits and harms: We have very low confidence that percutaneous laser discectomy is non-inferior to microdiscectomy with regard to function and may be associated with slightly worse leg pain. The possible benefit of fewer adverse events does not outweigh the much higher harm associated with a need for repeat surgery compared to microdiscectomy.

13 Center For Evidence-based Policy Percutaneous laser disc decompression

Guidelines North American Spine Society’s 2014 guideline, An Evidence-Based Clinical Guideline for the Diagnosis and Treatment of Lumbar Disc Herniation with Radiculopathy • Insufficient evidence to make a recommendation for or against the use of low power laser in the treatment of lumbar disc herniation with radiculopathy American Society of Interventional Pain Physicians 2013 guideline, An Update of Comprehensive Evidence-Based Guidelines for Interventional Techniques in Chronic Spinal Pain • Evidence for percutaneous lumbar laser disc decompression is limited; may be performed when indicated

14 Center For Evidence-based Policy Percutaneous laser disc decompression

Payer Policies • Washington Medicaid – No coverage policy identified • Medicare – No NCD or LCD identified • Private Payers – Aetna, Cigna, Moda, and Regence do not cover percutaneous laser disc decompression because the technique is considered investigational

15 Center For Evidence-based Policy Percutaneous laser disc decompression

Resource Allocation: This is a relatively expensive intervention compared to many other treatments for low back pain.

Values and Preferences: Patients would likely prefer a treatment that offers rapid relief and helps them to avoid additional procedures, but would prefer to avoid treatments that are more invasive or associated with adverse effects. There would likely be low variability in patients’ interest in undergoing this procedure, given the need for additional surgical procedures.

Other Considerations: There were no significant differences in pain between percutaneous laser discectomy and microdiscectomy at 4-, 8-, or 52-week follow-up. At 26 weeks, there was a small benefit in favor of microdiscectomy for VAS back pain score. Overall, VAS leg pain score was better in patients with microdiscectomy (mean difference -6.9, 95% CI 12.6 to -1.3). Time to perceived recovery was slower for laser discectomy.

16 Center For Evidence-based Policy Percutaneous laser disc decompression

Rationale: We recommend against coverage based on the lack of clear benefit, the cost, and uncertainty about harms; it is a strong recommendation because cost is higher, alternatives are available, and the rehospitalization rate is higher.

DRAFT Coverage Guidance Percutaneous laser decompression is not recommended for coverage (strong recommendation).

17 Center For Evidence-based Policy Ozone injections

Intervention Description • Chemonucleolysis involves the injection of a substance into a herniated spinal disc to reduce the size of the disc • Ozone injections are one form of chemonucleolysis involving the release of ozone-oxygen mixture near a spinal disc

18 Center For Evidence-based Policy Ozone injections

Balance of benefits and harms: The benefits of improvement in pain and function over epidural steroid injections might outweigh the harms of rare but serious adverse events. However, the evidence is too limited to confidently support this balance in favor of ozone.

19 Center For Evidence-based Policy Ozone injections

Guidelines North American Spine Society’s 2014 guideline, An Evidence-Based Clinical Guideline for the Diagnosis and Treatment of Lumbar Disc Herniation with Radiculopathy • There is insufficient evidence to recommend for or against intradiscal ozone injections for the treatment of lumbar disc herniation with radiculopathy

20 Center For Evidence-based Policy Ozone injections

Coverage Policies • Washington Medicaid – No coverage policy was identified for ozone injections • Medicare – No NCD or LCD identified • Private payers – Not covered by Aetna, Cigna, Moda, or Regence

21 Center For Evidence-based Policy Ozone injections

Resource Allocation: Intramuscular ozone injection would likely be moderate cost; intradiscal or intraforaminal injection would be significantly higher cost compared with alternative treatments for low back pain.

Other Considerations: A separate May 2017 coverage guidance did not find that epidural steroid injections (the comparator) offered clear clinical benefit. For pain, ozone treatments provided at the level of the herniated disc improved short-and long-term pain relief (OR 2.66, 95% CI 1.94 to 3.63). However, the sham-controlled trial found no statistically significant difference in pain.

22 Center For Evidence-based Policy Ozone injections

Rationale: We recommend against coverage of ozone therapy based on our very low level of confidence of effectiveness, the cost of the intervention, and risk of rare but serious adverse events. It is a strong recommendation because of very limited evidence of benefit and some serious harms.

DRAFT Coverage Guidance Ozone therapy injections are not recommended for coverage for low back pain (strong recommendation).

23 Center For Evidence-based Policy Radiofrequency denervation

Intervention Description • Radiofrequency energy is delivered using an insulated needle to target nerves, which heats and denatures the nerves • Performed under local anesthesia or light sedation • Radiofrequency (RF) treatments commonly target nerves serving the facet joints, discs, and sacroiliac joints

24 Center For Evidence-based Policy Radiofrequency denervation for facet joint arthropathy Balance of benefits and harms: There is limited evidence of benefit on short- and long-term pain, and limited evidence of improved short and long term-function. There are mixed results on whether the functional benefits are clinically important or unimportant. Given that there is insufficient evidence about harms, the balance is neutral to positive.

25 Center For Evidence-based Policy Radiofrequency denervation for facet joint arthropathy

• For radiofrequency ablation for facet joint pain, public commenters stated that many of the studies were not conducted with what are considered optimal techniques nor on appropriately selected subjects • In a limited number of studies, the intervention approximated the techniques and patient selection criteria described as optimal by the public commenters • The subcommittee reviewed these specific studies to determine if sufficient evidence existed to support a subgroup of patients benefitting from the procedure • The subcommittee determined that the evidence did not support benefit in a selected or non-selected population

26 Center For Evidence-based Policy Radiofrequency denervation for facet joint arthropathy Guidelines National Institute for Health and Care Excellence (NICE) 2016 guideline, Low Back Pain and Sciatica • Consider referring patients with chronic low back pain for assessment of radiofrequency when non-surgical treatment has not been effective, medial branch nerve is the source of pain, and the patient has moderate or severe levels of localized back pain American Society of Interventional Pain Physicians 2013 guideline • Conventional radiofrequency denervation is recommended as a therapeutic lumbar/cervical facet joint intervention after diagnosis with diagnostic facet joint blocks

27 Center For Evidence-based Policy Radiofrequency denervation for facet joint arthropathy

Guidelines British Pain Society 2013 guideline, Low Back and Radicular Pain: A Pathway for Care Developed by the British Pain Society • Radiofrequency denervation is recommended for patients with persistent or severe pain in the context of a multidisciplinary treatment approach after the use of medial branch blocks to diagnose pain of facet joint origin

28 Center For Evidence-based Policy Radiofrequency denervation for facet joint arthropathy

Payer Policies • Washington Medicaid – Coverage for facet neurotomy requires: • Medical necessity review by Qualis Health • Patient must fail to respond to a three-month trial of conservative treatment

29 Center For Evidence-based Policy Radiofrequency denervation for facet joint arthropathy

Payer Policies • Six Medicare Local Coverage Determinations to cover radiofrequency denervation, with conditions: – Patients must have experienced at least three months of moderate to severe pain – Patients have failed to respond adequately to conservative treatment – Pain has contributed to functional impairment – Pain must be predominantly axial, not associated with radiculopathy or neurogenic claudication, and of facet joint origin – Procedure repeated only if the patient has experienced at least five to six months of significant pain relief

30 Center For Evidence-based Policy Radiofrequency denervation for facet joint arthropathy

Payer Policies • Private Payers – Aetna, Cigna, and Regence cover non-pulsed radiofrequency facet denervation for certain patients with back pain who have failed a trial of conservative treatment – Moda lists facet denervation as a procedure requiring prior authorization

31 Center For Evidence-based Policy Radiofrequency denervation for facet joint arthropathy

Resource Allocation: This is a relatively expensive intervention compared to other treatments for low back pain. Two separate diagnostic medical branch blocks may be required prior to the procedure, which increases the associated cost.

Values and Preferences: Patients would likely prefer a treatment that offers rapid and sustained relief, but would prefer to avoid treatments that are more invasive or associated with adverse effects. However, patients with chronic debilitating pain may be more willing to accept invasive treatments. We would expect moderate variability in these preferences.

Other Considerations: For pain outcomes, there is mixed evidence: One study showed benefit at one month and another showed no benefit; these studies had opposite results at longer-term follow-up.

Expert and public commenters suggested that the subcommittee focus their examination on studies using more stringent criteria for patient selection.

32 Center For Evidence-based Policy Radiofrequency denervation for facet joint arthropathy

Rationale: We recommend against coverage of radiofrequency denervation for facet joint arthropathy because of very low confidence in its effectiveness for improving pain and function. Given the lack of proven benefit, the relatively high resource allocation, and the availability of alternatives, it is a recommendation against coverage. It is a weak recommendation because of the reported discrepancy between the study inclusion criteria and locally defined optimal patient characteristics that may affect external validity, and the possibility that further studies examining this subgroup may reach different conclusions.

33 Center For Evidence-based Policy Radiofrequency denervation for facet joint arthropathy

DRAFT Coverage Guidance Radiofrequency denervation is not recommended for coverage for the treatment of facet joint arthropathy (weak recommendation).

34 Center For Evidence-based Policy Radiofrequency denervation for discogenic low back pain

Guidelines and other payer policies typically address RF denervation for facet joint pain, not discogenic low back pain.

35 Center For Evidence-based Policy Radiofrequency denervation for discogenic low back pain

Resource Allocation: This is relatively expensive compared to alternate therapies for low back pain. Improved long-term function may be cost- effective.

Values and Preferences: Patients would prefer interventions that result in rapid and sustained improvement in symptoms and less invasive procedures associated with few adverse events. We would expect low variability in these preferences.

Other considerations: For pain outcomes, there was low-quality evidence of no differences in VAS pain scores at up to 6 months. Beyond 6 months, there was moderate-quality evidence of a statistically significant improvement in VAS pain scores for RF treatment over placebo (mean difference -0.8, 95% CI -1.2 to -0.3).

36 Center For Evidence-based Policy Radiofrequency denervation for discogenic low back pain Rationale: We recommend against coverage based on moderate confidence that the benefits of this therapy do not meet commonly accepted thresholds of clinically meaningful differences and the cost. It is a weak recommendation because further evidence could change the recommendation.

DRAFT Coverage Guidance Radiofrequency denervation of lumbar discs is not recommended for coverage for the treatment of discogenic low back pain (weak recommendation).

37 Center For Evidence-based Policy Radiofrequency denervation for sacroiliac joint pain

Balance of benefits and harms: We have very low confidence that short-term function (between one to six months) may be improved. There is insufficient data about adverse effects. Our very low confidence in the evidence makes the balance of benefits and harms uncertain.

Guidelines and other payer policies typically address RF denervation for facet joint pain, not sacroiliac joint pain.

38 Center For Evidence-based Policy Radiofrequency denervation for sacroiliac joint pain

Resource Allocation: This treatment is relatively expensive compared to alternate therapies for low back pain. Improved long-term function may be cost-effective.

Other Considerations: For pain outcomes, there was very low-quality evidence of no differences in VAS pain scores at one month. Between one and six months, there was low-quality evidence of a statistically significant improvement in VAS pain scores for RF treatment over placebo (mean difference -1.3, 95% CI -2.1 to -0.5).

39 Center For Evidence-based Policy Radiofrequency denervation for sacroiliac joint pain

Rationale: We recommend against coverage because of the uncertainty about the benefits, unknown harms, and high associated costs. It is a weak recommendation because further evidence could change the recommendation.

DRAFT Coverage Guidance Radiofrequency denervation for sacroiliac joint pain is not recommended for coverage (weak recommendation).

40 Center For Evidence-based Policy

HERC Coverage Guidance: Low Back Pain: Minimally Invasive and Non-Corticosteroid Percutaneous Interventions Disposition of Public Comments

Table of Contents Commenters...... 1 Public Comments ...... 1 References Provided by Commenters ...... 9

Commenters Identification Stakeholder A David M. Sibell, MD [Submitted September26, 2017] B Belinda Duszynski, Senior Director of Policy and Practice, Spine Intervention Society on behalf of American Academy of Pain Medicine, American Academy of Physical Medicine and Rehabilitation, American College of Radiology, American Pain Society, American Society of Anesthesiologists, American Society of Neuroradiology, American Society of Regional Anesthesia and Pain Medicine, American Society of Spine Radiology, North American Neuromodulation Society, North American Spine Society, Society of Interventional Radiology, Spine Intervention Society [Submitted October 16, 2017]

Public Comments ID/# Comment Disposition A1 I am writing this from the point of view as a physician specializing in Pain Medicine, Thank you for your comments and participation in our and as a taxpayer in the State of Oregon. I am not representing any institution or process. organization with this opinion. As I reflect on the current state of my specialty, with Coverage of pain medicine visits differs throughout the respect to Oregon Health Authority and Health Evidence Review Commission policy state, by plan, and by availability of some of the decisions, I feel the need to point out resultant inconsistencies in my ability to treat interventions (such as pain-focused cognitive behavioral patients covered by Oregon Health Authority. These inconsistencies may not be therapy). Coverage of consultations with a specific provider type (i.e., interventional pain physicians) is

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HERC Coverage Guidance: Low Back Pain: Minimally Invasive and Non-Corticosteroid Percutaneous Interventions Disposition of Public Comments ID/# Comment Disposition evident to other providers, though I suspect that Primary Care Providers attempting to outside of the scope of this coverage guidance. These arrange care for their patients may also be frustrated by them. insights and concerns will be shared with the relevant stakeholders. I should also point out that I have worked with the Evidence-based Guidelines Subcommittee (EbGS) on several occasions, advocating for a reasonable, limited coverage for treatment of patients covered by OHA (similar to that offered patients covered by Medicare in this region). In 2013, I was a consultant to the Subcommittee on cervical interventional procedures. After a detailed and balanced review period, we crafted a recommendation that would have allowed some patients access to treatment, based on strict criteria. After the Subcommittee submitted this recommendation, subsequent processing within the HERC system led to denial of all coverage for these treatments. In the most recent deliberations over treatments for low back pain, the EbGS elected to deny coverage for all treatments we might offer that were considered. Effectively, this has removed any of the treatments that we would be able to offer patients, which would require a Pain Medicine Medical Doctor’s contribution. The medications that might be applicable are all handled by Primary Care Providers, and do not require our input (or, in the case of opioid use disorder, which is often referred to Pain Medicine specialists, may actually require the treatment of a chemical dependence specialist). The Complementary and Alternative Medicine practices that are approved by OHA do not require evaluation by or referral from a Pain Medicine specialist. In the EbGS’s latest deliberations, there was mention of future study in the area of the treatment of low back pain, specifically one study at Johns Hopkins. However, reviewing the details of this study (available here), it appears that it is fairly open- ended, and is an observational cohort, not a prospective randomized controlled trial. This trial is not likely to contribute in a meaningful way to this debate.

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HERC Coverage Guidance: Low Back Pain: Minimally Invasive and Non-Corticosteroid Percutaneous Interventions Disposition of Public Comments ID/# Comment Disposition The current OHA policy allows for patients to have a one-time referral to a Pain Medicine specialist, which can be repeated every 3 years. We are not allowed to provide any treatments to patients and can only make recommendations to Primary Care Providers, usually for other treatments that OHA does not cover, or treatments that the Primary Care Providers could have provided on their own, without our input (e.g., “try gabapentin”). This often results in extremely dissatisfied patients, some of whom are referred specifically for treatments that the referring providers know OHA prevents us from offering. These patients are already economically stressed, and they have had to arrange and pay for transportation, childcare, missing work, and other expenses just to get to their appointment. For them to walk away with no new treatment options is extremely disappointing and a major waste of their already stressed resources. Almost every meeting with these patients results in their dissatisfaction with walking out of the clinic with somewhere between zero and not much value added to their care. As far as I am aware, there is no evidence in the peer reviewed literature supporting sending Oregon patients, insured by Medicaid, to seek care by Pain Medicine specialists. The current strategy appears to offer patients care by the specialty of Pain Medicine, but in reality, all the treatments that we could offer are either already available to Primary Care Providers, without our involvement, (e.g., acupuncture, generic medications) or not available to the patients, at all. With this in mind, I request that the EbGS end coverage for consultations with Pain Medicine specialists for OHA-covered patients. The current state is completely dysfunctional and results in significant patient dissatisfaction. Because no actual treatment can ensue, it is a waste of taxpayer money to have these consultations in the first place. I have already stated that it is a waste of patient resources. OHA has set up a system that does not allow for Pain Medicine specialists to offer treatment, or

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HERC Coverage Guidance: Low Back Pain: Minimally Invasive and Non-Corticosteroid Percutaneous Interventions Disposition of Public Comments ID/# Comment Disposition from a value-based point of view, to offer value to the customer (patient). By preventing any of the treatments we offer, and through a policy that prevents us from seeing patients more than once every three years, these consultation are an exercise in utter futility. In that case, it is not rational to continue to cause patients covered by OHA to have Pain Medicine consultations. Hopefully, EbGS (and later, the Value-based Benefits Subcommittee) will remain consistent with its policy determinations on spinal procedures and focus only on the peer-reviewed literature surrounding Pain Medicine consultations for Oregon patients covered by Medicaid. There are no prospective randomized controlled trials supporting this practice. There is no value to the patients or the system to the current practice. If all the tools that we would use for other patients are unavailable to these patients, and if the direction OHA is heading with treating chronic pain is away from allopathic medicine, and if there is no perceived value from the treatments that Pain Medicine specialists offer, there is no rational explanation for continuing this practice. If we cannot participate in patients’ care in a meaningful way, we should not be asked to do so in a way that is without meaning. Since there is no evidence that supports one-time consultations resulting in no form of specialty treatment, EbGS should make a strong recommendation, based on the absence of any positive evidence, to stop this practice. If the Subcommittee conducts as rigorous an analysis of this system as it has with the treatments recently reviewed, it will find that the current state of Pain Medicine consultation policy does not meet the Subcommittee’s standards for coverage. This will end the waste of patient resources and hope, and taxpayer money, funding these futile consultations. I should also mention that, at the same time that I am writing this, I am continuing to advocate for patients’ access to chronic pain therapy by participating in the HERC Chronic Pain Task Force. This entity is seeking to find ways to treat chronic pain that

