2025-00548. Supplemental Evidence and Data Request on The Performance of Fusion Procedures for Degenerative Disease of the Lumbar Spine

Table 1—EPC Proposed PICOTS and Corresponding Inclusion and Exclusion Criteria Key Questions 1,2,3 and 4 on Surgery

	Inclusion	Exclusion
Population	Key Questions (1-3) • Symptomatic adult patients with a radiographic diagnosis (based on dynamic (flexion and extension radiographs) of degenerative lumbar spondylolisthesis (any grade) who remain symptomatic following conservative treatment • Patients with or without evidence of nerve compression (radiculopathy, neurogenic claudication) KQ 1 • Stable (non-mobile, static) DLS (<3 mm slip on extension/flexion radiographs) KQ 2, 3 • Patients with unstable or stable DLS on radiographs KQ 4 • Patients with symptomatic degenerative lumbar spine disease undergoing fusion of 5 or fewer levels (stratify by presence of DLS)	ALL Key Questions • Patients <18 years old. • Asymptomatic patients. • Other forms of spondylolisthesis are excluded ( i.e., excluding dysplastic, isthmic, traumatic, and pathologic causes/forms). • Patients with osteoporosis, vertebral compression fractures. • Exclude pts undergoing revisions or repeat procedures. • Patients having reoperation/repeat procedures. KQs 1-3 • Patients without degenerative spondylolisthesis. • Studies with <80% of patients have spondylolisthesis. KQ 1 • Patients with unstable (dynamic) DLS: (exclude study if stable is not specified, is unclear).
Interventions	ALL Key Questions • FDA approved devices or materials (or in Phase III trials) as applicable to the KQ • Open and minimally invasive ( e.g., endoscopic) procedures KQ 1 • Decompression (discectomy, indirect and direct methods) with instrumented spinal fusion ( e.g., with pedicle screws, interbody cages, or other hardware) KQ 2 • Surgical decompression and instrumented posterolateral fusion ( e.g., using pedicle screws) with addition of interbody cage (expandable or static, ALIF, TLIF, LLIF) KQ 3 • Decompression and spinal fusion using bone graft extenders or biologic substitutes (demineralized bone matrix, cadaveric allograft, cortical fibers, bone morphogenic protein, cellular allografts KQ 4 • IONM (Motor Evoked Potentials (MEP), Somatosensory Evoked Potentials (SSEP), Free Running EMG (electromyography) Direct Stimulation	ALL Key Questions • Devices or materials that are not FDA approved or in Phase III trials (as applicable to the question) or not available in the U.S. • Mesenchymal stem cells (MSCs) • Procedures that don't include decompression • Non-instrumented fusions • Coflex, interspinous fixation • Minimally invasive lumbar decompression (MILD) procedure • Surgical procedures not listed KQ 4 • Other monitoring formats ( e.g., imaging, computer assisted navigation systems, etc.) • Combinations of graft materials (other than with autograft) • Comparison of graft materials with each other
( print page 3216)
