Regulation of Peripheral Nerve Stimulation Technology.

BACKGROUND: Greater occipital neuralgia (GON), a cause of chronic headaches, can be debilitating and vastly affect one’s quality of life. Recent strides in comprehending the pathophysiology of GON and the ongoing evolution of approaches to the condition’s treatment have led to the pursuit of more effective interventions. Among these, temporary peripheral nerve stimulation (PNS) devices have surfaced as an avenue for management, presenting a minimally invasive yet highly efficient alternative in treating other chronic pain conditions. This study discusses a case of GON successfully managed with temporary (60-day) PNS. CASE REPORT: A 35-year-old man presented with a nearly 8-month history of intractable headaches without any inciting event along the left greater occipital nerve distribution. The patient underwent a series of 2 diagnostic GON blocks and experienced 90% pain relief. A 60-day PNS device was implanted to treat the patient’s left-side GON, and during the 6-month period, the patient received 75% pain with no complications. CONCLUSIONS: Temporary PNS is a promising treatment for painful mononeuropathies. Most PNS devices are implanted permanently to provide benefits, but this new development allows temporary stimulation devices to manage chronic pain. This case demonstrates another potential therapeutic option for pain management providers to alleviate pain in patients suffering from GON. KEY WORDS: Peripheral nerve stimulation, occipital neuralgia, chronic headache, neuromodulation, pain medicine

e18501 Background: Cancer clinical trials based in the United States (US) have lacked adequate representation of racial and ethnic minorities, the elderly, and women. Pivotal clinical trials leading to United States Food and Drug Administration (FDA) approval are often multi-national trials and may also lack generalizability to underrepresented populations in the United States. We determined the racial, ethnic, age, and sex enrollment in pivotal trials relative to the US cancer population. Methods: We reviewed the FDA’s Drug Approvals and Databases for novel and new use drug approvals for breast, colorectal, lung, and prostate cancer indications from 2008 through 2020. Drugs@FDA was searched for drug approval summaries and FDA labels to identify clinical trials used to justify clinical efficacy that led to FDA approval. For eligible trials, enrollment data were obtained from FDA approval summaries, FDA labels, ClinicalTrials.gov, and corresponding journal manuscripts. Enrollment Fraction (EF) was calculated as enrollment in identified clinical trials divided by 2017 SEER cancer prevalence. All data sources were publicly available. Results: From 2008 through 2020, 60 drugs received novel or new use drug approval for breast, colorectal, lung, or prostate cancer indications based on 66 clinical trials with a total enrollment of 36,830. North America accounted for 9,259 (31%) enrollees of the 73% of trials reporting location of enrollment. Racial demographics were reported in 78% of manuscripts, 66% of ClinicalTrials.gov pages, and 98% of FDA labels or approval summaries. Compared with a 0.4% enrollment fraction among White patients, lower enrollment fractions were noted in Hispanic (0.2%, odds ratio [OR] vs White, 0.46; 95% confidence interval [CI], 0.43 to 0.49, P< 0.001) and Black (0.1%, OR 0.29; 95% CI 0.28 to 0.31, P< 0.001) patients. Elderly patients (age ≥ 65 years) were less likely than younger patients to be enrollees (EF 0.3% vs 0.9%, OR 0.27; 95% CI 0.26 to 0.27, P< 0.001) despite accounting for 61.3% of cancer prevalence. For colorectal and lung cancer trials, females were less likely than males (EF 0.7% vs 1.1%, OR 0.66; 95% CI 0.63 to 0.68, P< 0.001) to be enrolled. Conclusions: Black, Hispanic, elderly, and female patients were less likely to enroll in cancer clinical trials leading to FDA approvals from 2008 to 2020. Race and geographic enrollment data were inconsistently reported in journal manuscripts and ClinicalTrials.gov. The lack of appropriate representation of specific patient populations in these key clinical trials limits their generalizability. Future efforts must be made to ensure equitable access, representation, and reporting of enrollees that adequately represent the US population of patients with cancer.