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HERC Coverage Guidance: Low Back Pain: Minimally Invasive and Non-Corticosteroid Percutaneous Interventions Disposition of Public Comments ID/# Comment Disposition OHA does not currently allow. If the deliberations of this body should include any of the treatments that my specialty offers, that would certainly change my point of view. However, it seems somewhat unlikely that this will be the case, and in any event, would occur long after the period of public input to this recommendation. Therefore, I am submitting this request during the period of response that is available. B1 Surely significant relief of pain, with restoration of function and return to work, as well Thank you for your comments. as decreased utilization of other healthcare resources is an outcome that you do not want to deny to patients covered by the Oregon Health Authority. Those outcomes can be achieved by the responsible application of lumbar medial branch thermal radiofrequency neurotomy (LMBTRFN) when performed correctly for appropriately selected patients. B2 The recently published systematic review by Maas et al.1 poorly serves the needs of The subcommittee heard extensive testimony relating to payers and patients because it does not consider correct performance or appropriate the limitations of studies included in the Maas review, patient selection for LMBTRFN. While such reports apply the basic requirements of particularly as they pertain to patient selection and systematic reviews, their depiction of the evidence is flawed due to lack of insight into procedural technique. As a result of this testimony, the these critical clinical practice parameters inherent to the procedures being assessed. subcommittee requested additional details on specific The literature on facet RFN must be meticulously stratified by technique, selection, trials. and outcome. Based on testimony establishing that the optimal selection For a variety of reasons, practitioners use different techniques (e.g., LMBTRFN, pulsed and technique was described by Dreyfuss in 2000, the RF), yet call their procedure by the same name. These procedures are not the same subcommittee considered the studies by Tekin (2007), and must be assessed separately. Likewise, different clinical conditions result in Nath (2008), and Lakemeier (2013) in greater depth. Most different targets (e.g. medial branch nerves, dorsal root ganglion, sacroiliac joint) and attention was focused on a review of the data from Nath must be assessed separately. Hereafter, our comments focus solely on evidence because it most closely approximated the details of the addressing LMBTRFN technique, selection, and outcome. Dreyfuss study. The subcommittee expressed concern about the small size and single center/single operator

design of the Nath trial, in addition to differences between Comments received 9/15/2017 to 10/17/2017 Page 5 Center for Evidence-based Policy

HERC Coverage Guidance: Low Back Pain: Minimally Invasive and Non-Corticosteroid Percutaneous Interventions Disposition of Public Comments ID/# Comment Disposition Technique the experimental and control groups in baseline pain scores. The subcommittee considered the outcomes For facet RFN to have face validity the electrode must be accurately placed for the reported here, but raised further concern that these resulting thermal lesion to optimally capture the target nerve. Basic science studies differences might not be clinically important. Questions indicate that lesions from perpendicular electrode placements can fail to capture the were also raised about the large number of patients who target nerve while lesions from parallel electrode placements are more likely to obtained prolonged pain relief from their diagnostic block. capture the target nerve and to do so along a substantial length of the nerve.2-5 Thus, In the Tekin trial, the subcommittee believed that the the orientation of the electrode is likely to be pivotal to clinical outcome, with differences in pain relief and Oswestry Disability Index perpendicular placements expected to have lower success rates and shorter durations between groups, although statistically significant, might of effect compared to parallel placements with greater success rates for longer not rise to a level of clinical significance. periods. Indeed, this is borne out in the literature. Several RCTs do not qualify as providing evidence of efficacy because their active treatment arm lacked face validity The subcommittee considered an option for coverage that by using the insufficient perpendicular technique.6-8 Censoring these studies leaves was similar to the criteria outlined in the Noridian Local only those of Nath 2008, Tekin 2007, and van Kleef 1999 eligible to provide evidence.9- Coverage Determination. 11 Citations 22 and 23 are not randomized controlled trials, Tekin showed statistically significant differences in favor of active RFN at six months and therefore were not considered by the subcommittee and at one year for group scores for back pain and for disability, with a significantly except to help establish the optimal patient selection and greater proportion of patients reporting an excellent outcome.10 Nath showed a procedural techniques. difference in favor of facet RFN that was significant for relief of leg pain, global The subcommittee acknowledges the limitations of the perceived effect, and consumption of analgesics, although not for relief of back pain evidence, particularly the small number of RCTs that have at six months.9 For the relief of back pain, van Kleef showed a difference in favor of been conducted using the optimal selection and procedural RFN that was not significant statistically, but survival analysis showed a statistically techniques. The subcommittee’s choice of a weak significant greater success rate from three months to one year after facet RFN.11 recommendation reflects very low confidence in the Selection estimates of effect and the likelihood that additional well- conducted RCTs could change that estimate. The guidelines cited in your report, and others, specify that LMBTRFN only be considered when other non-surgical treatments have proven ineffective. Thus, your

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HERC Coverage Guidance: Low Back Pain: Minimally Invasive and Non-Corticosteroid Percutaneous Interventions Disposition of Public Comments ID/# Comment Disposition claim about existing treatment alternatives ignores the clinical circumstances of these The HERC does support interventions that have been patients. Fortunately, useful criteria for appropriate patient selection exist, such as proven to offer significant benefit to patients. The evidence the Noridian Local Coverage Determination (LCD)12 (which covers Medicare patients in reviewed for radiofrequency neurotomy did not show, on Oregon and is consistent with LCDs applied across the United States) and the North balance, that it would result in a clinically important American Spine Society’s Facet Joint Interventions Coverage Policy improvement in pain or function. Recommendations.13 Both address appropriate patient selection for LMBTRFN, as supported by the scientific literature and originating from consensus recommendations of the spine care and interventional pain community. In brief, sufficient pain relief following appropriately performed diagnostic medial branch nerve blocks determines patient selection for LMBTRFN. Low amounts of pain relief following a block, or a patient’s response to a single diagnostic block are unacceptable selection methods due to high false-positive rates. Specifically, the single block false- positive rate is between 25-45%, and this is significantly reduced by performance of a second comparative block.14-21 Both of the benchmark studies of LMBTRFN used appropriate patient selection and treatment technique; 22,23 selection was based on a minimum of 80% relief following comparative local anesthetic blocks. Both studies achieved the best results heretofore reported in the literature. The first study reported 60% of patients maintaining at least 80% relief for 12 months.22 The second study reported complete relief of pain for at least 6 months in 55% of patients, accompanied by restoration of function, return to work, and no need for other health care, for a median duration of 15 months per treatment.23 The results of these two studies illustrate what can be achieved by LMBTRFN if performed correctly and in appropriately selected patients. In both instances the technique used for LMBTRFN was that recommended by current LCDs and supported by broad consensus.12,13 An impressive 55-60% of patients experience at least 80% Comments received 9/15/2017 to 10/17/2017 Page 7 Center for Evidence-based Policy

HERC Coverage Guidance: Low Back Pain: Minimally Invasive and Non-Corticosteroid Percutaneous Interventions Disposition of Public Comments ID/# Comment Disposition pain relief. No other intervention of any kind, for any form of back pain, provides this size of effect at this level of success. Outcomes The outcomes of facet RFN should be quantified in several domains:  Success rate: the proportion of patients who achieve a successful outcome  Degree of relief that constitutes success  Duration of relief  Corroboration of relief by improvements in critical domains such as restoration of function, return to work, and use of other health care Based on the most rigorous studies using appropriate diagnostic techniques to select patients and using optimal treatment techniques of LMBTRFN,  Over 50% of patients treated with LMBTRFN can expect to achieve 80-100% relief of pain,22,23 accompanied by restoration of activities of daily living, resumption of work, and no need for other health care for their back pain, for a median duration of 15 months, with an interquartile range of 10-28 months.23  In the event of recurrence of pain, complete relief can be reinstated by repeating the treatment.23 Surely OHA would support practices that achieve such outcomes and would ensure that they are available to patients.

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HERC Coverage Guidance: Low Back Pain: Minimally Invasive and Non-Corticosteroid Percutaneous Interventions Disposition of Public Comments

References Provided by Commenters ID/# References B 1. Maas ET, Ostelo RW, Niemisto L, Jousimaa J, Hurri H, Malmivaara A, van Tulder MW. Radiofrequency denervation for chronic low back pain. Cochrane Database Syst Rev 2015;(10), CD008572. 2. International Spine Intervention Society. Lumbar medial branch thermal radiofrequency neurotomy. In: Bogduk N (ed). Practice Guidelines for Spinal Diagnostic and Treatment Procedures, 2nd edn. International Spine Intervention Society, San Francisco, 2013:601-641. 3. Lau P, Mercer S, Govind J, Bogduk N. The surgical anatomy of lumbar medial branch neurotomy (facet denervation). Pain Med 2004; 5:289-298. 4. Bogduk N, Macintosh J, Marsland A. A technical limitation to efficacy of radiofrequency neurotomy for spinal pain. Neurosurgery 1987; 20:529-535. 5. Feigl GC, Dreu M, Kastner M, Rosmarin W, Ulz H, Kniesel B, Likar R. Thermocoagulation of the medial branch of the dorsal branch of the lumbar spinal nerve: fluoroscopy versus CT. Pain Med 2017;18:36-40. 6. Gallagher J, Petriccione di Valdo PL, Wedley JR, Hamann W, Ryan P, Chikanza I, Kirkham B, Price R, Watson MS, Grahame R, Wood S. Radiofrequency facet joint denervation in the treatment of low back pain: a prospective controlled double-blind study to assess its efficacy. The Pain Clinic 1994; 7:193-198. 7. Leclaire R, Fortin L, Lambert R, Bergeron YM, Rossignol M. Radiofrequency facet joint denervation in the treatment of low back pain: a placebo-controlled clinical trial to assess efficacy. Spine 2001; 26:1411-1416. 8. van Wijk RMA, Geurts JWM, Wynne HJ, Hammink E, Buskens E, Lousberg R, Knape JTA, Groen GJ. Radiofrequency denervation of lumbar facet joints in the treatment of chronic low back pain. A randomized, double-blind sham lesion-controlled trial. Clin J Pain 2004; 21:335-344. 9. Nath S, Nath CA, Pettersson K. Percutaneous lumbar zygapophysial (Facet) joint neurotomy using radiofrequency current, in the management of chronic low back pain: A randomized double-blind trial. Spine 2008; 33:1291-7. 10. Tekin I, Mirzai H, Ok G, Erbuyun K, Vatansever D. A comparison of conventional and pulsed radiofrequency denervation in the treatment of chronic facet joint pain. Clin J Pain 2007; 23524-9. 11. Lakemeier S, Lind M, Schultz W, Fuchs-Winkelmann S, Timmesfeld N, Foelsch C, Peterlain CD. A comparison of intraarticular lumbar facet joint steroid injections and lumbar facet joint radiofrequency denervation in the treatment of low back pain: A randomized, controlled, double-blind trial. Anesth Analg 2013; 117:228-235. 12. Noridian Healthcare Solutions, LLC. Local Coverage Determination (L34955): Facet Joint Injections, Medial Branch Blocks, and Facet Joint Radiofrequency Neurotomy. 13. North American Spine Society. Coverage Policy Recommendations: Facet Joint Interventions. 2016. https://www.spine.org/PolicyPractice/CoverageRecommendations/PayorAccess.aspx 14. Barnsley L, Lord S, Bogduk N. Comparative local anaesthetic blocks in the diagnosis of cervical zygapophysial joint pain. Pain 1993; 55:99-106. 15. Lord SM, Barnsley L, Bogduk N. The utility of comparative local anaesthetic blocks versus placebo-controlled blocks for the diagnosis of cervical zygapophysial joint pain. Clin J Pain 1995; 11:208-213.

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HERC Coverage Guidance: Low Back Pain: Minimally Invasive and Non-Corticosteroid Percutaneous Interventions Disposition of Public Comments ID/# References 16. Schwarzer AC, Aprill CN, Derby R, Fortin J, Kine G, Bogduk N. The false-positive rate of uncontrolled diagnostic blocks of the lumbar zygapophysial joints. Pain 1994; 58:195-200. 17. Manchikanti L, Pampati V, Fellows B, Bakhit CE. Prevalence of lumbar facet joint pain in chronic low back pain. Pain Physician 1999; 2:59‐64. 18. Manchikanti L, Pampati V, Fellows B, Bakhit CE. The diagnostic validity and therapeutic value of lumbar facet joint nerve blocks with or without adjuvant agents. Curr Rev Pain 2000; 4:337-44. 19. Manchikanti L, Boswell MV, Singh V, Pampati V, Damron KS, Beyer CD. Prevalence of facet joint pain in chronic spinal pain of cervical, thoracic, and lumbar regions. BMC Musculoskeletal Disorders 2004; 5:15. 20. Manchukonda R, Manchikanti KN, Cash KA, Pampati V, Manchikanti L. Facet joint pain in chronic spinal pain: an evaluation of prevalence and false-positive rate of diagnostic blocks. J Spinal Disord Tech 2007; 20:539-545. 21. Barnsley L, Lord S, Wallis B, Bogduk N. False-positive rates of cervical zygapophysial joint blocks. Clin J Pain 1993; 9:124-130. 22. Dreyfuss P, Halbrook B, Pauza K, Joshi A, McLarty J, Bogduk N. Efficacy and validity of radiofrequency neurotomy for chronic lumbar zygapophysial joint pain. Spine 2000; 25:1270-1277. 23. MacVicar J, Borowczyk JM, MacVicar AM, Loughnan BM, Bogduk N. Lumbar medial branch radiofrequency neurotomy in New Zealand. Pain Med 2013; 14:639- 645.

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Section 4.0 Coverage Guidances

Health Evidence Review Commission (HERC) Coverage Guidance: Gene Expression Profiling for Prostate Cancer DRAFT for 1/18/2018 VbBS/HERC meeting materials

HERC Coverage Guidance Gene expression profiling tests for prostate cancer (including Prolaris, Oncotype DX, and Decipher) are not recommended for coverage (strong recommendation).

Note: Definitions for strength of recommendation are in Appendix A. GRADE Informed Framework Element Description.

Table of Contents

HERC Coverage Guidance ...... 1 Rationale for development of coverage guidances and multisector intervention reports ...... 3 GRADE-Informed Framework ...... 4 Should gene expression profiling tests be recommended for coverage for prostate cancer? ...... 4 Clinical Background ...... 7 Indications ...... 8 Technology Description ...... 8 Evidence Review ...... 8 Prolaris ...... 8 Oncotype Dx Prostate ...... 10 Decipher ...... 13 Evidence Summary ...... 15 Policy Landscape ...... 16 Payer Coverage Policies ...... 16 Professional Society Guidelines ...... 17 Quality Measures ...... 18 References ...... 19 Evidence Sources ...... 19 Other Citations ...... 20 Appendix A. GRADE-Informed Framework Element Descriptions ...... 23 Appendix B. GRADE Evidence Profile ...... 25 Appendix C. Methods ...... 26 Scope Statement ...... 26 Search Strategy ...... 26 Appendix D. Applicable Codes ...... 28

2 │ Gene Expression Profiling for Prostate Cancer DRAFT for 1/18/2018 VbBS/HERC meeting materials

Rationale for development of coverage guidances and multisector intervention reports Coverage guidances are developed to inform coverage recommendations for public and private health plans in Oregon as plan administrators seek to improve patient experience of care, population health, and the cost-effectiveness of health care. In the era of public and private sector health system transformation, reaching these goals requires a focus on maximizing the benefits and minimizing the harms and costs of health interventions. Multisector intervention reports will be developed to address these population-based health interventions or other types of interventions that occur outside of the typical clinical setting. HERC uses the following principles in selecting topics for its reports to guide public and private payers:

 Represents a significant burden of disease or health problem  Represents important uncertainty with regard to effectiveness or harms  Represents important variation or controversy in implementation or practice  Represents high costs or significant economic impact  Topic is of high public interest HERC bases its reports on a review of the best available research applicable to the intervention(s) in question. For coverage guidances, which focus on clinical interventions and modes of care, evidence is evaluated using an adaptation of the GRADE methodology. For more information on coverage guidance methodology, see Appendix A. Multisector interventions can be effective ways to prevent, treat, or manage disease at a population level. In some cases, HERC has reviewed evidence and identified effective interventions, but has not made formal coverage recommendations when these policies are implemented in settings other than traditional health care delivery systems because effectiveness may be dependent on the environment in which the intervention is implemented.

3 │ Gene Expression Profiling for Prostate Cancer DRAFT for 1/18/2018 VbBS/HERC meeting materials

GRADE-Informed Framework HERC develops recommendations by using the concepts of the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. GRADE is a transparent and structured process for developing and presenting evidence and for performing the steps involved in developing recommendations. The table below lists the elements that determine the strength of a recommendation. HERC reviews the evidence and makes an assessment of each element, which in turn is used to develop the recommendations presented in the coverage guidance box. Estimates of effect are derived from the evidence presented in this document. Assessments of confidence are from the published systematic reviews and meta-analyses, where available and judged to be reliable. In some cases, no systematic reviews or meta-analyses encompass the most current literature. In those cases, HERC may describe the additional evidence or alter the assessments of confidence in light of all available information. Such assessments are informed by clinical epidemiologists from the Center for Evidence-based Policy. Unless otherwise noted, estimated resource allocation, values and preferences, and other considerations are assessments of HERC.

Should gene expression profiling tests be recommended for coverage for prostate cancer? Estimate of Effect for Outcome/ Values and Other Outcomes Resource Allocation Confidence in Estimate Preferences Considerations Prostate cancer Insufficient data In light of the Men with prostate There was extensive mortality prevalence of localized cancer would highly industry (Critical outcome) prostate cancer in US value testing that involvement in the men, utilization of allows them to sponsorship of the Prostate cancer Insufficient data Prolaris or Oncotype avoid unnecessary studies available for morbidity DX in such cases would invasive treatments review of these (Critical outcome) add significant cost. To if they are at low tests, and many of Quality of life Insufficient data the extent that reliance risk for progression, the authors (Important on these tests results in or to avoid the risks disclosed financial outcome) increased active of watchful waiting or other conflicts of Change in Mainly indirect evidence from observational surveillance for those if they are at high interest. management studies of treatment recommendations shows that with lower-risk test risk for progression. (Important gene expression testing may result in changes to scores, there could be We expect that In the past several outcome) prostate cancer management offsetting savings in most men would years there has ●◌◌◌ (Very low confidence, based on 11 treatment costs. want the been an increase in observational studies)

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Should gene expression profiling tests be recommended for coverage for prostate cancer? Estimate of Effect for Outcome/ Values and Other Outcomes Resource Allocation Confidence in Estimate Preferences Considerations Harms Insufficient data There is also the information active surveillance (Important potential for savings in provided by gene as the management outcome) patients with higher profile testing. For approach for risk scores. Early active men with results localized prostate treatment of more indicating low risk, cancer, and this aggressive tumors the preference to coincides with the (while still localized) have a cancer study period in all of could be less costly removed may still the included than unsuccessful outweigh any publications (which active surveillance with reassurance generally used subsequent need for provided by the historical controls). more extensive test. interventions. The Watchful waiting magnitude of such causes anxiety for savings attributable to some men gene profile testing diagnosed with would be difficult to prostate cancer, and establish, however. reliance on test results will have The Decipher test is significant used for a smaller variability. For men population of men with with results prostate cancer post- indicating a high risk radical prostatectomy, of progression, we and savings in expect that most radiotherapy costs would pursue active could potentially offset treatment. testing costs.