Comparators	ALL Key Questions • FDA approved devices or materials (or in Phase III trials) as applicable to the KQ • Open and minimally invasive ( e.g., endoscopic) procedures KQ 1 • Decompression alone KQ 2 • Decompression and instrumented posterolateral spinal fusion ( e.g., using pedicle screws alone) KQ 3 • Decompression and instrumented spinal fusion using autograft KQ 4 • No use of IONM	ALL Key Questions • Conservative care, non-operative care, usual care • Devices or materials that are not FDA approved or in Phase III trials (as applicable to the question) or not available in the U.S. • Mesenchymal stem cells (MSCs) KQ 1 • Other surgical procedures KQ 2, 3 • Non-instrumented fusion, • Instrumentation prior to 2000 • Coflex, interspinous fixation KQ 3 • Combinations of graft materials with autograft
Outcomes	ALL Key Questions • Validated measures for pain and symptoms ○ Pain ( e.g., VAS) ○ Function ( e.g., ODI) ○ Quality of Life ( e.g., SF-36, SF-12) • Peri- and post-operative harms (including serious AEs/harms, persistent pain, sacro-iliac joint pain, instrument failure) Additional outcomes by KQ KQ 1: Reoperation rates KQ 2: Fusion (arthrodesis) rates KQ 3: Fusion (arthrodesis) rates KQ 4: Persistent neurological damage based on clinical exam ( e.g., foot drop)	ALL Key Questions • Measures of pain, function that are not validated • Measures/outcomes not listed • Radiographic parameters ( e.g., evidence of global spinal alignment)
Timing	Key Questions 1-3 • Pain, function, reoperation: 3, 6 and ≥12 months (up to 60 months) • Reoperation-any time (KQ 2): • Harms: any time KQ 4 • Any time during post-operative followup	KQ 1 • Re-operation beyond 12 months KQs 1-3 • Outcomes measured less than 3 months (except harms) KQ 4 • Alerts and responses to alerts during surgery
Settings	ALL Key Questions • Inpatient care followed by care in specialty and primary care clinics • Outpatient ambulatory surgery centers
Study designs	ALL Key Questions • RCTs for effectiveness/efficacy outcomes • FDA SSED if there is inadequate information from published studies • Studies published in 2000 or later KQ 1-3: NRSIs will be considered for harms only and must be specifically designed to evaluate/report on AE/harms and control for confounding and focused on rare or long-term harms. KQ 4: NRSIs on effectiveness and harms	ALL Key Questions • NRSI that do not control for confounding • NRSI that include historical controls • NRSI of treatment with fewer than 50 patients per treatment arm • Case reports, case-series, single-arm and pre-post studies • Publication types: Conference abstracts or proceedings, editorials, letters, white papers, citations that have not been peer-reviewed, single site reports of multi-site studies • Studies published prior to 2000 • Studies not in English KQ 1-3 • Trials with fewer than 15 patients per treatment arm
Serious adverse events are defined as events that are life-threatening or require additional medical attention. AE = adverse event; ALIF = anterior lumbar interbody fusion; DLS = degenerative lumbar spondylolisthesis; EQ-5D = EuroQol 5D scale; FDA = Food and Drug Administration; IONM = intraoperative neurological monitoring; KQ = Key Question; LLIF = lateral lumbar interbody fusion; MCID = minimum clinically important difference; NRSI = nonrandomized studies of intervention; ODI = Oswestry Disability Index; RCT = randomized controlled trial; RMD = Roland-Morris Disability Questionnaire; SSED = Summary of Safety and Effectiveness Data; SF-36/12 = Short Form 36 or 12 questionnaire; TLIF = transforaminal lumbar interbody fusion; U.S. = United States; VAS = visual analog scale.