Section Editors: Marc Fisher MD Antoni Davalos MD The Food and Drug Administration (FDA) evaluates applications for new human drugs, biologics, and complex medical devices. Companies must obtain FDA approval to legally market these products. In August, the FDA gave Concentric Medical clearance to market its Merci Retriever system to “remove blood clots from the brain in patients experiencing an ischemic stroke.” Given that the FDA is charged with “protecting the public health by assuring the safety, efficacy, and security of… biological products and medical devices…, ” “advancing public health by helping to speed innovations that make medicines … more effective, safer, and more affordable,” and “helping the public get the accurate, science-based information they need to use medicines … to improve their health,”1 the FDA’s decision to approve the Merci Retriever system is of concern. The pathways to approval are reviewed by Felten et al in the accompanying article and are outlined in Figure 1. Figure 1. Potential pathways for device approval. The decision to approve the Merci Retriever was based on data from the MERCI (Mechanical Embolus Removal in Cerebral Ischemia) Trial; the approval was granted through the 510(k) process. The Merci Retriever system includes a flexible nickel titanium (nitinol) wire that obtains a helical shape once it is passed through the tip of the guidance catheter. In practice, the catheter/wire is passed distal to the thrombus, the catheter is removed, and the helical configuration assumed by the wire; the clot is then trapped in the helix and withdrawn from the vasculature (Figure 2). The 510(k) clearance means that the Merci Retriever was felt to be substantially equivalent to a predicate device. In this case, the predicate device was the Concentric Retriever, which itself received 510(k) clearance by the FDA in May 2001 for “use in …

Several studies have estimated the financial inputs for successful drug development. Such analyses do not capture the large investment that patient study participants commit to drug development. To estimate the volume of patients required to achieve a first US Food and Drug Administration (FDA) approval for a new anticancer drug or biologic therapy. This cohort study included a random sample of prelicense oncology drugs and biologics with a trial site in the United States that were launched into clinical efficacy testing between January 1, 2006, and December 31, 2010. Drugs and biologics were identified using ClinicalTrials.gov registration records. Total patient enrollment was captured over an 8-year span, and each intervention was classified based on whether it received FDA approval and was deemed as having intermediate or substantial value according to the American Society of Clinical Oncology Value Framework (ASCO-VF) score. Secondarily, the association between patient numbers and intervention characteristics was tested. Data were analyzed in February 2020. The prespecified primary outcome was the number of patients enrolled in prelicense trials per FDA approval. A total of 120 drugs and biologics were included in our study, with 84 (70.0%) targeted agents, 20 (16.7%) immunotherapies, and 71 (59.2%) novel agents. A total of 13 drugs and biologics (10.8%; 95% CI, 5.3%-16.8%) in our sample gained FDA approval within 8 years, of which 1 (7.7%) was deemed of intermediate value and 3 (23.1%) were deemed of substantial value using ASCO-VF scoring. Overall, 158 810 patients were enrolled in 1335 trials testing these drugs and biologics, 47 913 (30.2%) in trials that led to FDA approval and 110 897 (69.8%) in trials that did not. An estimated 12 217 (95% CI, 7970-22 215) patient study participants contributed to prelicense trials per FDA approval. The estimated number of patients needed to produce a single FDA-approved drug or biologic of intermediate or substantial ASCO-VF clinical value was 39 703 (95% CI, 19 391-177 991). The results of this cohort study make visible the substantial patient investment required for prelicense oncology drug development. Such analyses can be used to devise policies that maximize the clinical impact of research on a per-patient basis.

e18202 Background: Patient-reported outcomes (PROs) are increasingly valued as a key tool in patient-focused treatment decisions. However, a lack of standardization leads to significant variability in PRO collection and reporting in ground-breaking clinical trials of novel agents. We sought to characterize the mechanisms of assessment and variability by which PROs are reported for newly approved anti-cancer therapies. Methods: We reviewed the U.S. Food and Drug Administration (FDA) approvals between 2011 and 2017 for anti-cancer new molecular entities (NMEs) and new biologic approvals (BLAs). For each therapy, the pivotal clinical trial leading to FDA approval was identified using the national clinical trial (NCT) number and assessed for inclusion of PROs. A separate PubMed search was conducted to evaluate for PRO publication distinct from the original trial based on national clinical trial registry number. Results: From 2011 to 2017, the FDA approved 66 NMEs/BLAs based on 74 clinical trials for cancer treatment. Of the 74 clinical trial publications, 21 (28%) of the trials published PRO data in their original clinical publication, 18 (24%) published a separate PRO analysis, and 35 (47%) did not publish PRO data in either format. Among the 32 clinical trials (43%) that listed PROs as pre-specified outcomes, 72% published PROs (23/32). The separate PRO analyses (N = 18) were published considerably later following FDA approval (mean 605 days) than the original clinical trials (mean 20 days, N = 74, P < 0.001). Conclusions: As cancer treatment options expand, therapy decisions become increasingly nuanced. PROs assist decision-making by providing detailed information on important aspects of quality of life and tolerability. Our research has identified a significant lag in the publication of companion studies of PRO data associated with pivotal clinical trials, representing a meaningful gap in information critical to patients and oncologists in the process of making informed decisions.