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Should gene expression profiling tests be recommended for coverage for prostate cancer? Estimate of Effect for Outcome/ Values and Other Outcomes Resource Allocation Confidence in Estimate Preferences Considerations Balance of benefits and harms: Evidence on gene expression profiling tests (including Prolaris, Oncotype DX, and Decipher) is insufficient to determine the balance of population benefits and harms. Although the tests have clinical validity, we have very low confidence that they actually change management, and insufficient evidence regarding the other critical and important outcomes. There are no safety concerns or direct harms associated with these prostate tissue tests. Use of these tests for decisions regarding intervention vs. active surveillance may lower the rates of prostate surgery and radiation treatments, with associated lessening of complications and adverse effects, but those benefits have not been established. Rationale: The published evidence on gene expression profiling tests for prostate cancer (including Prolaris, Oncotype DX, and Decipher) is currently limited to observational studies on treatment decision changes only. Overall, these studies provide very low confidence that gene expression testing results in changes to prostate cancer management plans. Evidence is insufficient for other critical and important outcomes, including the effects of test utilization on prostate cancer morbidity and mortality or quality of life. In the absence of clinical outcomes evidence, treatment cost savings can be theorized, but not established. Our recommendation for non-coverage is strong, based on very limited and indirect evidence of any benefit. Recommendation: Gene expression profiling tests for prostate cancer (including Prolaris, Oncotype DX, and Decipher) are not recommended for coverage (strong recommendation). Note: GRADE-informed framework elements are described in Appendix A. A GRADE Evidence Profile is in Appendix B.

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Clinical Background Prostate cancer is the second leading cause of death from cancer in men, with an estimated 27,000 deaths in the United States in 2017 (National Cancer Institute [NCI], 2017). The lifetime risk of developing prostate cancer is 12%, and there were an estimated 160,000 new cases in 2017 (NCI, 2017). The five-year survival rate for prostate cancer is 98.6% (NCI, 2017). Prostate cancer is more common in older men and is more likely to occur in men with a family history of prostate cancer and men of African American descent (NCI, 2017). The most commonly used staging system for prostate cancer is the American Joint Committee on Cancer TNM system (American Cancer Society, 2017). The T categories (clinical) are used to describe the local extent of a prostate tumor: T1: Clinician cannot feel the tumor or see it with imaging such as transrectal ultrasound. T1a: Cancer is found incidentally during a transurethral resection of the prostate (TURP) conducted for benign prostatic hyperplasia (BPH). Cancer is in no more than 5% of the tissue removed. T1b: Cancer is found during a TURP but is in more than 5% of the tissue removed. T1c: Cancer is found by needle biopsy performed because of an increased prostate-specific antigen (PSA). T2: Clinician can feel the cancer with a digital rectal exam (DRE) or see it with imaging such as transrectal ultrasound, but it still appears to be confined to the prostate. T2a: The cancer is in one half or less of only one side of the prostate. T2b: The cancer is in more than half of only one side of the prostate. T2c: The cancer is in both sides of the prostate. T3: The cancer has grown outside the prostate and may have grown into the seminal vesicles. T3a: The cancer extends outside the prostate but not to the seminal vesicles. T3b: The cancer has spread to the seminal vesicles. T4: The cancer has grown into tissues next to the prostate (other than the seminal vesicles), such as the urethral sphincter, rectum, bladder, or wall of the pelvis. Common treatments for prostate cancer include:  Active surveillance that closely monitors the prostate cancer by regularly performing PSA and DRE tests, and treating the cancer only if it grows or causes symptoms.  Surgery, such as a prostatectomy that removes the prostate, or a radical prostatectomy that also removes the surrounding tissue.  External radiation therapy or internal radiation therapy (brachytherapy) in which radioactive seeds or pellets are surgically placed into or near the cancer to destroy the cancer cells.  Hormone therapy that blocks cancer cells from receiving the hormones they need to grow (Centers for Disease Control and Prevention [CDC], 2016). Even in the absence of treatment, prostate cancer does not progress in some patients (Lu-Yao et al., 2009). Studies have shown that low-risk patients fare no better with radical treatment than with “watchful waiting” by only monitoring the cancer (Wilt et al., 2012). Accurate risk stratification is

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important for effective clinical management and for avoiding unnecessary invasive treatment. The most common stratification system for prostate cancer patients uses PSA concentration, biopsy Gleason grade, and clinical stage to classify patients as low, intermediate, or high risk (Gnanapragasam et al., 2016). Recently, gene expression tests have been developed to predict prostate cancer aggressiveness, including Decipher, Oncotype DX, and Prolaris. The clinical validity of these tests to improve prognostication for various prostate cancer-related outcomes has been demonstrated in systematic reviews (Spratt et al., 2017; Brand et al., 2016; Sommariva et al., 2016). Indications Oncotype DX and Prolaris are used after an initial diagnosis of prostate cancer to predict the cancer’s aggressiveness, and thereby inform decision making on treatments versus active surveillance. Decipher is used after a radical prostatectomy to predict the probability of metastasis, and thus inform clinical decisions on the potential use of additional (adjuvant) prostate cancer treatments. Technology Description Decipher is a test designed to predict the probability of metastasis within five years of radical prostatectomy surgery. Decipher measures the expression levels of 22 RNA biomarkers involved in biological pathways across the genome that are associated with aggressive prostate cancer (GenomeDx, 2017). The Oncotype DX genomic prostate score assay analyzes prostate cancer gene activity to predict disease aggressiveness among men with clinically low-risk prostate cancer. The test measures the expression of 17 genes across four genetic pathways. Gene expression and clinical risk factors are combined to predict the likelihood of adverse pathology, with a score ranging from zero to 100 (Genomic Health, 2017). Prolaris is a test to determine cancer aggressiveness and predict the probability of disease progression using traditional risk factors and molecular assessment of a patient’s cancer. Prolaris uses a 46-gene expression signature including cell cycle progression genes selected based upon correlation with prostate tumor cell proliferation (Myriad Genetics, 2017). Evidence Review Prolaris Shore et al., 2014 This study surveyed 15 community urologists in 12 states to determine the utility of information provided by the cell cycle progression (CCP) score. Three hundred patients with recently diagnosed localized prostate cancer (T1-T3b with no nodal or distant metastases) of any Gleason score had a CCP score calculated from analysis of the biopsy specimen (294 scores were provided to the urologists because six of the tests failed). All but 30 of the 300 patients had already chosen or received initial treatment. The survey asked the urologists “If this had been a clinical result rather than a research result, would you have changed your treatment decision for the patient?” In 10 cases (3%), the clinicians indicated that the CCP results would have changed the treatment decision; in 85 cases (29%) they indicated that the CCP results “maybe” would have changed their decision. In 199 cases (68%), the clinicians stated that the CCP results would not have changed their treatment recommendations. The authors did not collect data on how treatment recommendations would have changed, but they

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speculated that because most of the definite or possible changes involved patients with low CCP scores, the putative changes would favor less aggressive treatments. One important limitation of this study is that the content of the report provided to the clinicians differs from the content of the commercial report generated outside of a research context. The study was funded by Myriad Genetics, and two authors were employees of Myriad Genetics. Crawford et al., 2014 This study reported the findings of a registry-based study of the effects of CCP score on treatment recommendations for men with localized prostate cancer. Beginning in July 2013, the manufacturer of the test established a registry of CCP tests ordered while collecting voluntarily submitted information from clinicians on treatments that were being considered prior to the CCP test results. Clinicians were asked to voluntarily submit information on the treatment that was ultimately selected and to rate the influence of the CCP test on their treatment recommendations. In making their initial (pre-CCP score) treatment recommendations, clinicians provided information on the PSA, Gleason score, clinical stage, and percentage of positive biopsy cores, as well as their treatment recommendation. The CCP test report provided to clinicians included the CCP score and the standard American Urological Association (AUA) risk assessment. In the posttest survey, clinicians reported their “intended selection of treatment” after receiving the CCP test report. For posttest surveys older than 45 days, a chart review was conducted to determine concordance between the posttest clinician recommendation and the actual treatment.

Of the 305 patients in the registry, the vast majority had stage T1c prostate adenocarcinoma (83%) and Gleason scores of 6 or 7 (92%); most of the patients fell in the low or intermediate AUA risk category. The tests were ordered mainly by urologists in 31 states. In 198 cases, there was a change between the pretest and posttest treatment recommendations (64.9% of cases, 95% CI 59.4% to 70.1%). Treatments were dichotomized between non-interventional (active surveillance or watchful waiting) and interventional (all other treatments, but mainly radiation or prostatectomy) approaches. Of 164 patients with an interventional pretest treatment recommendation, 61 treatment recommendations were changed to non-interventional after receiving the CCP results (37.2%, 95% CI 30.2% to 44.8%). Among the 141 patients with a non-interventional pretest treatment recommendation, 33 treatment recommendations were switched to interventional after receiving the CCP results (23.4%, 95% CI 17.1% to 31.1%). Treatment changes mainly occurred when higher CCP scores were reported in AUA low-risk patients or when low CCP sores were reported for AUA intermediate-risk patients. In assessing concordance of posttest treatment recommendations with actual treatments rendered, 116 registry patients had evaluable data. The treatments rendered were concordant in 80% of cases (95% CI 71.9% to 86.5%). Approximately 55% of the ordering clinicians rated the influence of the CCP score on treatment recommendations as high or very high; an additional 33% of clinicians rated the influence as moderate.

The major limitation of this study (aside from its non-comparative design) stems from a high risk of selection bias, both for patients who received the test and for the likelihood that the results would influence the ordering clinician (i.e., clinicians who ordered the test might have been more predisposed to make changes based on the results). Additionally, changes in the recommended treatment were not definitively attributable to CCP scores, information on the actual treatments rendered was available for fewer than half the patients in the registry, and there was no information on long-term clinical

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outcomes. The study was funded by Myriad Genetics, three authors were employees of Myriad, and two authors reported receiving research funding or honoraria from Myriad. Shore et al., 2016 This study reported the findings of a registry-based study of CCP score on treatment selection for men with localized prostate cancer. For this study, 124 physicians practicing in selected medical groups and academic institutions in 21 states contributed 1,596 patients to the registry, of whom 1,206 had fully evaluable data. Patients with newly diagnosed (within six months) localized prostate cancer were eligible for the registry if they had not received any treatment and did not have hypogonadism or previous hormonal therapy, and had sufficient biopsy tissue on which to perform the CCP testing. Clinicians completed a pre-CCP score survey of their treatment recommendations, which included information on PSA, Gleason score, clinical stage, and percentage of positive biopsy cores. A second survey of treatment recommendations was conducted after the clinician received the CCP score, but before discussing treatment options with the patient. A third survey recorded the agreed upon treatment plan after CCP score and the clinician-patient consultation. A fourth and final survey, administered between three and six months after the clinician-patient consultation, recorded the actual treatments rendered up to that point. Most of the patients in the registry were Caucasian (77%), and had low- (40%) or intermediate-risk (42%) disease by AUA classification. Most of the enrolled patients were otherwise healthy, having a Charlson comorbidity index of zero (72%) or one (18%).

Overall, 47.8% of pre-CCP treatment recommendations had changed when actual treatments were recorded; of these changes, 72% were regarded as moving from a higher treatment intensity to a lower treatment intensity. When treatments were dichotomized as interventional and non-interventional, the initial pre-CCP recommendation was for non-interventional treatment in 417 patients (35%) and interventional in 789 patients (65%). In total, 213 patients (17.6%) switched from an interventional to a non-interventional strategy or vice versa. Among 789 patients with a pre-CCP recommendation for interventional treatment, 112 (14.2%) switched to non-interventional treatment. Among 417 patients with a pre-CCP recommendation for non-interventional treatment, 101 (24%) switched to interventional treatments. Like the other registry study, the major limitation of this study is selection bias. Although physicians were encouraged to enroll all consecutively eligible patients, this was not a requirement. Changes in the treatment plan cannot be definitively attributed to the CCP score. Information on actual treatments provided was only recorded between three and six months, and any changes to the treatment plans after six months would not have been captured in this study. The study was supported by Myriad Genetics, and six of the authors disclosed financial or other relationships with Myriad. Oncotype DX Prostate Dall’Era et al., 2015 This is a manufacturer database and retrospective chart review study of the effects of the 17-gene genomic prostate score (GPS) on treatment recommendations and selection in men with localized prostate cancer. The GPS group consisted of 124 patients who had received GPS testing ordered by one of 15 physicians between May 2013 and February 2014. A non-GPS comparison group (n=87) was assembled by asking the participating clinicians to identify six men with Gleason 3+3 disease and one patient with Gleason 3+4 disease who had been treated between May 2012 and May 2013; these comparison patients also had to have a PSA ≤20 ng/ml and a clinical stage of T1c to T2c (the GPS group

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could include stage T1a/b patients). The documentation of treatment recommendations and treatment selections was done routinely and not as part of study protocol. The GPS and comparison groups were similar, although the comparison group was slightly younger and there were slight differences in the distribution of clinical stage and National Comprehensive Cancer Network (NCCN) risk categories (e.g., all three patients with T2b disease were in the comparison group and all four patients with T1a/b disease were in the GPS group). A recommendation of active surveillance or watchful waiting was made for 61% of the patients in the GPS group compared to 50% of the comparison group (p=0.11). Active surveillance or watchful waiting was the actual treatment received for 67% of the GPS group and 43% (p<0.001) of the comparison group.

This study is limited by its retrospective observational design and, in particular, by its use of historical controls during a period in which the use of non-interventional treatments was growing. The risk of selection bias was heightened by the fact that only clinicians who had ordered four or more GPS tests were used to identify the patients for the GPS group. The authors did not describe methods to confirm that treatment recommendations and selections were made after GPS data were available to the clinicians. There was no information on clinical outcomes or the durability of treatment decisions beyond the period of the study. Study funding was not reported; all authors disclosed a financial or other relationship with Genomic Health. Badani, Kemeter et al., 2015 This study surveyed clinicians at three sites to determine the effects of GPS on treatment recommendations for men with localized prostate cancer. Patients were eligible for inclusion if they had been diagnosed with prostate cancer in the last six months, were classified by the NCCN risk categories as very low, low, or low-intermediate risk disease, and were older than age 50 with greater than 10-year life expectancy. Patients with higher-risk disease, those with total Gleason scores of 4 or 5, or previous treatment with androgen deprivation therapy were excluded. At the time of ordering the GPS, the participating clinicians submitted a pre-GPS assessment of the patient’s risk using standard clinic- pathologic data and an initial treatment recommendation. A post-GPS survey was used to ascertain treatment recommendations and the clinician’s perceived utility of the GPS score. Of 201 potential patients across the three sites, 158 were eligible and had evaluable data for the study. In general, study patients were in their mid-60s, predominantly Caucasian, had a mean PSA of six, and had stage T1c or T2a prostate cancer. Most of the patients had a Gleason score of 3+3 (70%); the remainder had a Gleason score of 3+4. For the NCCN risk group, 22% of patients were very low risk, 45% low risk, and 33% low-intermediate risk.

In the overall analysis, 18% of treatment recommendations changed after GPS results were obtained. Reported treatment recommendations for active surveillance increased from 41% to 51% after GPS results were received. Treatment changes mainly occurred for the NCCN low-risk patients. In 60% of cases, clinicians agreed or strongly agreed that the GPS results made them more confident in their treatment recommendation; in 56% of cases, clinicians rated the GPS results as useful or extremely useful in their decision making. This study is limited by its non-comparative self-reported survey design and a high risk of selection bias for patients and clinicians who might have been more predisposed to change treatment recommendations based on the GPS score. There was no information on the actual treatments provided, nor on clinical outcomes for patients. The study was supported by Genomic Health, and all but one of the authors disclosed a financial or other relationship with Genomic Health.

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Eure et al., 2017 This is a cohort study of the effects of GPS score on treatment decisions (with comparison to an historical control cohort) for men with localized prostate cancer. The study included an assessment of the durability of active surveillance treatment decisions at one year. This study reported results on the first 297 patients from 26 community-based urology practices with fully evaluable data who were enrolled in the GPS between July 2014 and September 2015. The historical cohort (n=247) was assembled by reviewing charts (from January 2012 to September 2014) at nine of the participating sites, and patients were selected based on the same inclusion and exclusion criteria for patients in the GPS cohort. The GPS and historical control cohorts had slight differences in age, race/ethnicity, clinical stage, and the distribution of NCCN risk group (such that a greater proportion of the GPS cohort were NCCN low risk).

Among 111 patients with NCCN low-risk disease, the treatment plan changed for 31 patients (28%) after reviewing the GPS score as part of the shared decision-making visit. Of 41 NCCN low-risk patients whose initial treatment recommendation was for immediate treatment, 21 (51%) selected active surveillance after reviewing the GPS score as part of the shared decision-making visit. Of the 70 NCCN low-risk patients whose initial treatment recommendation was for active surveillance, 10 (14%) selected immediate treatment after reviewing the GPS score as part of the shared decision-making visit. Overall, 62% of the GPS cohort selected active surveillance after shared decision making, compared to 40% in the historical cohort. The overall active surveillance persistence rate at 12 months was 89% in the GPS cohort compared to 86% in the historical cohort. Patients and physicians rated the usefulness of the GPS score highly, and a measure of decisional conflict was lower after GPS testing and shared decision making.

This study is limited by its observational design and the use of an historical comparison cohort during a period in which the use of non-interventional treatments was growing. Furthermore, the comparison cohort was assembled from patients at only nine of the 26 participating sites, creating a greater risk of selection bias. Although the study provides information on persistence in active surveillance at 12 months, it does not provide information on clinical outcomes. The study was sponsored by Genomic Health, and all of the authors disclosed financial relationships with Genomic Health. Albala et al., 2016 This is a single-practice cohort study of the effects of GPS score on treatment decisions and total treatment cost (with comparison to an historical control cohort) for patients with localized prostate cancer. The study compared treatment decisions in 80 patients who received GPS scores to treatment decisions in 100 historical control patients from the same practice. There were small differences between the GPS and historical cohorts with respect to age (patients in the GPS cohort were younger), Gleason score (more patients in the GPS cohort had higher Gleason scores), and stage (more patients in the GPS cohort had lower-stage disease). All of the patients in both cohorts were covered by a single private insurer, thus allowing direct calculation of total treatment cost. For men in the very low-risk and low-risk groups, the use of active surveillance was 21% higher in the GPS cohort compared to the historical cohort. In considering only very low- and low-risk populations, the average per-patient savings in the GPS cohort in the first 180 days after diagnosis was $2,286 (including the cost of the GPS test). On the other hand, when considering the entire NCCN risk population, the average per-patient costs in the first 180 days after diagnosis increased by $1,023 in the GPS cohort (including the cost of the GPS test).