KQ 5 and 6: Questions on Non-Surgical Procedures for Chronic Low Back Pain Due To Degenerative Spine Disease

Key Question 5. In adult patients with chronic low-back pain (≥3 months) resulting from degenerative disease what are the benefits and harms of lumbar epidural steroid injections, intra-articular (facet) injection, medial branch blocks, or radio frequency ablation?

Key Question 6. In adult patients with chronic low-back pain (≥3 months) resulting from degenerative disease of the lumbar spine, does symptomatic improvement to therapeutic challenge with lumbar epidural steroid injections, intra-articular (facet) injection, medial branch blocks or radio frequency ablation predict positive outcomes after lumbar fusion surgery?

Special populations and factors for Key Questions 5 and 6: Age, sex, BMI, presence of psychological comorbidities, presence of medical comorbidities, baseline pain severity, presence and type of concomitant degenerative lumbar spine disease, presence and severity of DLS. ( print page 3217)

Table 2—EPC Proposed PICOTS and Corresponding Inclusion and Exclusion Criteria: Key Questions 5 and 6 on Specific Procedures in Patients With Chronic Low Back Pain Due To Degenerative Spine Disease

	Inclusion	Exclusion
Population	KQ 5, 6 • Adult patients with chronic low-back pain (≥3 months duration) resulting from degenerative disease	KQ 5, 6 • Patients with acute or subacute LBP • Patients with disc herniation • Patients with failed back surgery syndrome • Sacroiliac pain • Patients having reoperation
Interventions	KQ 5, 6 • Epidural steroid injections (ESI) • Intra-articular (facet) injections • Radiofrequency Ablation (RFA) • Medial branch blocks	KQ 5, 6 • Discoblock, provocative discography • Neuromodulation ( e.g., spinal cord, dorsal column, dorsal root stimulation, peripheral nerve stimulation) • Injections: exclude other biologics ( e.g., PRP), intradiscal injections • Minimally invasive lumbar decompression (MILD), percutaneous decompression • Selective nerve root blocks • Intraosseous basivertebral nerve ablation • Combinations of procedures; Studies evaluating additive benefits of one procedure with another
Comparators	KQ 5 • Other nonoperative treatment, no treatment, sham KQ 6 • No therapeutic challenge; (prognostic/predictive modeling study)	KQ 5, 6 • Combinations of procedures; Studies evaluating additive benefits of one procedure to another KQ 5 • For ESI, exclude comparison with disc procedures ( e.g., discography); comparisons of medications • For RFA exclude comparisons of different types of neurotomy (conventional vs. pulsed [cooled] RF; RF vs. alcohol ablation)
Outcomes	KQ 5 and 6: Harms ( e.g., serious peri-procedural and post-procedural harms) KQ 5 • Validated measures for pain and symptoms ○ Pain ( e.g., VAS, NRS) ○ Function ( e.g., ODI) ○ Quality of Life ( e.g., SF-36, SF12) KQ 6 • Response to challenge: Improvement in symptoms vs. non-improvement; [stratify other outcomes by response] • Validated measures for pain and symptoms following fusion surgery ○ Pain ( e.g., VAS, NRS) ○ Function ( e.g., ODI) ○ Quality of Life ( e.g., SF-36, SF-12) ○ Symptoms associated with neural compression • Successful arthrodesis [as radiographically determined via x-ray/computed tomography or by proxy ( e.g., lack of revision, pedicle screw loosening)]	KQ 5, 6 • Measures of pain, function that are not validated • Measures/outcomes not listed
Timing	KQ 5 and 6 • Serious harms—periprocedural KQ 5 • 3-month and 6-month periods following the procedure KQ 6 • Outcomes measured at 3, 6 and ≥12 months after surgical procedure (up to 24 months)
Settings	KQ 5 • Outpatient KQ 6 • Outpatient care for therapeutic challenge. Inpatient care followed by care in specialty and primary care clinics for surgical procedure • Outpatient ambulatory surgery centers for surgery
( print page 3218)
Study designs	KQ 5 • RCTS for effectiveness/efficacy outcomes • Prospective NRSIs that control for confounding will be considered for effectiveness in the absence of RCTs • NRSIs for harms must be specifically designed to evaluate/report on serious AE/harms and that control for confounding OR focused on rare or long-term harms KQ 6 • Predictive/prognostic modeling studies evaluating the association of procedure response impact on outcomes that control for confounding	KQ 5, 6 • NRSI that do not control for confounding • NRSI that include historical controls • NRSI with fewer than 50 patients per treatment arm • Case reports, case-series, single-arm and pre-post studies • Publication types: Conference abstracts or proceedings, editorials, letters, white papers, citations that have not been peer-reviewed, single site reports of multi-site studies • Studies not in English
Serious adverse events are defined as events that are life-threatening or anything needing additional medical attention. AE = adverse event; DLS = degenerative lumbar spondylolisthesis; EQ-5D = EuroQol 5D scale; ESI = epidural steroid injection; FDA = Food and Drug Administration; IONM = intraoperative neuro monitoring; KQ = Key Question; LBP = low back pain; MCID = minimum clinically important difference; NRSI = nonrandomized studies of intervention; ODI = Oswestry Disability Index; RCT = randomized controlled trial; RF = radiofrequency ablation; RMD = Rolland-Morris Disability Questionnaire; SSED = Summary of Safety and Effectiveness Data; SF-36/12 = Short Form 36 or 12 questionnaire; VAS = visual analog scale.