should decrease pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR), without affecting systemic arterial pressure (SAP), and potentially improve oxygenation by redistributing pulmonary blood flow to ventilated areas of lung. INO (INO Therapeutics Inc., Clinton NJ) possesses these properties and has gained approval from the Food and Drug Administration (FDA) for the care of neonates with acute lung injury and pulmonary hypertension (PH), and widespread clinical acceptance (but not FDA approval) for adults with PH with or without lung injury. Delivered as a gas, INO is preferentially distributed to the ventilated areas of the lung, where it produces relaxation of pulmonary vascular smooth muscle via activation of guanylate cyclase and the conversion of guanosine-5-triphosphate to cyclic guanosine monophosphate. 1 Absorbed INO is rapidly inactivated by hemoglobin, thereby preventing systemic effects and confining its vasodilator properties to the pulmonary circulation. 1 The search for inhaled selective pulmonary vasodilators was an active area of research, particularly in Europe and Australia, before the widespread publicity and testing of INO in the early 1990s. However, research on this subject appears to have declined inversely with the growing acceptance and use of INO. Until FDA approval had been granted, INO had been supplied free of charge in the United States on an investigational-drug basis. However, after FDA approval, the cost of treatment with INO became very expensive. This prompted a search at our institution for alternative agents to INO. The purpose of this article is to review the published experience concerning alternative inhaled vasodilators and, when possible, compare their reported efficacy with that of INO.

Introduction

As new devices and technologies specifically designed for peripheral nerve stimulation (PNS) emerge, they promise a number of potential advantages over current PNS devices or spinal cord stimulation (SCS) devices currently used for PNS applications. One emerging trend is the miniaturization of the PNS system itself. Such devices present several advantages over larger devices, such as decreased trauma from surgery; easier, less invasive placement; the lack of extensive tunneling in some patients; and reduced discomfort from the size and weight of the internal pulse generator (IPG) once it has been implanted. The miniaturization of the device may also make it possible to treat conditions that have been untreated up to the present time because of the disadvantages or difficulties using existing systems. PNS devices are also currently being tested that use leads made from more flexible materials than traditional neurostimulation leads. Lead flexibility may decrease the chance of lead fracture or migration.

Chronic pain is a growing problem across the world, and in the midst of an opioid epidemic, it is imperative that alternative treatment measures are identified to help alleviate the pain experienced by these patients. Chronic pain greatly affects ones quality of life and many patients do not experience adequate relief with conventional treatment measures. The purpose of this retrospective analysis is to assess the efficacy of peripheral nerve stimulation (PNS) therapy in adult patients suffering from chronic pain refractory to conventional treatment measures who underwent therapy on various anatomical locations. This retrospective analysis consisted of data collected from electronic health records for n = 89 patients who underwent PNS therapy. Data collected relates to patient age, sex, weight, height, body mass index (BMI), diagnosis, targeted nerves, follow-up encounters, pain scores from before and after PNS therapy, and duration of improvement. Statistical analysis used SPSS software, version 26 (IBM), using a paired ttest to assess significance between pre and post PNS therapy pain scores. P values were significant if found to be ≤ 0.05. Further analysis assessed the correlation between age and BMI with visual analog scale (VAS) pain improvement and subjective percentage pain relief. The mean pre-operative (pre-op) pain score before PNS therapy was 6.36 (standard deviation (SD) = 2.18, SEM = 0.23) and the mean post-operative (post-op) pain score after PNS therapy was 4.19 (SD = 2.70, SEM = 0.29). The mean patient-reported percent improvement in pain following PNS therapy was 49.04% (SD = 34.79). The improvement in pain scores between pre-op and post-op was statistically significant (M = 2.17, SD = 2.82, SEM = 0.30, t(88) = 7.26, p < .001), 95% confidence interval (CI) [1.57, 2.76]. The mean duration of improvement for patients was 123days after therapy initiation (min = 6, max = 683, SD = 126). This study demonstrated the potential role for PNS therapy in improving patient-reported pain levels for various neuropathies, targeting various nerves. With PNS therapy's use as a chronic pain treatment and available research being limited, further study needs to be done on the efficacy of PNS therapy for pain management and complications associated with PNS device placements at various locations.