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This study is limited by its observational design and the use of an historical comparison cohort. Additionally, there was no information on clinical outcomes or the durability of active surveillance decisions or treatment costs beyond six months. The study’s generalizability is limited by its single- practice and single-insurer setting. Study sponsorship and financial disclosures were not reported. Decipher Gore et al., 2017 This study is a two-arm cohort study of the effects of the Decipher genomic classifier (GC) test on treatment recommendations and decisional conflict and anxiety for men considering adjuvant or salvage radiotherapy (ART or SRT) after radical prostatectomy. Patients were eligible for enrollment in the ART arm if they had stage T3 disease or positive surgical margins and had undergone prostatectomy in the preceding 12 months. Patients with confirmed biochemical recurrence were eligible for enrollment in the SRT arm. In both arms, patients’ PSA levels must have dropped to <0.1 ng/ml within three months of surgery. Patients with metastatic disease were excluded, as were patients who had received neoadjuvant androgen deprivation therapy (ADT). In the ART arm, patients receiving adjuvant chemotherapy were excluded.

Over the course of one year, patients completed two study visits. At the first visit, treatment recommendations without GC results were recorded. At the second visit, treatment recommendations were recorded after reviewing the GC results. In total, 265 patients completed both visits (150 in the ART arm and 115 in the SRT arm). In the group considering ART, the initial treatment recommendation was for observation for 133 patients (88.7%) and for ART in 17 patients (11.3%). After the GC results were reviewed, the treatment recommendation changed from observation to ART (with or without ADT) for 19 patients (14%), and changed from ART to observation in six patients (35%). In the group considering SRT, the initial treatment recommendation was for observation in 67 patients (58.3%), for SRT in 37 patients (32.2%), and for either ADT or ADT with SRT in 11 patients (9.6%). After the GC results were reviewed, the treatment recommendation changed from observation to SRT (with or without ADT) in 17 patients (25%) and to ADT for one patient (1%), and changed from SRT (with or without ADT) to observation in 11 patients (38%).

In the ART arm, the median decisional conflict score (DCS) for patients was 25 before GC and 19 after GC (p<0.01). In the SRT arm, median DCS for patients was 27 before GC and 23 after GC (p<0.01). Measures of DCS for clinicians also showed statistically significant decreases after GC. However, among the group of ART patients whose treatment recommendation changed between Visit 1 and Visit 2, the changes in DCS were not statistically significant. Prostate cancer-specific anxiety as measured by the MAX-PC score was not statistically significantly different after GC results were provided.

The study is limited by its non-comparative observational study design, although the enrollment of consecutively eligible patients reduced the risk of selection bias. The study did not provide information on the actual treatment rendered, although a future analysis for that outcome is planned. The study was sponsored by GenomeDx Biosciences, and several of the authors disclosed financial or employment relationships with the company.

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Nguyen et al., 2015 This is a survey-based study of the effects of Decipher GC on adjuvant treatment recommendations after radical prostatectomy. The study enrolled 26 radiation oncologists and 20 urologists. These clinicians were presented with 11 de-identified case histories including information on age, preoperative PSA, stage, Gleason score (both biopsy and surgical), information on seminal vesicle involvement or extraprostatic extension and surgical margins, and lymph node involvement. Treatment recommendations based on this information were recorded. The cases were reordered and then presented to the same clinicians with the above information and the GC results. Among the 11 cases presented, the median age was 61 years and the majority had stage T3 disease, positive surgical margins, and a surgical Gleason score of seven or greater. Based on the clinical information alone, urologists recommended observation in 42% of the cases and radiation oncologists recommended observation in 23% of the cases. Overall, GC information led to a change in treatment recommendation 35% of the time for radiation oncologists and 45% of the time for urologists.

When the GC showed a high-risk result, more clinicians recommended adjuvant treatment (62% pretest to 91% with GC for urologists, 79% pretest to 89% with GC for radiation oncologists). When the GC showed a low-risk result, more clinicians recommended observation (48% pretest to 78% with GC for urologists, 28% pretest to 49% with GC for radiation oncologists). The use of GC was associated with greater concordance between urologists and radiation oncologists for treatment recommendations. However, the net effect of the GC on the recommendation for adjuvant therapy was not significantly different for either specialty (urologists recommended adjuvant therapy in 42% of cases without GC and 40% of cases with GC; radiation oncologists recommended adjuvant therapy in 76% of cases without GC and 75% of cases with GC).

The study is limited by its non-comparative observational design and small sample size. There is a high risk of selection bias because participating clinicians were self-selected among invitees. Although there was an attempt to reduce the risk of recall bias, the small number of cases means that clinicians could have been aware of their previous recommendations for the same case. The clinicians were aware that they were not making actual treatment recommendations. The clinicians were given information stating that the GC “has been shown to outperform clinicopathologic features in a 2013 validation study” before they received the GC results. The study does not provide information on actual treatments nor on clinical outcomes for patients. GenomeDx Biosciences was one of several sponsors of the study; all but three of the authors disclosed financial or other relationships with GenomeDx Biosciences. Michalopoulos et al., 2014 This was a survey-based study of the effects of the Decipher GC on adjuvant treatment recommendations for patients with stage T3 disease or positive surgical margins after prostatectomy. Eighteen community urologists who ordered a GC test were asked to record their pre-GC treatment recommendations and their treatment recommendation after receiving the GC results. Patients were excluded if they had received any neoadjuvant or adjuvant therapy, did not reach a PSA nadir within 30 days of prostatectomy, or had metastatic disease. GC tests were ordered for 167 patients, of whom 146 met inclusion criteria. The median age of included patients was 63, and most patients had surgical Gleason scores of six or seven. Before the GC results, adjuvant therapy was recommended for 40 patients (27.4%) and observation for 102 (70%). Initial treatment recommendations for adjuvant

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therapy were changed to observation in 17 cases (42.5%). Initial treatment recommendations for observation were changed to adjuvant treatment in 18 cases (17.6%).

The study is limited by its non-comparative observational design and the high risk of selection bias (the authors acknowledged that participating clinicians were “early adopters”). There was no information on actual treatments rendered or clinical outcomes. The study was funded by GenomeDx Biosciences. All but three of the authors disclosed employment, financial, or other relationships with GenomeDx Biosciences. Peer reviewers received honoraria from the journal. Badani, Thompson et al., 2015 This is a survey-based study of the effects of Decipher GC on adjuvant treatment recommendations after prostatectomy. For this study, 51 urologists were presented with 10 case histories and asked to provide pre-GC and post-GC treatment recommendations. The 10 case histories were randomly selected from a pool of 110 case histories, mainly of patients in their early 60s with T3 disease or positive surgical margins at prostatectomy. This allowed for 530 pre-GC treatment recommendations and 530 post-GC treatment recommendations. The initial pre-GC treatment recommendation was for observation in 303 cases (57%), ART in 193 cases (36%), and other treatments in 34 cases (7%). Among patients with an initial recommendation for ART, the post-GC treatment recommendation changed to observation in 77 cases (40%). Among patients with an initial recommendation for observation, the post-GC treatment recommendation changed to ART in 38 cases (13%).

This study is limited by its non-comparative observational design and the high risk of selection bias (a portion of the participating clinicians were referred by the study authors). Although there was an attempt to reduce the risk of recall bias, the small number of cases means that clinicians could have been aware of their previous recommendations for the same case. The clinicians were aware that they were not making actual treatment recommendations. The study did not provide information on actual treatment decisions or clinical outcomes. The study was supported, in part, by GenomeDx Biosciences. All but four of the authors disclosed financial or other relationships with GenomeDx Biosciences. Evidence Summary Several studies of the clinical utility of various prostate cancer gene expression tests have been published, but none of the studies provided information on the effects of these tests on clinical outcomes from prostate cancer. Although many studies concluded that gene expression tests led to changes in treatment recommendations, few reported on actual treatment decisions, and only one described the durability of actual treatment decisions at 12 months. The studies are limited by their observational designs, the use of historical cohorts, and a high risk of selection bias resulting from a potential predisposition of participants to make treatment changes based on the results of the gene expression tests. There was extensive industry involvement in the sponsorship of the studies, and many of the authors disclosed financial or other conflicts of interest. Overall, these studies provide very low confidence that gene expression testing results in changes to prostate cancer management plans.

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Policy Landscape Payer Coverage Policies Medicaid No coverage policies for Decipher, Prolaris, or Oncotype DX genomic prostate score assay were found for the Washington Medicaid program. Medicare No Medicare National Coverage Determinations were identified for Decipher, Polaris, or Oncotype DX Prostate Cancer Assay. Medicare Local Coverage Determinations (LCDs) were found for each of these three tests, covering the same 42 states. The LCDs for Decipher specify coverage when all of the following conditions are met:  Patient with prostate cancer who has undergone a radical prostatectomy within the previous 60 months and is being considered for postoperative secondary therapy due to one or more cancer- recurrence risk factors  Patient must have achieved initial PSA nadir (defined as undetectable PSA) within 30 days of radical prostatectomy surgery  Patient must not have any evidence of distant metastasis  Patient must not have received any neo-adjuvant treatment prior to surgery  Decipher GC is performed on a patient’s radical prostatectomy specimen  Patient’s surgical pathology report or medical records must have documented presence of adverse pathology: o Pathological stage T2 disease with a positive surgical margin, or o Pathological stage T3 disease (e.g., extraprostatic extension, seminal vesicle invasion, bladder neck invasion), or o Rising PSA after initial PSA nadir  Testing has been ordered by a physician who is certified in the GenomeDx Decipher Certification and Training Registry The LCDs for Prolaris specify coverage when all of the following conditions are met:  Needle biopsy with localized adenocarcinoma of prostate (no clinical evidence of metastasis or lymph node involvement)  Patient stage as defined by the one of the following: o FFPE prostate biopsy specimen with at least 0.5 mm of cancer length, and o Very low-risk disease (T1c AND Gleason Score ≤6 AND PSA ≤10 ng/mL AND <3 prostate cores with tumor AND ≤50% cancer in any core AND PSA density of <0.15 ng/mL/g) OR o Low-risk disease (T1-T2a AND Gleason Score ≤6 AND PSA ≤10 ng/mL)  Patient has an estimated life expectancy of greater than or equal to 10 years  Patient is a candidate for and is considering conservative therapy and would be eligible for definitive therapy (radical prostatectomy, radiation therapy, or brachytherapy)  Result will be used to determine treatment between definitive therapy and conservative management  Patient has not received pelvic radiation or androgen deprivation therapy prior to the biopsy

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 Test is ordered by a physician certified in the Myriad Prolaris™ Certification and Training Registry (CTR)  Patient is monitored for disease progression according to established standard of care  Physician must report the development of metastasis or prostate cancer deaths in patients not treated definitively who were deemed low risk by the assay The LCDs for Oncotype DX Prostate Cancer Assay specify coverage when all of the following conditions are met:  Needle biopsy with localized adenocarcinoma of prostate (no clinical evidence of metastasis or lymph node involvement)  Patient stage as defined by the one of the following: o Very low-risk disease (T1c AND Gleason Score = 6 AND PSA = 10 ng/mL AND <3 prostate cores with tumor AND = 50% cancer in any core AND PSA density of <0.15 ng/mL/g) OR o Low-risk disease (T1-T2a AND Gleason Score = 6 AND PSA = 10 ng/mL)  Patient has a life expectancy of 10-20 years  Patient is a candidate for and is considering conservative therapy and would be eligible for definitive therapy (radical prostatectomy, radiation therapy, or brachytherapy)  Patient has not received pelvic radiation or androgen deprivation therapy prior to the biopsy  Test is ordered by a physician certified in the Genomic Health Oncotype DX Prostate Cancer Assay Certification and Training Registry  Patient is monitored for disease progression according to active surveillance guidelines as recorded in NNCN guidelines  Physician must report the development of metastasis or prostate cancer deaths in patients not treated definitively who were deemed low risk by the assay Private Payers Coverage policies were searched for Aetna, Cigna, Moda, and Regence, and no policies were identified that provide coverage for Decipher, Prolaris, or Oncotype DX Prostate Cancer Assay. Aetna and Regence consider Decipher, Prolaris, and Oncotype DX Prostate Cancer Assay to be experimental or investigational. Cigna does not include Decipher, Prolaris, or Oncotype DX Prostate Cancer Assay in the list of medically necessary prostate cancer screening and prognostic tests. Moda considers Oncotype DX Prostate Cancer Assay to be experimental and investigational, and no coverage policies were identified for Decipher or Prolaris. Professional Society Guidelines Two guidelines were identified that make recommendations on the use of Decipher, Prolaris, and Oncotype DX Prostate Cancer Assay. The NCCN guidelines on prostate cancer state that men with clinically localized prostate cancer may consider the use of tumor-based molecular assays, and specific recommendations are included on the use of Decipher, Prolaris, and Oncotype DX Prostate Cancer Assay. NCCN recommends Decipher after a radical prostatectomy for patients with pT2 with positive margins, any pT3 disease, and rising PSA. The NCCN guidelines recommend Prolaris and Oncotype DX Prostate Cancer Assay post-biopsy for very low- and low-risk prostate cancer in patients with at least 10 years of life expectancy who have not received

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treatment for prostate cancer and who are candidates for active surveillance or definitive therapy (NCCN, 2017). The guideline Clinically Localized Prostate Cancer has been published by the American Urological Association, American Society for Radiation Oncology, and Society of Urologic Oncology (Sanda et al., 2017). These guidelines include the following recommendation, based on expert opinion: “Tissue-based genomic biomarkers have not shown a clear role in active surveillance for localized prostate cancer and are not necessary for follow up” (Sanda et al., 2017). Quality Measures No quality measures were identified for prostate cancer gene expression testing when searching the National Quality Measures Clearinghouse.

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References Evidence Sources Albala, D., Kemeter, M. J., Febbo, P. G., Lu, R., John, V., Stoy, D., . . . Dubeck, F. (2016). Health economic impact and prospective clinical utility of Oncotype DX(R) Genomic Prostate Score. Reviews in Urology, 18(3), 123-132. doi: 10.3909/riu0725 Badani, K. K., Thompson, D. J., Brown, G., Holmes, D., Kella, N., Albala, D., . . . Hornberger, J. (2015). Effect of a genomic classifier test on clinical practice decisions for patients with high-risk prostate cancer after surgery. BJU International, 115(3), 419-429. doi: 10.1111/bju.12789 Badani, K. K., Kemeter, M. J., Febbo, F. G., Lawrence, H. J., Denes, B. S., Rothney, M. P., . . . Brown, G. A. (2015). The impact of a biopsy based 17-gene genomic prostate score on treatment recommendations in men with newly diagnosed clinically prostate cancer who are candidates for active surveillance. Urology Practice, 2(4), 181-189. doi:10.1016/j.urpr.2014.10.010 Crawford, E. D., Scholz, M. C., Kar, A. J., Fegan, J. E., Haregewoin, A., Kaldate, R. R., & Brawer, M. K. (2014). Cell cycle progression score and treatment decisions in prostate cancer: Results from an ongoing registry. Current Medical Research and Opinion, 30(6), 1025-1031. doi: 10.1185/03007995.2014.899208 Dall’Era, M. A., Maddala, T., Polychronopoulos, L., Gallagher, J. R., Febbo, P. G., & Denes, B. S. (2015). Utility of the Oncotype DX® Prostate Cancer Assay in clinical practice for treatment selection in men newly diagnosed with prostate dancer: A retrospective chart review analysis. Urology Practice, 2(6), 343-348. doi: 10.1016/j.urpr.2015.02.007 Eure, G., Germany, R., Given, R., Lu, R., Shindel, A. W., Rothney, M., . . . Denes, B. (2017). Use of a 17- gene prognostic assay in contemporary urologic practice: Results of an interim analysis in an observational cohort. Urology. doi: 10.1016/j.urology.2017.02.052 Gore, J. L., du Plessis, M., Santiago-Jimenez, M., Yousefi, K., Thompson, D. J. S., Karsh, L., . . . Lin, D. W. (2017). Decipher test impacts decision making among patients considering adjuvant and salvage treatment after radical prostatectomy: Interim results from the Multicenter Prospective PRO- IMPACT study. Cancer. doi: 10.1002/cncr.30665 Michalopoulos, S. N., Kella, N., Payne, R., Yohannes, P., Singh, A., Hettinger, C., . . . Hornberger, J. (2014). Influence of a genomic classifier on post-operative treatment decisions in high-risk prostate cancer patients: Results from the PRO-ACT study. Current Medical Research and Opinion, 30(8), 1547-1556. doi: 10.1185/03007995.2014.919908 Nguyen, P. L., Shin, H., Yousefi, K., Thompson, D. J., Hornberger, J., Hyatt, A. S., . . . Feng, F. Y. (2015). Impact of a genomic classifier of metastatic risk on postprostatectomy treatment recommendations by radiation oncologists and urologists. Urology, 86(1), 35-40. doi: 10.1016/j.urology.2015.04.004 Shore, N., Concepcion, R., Saltzstein, D., Lucia, M. S., van Breda, A., Welbourn, W., . . . Brawer, M. K. (2014). Clinical utility of a biopsy-based cell cycle gene expression assay in localized prostate cancer. Current Medical Research and Opinion, 30(4), 547-553. doi: 10.1185/03007995.2013.873398

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Shore, N. D., Kella, N., Moran, B., Boczko, J., Bianco, F. J., Crawford, E. D., . . . Gonzalgo, M. L. (2016). Impact of the cell cycle progression test on physician and patient treatment selection for localized prostate cancer. Journal of Urology, 195(3), 612-618. doi: 10.1016/j.juro.2015.09.072

Other Citations American Cancer Society. (2017). Prostate cancer stages. Retrieved from https://www.cancer.org/cancer/prostate-cancer/detection-diagnosis-staging/staging.html Brand, T. C., Zhang, N., Crager, M. R., Maddala, T., Dee, A., Sesterhenn, I. A., … Lawrence, H. J. (2016). Patient-specific meta-analysis of 2 clinical validation studies to predict pathologic outcomes in prostate cancer using the 17-gene genomic prostate score. Urology, 89, 69-75. Centers for Disease Control and Prevention. (2016). How is prostate cancer treated?. Retrieved from https://www.cdc.gov/cancer/prostate/basic_info/treatment.htm GenomeDx. (2017). What is the Decipher® prostate cancer test?. Retrieved from https://genomedx.com/decipher-test/decipher-prostate-cancer-test/ Genomic Health. (2017). About the Oncotype DX genomic prostate score assay. Retrieved from http://www.oncotypeiq.com/en-US/prostate-cancer/healthcare-professionals/oncotype-dx- genomic-prostate-score/about-the-test?gclid=Cj0KCQjwn6DMBRC0ARIsAHZtCePeqcP- fkUx7lKcuPf9HdxGJ930eEi73CWHXHYG6fI2uMYmM08oXIQaAgc4EALw_wcB Gnanapragasam, V. J., Lophatananon, A., Wright, K. A., Muir, K. R., Gavin, A., & Greenberg, D. C. (2016). Improving clinical risk stratification at diagnosis in primary prostate cancer: A prognostic modelling study. PLoS Medicine, 13(8), e1002063. doi: 10.1371/journal.pmed.1002063 Lu-Yao, G. L., Albertsen, P. C., Moore, D. F., Shih, W., Lin, Y., DiPaola, R. S., ... Yao, S. L. (2009). Outcomes of localized prostate cancer following conservative management. JAMA, 302(11), 1202-1209. doi: 10.1001/jama.2009.1348 Myriad Genetics. (2017). What is Prolaris?. Retrieved from https://prolaris.com/prolaris-for- physicians/what-is-prolaris/ National Cancer Institute. (2017). Cancer stat facts: Prostate cancer. Retrieved from https://seer.cancer.gov/statfacts/html/prost.html National Comprehensive Cancer Network. (2017). NCCN clinical practice guidelines in oncology: Prostate cancer. Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf Sanda, M. G., Chen, R. C., Crispino, T., Freedland, S., Greene, K., Klotz, L. H., … Cadeddu, J. A. (2017). Clinically localized prostate cancer: AUA/ASTRO/SUO Guideline. Retrieved from http://www.auanet.org/guidelines/clinically-localized-prostate-cancer-new-(aua/astro/suo- guideline-2017) Sommariva, S., Tarricone, R., Lazzeri, M., Ricciardi, W., & Montorsi, F. (2016). Prognostic value of the cell cycle progression score in patients with prostate cancer: A systematic review and meta-analysis. European Urology, 69(1), 107-115.

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Spratt, D. E., Yousefi, K., Deheshi, S., Ross, A. E., Den, R. B., Schaeffer, E. M., … Feng, F. Y. (2017). Individual patient-level meta-analysis of the performance of the Decipher genomic classifier in high-risk men after prostatectomy to predict development of metastatic disease. Journal of Clinical Oncology, 35(18), 1991-1998. Wilt, T. J., Brawer, M. K., Jones, K. M., Barry, M. J., Aronson, W. J., Fox, S., . . . Wheeler, T. (2012). Radical prostatectomy versus observation for localized prostate cancer. New England Journal of Medicine, 367(3), 203-213. doi: 10.1056/NEJMoa1113162

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Coverage guidance is prepared by the Health Evidence Review Commission (HERC), HERC staff, and subcommittee members. The evidence summary is prepared by the Center for Evidence-based Policy at Oregon Health & Science University (the Center). This document is intended to guide public and private purchasers in Oregon in making informed decisions about health care services. The Center is not engaged in rendering any clinical, legal, business or other professional advice. The statements in this document do not represent official policy positions of the Center. Researchers involved in preparing this document have no affiliations or financial involvement that conflict with material presented in this document.

Suggested citation: Obley, A., Mosbaek, C., King, V., & Shaffer, W. (2017). Coverage guidance: Gene expression profiling for prostate cancer. Portland, OR: Center for Evidence-based Policy, Oregon Health & Science University.

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Appendix A. GRADE-Informed Framework Element Descriptions

Strong recommendation In Favor: The subcommittee concludes that the desirable effects of adherence to a recommendation outweigh the undesirable effects, considering the balance of benefits and harms, resource allocation, values and preferences and other factors. Against: The subcommittee concludes that the undesirable effects of adherence to a recommendation outweigh the desirable effects, considering the balance of benefits and harms, resource allocation, values and preferences and other factors. Weak recommendation In Favor: The subcommittee concludes that the desirable effects of adherence to a recommendation probably outweigh the undesirable effects, considering the balance of benefits and harms, resource allocation, values and preferences and other factors., but further research or additional information could lead to a different conclusion. Against: The subcommittee concludes that the undesirable effects of adherence to a recommendation probably outweigh the desirable effects, considering the balance of benefits and harms, cost and resource allocation, and values and preferences, but further research or additional information could lead to a different conclusion. Confidence in estimate rating across studies for the intervention/outcome Assessment of confidence in estimate includes factors such as risk of bias, precision, directness, consistency and publication bias. High: The subcommittee is very confident that the true effect lies close to that of the estimate of the effect. Typical sets of studies are RCTs with few or no limitations and the estimate of effect is likely stable.

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Moderate: The subcommittee is moderately confident in the estimate of effect: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Typical sets of studies are RCTs with some limitations or well-performed nonrandomized studies with additional strengths that guard against potential bias and have large estimates of effects. Low: The subcommittee’s confidence in the estimate of effect is limited: The true effect may be substantially different from the estimate of the effect. Typical sets of studies are RCTs with serious limitations or nonrandomized studies without special strengths. Very low: The subcommittee has very little confidence in the estimate of effect: The true effect is likely to be substantially different from the estimate of effect. Typical sets of studies are nonrandomized studies with serious limitations or inconsistent results across studies.

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Appendix B. GRADE Evidence Profile

Quality Assessment (Confidence in Estimate of Effect) No. of Risk of Studies Study Design(s) Bias Inconsistency Indirectness Imprecision Other Factors Quality Prostate cancer mortality 0 Insufficient data Prostate cancer morbidity 0 Insufficient data Quality of life 0 Insufficient data Change in management 11 Observational High None Serious Not estimable Industry Very low sponsorship and ●◌◌◌ conflict of interest Harms 0 Insufficient data

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Appendix C. Methods Scope Statement Populations Men with prostate cancer Population scoping notes: None Interventions Gene expression profiling on cancer tissue Intervention exclusions: None Comparators Usual care, other methods of risk stratification (e.g., Gleason score, tumor stage, PSA values), gene expression profiling tests compared to each other Outcomes Critical: Prostate cancer morbidity, prostate cancer mortality Important: Quality of life, harms, change in management of prostate cancer Considered but not selected for the GRADE table: Analytic validity, clinical validity Key Questions KQ1: What is the comparative effectiveness of gene expression profiling for prostate cancer? KQ2: How does the comparative effectiveness of gene expression profiling for prostate cancer vary by:  Age  Race or ethnicity  Patient and family history  Previous treatments and response  Life expectancy  Clinical-pathologic characteristics (e.g., PSA level, tumor size, type of tumor, Gleason score, proliferation rate, cancer stage) KQ3: What are the harms of gene expression profiling for prostate cancer? Search Strategy A full search of the core sources was conducted to identify systematic reviews, meta-analyses, and technology assessments that met the criteria for the scope described above. Searches of core sources were limited to citations published after 2012. The core sources searched included: Agency for Healthcare Research and Quality (AHRQ) Blue Cross/Blue Shield Center for Clinical Effectiveness Canadian Agency for Drugs and Technologies in Health (CADTH) Cochrane Library (Wiley Online Library)

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Institute for Clinical and Economic Review (ICER) Medicaid Evidence-based Decisions Project (MED) National Institute for Health and Care Excellence (NICE) Tufts Cost-effectiveness Analysis Registry Veterans Administration Evidence-based Synthesis Program (ESP) Washington State Health Technology Assessment Program

A MEDLINE® search was also conducted to identify systematic reviews, meta-analyses, and technology assessments, using the search terms (Prolaris or Oncotype or Decipher or Cell-Cycle Progression Gene Panel) and (prostate cancer or prostatectomy). The search was limited to publications in English published since 2012. In addition, a MEDLINE® search was conducted for randomized controlled trials published after the search dates of the most recent systematic review selected for each intervention. Searches for clinical practice guidelines were limited to those published since 2012. A search for relevant clinical practice guidelines was also conducted using MEDLINE® and the following sources: Australian Government National Health and Medical Research Council (NHMRC) Canadian Agency for Drugs and Technologies in Health (CADTH) Centers for Disease Control and Prevention (CDC) – Community Preventive Services National Guidelines Clearinghouse National Institute for Health and Care Excellence (NICE) Scottish Intercollegiate Guidelines Network (SIGN) United States Preventive Services Task Force (USPSTF) Veterans Administration/Department of Defense (VA/DOD) Clinical Practice Guidelines Inclusion/Exclusion Criteria Studies were excluded if they were not published in English, did not address the scope statement, or were study designs other than systematic reviews, meta-analyses, technology assessments, randomized controlled trials, or clinical practice guidelines.

27 │ Gene Expression Profiling for Prostate Cancer DRAFT for 1/18/2018 VbBS/HERC meeting materials Appendix D. Applicable Codes

CODES DESCRIPTION CPT Codes 81479 Unlisted Molecular Pathology Procedure (Decipher, Oncotype DX, Prolaris) Note: Inclusion on this list does not guarantee coverage.

28 │ Gene Expression Profiling for Prostate Cancer DRAFT for 1/18/2018 VbBS/HERC meeting materials Question: How should the draft Coverage Guidance on Gene Expression Profiling for Prostate Cancer be applied to the Prioritized List?

Question source: HERC Staff, HTAS

Issue: The HTAS approved the following draft “box language”:

DRAFT HERC Coverage Guidance Gene expression profiling tests for prostate cancer (including Prolaris, Oncotype DX, and Decipher) are not recommended for coverage (strong recommendation).

Rationale for Recommendations: Accurate risk stratification is important for effective clinical management of prostate cancer, to avoid unnecessary invasive treatment. Oncotype DX and Prolaris can be used after an initial diagnosis of prostate cancer, to predict the cancer’s aggressiveness, and thereby inform decision making on treatment versus active surveillance. Decipher can be used after a radical prostatectomy to predict the probability of metastasis, and thus inform clinical decisions on the potential use of additional (adjuvant) radiation therapy. The published evidence on gene expression profiling tests for prostate cancer (including Prolaris, Oncotype DX, and Decipher) is currently limited to observational studies on treatment decision changes only. Overall, these studies provide very low confidence that gene expression testing results in changes to prostate cancer management plans. None of the published clinical utility studies provide information on the effects of these tests on clinical outcomes from prostate cancer. Evidence is insufficient for critical and important outcomes, including the effects of test utilization on prostate cancer morbidity and mortality or quality of life. In the absence of clinical outcomes evidence, treatment cost savings can be theorized, but not established. These tests are at the beginning of the validation pathway. Future research may allow these tests to gain additional evidence regarding their clinical utility for better risk stratification of men with prostate cancer.

Current Prioritized List Status: Codes

Prior to 2018, CPT 81479 (unlisted molecular pathology procedure) was used for these three prostate gene expression tests (Oncotype DX, Prolaris, Decipher). This non- specific procedure code does not appear on the Prioritized List. A new 2018 CPT code (81541) is now available to use for Prolaris. HERC placed this code on Line 660 for the January 1, 2018 Prioritized List, based on a previous coverage guidance. Current Prioritized List Guideline:

GUIDELINE NOTE 148, BIOMARKER TESTS OF CANCER TISSUE Lines 157,184,191,230,263,271,329

The use of multiple molecular testing to select targeted cancer therapy (CPT 81504) is included on the Services recommended for non-coverage table.

For breast cancer, Oncotype Dx testing (CPT 81519, HCPCS S3854) is included on Line 191 only for early stage breast cancer when used to guide adjuvant chemotherapy treatment decisions for women who are lymph node negative. Oncotype Dx is not included on this line for lymph node-positive breast cancer. Mammaprint, ImmunoHistoChemistry 4 (IHC4), and Mammostrat for breast cancer are included on the Services recommended for noncoverage table.

For melanoma, BRAF gene mutation testing (CPT 81210) is included on Line 230.

For lung cancer, epidermal growth factor receptor (EGFR) gene mutation testing (CPT 81235) is included on Line 263 only for non-small cell lung cancer. KRAS gene mutation testing (CPT 81275) is not included on this line. For colorectal cancer, KRAS gene mutation testing (CPT 81275) is included on Line 157. BRAF (CPT 81210) and Oncotype DX are not included on this line. Microsatellite instability (MSI) is included on the Services recommended for noncoverage table.

For bladder cancer, Urovysion testing is included on Services recommended for noncoverage table.

For prostate cancer, Oncotype DX is not included on Line 329 and Prolaris is included on the Services recommended for noncoverage table.

The development of this guideline note was informed by a HERC coverage guidance. See http://www.oregon.gov/oha/HPA/CSI-HERC/Pages/Evidence-based-Reports.aspx.

HERC Staff Recommendation:

1) Affirm placement of Prolaris (CPT 81541) on Line 660, and add Oncotype DX and Decipher (utilizing CPT 81479) to Line 660. Add an entry to GN 173 as shown below:

GUIDELINE NOTE 173, INTERVENTIONS THAT ARE UNPROVEN, HAVE NO CLINICALLY IMPORTANT BENEFIT OR HAVE HARMS THAT OUTWEIGH BENEFITS FOR CERTAIN CONDITIONS

The following interventions are prioritized on Line 660 CONDITIONS FOR WHICH CERTAIN INTERVENTIONS ARE UNPROVEN, HAVE NO CLINICALLY IMPORTANT BENEFIT OR HAVE HARMS THAT OUTWEIGH BENEFITS:

Procedure Intervention Description Rationale Last Review Code 81504 Biomarker tests for tumor tissue: Insufficient evidence of August, 2015  Mammaprint, Mammostrat and effectiveness. More costly than ImmunoHistoCHemistry 4 (IHC4) for equally effective therapies for this Coverage Guidance breast cancer condition Blog Procedure Intervention Description Rationale Last Review Code  Microsatellite instability (MSI) for colorectal cancer  Urovysion for bladder cancer  Prolaris for prostate cancer  Multiple molecular testing to select targeted cancer therapy …

81541 Prolaris. Oncology (prostate), mRNA Unproven interventions January, 2018 gene expression profiling by real-time RT- PCR of 46 genes (31 content and Coverage Guidance 15 housekeeping) Blog

81479 Oncotype DX Genomic Prostate Score Assay, Decipher Prostate RP

1) Revise Guideline Note 148, as follows:

GUIDELINE NOTE 148, BIOMARKER TESTS OF CANCER TISSUE Lines 157,184,191,230,263,271,329 The use of multiple molecular testing to select targeted cancer therapy (CPT 81504) is included on the Services recommended for non-coverage table.

For melanoma, BRAF gene mutation testing (CPT 81210) is included on Line 230.

For colorectal cancer, KRAS gene mutation testing (CPT 81275) is included on Line 157. BRAF (CPT 81210) and Oncotype DX are not included on this line. Microsatellite instability (MSI) is included on the Services recommended for noncoverage table.

For bladder cancer, Urovysion testing is included on Services recommended for noncoverage table.

For prostate cancer, Oncotype DX Genomic Prostate Score, Prolaris Score Assay, and Decipher Prostate RP are included on Line 660. For prostate cancer, Oncotype DX is not included on Line 329 and Prolaris is included on the Services recommended for noncoverage table.

The development of this guideline note was informed by a HERC coverage guidance. See http://www.oregon.gov/oha/HPA/CSI-HERC/Pages/Evidence-based-Reports.aspx.

Gene Expression Profiling for Prostate Cancer Draft Coverage Guidance for HERC Consideration January 18, 2018

Center For Evidence-based Policy Background

• Prostate cancer is the second leading cause of death from cancer in men – Estimated 27,000 deaths in the U.S. in 2017 • Lifetime risk of developing prostate cancer is 12% • Estimate 160,000 new cases of prostate cancer in 2017 • Five-year survival rate for prostate cancer is 98.6% • Risk factors for prostate cancer – Older age – Family history of prostate cancer – African American descent

2 Center For Evidence-based Policy Background

• Common treatments for prostate cancer – Active surveillance: closely monitor the cancer by regularly performing prostate-specific antigen (PSA) and digital rectal exam tests, and treating the cancer only if it grows or causes symptoms – Surgery: prostatectomy that removes the prostate, or radical prostatectomy that also removes the surrounding tissue – Radiation therapy: External or internal radiation therapy (brachytherapy) – Hormone therapy: Blocks cancer cells from receiving the hormones they need to grow

3 Center For Evidence-based Policy Background

• Low-risk patients fare no better with radical treatment than with “watchful waiting” • Thus, accurate risk stratification is important for effective clinical management and for avoiding unnecessary invasive treatment • Most common risk stratification system for prostate cancer patients uses PSA concentration, biopsy Gleason grade, and clinical stage • Recently, gene expression tests have been developed to predict prostate cancer aggressiveness: Decipher, Oncotype DX Prostate Cancer Assay, and Prolaris

4 Center For Evidence-based Policy Background

• Decipher – Designed to predict the probability of metastasis within five years of radical prostatectomy surgery – Measures the expression levels of 22 RNA biomarkers involved in biological pathways across the genome that are associated with aggressive prostate cancer

5 Center For Evidence-based Policy Background

• Oncotype DX Prostate Cancer Assay – Analyzes prostate cancer gene activity to predict disease aggressiveness among men with clinically low-risk prostate cancer – Measures the expression of 17 genes across four genetic pathways – Gene expression and clinical risk factors are combined to predict the likelihood of adverse pathology

6 Center For Evidence-based Policy Background

• Prolaris – Test to determine cancer aggressiveness and predict the probability of disease progression using traditional risk factors and molecular assessment of a patient’s cancer – Uses a 46-gene expression signature including cell cycle progression genes selected based upon correlation with prostate tumor cell proliferation

7 Center For Evidence-based Policy Background

• All three tests have been shown to improve prognostication for various prostate cancer related- outcomes in systematic reviews (i.e., clinical validity) • Clinical utility—whether and how the use of the tests alters treatment decisions or clinical outcomes—has been the subject of less study

8 Center For Evidence-based Policy Evidence Sources

• Prolaris – Three observational studies • Oncotype DX Prostate – Four observational studies • Decipher – Four observational studies