Over 20% of adults are affected by chronic shoulder pain that can limit the use of the upper extremity and decrease the overall quality of life. Peripheral nerve stimulation (PNS) is an emerging treatment for refractory cases of chronic pain that has been receiving heightened attention in recent years with growing documentation of favorable results. This report discusses a case of chronic shoulder pain effectively managed with PNS. A 58-year-old man, with a history of cervical laminectomy presented with persistent pain of the left shoulder, radiating down the medial aspect of the left upper arm to the elbow, and pain along the upper trapezius between the neck and shoulder that did not ease after successful shoulder joint replacement. The pain averaged 8/10 and escalated to 10/10 with arm movement or lifting over 5 pounds. Once agitated, the pain would stay elevated for several hours. The patient eventually withdrew completely from social activities and stopped leaving his home except when absolutely necessary to avoid additional pain brought on by activity. Previous treatments, including physical therapy, opioids, nonsteroidal anti-inflammatory drugs (NSAIDS), and cervical epidural steroid injection, were unsuccessful in managing pain. The patient did, however, achieve relief with peripheral nerve stimulation. Pain scores at 3-month follow-up decreased from 8/10 without and 10/10 with activity to an average of 1/10 with increased activity, complete cessation of pain medication, and reported improvement in quality of life. These results have been maintained at 12 months post-implant. Sub-threshold peripheral nerve stimulation with an externally powered system at the suprascapular and supraclavicular nerves was an effective treatment for a patient suffering from debilitating pain in the shoulder, upper arm, and upper trapezius after a successful, structurally sound shoulder replacement did not reduce persistent chronic pain.

e20550 Background: Soon after the publication of the PACIFIC trial, the Food and Drug Administration (FDA) approved durvalumab following definitive chemoradiation in patients with unresectable stage III non-small cell lung cancer (NSCLC). However, patterns of durvalumab adoption within the United States are currently unknown. We investigated the pace of uptake of durvalumab as well as patient and tumor characteristics associated with receipt of durvalumab following FDA approval. Methods: This study used the nationwide Flatiron Health database, a longitudinal electronic health record-derived de-identified database. During the study period, the de-identified data originated from approximately 280 US cancer clinics (̃800 sites of care). From this de-identified database, we selected patients with stage IIIB-C NSCLC who completed at least two cycles of first-line (1L) platinum doublet chemotherapy between February 16, 2018 (FDA approval date for durvalumab) and August 16, 2019, and did not develop disease progression over a follow-up period of at least 120 days after 1L chemotherapy. In the absence of radiation therapy and surgery details in the database, these criteria served as a proxy for selecting patients who were most likely to be eligible for consolidative durvalumab. We evaluated temporal trends in the uptake of durvalumab after completion of 1L chemotherapy using the Cochran-Armitage test, clustering the time periods in 3-month intervals. We also characterized patient and tumor characteristics associated with durvalumab receipt using the chi-square test and multivariable logistic regression. Results: A total of 424 patients were included in our study sample, among whom 282 (66.5%) patients had documentation of having received durvalumab after 1L chemotherapy. Within the first 3 months after FDA approval, 60.4% of potentially eligible patients received durvalumab, while in the final 3 months of the study period, this proportion rose modestly to 68.3% (p = 0.19). On univariable and multivariable analysis, patient characteristics like age, sex, race, insurance, smoking status, performance status, and comorbidity score, as well as tumor characteristics like histology, EGFR status, and PD-L1 status, were not significantly associated with receipt of durvalumab. However, there was significant geographic variability in receipt of durvalumab, ranging from 65.7% in the South to 85.3% in the Midwest (chi-square p = 0.04). Conclusions: Early adoption of durvalumab upon completion of 1L chemotherapy for stage IIIB-C lung cancer was rapid across the United States, starting at over 60% in the first three months after FDA approval. Regional variation appears to be a more powerful driver than patient characteristics in discrepancies of durvalumab dissemination. Further exploration into these regional variations may help improve guideline-concordant care.