9 Center For Evidence-based Policy Evidence Sources

• Examples of studies – Badani, Kemeter et al., 2015: survey study of clinicians to determine the effects of Oncotype DX on treatment recommendations for men with localized prostate cancer – Gore et al., 2017: Two-arm cohort study of the effects of the Decipher genomic classifier test on treatment recommendations and decisional conflict and anxiety for men considering adjuvant or salvage radiotherapy after radical prostatectomy – Eure et al., 2017: Cohort study of the effects of Oncotype DX on treatment decisions (with comparison to an historical control cohort) for men with localized prostate cancer

10 Center For Evidence-based Policy Evidence Summary

• Several studies of the clinical utility of various prostate cancer gene expression tests have been published, but none of the studies provided information on the effects of these tests on clinical outcomes • Many studies concluded that gene expression tests led to changes in treatment recommendations, but few reported on actual treatment decisions, and only one described the durability of actual treatment decisions at 12 months

11 Center For Evidence-based Policy Evidence Summary

• Studies are limited by their observational designs, the use of historical cohorts, and a high risk of selection bias resulting from a potential predisposition of participants to make treatment changes based on the results of the tests • There was extensive industry involvement in the sponsorship of the studies, and many of the authors disclosed financial or other conflicts of interest • These studies provide very low confidence that gene expression testing results in changes to prostate cancer management plans

12 Center For Evidence-based Policy Evidence Review

Estimate of Effect for Outcome/ Outcomes Confidence in Estimate Prostate cancer mortality Insufficient data (Critical outcome) Prostate cancer morbidity Insufficient data (Critical outcome)

13 Center For Evidence-based Policy Evidence Review

Estimate of Effect for Outcome/ Outcomes Confidence in Estimate Quality of life (Important Insufficient data outcome) Change in management Mainly indirect evidence from observational (Important outcome) studies of treatment recommendations shows that gene expression testing may result in changes to prostate cancer management ●◌◌◌ (Very low confidence, based on 11 observational studies) Harms Insufficient data (Important outcome)

14 Center For Evidence-based Policy Guidelines

• Clinically Localized Prostate Cancer – American Urological Association, American Society for Radiation Oncology, and Society of Urologic Oncology (2017) – “Tissue-based genomic biomarkers have not shown a clear role in active surveillance for localized prostate cancer and are not necessary for follow up”

15 Center For Evidence-based Policy Guidelines

• National Comprehensive Cancer Network (2017) – NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer – Men with clinically localized prostate cancer may consider the use of tumor-based molecular assays – Recommends Prolaris and Oncotype DX Prostate Cancer Assay post-biopsy for very low- and low-risk prostate cancer in patients with at least 10 years of life expectancy who have not received treatment for prostate cancer and who are candidates for active surveillance or definitive therapy – Recommends Decipher after a radical prostatectomy for patients with pT2 with positive margins, any pT3 disease, and rising PSA

16 Center For Evidence-based Policy Policy Landscape: Public Payers

• Washington Medicaid – No coverage policies for Prolaris, Oncotype DX Prostate Cancer Assay, or Decipher were found

• Medicare – Local Coverage Determinations (LCDs) covering 42 states provide coverage for each of these three tests with specified criteria

17 Center For Evidence-based Policy Policy Landscape: Private Payers

• No policies were identified that provide coverage for Decipher, Prolaris, or Oncotype DX Prostate Cancer Assay for Aetna, Cigna, Moda, and Regence – Aetna and Regence consider Decipher, Prolaris, and Oncotype DX Prostate Cancer Assay to be experimental or investigational – Cigna does not include Decipher, Prolaris, or Oncotype DX Prostate Cancer Assay in the list of medically necessary prostate cancer screening and prognostic tests – Moda considers Oncotype DX Prostate Cancer Assay to be experimental and investigational, and no coverage policies were identified for Decipher or Prolaris

18 Center For Evidence-based Policy Discussion

Values and Preferences Men with prostate cancer would highly value testing that allows them to avoid unnecessary invasive treatments if they are at low risk for progression, or to avoid the risks of watchful waiting if they are at high risk for progression. We expect that most men would want the information provided by gene profile testing. For men with results indicating low risk, the preference to have a cancer removed may still outweigh any reassurance provided by the test. Watchful waiting causes anxiety for some men diagnosed with prostate cancer, and reliance on test results will have significant variability. For men with results indicating a high risk of progression, we expect that most would pursue active treatment.

19 Center For Evidence-based Policy Discussion

Resource Allocation In light of the prevalence of localized prostate cancer in men in the U.S., utilization of Prolaris or Oncotype DX in such cases would add significant cost. To the extent that reliance on these tests results in increased active surveillance for those with lower risk test scores, there could be off-setting savings in treatment costs. There is also the potential for savings in those cases with higher risk scores. Early active treatment of more aggressive tumors (while still localized) could be less costly than unsuccessful active surveillance with subsequent need for more extensive interventions. The magnitude of such savings attributable to gene profile testing would be difficult to establish, however. The Decipher test is used for a smaller population of men with prostate cancer post-radical prostatectomy, and savings in radiotherapy costs could potentially offset the costs of testing.

20 Center For Evidence-based Policy DRAFT: Coverage Guidance

Rationale The published evidence on gene expression profiling tests for prostate cancer (including Prolaris, Oncotype DX, and Decipher) is currently limited to observational studies on treatment decision changes only. Overall, these studies provide very low confidence that gene expression testing results in changes to prostate cancer management plans. Evidence is also insufficient for other critical and important outcomes, including the effects of test utilization on prostate cancer morbidity and mortality or quality of life. In the absence of clinical outcomes evidence, treatment cost savings can be theorized, but are not established. Our recommendation for non-coverage is strong, based on very limited and indirect evidence of any benefit. Gene expression profiling tests for prostate cancer (including Prolaris, Oncotype DX, and Decipher) are not recommended for coverage (strong recommendation).

21 Center For Evidence-based Policy

HERC Coverage Guidance: Gene Expression Profiling for Prostate Cancer Disposition of Public Comments

Table of Contents Discussion Table ...... 1 Commenters...... 2 Public Comments ...... 3 References Provided by Commenters ...... 23

Discussion Table IDs/#s Summary of issue Subcommittee response 1: A1, G1, Prostate gene expression tests are useful in clinical The vast majority of prostate cancer cases are low risk by H1, I1 management of prostate cancer only in limited clinicopathologic criteria, and given the prevalence of prostate scenarios (low- to intermediate-risk cases), so utilization cancer in the U.S. population, asset allocation for gene expression and the related cost impact of testing are reasonable. testing is significant. 2: B2, E3, Utilization of these tests will encourage the trend Limitations of the clinical utility studies establishing the increased E6, E9, J1 towards active surveillance. use of active surveillance were reviewed in the coverage guidance. 3: B2, C2, Prospective studies are unrealistic because of the long The subcommittee does not believe that prospective studies are G1 clinical course of most prostate cancer cases. unrealistic. NCCN authors expressed expectations for future studies: “Future comparative effectiveness research may allow these tests and others like them to gain additional evidence regarding their utility for better risk stratification of men with prostate cancer.” 4: C2,C4, Clinical validity studies plus studies demonstrating the The use of chain-of-evidence approaches was considered by the E2 impact of gene profile tests on clinical decision making subcommittee. The subcommittee believes that empirical evidence create a chain of evidence that supports coverage. of treatment avoidance without adverse clinical outcomes is needed.

Comments received 9/15/2017 to 10/17/2017 Page 1 Center for Evidence-based Policy

HERC Coverage Guidance: Gene Expression Profiling for Prostate Cancer Disposition of Public Comments IDs/#s Summary of issue Subcommittee response In addition, treatment recommendations may differ from the treatments ultimately selected by patients. 5: B2, C5, Medicare allows coverage of these tests. The relevant Medicare coverage determinations were included in the D1, F1, G1, coverage guidance and reviewed by the committee; they are notable J1 in that they require reporting of certain outcomes after testing, which acknowledges uncertainty about the long-term effects of decisions made on the basis of these tests. 6: B2, D1, NCCN guidelines allow consideration of gene assays by The 2017 NCCN guidelines were included in the coverage guidance E3, F1, G1, men with prostate cancer. and reviewed by the subcommittee. NCCN Guidelines Discussion J1 (Version 2.2017) includes the following statements: “No randomized controlled trials have studied the utility of these tests.” “Future comparative effectiveness research may allow these tests and others like them to gain additional evidence regarding their utility for better risk stratification of men with prostate cancer.”

Commenters Identification Stakeholder A Leo Kusuda, MD, FACS [Submitted October 12, 2017] B Jeffrey Evans, MD and Jeffrey Frankel, MD, on behalf of the Washington State Urology Society [Submitted October 12, 2017] C Johnathan Lancaster, MD, Chief Medical Officer, Myriad Genetic Laboratories [Submitted October 13, 2017] D Charles A. McWilliams, MD, President, and R. Jonathan Henderson, MD, Health Policy Chair, American Association of Clinical Urologists [Submitted October 16, 2017]

Comments received 9/15/2017 to 10/17/2017 Page 2 Center for Evidence-based Policy

HERC Coverage Guidance: Gene Expression Profiling for Prostate Cancer Disposition of Public Comments E Jack Spicer, MD, Medical Director, Genomic Health [Submitted October 16, 2017] F Chuck Strand, Chief Executive Officer, Us TOO International Prostate Cancer Education & Support [Submitted October 16, 2017] G Robert E. Skinner, MD, President, Oregon Urological Society [Submitted October 16, 2017] H Bruce Barrows, MD [Submitted October 16, 2017] I Matthew Simmons, MD, PhD, FACS [Submitted October 16, 2017] J Merel Grey Nissenberg, President, National Alliance of State Prostate Cancer Coalitions [Submitted October 16, 2017]

Public Comments ID/# Comment Disposition A1 I am a practicing board certified urologist. I have no commercial affiliation. Thank you for your comments. The subcommittee appreciates input from practicing clinicians on their use of I actually find the Oncotype DX more useful for the patient with Gleason 3+4, with these tests. PSA <10, with history of slow rising PSA, T1c or T2a, low volume disease on biopsy where they appear to behave like Low risk disease but by NCCN guidelines recommend aggressive therapy for intermediate risk. If they fall into the favorable category, I would elect to do active surveillance. I have not found it useful for evaluating Low and Very Low risk patients. B1 We are writing as leaders, representing the Washington State Urology Society, to Thank you for your comments. provide public comment regarding the HERC recommendation to not cover genetic testing on prostate cancer tissue. We ask that the HERC committee continue to allow access for patients to this technology.

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HERC Coverage Guidance: Gene Expression Profiling for Prostate Cancer Disposition of Public Comments ID/# Comment Disposition B2 Urologists periodically utilize these advanced diagnostic tests when deciding The 2017 NCCN guidelines were included in the coverage treatment options for patients with adenocarcinoma of the prostate. The 2017 NCCN guidance and reviewed by the subcommittee. Clinical guidelines allow for consideration of tumor-based molecular assays in men with validity studies were beyond the scope of this coverage clinically localized disease. Retrospective case cohort studies have shown that guidance, but were acknowledged in the background. The molecular assays provide prognostic information independent of other NCCN risk relevant Medicare coverage determinations were also groups. These include, but are not limited to, likelihood of death with conservative included in the coverage guidance and reviewed by the management, likelihood of biochemical progression after radical prostatectomy or committee; they are notable in that they require reporting radiation treatment. of certain outcomes after testing, which acknowledges uncertainty about the long-term effects of decisions made We are seeing an increasing trend toward active surveillance in low risk prostate on the basis of these tests. cancer and these tests are particularly helpful in deciding if avoidance of therapy or intervention is warranted. Medicare has reviewed the literature and has made a positive coverage decision. Cell cycle progression scores as measured by the Prolaris test has been well studied and published in peer-reviewed publications. The HERC recommendations suggest that prospective studies are required before approval, but in this clinical condition it is unrealistic. We agree that prospective trials are more powerful, but the long clinical course of most patients with prostate cancer make these types of studies impractical. Basing your determination on the lack of prospective studies will penalize current patients with this disease. We currently utilize this class of tests for select patients with prostate cancer and recommend they be covered. We are not recommending any particular company’s assay. Medicare patients already have access to these tests and we feel that the Medicaid beneficiaries deserve the same coverage. We appreciate your review of our comments and addressing the issues that affect men with prostate cancer. Feel free to contact us with any questions.

Comments received 9/15/2017 to 10/17/2017 Page 4 Center for Evidence-based Policy

HERC Coverage Guidance: Gene Expression Profiling for Prostate Cancer Disposition of Public Comments ID/# Comment Disposition C1 Thank you for the opportunity to provide comments on the draft Coverage Guidance, Thank you for your comments. Gene Expression Profiling for Prostate Cancer. We commend the Subcommittee for selecting this topic, since, as noted, prostate cancer represents a significant disease burden with widespread uncertainty and variation in treatment, resulting in high economic and morbidity costs. C2 While a prospective, randomized trial would be ideal for proving clinical utility, this is The subcommittee heard testimony regarding the highly unlikely for prostate cancer prognostics because the standard of care is challenges of conducting randomized trials in this setting, variable among physicians and the size of the treatment effect is small, resulting in a as well as an endorsement of so-called chain-of-evidence prohibitively large sample size requirement. Given the lengthy natural history of approaches. prostate cancer, a prospective trial would take so long to produce acceptable data, The manuscript by Simon and colleagues suggests caution that the technology would likely be outdated. Simon1 published a framework for in using Category C studies: evaluating tumor biomarkers, adopted by ASCO,2 that describes an alternative approach in which archived specimens are used in a “prospective-retrospective” “Category C biomarker studies use prospective patient manner, to not only validate the prognostic ability of the tumor marker, but also registries in which subjects are treated and followed prove its medical utility. We submit that the published data support that Prolaris has according to standards of care. Specimens are collected, achieved a level of evidence (LOE) II, according to the standards proposed by Simon. processed, and archived prospectively, using generic Given the current state of clinical equipoise, and the demonstration of Prolaris’ standard operating procedures, but are assayed after the impact on clinical decisions,3,4 we suggest that this LOE is acceptable for coverage of study has completed patient accrual. Tumor marker studies Prolaris. Two of the clinical validity studies were performed on archived biopsy conducted using these specimens are often not samples from conservatively managed patients.5,6 These represent the intended use prospectively powered at all. Because of the lack of control of Prolaris, i.e., to predict prognosis after biopsy diagnosis to help decision-making of treatment assignment, specimen collection, and data regarding interventional therapies vs conservative management. These prospective collection, such settings are generally more susceptible to registry studies are defined by Simon as Category C, and similar findings in these two selection biases for patients, specimens, and clinical data non-overlapping cohorts elevates this to LOE II per Simon. that include outcomes. This concern may not be the case in some tightly controlled population-based registries. Category C studies are more likely confounded by unrecognized biases, and their results are more likely to result from chance than those of categories A and B. Comments received 9/15/2017 to 10/17/2017 Page 5 Center for Evidence-based Policy

HERC Coverage Guidance: Gene Expression Profiling for Prostate Cancer Disposition of Public Comments ID/# Comment Disposition Category C studies may be validated to LOE II if two or more subsequent studies provide similar results. However, it is unlikely that category C studies would ever be sufficient to change practice, except under particularly compelling circumstances.” The referenced ASCO use of these standards was in its review of genome expression tests for breast cancer, an area in which a number of Category A and B studies are available. C3 In the Prolaris clinical utility studies,3,4 the test was ordered when physicians and Both of the cited clinical utility studies were reviewed in the patients were interested in using the results to inform treatment. Rather than coverage guidance. representing “bias”, this is a strength of the studies since it is “real-world” as opposed to test ordering based on a protocol. The comparative design included using each patient as his own control, given the wide heterogeneity of the disease and lack of uniformity in treatment between physicians. The planned treatment prior to obtaining the Prolaris result was compared with the actual treatment administered after Prolaris, thus ensuring that changes in treatment could be attributed to the Prolaris result, and not relying on historical rates of active surveillance. For every 1- unit decrease in predicted mortality risk, there was a corresponding 2.7% decrease in the amount of treatment, confirming that treatment decisions were aligned with Prolaris results.4 Almost 90% of ordering clinicians rated the influence of the Prolaris score on treatment recommendations as high, very high or moderate, 3 confirming that treatment changes were influenced by the Prolaris score. Regarding durability of treatment decisions, approximately 24% of patients undergoing active surveillance “switch” to interventional treatment within 5 years and 36% within 10 years.7 With Prolaris, more patients enter the active surveillance “track.” Even if 24-36% switch to interventional treatment over 5-10 years, relatively more men will have been in

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HERC Coverage Guidance: Gene Expression Profiling for Prostate Cancer Disposition of Public Comments ID/# Comment Disposition active surveillance for more years than without Prolaris, sparing those men potentially long-term treatment-related morbidities during those years. C4 The outcome of Prolaris on prostate cancer mortality and morbidity can be inferred The use of chain-of-evidence approaches and the cited from a chain of evidence which links separate pieces of published evidence to prove clinical utility studies were considered by the subcommittee. clinical utility. This is an acceptable approach when a randomized controlled trial is The subcommittee believes that empirical evidence of not possible, according to the Effectiveness Guidance Document published by the treatment avoidance without adverse clinical outcomes is Center for Medical Technology Policy (CMTP).8,9 Clinical utility studies demonstrate a needed. net reduction in prostatectomies and radiation therapies and an increase in active surveillance when Prolaris is used.3,4 Prostatectomy and radiation have been demonstrated to increase treatment-related morbidities10-13 without providing a mortality benefit for low risk prostate cancer compared to active surveillance.14-16 Therefore, a chain of evidence allows us to conclude that the same mortality outcomes can be achieved with fewer treatment-related morbidities with the use of Prolaris. C5 Medicare granted coverage for low risk patients in July of 2015.17 Medicare The relevant Medicare coverage determinations were determined physicians would understand how to use Prolaris results appropriately included in the coverage guidance and reviewed by the when trained (all ordering physicians undergo training) and to date there have not committee; they are notable in that they require reporting been any reported adverse events (defined by Medicare as prostate cancer related of certain outcomes after testing, which acknowledges death or metastasis in Prolaris-defined low risk patients.) Recently, Medicare uncertainty about the long-term effects of decisions made expanded coverage for Prolaris to favorable intermediate risk prostate cancer,18 thus on the basis of these tests. widening even further the disparity of prostate cancer care between Medicaid beneficiaries and those who are dual eligible or receive Medicare benefits.

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HERC Coverage Guidance: Gene Expression Profiling for Prostate Cancer Disposition of Public Comments ID/# Comment Disposition C6 The Subcommittee suggested that tumor biomarkers should demonstrate a Clinical validity studies were beyond the scope of this predictive ability as opposed to a prognostic ability. However, prognostic tests are coverage guidance. valuable because the subsequent clinical management of patients will be more appropriate, based on an improved discrimination of risk at diagnosis compared to using clinical variables alone. While samples from a randomized trial would be necessary to prove a predictive claim, registry studies like those used to validate Prolaris are well suited for validation of prognostic markers, because they tend to include a wide range of patient risk profiles and clinical settings. C7 The Subcommittee questioned how often Prolaris would report a high score on a The cited clinical utility studies were included in the patient with “low grade” prostate cancer and vice versa. Crawford19 reported coverage guidance and considered by the subcommittee. significant amounts of risk reclassification to both higher and lower risk groups in 16,442 patients tested clinically with Prolaris. Although the vast majority of men have low risk cancer by clinicopathologic features, due to uncertainty about the risk of disease progression, most receive interventional therapies.20 Since Prolaris has been well validated to predict outcomes, even when it coincides with the clinicopathologic features in predicting low risk, the patient and physician are more likely to pursue active surveillance.3,4 C8 We respectfully request that Oregon Medicaid cover Prolaris similar to Medicare: for Thank you for your comments. very low, low and favorable intermediate risk prostate cancer when the information is needed to make treatment decisions.

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HERC Coverage Guidance: Gene Expression Profiling for Prostate Cancer Disposition of Public Comments ID/# Comment Disposition D1 We appreciate the opportunity to comment on the Health Evidence Review Thank you for your comments. Commission's "Gene Expression Profiling for Prostate Cancer" coverage guidance. The 2017 NCCN guidelines were included in the coverage Representing our urologist members in Oregon, the American Association of Clinical guidance and reviewed by the subcommittee. Clinical Urologists (AACU) urges reconsideration of the draft recommendation to ensure that validity studies were beyond the scope of this coverage patients have access to technology that has been proven to be beneficial in prostate guidance, but were acknowledged in the background. The cancer treatment decision-making. relevant Medicare coverage determinations were also There is an important need for prognostic biomarkers for biopsy confirmed prostate included in the coverage guidance and reviewed by the cancer. Patients and physicians desire tools to provide support for their shared committee; they are notable in that they require reporting decision about the option of active surveillance for the individual patient. The of certain outcomes after testing, which acknowledges consequences of definitive treatment and related side effects will frequently change uncertainty about the long-term effects of decisions made a patient’s quality of life very significantly. As physicians, we use the results of these on the basis of these tests. tests to make treatment recommendations as they provide useful additional information not available through clinical or pathological features. Gene expression profiling tests for prostate cancer have already been incorporated within influential societal guidelines. Page PROS-1 in Version 2.2017 of the Prostate Cancer Guidelines from the National Comprehensive Cancer Network (NCCN) 1 shows that men with clinically localized disease may consider the use of tumor-based molecular assays. The Discussion Section outlines these tests and their published support. The Molecular Diagnostic Services Program of CMS (MolDX) has issued recommendations2 to cover Prolaris and OncotypeDX in patients with low-risk and favorable intermediate-risk prostate cancer for Medicare beneficiaries. We urge the HERC HTA Subcommittee to recommend coverage for Medicaid beneficiaries as well, to enable continuity of care and equal access to this important technology.

Comments received 9/15/2017 to 10/17/2017 Page 9 Center for Evidence-based Policy

HERC Coverage Guidance: Gene Expression Profiling for Prostate Cancer Disposition of Public Comments ID/# Comment Disposition E1 Genomic Health Inc, the lab that developed and performs the Oncotype DX® Thank you for your comments. Genomic Prostate Score (GPS) assay, wishes to provide the following information regarding the above referenced document. E2 The GPS improves health outcomes. The use of chain-of-evidence approaches and the cited clinical utility studies were considered by the subcommittee. To address the general theme in the review that there is little evidence The subcommittee believes that direct empirical evidence is demonstrating improved outcomes we provide the following chain of evidence to needed showing that the use of genome expression tests show how outcomes are improved by the GPS assay. results in improvement in patient-important outcomes. 1) There is a 30-40% discordance between the Gleason Score from the biopsy vs the All of the published clinical utility studies cited in the table Gleason Score determined at Radical Prostatectomy (RP)1,2 resulting in some patients were included in the coverage guidance and considered by being under-treated while some are overtreated. the subcommittee. 2) This discordance can be addressed by determining the likelihood of adverse The NCCN recommendations were reviewed in the coverage pathology from the prostate biopsy (Gleason Score >= 4 or the presence of pT3 guidance, as were the AUA/ASTRO/SUO recommendations, disease). which stated that genomic tests had not shown a clear role A. A high likelihood of Adverse Pathology (AP) accurately predicts poor long-term for the selection of patients for active surveillance (expert outcomes suggesting that immediate treatment may be the best course of opinion). treatment.3 B. Conversely a low likelihood of AP is associated with good long-term outcomes providing patients and physicians the confidence to choose Active Surveillance (AS)4,5 3) The GPS has been validated to accurately predict the likelihood of AP,6,7 biochemical recurrence6, metastasis and prostate cancer death.8 4) Major guidelines such as NCCN9 and AUA10 support use of AS in men with very- low, low, and a subset of intermediate-risk men

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HERC Coverage Guidance: Gene Expression Profiling for Prostate Cancer Disposition of Public Comments ID/# Comment Disposition 5) Appropriately selected men who undergo AS have very similar survival rates as do men treated with RP or radiation. 11-13 6) Men who undergo immediate treatment (RP or radiation) for Prostate Cancer (PCa) experience significant morbidity including erectile dysfunction and urinary incontinence. (REF Wilt) A. Low risk men who undergo GPS testing and chose AS avoid the adverse events of invasive treatments. 7) Clinical utility studies show that men who undergo GPS testing chose AS more often than untested men, show increased confidence in their choice of AS4 and have higher rates of persistence on AS at one year14 (see Table 2 below) 8) Use of GPS leads to greater adherence to guideline based management of low risk PCa as more men choose AS. E3 In addition to this chain of evidence we provide the below comments in response to The subcommittee shares the hope of the NCCN authors specific statements found in the draft review: that, “Future comparative effectiveness research may allow these tests and others like them to gain additional evidence Comment: Insufficient data to assess impact on prostate cancer mortality regarding their utility for better risk stratification of men Genomic Health Response: Due to the long-term nature of PCa this data will be with prostate cancer.” extremely difficult to obtain. NCCN8 acknowledges this on page MS-5 with the The limitations of the clinical utility studies establishing the statement regarding biomarkers “Although full assessment of their clinical utility increased use of active surveillance were reviewed in the requires prospective randomized trials, which are unlikely to be done…” coverage guidance. Increasing the use of active surveillance (AS) avoids complications such as impotence

and incontinence seen with invasive treatments without negatively impacting long

term outcomes (REF PIVOT and ProtecT studies). Table 2 below demonstrates that use of the assay consistently increases the use of AS as compared to cohorts that did not receive the assay.

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HERC Coverage Guidance: Gene Expression Profiling for Prostate Cancer Disposition of Public Comments ID/# Comment Disposition E4 Comment: Extensive industry involvement in studies Information on industry involvement in peer-reviewed scientific studies is offered to the subcommittee on the basis Genomic Health Response: All FDA approved drugs and devices are approved based of evidence that industry-sponsored trials are likely to on industry sponsored studies so industry sponsor studies are the norm, not the overstate the benefits of drugs, devices, and technologies exception. Regarding GPS, studies were all conducted under scientific protocols that independent of traditional risk-of-bias assessments. were IRB approved. We are not aware that any investigators had any equity interest in GHI and they were reimbursed for their study related efforts as investigators based on fair market value of the work effort provided. E5 Comment: For men with results indicating low risk, the preference to have a cancer Treatment recommendations may differ from the removed may still outweigh any reassurance provided by the test. treatments ultimately selected by patients. The limitations of the clinical utility studies were reviewed in the coverage Genomic Health Response: We have shown that treatment recommendations are guidance. directionally consistent with GPS results E6 Comment: We have very low confidence that they (genomic assays) actually change The Dall’ Era study was included in the coverage guidance management and considered by the subcommittee. Genomic Health Response: Dall’ Era5 showed rates of use of AS (not just treatment recommendations) were higher for men in each NCCN risk group who had a GPS vs baseline cases who did not have a GPS. E7 Comment: Use of these tests for treatment decisions may lower the rates of prostate Thank you for your comment. surgery and radiation treatments Genomic Health Response: The actual goal of a GPS assay is to steer the right patient to the right treatment.

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HERC Coverage Guidance: Gene Expression Profiling for Prostate Cancer Disposition of Public Comments ID/# Comment Disposition E8 Comment: Response to comment in Discussion section p. 8. Gene expression and Clinical validity studies were beyond the scope of this clinical risk factors are combined to predict the likelihood of adverse pathology coverage guidance. Genomic Health Response: The GPS assay has been validated not only for the likelihood of adverse pathology but also for the endpoints of biochemical recurrence, metastasis, and prostate 6,7,15 cancer death. E9 Table 2. Use of GPS consistently increases use of Active Surveillance As noted above, these studies were reviewed in the coverage guidance and considered by the subcommittee.

Dall’Era – citation 5 below. Albala citation 15 below. Eure citation 13 below.

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HERC Coverage Guidance: Gene Expression Profiling for Prostate Cancer Disposition of Public Comments ID/# Comment Disposition E10 Summary Thank you for your comments. Traditionally, prostate cancer treatment decisions have relied on clinical and pathologic factors (e.g., age, PSA level, biopsy Gleason Score). However, the biopsy derived Gleason Score is often inconsistent with surgical GS (REF). This disparity reduces confidence in biopsy findings to guide therapy and may result in over- utilization of invasive treatments with minimal survival benefit and significant potential for morbidity in men with indolent Prostate Cancer compared to Active Surveillance. (REF WILT). Conversely, some cancers that appear indolent based on pathologic factors may have occult aggressive features leading patients to opt for surveillance when a more aggressive approach is warranted. The GPS refines treatment planning by assessing underlying tumor biology and adding independent predictive information. Studies have shown that the GPS adds accuracy and clinical value in predicting important endpoints such as adverse pathology, biochemical recurrence, metastasis, and prostate cancer death. The use of the GPS test in prospective studies has been associated with increased utilization of AS (Table 2), decreased patient decisional conflict (REF Eure), and an 89% persistence on AS at one-year post-diagnosis in men who chose AS (REF Eure). Thank you for this opportunity to provide comments on this review.

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HERC Coverage Guidance: Gene Expression Profiling for Prostate Cancer Disposition of Public Comments F1 Us TOO International is a prostate cancer nonprofit that provides educational Thank you for your comments. resources and support services to the prostate cancer community at no charge. We The 2017 NCCN guidelines were included in the coverage are grateful for the opportunity to comment on the Health Evidence Review guidance and reviewed by the subcommittee. The relevant Commission’s “Gene Expression Profiling for Prostate Cancer” coverage guidance. As Medicare coverage determinations were also included in an advocate for patients diagnosed with prostate cancer, we strongly urge you to the coverage guidance and reviewed by the committee; cover gene expression profiling tests for prostate cancer, so that patients can have they are notable in that they require reporting of certain access to technology that has been proven to be beneficial in prostate cancer outcomes after testing, which acknowledges uncertainty treatment decision-making. about the long-term effects of decisions made on the basis There is an important need for prognostic biomarkers for biopsy confirmed prostate of these tests. cancer. Patients and physicians desire tools to provide support for their shared decision about the option of active surveillance for the individual patient. The consequences of definitive treatment and related side effects will frequently change a patient’s quality of life very significantly. Physicians use the results of these tests to make treatment recommendations as they provide useful additional information not available through clinical or pathological features. Gene expression profiling tests for prostate cancer have already been incorporated within influential societal guidelines. Page PROS-1 in Version 2.2017 of the Prostate Cancer Guidelines from the National Comprehensive Cancer Network (NCCN)1 shows that men with clinically localized disease may consider the use of tumor-based molecular assays. The Discussion Section outlines these tests and their published support. The Molecular Diagnostic Services Program of CMS (MolDX) has issued recommendations to cover Prolaris and OncotypeDX in patients with low-risk and favorable intermediate-risk prostate cancer for Medicare beneficiaries. We encourage the HERC HTA Subcommittee to recommend coverage for Medicaid beneficiaries as well, to enable continuity of care and equal access to this important technology.

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HERC Coverage Guidance: Gene Expression Profiling for Prostate Cancer Disposition of Public Comments G1 We represent the urologists of the State of Oregon, and encourage HERC to Thank you for your comments. recommend coverage for specific genomic testing for prostate cancer. The recommendations of the NCCN have been noted. These tests do not lend themselves to overuse, and have relatively specific The 2017 AUA/ASTRO/SUO guideline discussion offers indications. As the assays must be performed on prostate tissue (obtained by biopsy), additional cautions about the use of these tests: rather than simply a blood sample, this test will remain within the purview of the urologist. “Earlier identification of patients with co-existent higher- grade cancer is a major unmet need in the field. The We have found that observation, or "active surveillance" may be appropriate for challenge for tissue-based genetic tests is to provide more some patients whom we feel may have a prostate cancer with a lower likelihood of accurate risk stratification than currently available progression or spread. Our current clinical staging to make this determination optimally used clinical tools and predictive modeling in a (without genomic testing) is limited, and these assays may prevent unnecessary way that is reasonably cost effective. surgery, treatment complications, and expense. Conversely, they may indicate when observation is not appropriate and thus help us proceed with early definitive The role of tissue based genomic biomarkers for patients on treatment, and prevent expensive salvage therapy. active surveillance during follow up remains uncertain. RNA expression profiles of selected gene panels can be Definitive treatment for prostate cancer (surgery and/or radiation) can occasionally performed on small samples of cancer in biopsy specimens result in significant complications, or may be insufficient. We have found that our to predict prognosis more accurately. Genomic analyses of current risk assessment using pathologic stage, grading system and PSA values alone prostate cancer reveal distinct patterns of alterations in the have their limitations. Genomic testing has been helpful in these situations where genotype that may predict prognosis more accurately. treatment may be advisable but not entirely obvious. While such assays have sufficient analytic and clinical Current recommendations by the National Comprehensive Cancer Network (NCCN) validity, their clinical utility in active surveillance remains allow for the inclusion of genomic assays for determination of risk of tumor to be established. In particular, these assays were validated progression. The NCCN does acknowledge, as do we, that our best evidence is a in the pre-MRI era. Their incremental value in the context of prospective randomized controlled trial. However, given the general slower clinical men who have had a mpMRI is unclear. An additional course of prostate cancer, coupled with the relatively smaller numbers of patients for concern regarding the use of biopsy-based molecular which these tests are appropriate, these studies are extremely difficult to obtain. The biomarkers is the sampling error inherent in prostate biopsy following statement is an excerpt from these NCCN guidelines: "...the panel believes given known tumor heterogeneity. that men with clinically localized disease may consider the use of tumor-based molecular assays at this time." The proportion of men whose clinical risk category is substantially altered by molecular tests, particularly in Comments received 9/15/2017 to 10/17/2017 Page 16 Center for Evidence-based Policy

HERC Coverage Guidance: Gene Expression Profiling for Prostate Cancer Disposition of Public Comments ID/# Comment Disposition In discussion of American Urological Association’s Guideline for management of men with low-risk disease, is relatively minor. However, in clinically localized prostate cancer, in Guideline Statement 32, they emphasize the the future these assays may have the greatest incremental potential utility of this testing – value at the time of diagnosis in reassuring selected men who have ‘low-risk’ (versus very low-risk) disease (for "... these assays may have the greatest incremental value at the time of diagnosis in example, men with extensive Gleason 6 cancer and/or high reassuring selected men who have ‘low-risk’ (versus very low-risk) disease (for PSA density, or a strong family history of early death from example, men with extensive Gleason 6 cancer and/or high PSA density, or a strong prostate cancer); and in those in whom clinical findings are family history of early death from prostate cancer); and in those in whom clinical discordant with the pathological findings on follow up (for findings are discordant with the pathological findings on follow up (for example, men example, men with a PI-RADS 4-5 lesion on MRI whose with a PI-RADS 4-5 lesion on MRI whose targeted biopsy is negative or shows only targeted biopsy is negative or shows only Gleason 6 Gleason 6 cancer)." cancer).” [emphasis added] Medicare recipients currently receive coverage for these tests, and we feel that our The relevant Medicare coverage determinations were patients under Medicaid should have similar access. included in the coverage guidance and reviewed by the We have enclosed additional opinions from other Oregon physicians who have committee; they are notable in that they require reporting utilized this testing. The Oregon Urological Society is keenly aware of the need to of certain outcomes after testing, which acknowledges practice economical medicine and we will continue to strive to contain costs. Our uncertainty about the long-term effects of decisions made hope is that the Oregon Health Authority will continue to cover and allow for this on the basis of these tests. testing, and that we may work collaboratively to guide the appropriate utilization. Thank you very much for this consideration. We hope you will continue to partner with us in the arena of men's health in the state of Oregon. Please feel free to contact us with any other questions or concerns.

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HERC Coverage Guidance: Gene Expression Profiling for Prostate Cancer Disposition of Public Comments ID/# Comment Disposition H1 I find these tests helpful in counseling patients with low to intermediate risk prostate Thank you for your comments. cancers. They help confirm the risk group and make expectant management more comfortable for my patients. I have also had patients in who observation was recommended by Medical Oncology but the Decipher test suggested higher risk disease (which was confirmed on final pathology). Lastly, the Decipher post op test is helpful in terms of determining when to use adjuvant XRT.