Use of Gabapentin and Pregabalin for Hand Surgery Patients

Background: Peripheral nerve stimulators (PNS) are an option when medications, injections, physical therapy, and transcutaneous electrical stimulation are not effective. Rotator cuff muscle disorders and acromioclavicular or glenohumeral joint pathologies commonly lead to chronic shoulder pain. However, this case report documents a PNS treating chronic shoulder pain following traumatic humeral fracture. Case Report: Our patient presented years after her orthopedic team recommended nonoperative management for her traumatic humeral fracture. She described pain at rest (3-5/10), which was exacerbated by forward flexion and abduction (9/10). After her PNS, she noted greater than 80% pain relief (rating it a 3/10), as well as improved range of motion and improved pain with movement, 4/10 with movement. Conclusion: This case is the first report of PNS use for traumatic humeral fracture, when the patient’s clinical status precluded operative intervention. Our patient reported satisfaction with her pain relief and improved range of motion. Key words: Peripheral nerve stimulation (PNS), neuromodulation, interventional pain, chronic shoulder pain, shoulder pain, chronic pain, humeral fracture, trauma

Novel minimally invasive short-term and long-term peripheral nerve stimulation (PNS) systems have revolutionized targeted treatment of chronic neuropathic pain. We present an international survey of PNS-implanting pain physicians to assess what factors they consider when offering permanent PNS. This cross-sectional study consisted of a survey (Qualtrics) that was distributed to PNS-implanting physicians in a device supplier's entire email database on November 13, 2020, with 3weeks of response time. Physicians' contact information in the form of their email addresses had been previously collected by the supplier upon device distribution with permission to use survey responses for research. Of 2032 database physicians, 40 physicians representing 37 institutions responded to the survey. The most common application of PNS was mononeuropathic pain (57%). The most frequently targeted nerve was the suprascapular nerve (29%). 14% of physicians reported 81-100% of their implants were dual-lead. The representative physicians ranged broadly in their most frequently targeted nerves. Although mononeuropathic pain was the most common indication for PNS, there was still varied response regarding other indications such as CRPS and post-surgical chronic pain. In context of a low response rate, identifying such factors can help update the prevailing treatment algorithm for interventional therapies, assist pain physicians in better identifying which patients are the best candidates for PNS, and inform future clinical trial design on PNS efficacy.

e13655 Background: Over the past decades, US congress enabled the US Food and Drug Administration (FDA) to facilitate and expedite drug development for serious conditions filling unmet medical needs with five special designations: orphan, fast track, accelerated approval, priority review, and breakthrough therapy. It remains unclear whether multiple designations per indication are redundant. This study analyzes cancer drugs with multiple special designations regarding their FDA approval timelines, evidence, benefit, epidemiology and price. Methods: All anti-cancer drugs and their supplemental indication approvals were identified in the Drugs@FDA database from 2000 to 2022. For each indication, clinical trial characteristics, epidemiologic, and price data were collected from FDA labels, the Global Burden of Disease Study, and Medicare &amp; Medicaid Part B and D, respectively. The association between overall survival (OS) and progression-free survival (PFS) hazard ratios (HR) and drug indications’ number of special designations were compared in meta-analyses and meta-regressions. Results: We identified 170 anti-cancer drugs with FDA approval in 455 indications. The median time to first FDA approval was 13.8 years for drugs with zero, 7.3 years with one, 7.1 years with two, 7.8 with three, 5.8 with four, and 5.3 with five special designations (HR per additional designation: 1.27, 95%CI: 1.09-1.48, p=.002). Drug indications with more special designations were more frequently granted to rare diseases with fewer treatment options supported by smaller and shorter open-label phase 1/2 trials. OS HRs were 0.79 for indications with zero, 0.74 with one, 0.73 with two, 0.69 with three, 0.59 with four, and 0.52 with five special designations (p=.024). On average, each additional special designation was associated with lower HRs for OS (ß=-0.03, p=.002) and PFS (ß=-0.07, p&lt;.001). Each additional special designation was associated with a 19.05% (95%CI: 4.56-35.55, p=.013) higher drug price. Conclusions: The FDA’s special designations are non-redundant. Multiple special designations are associated with faster approval times and a greater efficacy for patients with high unmet needs, while multiple special designations are associated with less robust trial evidence and higher drug prices. This study supports the strategy of special FDA designations for unmet clinical needs.