Comments received 9/15/2017 to 10/17/2017 Page 18 Center for Evidence-based Policy

HERC Coverage Guidance: Gene Expression Profiling for Prostate Cancer Disposition of Public Comments I1 It has come to my attention that the Health Evidence Review Commission for Oregon Thank you for your comments. The subcommittee (HERC) has issued a recommendation strongly against coverage for prostate cancer appreciates input from practicing clinicians on their use of genomic testing. I wish to offer some input on this issue given that depriving patients these tests. of this testing would cause significant harm. Secondly, restricting access to this The subcommittee shares the author’s concern about the testing would prevent urologists from offering modern cancer care relative to the limitation of the clinical utility literature and the need for rest of the country. This would result in an efflux of patients from the state to clinical evidence of oncological outcomes. centers where advanced care is offered. First, we can all agree that genomic testing at this time has a limited role in clinical management. I specifically use it in 2 clinical scenarios. The first scenario is in patients being considered for active surveillance. Data support that the number needed to treat to prevent one prostate cancer death in patients with low risk disease is approximately 8. In my experience I have seen several low risk patients on surveillance progress to high risk disease, with one having metastatic progression. I conduct Decipher testing when sufficient tissue is present in the biopsy. Similar to reported data, I have found that about 10% of these patients have high risk Decipher genomic test scores. If the test score is low they can be safely observed. If the test score is high then I recommend primary therapy. The second scenario is in patients after prostatectomy who demonstrate PSA recurrence. Decipher testing is able to discern between patients who require salvage radiotherapy alone versus those who need combined androgen deprivation therapy and radiotherapy. In select patients with slowly progressing recurrence and a low genomic test score I will recommend no salvage therapy at all. Using genomic testing I have been able to spare many patients from the morbidity and cost these varied treatments. Genomic testing is the future of prostate cancer management. While Decipher testing currently provides an index for disease aggressiveness, it will expand to include indicators of radiosensitivity and hormonal sensitivity. This will allow treatment to be tailored to individual tumor biology. I expect that use of this

Comments received 9/15/2017 to 10/17/2017 Page 19 Center for Evidence-based Policy

HERC Coverage Guidance: Gene Expression Profiling for Prostate Cancer Disposition of Public Comments ID/# Comment Disposition information will be FDA-approved for management purposes within the next 5 years. Denying patients access to this testing would be a tremendous disservice. I would caution against reliability of several of the sources used by HERC to formulate their recommendation. Any survey study has potential for bias. Furthermore, the review processes for third tier journals such as Current Medical Research and Opinion and Reviews in Urology are lax and unscientific. Urology Practice is a monthly news report rather than a peer-reviewed journal. Many of these journals accept articles that were rejected from more reputable journal such as Journal of Urology or European Urology. Also, it should be mentioned that data pertaining to oncologic outcomes should be used as the basis for recommendations. In this case HERC seems to focus on the outcome of how it influences treatment which is not a valid way to determine the clinical benefit of new testing. Genomic testing in appropriate patients is not optional. It is emerging as standard of care. Denying coverage for this testing is unethical and unjustifiable. Doctors do not profit from this testing so there is no perverse incentive to over-test. I would caution HERC to heed the lessons of PCPT recommendations against PSA screening. In that case use of poor data resulted in misguided recommendations and great societal harm. Similarly, HERC is currently using unreliable and limited data to make a blanket recommendation against genomic testing. The best path forward would be to consult with urologists who are versed in the data to establish clear indications for testing.

Comments received 9/15/2017 to 10/17/2017 Page 20 Center for Evidence-based Policy

HERC Coverage Guidance: Gene Expression Profiling for Prostate Cancer Disposition of Public Comments J1 I am the President of the National Alliance of State Prostate Cancer Coalitions, Thank you for your comments. (NASPCC), a 501(c)(3) not-for-profit umbrella organization comprised of many state The peer-reviewed clinical utility literature was reviewed by prostate cancer organizations across the U.S., meaning that we represent a very large the subcommittee. number of prostate cancer patients across the country. The 2017 NCCN guidelines were included in the coverage Our patients have a pressing need to make informed decisions regarding both testing guidance and reviewed by the subcommittee. The relevant and treatment. The better informed the patients, the better their shared decision• Medicare coverage determinations were also included in making and the better the results. Biomarkers are among the types of information the coverage guidance and reviewed by the committee; that can dramatically help guide prostate cancer patients and their physicians in they are notable in that they require reporting of certain deciding the best course of action for them. outcomes after testing, which acknowledges uncertainty Prognostic biomarkers in the prostate cancer are especially important because their about the long-term effects of decisions made on the basis use can prevent overtreatment of an indolent cancer that will never metastasize or of these tests. cause death. Unneeded or excessive treatment exacts a huge toll in both medical and human costs, and impacts quality of life. Too often patients undergo active treatment and suffer side effects, when they would have been good candidates for active surveillance had they had the benefits of biomarker testing. It is crucial to note that biomarkers such as gene expression profiling tests like Prolaris can be a tool to help avoid overtreatment by showing which cancers do not require surgery or radiation – that is to say, when active surveillance would be an appropriate option. NASPCC is concerned about Medicaid patients' access to biomarker testing (including gene expression profiling tests, such as Prolaris). Prolaris has been well-studied and validated and has appeared in published, peer-reviewed articles. Prolaris is already covered by Medicare, and physicians need to be consistent in their care across their practice to cover the same tests for their non-Medicare patients, including Medicaid patients. And further, guidelines such as the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology Prostate Cancer Version 2.2017, support its use.

Comments received 9/15/2017 to 10/17/2017 Page 21 Center for Evidence-based Policy

HERC Coverage Guidance: Gene Expression Profiling for Prostate Cancer Disposition of Public Comments ID/# Comment Disposition We ask that HERC support the availability of biomarker testing for patients covered by Medicaid. Please feel free to contact me with any questions.

Comments received 9/15/2017 to 10/17/2017 Page 22 Center for Evidence-based Policy

HERC Coverage Guidance: Gene Expression Profiling for Prostate Cancer Disposition of Public Comments

References Provided by Commenters References C 1. Simon RM et al. Use of Archived Specimens in Evaluation of Prognostic and Predictive Biomarkers. J Natl Cancer Inst 2009;101: 1446 – 1452. 2. Harris LN, Ismaila N, McShane LM, et al; American Society of Clinical Oncology. Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women with Early-Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2016 Apr 1;34(10):1134-50. 3. Crawford ED, Scholz MC, Kar AJ, et al. Cell cycle progression score and treatment decisions in prostate cancer: results from an ongoing registry. Curr Med Res Opin 2014 Jun; 30(6):1025-31. 4. Shore N, Kella N, Moran B, et al. Impact of the cell cycle progression test on physician and patient treatment selection for localized prostate cancer. J Urol 2016 March; 195:612-18. 5. Cuzick J, Berney DM, Fisher G, et al. Transatlantic Prostate Group. Prognostic value of a cell cycle progression signature for prostate cancer death in conservatively managed needle biopsy cohort. Br J Cancer 2012 Mar 13; 106(6):1095-9. 6. Cuzick J, Stone S, Fisher G, et al. Validation of an RNA cell cycle progression score for predicting death from prostate cancer in a conservatively managed needle biopsy cohort. Br J Cancer. 2015; 113:382–9. 7. Klotz L, Vesprini D, Sethukavalan P, et al. Long-term follow-up of a large active surveillance cohort of patients with prostate cancer. J Clin Oncol 2015; 33:272. 8. Center for Medical Technology Policy (CMTP) Effectiveness Guidance Document: Evaluation of Clinical Validity and Clinical Utility of Actionable Molecular Diagnostic Tests in Adult Oncology. May 1, 2013. Accessed May 10th 2017 at http://www.cmtpnet.org/docs/resources/MDX_EGD.pdf 9. Deverka P, et al. Generating and evaluating evidence of the clinical utility of molecular diagnostic tests in oncology. Genet Med. 2016 Aug;18(8):780-7. 10. Donovan JL, Hamdy FC, Lane JA, et al. Patient-reported outcomes after monitoring, surgery or radiotherapy for prostate cancer. N Engl J Med 2016; 375(15):1425-37. 11. Barocas DA, Alvarez J, Resnick MJ, et al. Association between radiation therapy, surgery, or observation for localized prostate cancer and patient-reported outcomes after 3 years. JAMA 2017; 317(11): 1126-40. 12. Chen RC, Basak R, Meyer A, et al. Association between choice of radical prostatectomy, external beam radiotherapy, brachytherapy, or active surveillance and patient-reported quality of life among men with localized prostate cancer. JAMA 2017; 317(11): 1141-50. 13. Jeldres C, Cullen J, Hurwitz LM, et al. Prospective quality of life outcomes for low-risk prostate cancer: active surveillance versus radical prostatectomy. Cancer 2015; 121:2465-73. 14. Wilt TJ, Brawer MK, Jones KM, et al. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med 2012; 367:203-13. 15. Wilt TJ, Jones KM, Barry MF, et al. Follow-up of prostatectomy versus observation for early prostate cancer. N Engl J Med. 2017;377:132-42.

Comments received 9/15/2017 to 10/17/2017 Page 23 Center for Evidence-based Policy

HERC Coverage Guidance: Gene Expression Profiling for Prostate Cancer Disposition of Public Comments References 16. Hamdy FC, Donovan JL, Lane JA, et al; ProtecT Study Group. 10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer. N Engl J Med. 2016 Oct 13;375(15):1415-1424. 17. MolDX-CDD: Prolaris Prostate Cancer Genomic Assay (L36350), effective October 15, 2015. Available at www.cms.gov/medicare-coverage-database/ 18. MolDX: Prolaris Prostate Cancer Genomic Assay for Men with Favorable Intermediate Risk Disease (L37082), effective September 25, 2017. Available at www.cms.gov/medicare-coverage-database/ 19. Crawford ED, Stone S, Reid J, et al. Patient NCCN risk classification based on combined clinical cell cycle risk (CCR) score. J Urol. May 16, 2017; 197(4S):e1268. 20. Maurice MJ, et al. Research letter: Current status of prostate cancer diagnosis and management in the United States. JAMA Oncol. 2016; 2(11):1505-7. E 1. Epstein A, Zelefsky MJ, Sjoberd DD et.at. Contemporary Prostate Cancer Grading System: A Validated Alternative to the Gleason Score Eur Urol. 2012 May ; 61(5): 1019 -1024. 2. Pinthus JH, Witkos M, Fleshner NE, et al. Prostate cancers scored as Gleason 6 on prostate biopsy are frequently Gleason 7 tumors at radical prostatectomy: implication on outcome. Journal of Urology. 2006;176(3):979-84. PMID: 16890675 3. Kozminski MA, Tomlins S, Cole A et al. Standardizing the definition of adverse pathology for lower risk men undergoing radical prostatectomy Urol Oncol. 2016 Sep;34:415.e1-6. PMID: 27140065 4. Badani KK, Kemeter MJ, Febbo PG, et al. The impact of a biopsy based 17-gene Genomic Prostate Score on treatment recommendations in men with newly diagnosed clinically prostate cancer who are candidates for active surveillance. Urology Practice. 2015;2(4):181-9. 5. Dall'Era M, Maddala T, Polychronopoulos L, et al. Utility of the Oncotype DX prostate cancer assay in clinical practice for treatment selection in men newly diagnosed with prostate cancer: a retrospective chart review analysis. Urology Practice. 2015;2(6):343 -8. 6. Cullen J, Rosner IL, Brand TC, et al. A biopsy-based 17-gene Genomic Prostate Score predicts recurrence after radical prostatectomy and adverse surgical pathology in a racially diverse population of men with clinically low- and intermediate-risk prostate cancer. Eur Urol. 2014;68(1):123-31. PMID: 26723180 7. Klein EA, Cooperberg MR, Magi-Galuzzi C, et al. A 17-gene assay to predict prostate cancer aggressiveness in the context of Gleason grade heterogeneity, tumor multifocality, and biopsy undersampling. Eur Urol. 2014;66(3):550-60. PMID: 24836057 8. Van den Eeden S, Zhang N, Shan J, et al. A diagnostic biopsy-based Genomic Prostate Score as an independent predictor of prostate cancer death and metastasis in men with localized prostate cancer. Presented at the American Urologic Association meeting; May 2017; Boston, MA. 9. NCCN Prostate Cancer Guidelines version 2.2017 February 21 2017 10. AUA Clinically Localized Prostate Cancer: AUA/ASTRO/SUO Guideline 2017 11. Hamdy FC, Donovan JL, Lane JA et.al. 10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer. N Engl J Med. 2016 Oct 13;375(15):1415-1424. doi: 10.1056/NEJMoa1606220. Epub 2016 Sep 14. PMID: 27626136 12. Wilt TJ, Brawer MK, Jones KM, et al. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med. 2012;367(3):203-13. PMID: 22808955

Comments received 9/15/2017 to 10/17/2017 Page 24 Center for Evidence-based Policy

HERC Coverage Guidance: Gene Expression Profiling for Prostate Cancer Disposition of Public Comments References 13. Wilt TJ, Jones KM, Barry MJ, et.al. Follow-up of Prostatectomy versus Observation for Early Prostate Cancer. N Engl J Med. 2017 Jul 13;377(2):132-142. doi: 10.1056/NEJMoa161586. PMID: 28700844 14. Eure G, Germany R, Given R, et al. Use of a 17-gene prognostic assay in contemporary urologic practice: results of an interim analysis in an observational cohort. Urology. 2017 Apr 25. PMID: 28454985. 15. Albala D, Kemeter MJ, Febbo PG, et al. Health economic impact and prospective clinical utility of Oncotype DX Genomic Prostate Score. Rev Urol. 2016;18(3):123-132. PMID: 27833462 F 1. https://www.nccn.org/professionals/physician_gls/f_guidelines.asp#prostate G National Comprehensive Cancer Network. (2017). NCCN clinical practice guidelines in oncology: Prostate cancer. Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf Sanda, M. G., Chen, R. C., Crispino, T., Freedland, S., Greene, K., Klotz, L. H., … Cadeddu, J. A. (2017). Clinically localized prostate cancer: AUA/ASTRO/SUO Guideline. Retrieved from http://www.auanet.org/guidelines/clinically-localized-prostate-cancer-new-(aua/astro/suo-guideline-2017)

Comments received 9/15/2017 to 10/17/2017 Page 25 Center for Evidence-based Policy

Section 5.0 Conflict of Interest 2018 Conflict of Interest 2018

Question: Conflict of Interest 2018

Question source: HERC Staff

Issue: HERC’s existing conflict of interest form has some ambiguities. The attached form is an attempt to keep the conflict of interest form brief, simple and relevant. It includes a separate version for ad hoc experts (limited by topic).

Highlights:  Clarifies purpose is transparency, as most members and experts have some conflicts inherent in their roles which also give them relevant expertise.  Separate boxes for interests related to employment, serving patients affected by decisions and research on topics of interest.  Specifies minimum amounts of financial conflicts requiring disclosure ($200 personally or to family member; $1,000 to employer; 5 percent equity stake).  Specifies exclusions for retirement funds, service from advisory committees, review panels, etc. if the group sponsoring the committee or panel does not have advocacy positions related to the topics.  Similar exclusions for speaking engagements for groups without advocacy positions.  Makes transparent that HERC staff will check Dollars for Docs and CMS Open Payments, which collect reported financial transactions with certain industry groups.  Allows for disclosure of important non-financial interests.

Recommendations: Adopt new conflict of interest forms for members and ad hoc experts. The forms shown in the packet will be adapted so that they can be filled out using an online form.

Conflict of Interest 2018, Issue #1358 Page 1

DRAFT—HERC Disclosure Form

HERC ad hoc expert conflict of interest form

This conflict of interest form is designed for transparency in the perspective of appointed ad hoc experts who serve as volunteers for the Commission. We recognize that most experts are employed in a field related to the topic under consideration or have personal beliefs which will influence their testimony. This form allows the Commission and the public to better understand each expert’s perspective and the incentives they may be experiencing. We encourage full responses and explanations to provide the best understanding possible.

Topic: ______

Expert Name: ______

Employer(s)/Business(es): ______

Job Title(s): ______

Clinical/Academic Specialty (if relevant):______

Occupation/Employment

How does the topic relate to your principal occupation or employment (For instance, do you provide the service in question? □ Yes □ No Do you work for a manufacturer or another organization whose financial interests may be affected by the decision at hand? □ Yes □ No Do you serve patients who have the condition for which this service may be considered? □ Yes □ No Do you perform research on this service or condition? □ Yes □ No Other conflict related to occupation or employment? □ Yes □ No): Please explain each Yes answer above: ______

Financial Interests (other than remuneration for principal occupation)

 Only report financial relationships or interactions if they cumulatively total ≥ $200 personally or to your spouse or children, $1,000 in funds paid to your employer or institution on your behalf, or if they represent a 5 percent equity stake in an organization.  Report financial transactions with any stakeholder whose interests could be affected by topic at hand.  Include transactions within the last 36 months or planned future transactions. DRAFT—HERC Disclosure Form

You do NOT need to disclose:

 Income from mutual funds or retirement funds;  Income from service on advisory committees or review panels for public or nonprofit entities without advocacy positions related to the topic;  Income from seminars, lectures, or teaching engagements sponsored by public or nonprofit entities without advocacy positions related to the topic;  Income from public funding sources, such as government agencies.

Please describe these potential conflicts in the table below:

Date Payment Company or organization Services you Additional amount or provided information ownership share

Are there any errors in publicly available sources of interest on conflicts of interest (e.g. Dollars for Docs, CMS Open Payments) that HERC staff should be aware of? If so, please explain.

______

Non-financial interests

Most appointees will have strongly-held beliefs about a topic under discussion. As an aid to transparency, we request a brief explanation of any affiliations or positions which may be important in understanding your perspective.

Please describe any important non-financial interests you have in the topic, including research, publications, personal experiences, professional/personal affiliations or strongly-held beliefs relevant to the topic at hand which may affect your ability to work or comment on the topic in an unbiased manner:

______

______DRAFT—HERC Disclosure Form

I certify that the information above is true and complete. I am aware that HERC routinely searches publicly available sources for conflicts of interest which would be reportable on this form; the results of these searches will be provided to the Commission and Staff.

Name:

Date: DRAFT—HERC Disclosure Form

HERC Commission/Subcommittee conflict of interest form

This conflict of interest form is designed for transparency in the perspective of members of the Commission and its subcommittees. We recognize that most experts are employed in a field related to the topic under consideration or have personal beliefs which will influence their testimony. This form allows the Commission and the public to better understand each expert’s perspective and the incentives they may be experiencing. We encourage full responses and explanations to provide the best understanding possible.

Type of appointment (Commission, subcommittee): ______

Expert Name: ______

Employer(s)/Business(es): ______

Job Title(s): ______

Clinical/Academic Specialty (if relevant):______

Occupation/Employment

How does your principal occupation or employment relate to the work of the Commission?

Might your employment or how you do your job be affected by the Commission’s decisions? □ Yes □ No Do you work for a manufacturer or another organization whose financial interests may be affected by the Commission’s work? □ Yes □ No Do you have patients or clients who may be affected? □ Yes □ No Do you perform research related to the Commission’s work? □ Yes □ No Other conflict related to occupation or employment? □ Yes □ No):

Please explain each Yes answer above: ______

Financial Interests (other than remuneration for principal occupation)

DRAFT—HERC Disclosure Form

 Include transactions within the last 36 months or planned future transactions.

You do NOT need to disclose:

Please describe these potential conflicts in the table below:

Date Payment Company or organization Services you Additional amount or provided information ownership share

Are there any errors in publicly available sources of interest on conflicts of interest (e.g. Dollars for Docs, CMS Open Payments) that HERC staff should be aware of? If so, please explain.

______

Non-financial interests

______

DRAFT—HERC Disclosure Form

______

Name:

Date: