Post-marketing Study Research Articles

The MANTRA study: a new umbrella concept prospectively applied to assess implantable medical devices for heart valve procedures

BackgroundClinical evidence is commonly obtained through individual trials that are time-, cost- and resource-consuming, and which often leave unanswered clinically relevant questions. Umbrella studies have been developed to address the need for more efficient and flexible trial structures, predominantly for cancer treatments. The umbrella concept foresees data collection within a unifying trial structure, to which one or more substudies may be added at any time to address product- or therapy-specific questions. To our knowledge, the umbrella concept has not yet been used in the medical device area, but it may offer similar advantages as in other settings, particularly in areas where multiple therapies are available within one large treatment area.MethodsThe MANTRA study (NCT05002543) is a prospective, global, post-marketing clinical follow-up study. The aim is to collect safety and device performance data covering the Corcym cardiac surgery portfolio for the treatment of aortic, mitral, and tricuspid valve diseases. The study uses a master protocol that outlines the main common parameters, and the specific questions are addressed in three substudies. The primary endpoints are device success at 30 days. Secondary endpoints include safety- and device performance-related data at 30 days, 1 year, and then annually through to 10 years. All endpoints are defined according to the more recent guidelines for heart valve procedures. Additionally, procedure and hospitalization information are collected, including Enhanced Recovery after Surgery in sites using such protocols, and patient outcome measures such as New York Heart Association classification and quality-of-life questionnaires.ResultsThe study started in June 2021. Enrollment in all three substudies is ongoing.ConclusionsThe MANTRA study will provide contemporary information on the long-term outcomes of medical devices for the treatment of aortic, mitral, and tricuspid heart valve diseases in routine clinical practice. The umbrella approach adopted in the study has the potential of longitudinally assessing long-term efficacy of the devices and the flexibility to investigate new research questions as they arise.

IQOS® Cross-Sectional and Cohort US Study Documentation

BACKGROUND: The FDA’s modified risk authorization for IQOS® is contingent upon approved post-market surveillance studies. The IQOS® Cross-Sectional Post-Market Adult Consumer Study (hereinafter termed IQOS® CS PACS) and the IQOS® Longitudinal Cohort Post-Market Adult Consumer Study (hereinafter termed IQOS® LC PACS) are contiguous surveys designed to fulfill this proviso. OBJECTIVES: IQOS® CS PACS seeks to assess tobacco use patterns in IQOS® users, risk perceptions of IQOS®, and tobacco transition and cessation behaviors related to IQOS®. The IQOS® LC PACS aims to follow over time, and in comparison with cigarette users, these same parameters with additional emphasis on transitions and health outcomes. METHODS AND RESULTS: The IQOS® CS PACS is a repeated cross-sectional study to be conducted annually for four years. The IQOS® LC PACS is a longitudinal study, planned to follow a cohort of new IQOS® users for two years. Potential adult IQOS® consumers aged 21 and older will be recruited from an IQOS® consumer database. Both studies will use self-administered online screening and survey assessment. At least 250 adult ever established IQOS® users (current and former) constitute the target sample size for each administration of the IQOS® CS PACS. The target sample size for the IQOS® LC PACS is 2,100 adult IQOS® users and 1,600 adult cigarette smokers as control. Data analysis includes descriptive statistics for pre-defined outcomes and inferential statistics (e.g., generalized estimating equations and propensity scoring) to compare outcomes among IQOS® and cigarette smokers. The IQOS® CS PACS is designed to commence one year after IQOS® modified risk tobacco product authorization (MRTPA) and will recur annually over the course of four years. The IQOS® LC PACS will begin two years after issuance of the IQOS® modified risk order and has been designed to follow up with participants at 3-, 6-, 12-, 18-, and 24-months from initiation. Final reports will be generated and shared with the FDA when the studies are completed. CONCLUSIONS: Postmarket studies can help inform outcomes related to risk perceptions, tobacco use patterns, and health status related to IQOS® use in a real-world setting.

Abstract 5063: Optimizing benefit/risk in oncology: Review of post marketing dose optimization

Abstract Introduction: Molecularly targeted (MTAs) and immune-oncology (IO) agents are more selective with wider therapeutic window than cytotoxic agents resulting in maximal activity at doses < MTD. However, these agents commonly selected the MTD (or highest tested dose) which is assessed using dose-limiting toxicities in escalating doses in limited number of patients/dose. This led to several post-marketing requirement (PMR) studies to evaluate alternative dosing regimens to optimize the benefit-risk. Methods: Post-marketing dose optimization studies (required by FDA or sponsor initiated) for oncology MTAs/IO agents were reviewed. These studies/analyses were classified in to attempts to improve efficacy, safety, or ‘life cycle management’ (ie, fixed vs body size-based dosing, favorable route of administration, or extending the dosing interval). Approvals 1999-April/2022 were evaluated using FDA review documents and published literature. PMR studies for organ impairment, DDI, or food effect were excluded. Results: Overall, 27 (16 MTAs and 9 IO) out 126 FDA oncology approvals reviewed were identified to have conducted post-approval dose optimization studies (27/126, 21.4%). Dose optimization studies were either efficacy-driven (n = 4), safety-driven (n = 13), or to improve method of administration (ie, IV to SC route; body-weight to fixed dosing; less dosing frequency) (N = 14). Efficacy-driven PMRs evaluated a higher dose either for the overall population (1/4) or for a subgroup with lower exposure (3/4); the latter cases showed no clear benefit in this subgroup vs case-matched subgroup from the control arm. No changes of label dosing recommendations resulted from efficacy-driven PMRs. All safety-driven PMRs which evaluated lower doses were for drugs with a positive exposure-safety relationship and most had a flat exposure-efficacy relationship (9/13, 69%) suggesting that a lower dose might improve safety without compromising efficacy. Completed safety-driven PMR studies resulted in changing the approved dose in 2/7 cases (29%). Lower doses were commonly associated with better safety profiles, however, establishing efficacy non-inferiority vs approved doses was typically not successful except in 1 case where non-inferiority was met for the primary endpoint of overall survival; this did not lead to label change as secondary endpoints, eg, PFS, favored the higher dose.Attempts to improve method of administration tended to be feasible and resulted in a successful change of the label dose for drugs with relatively flat exposure-efficacy and safety profiles and with adequate efficacy/safety data at multiple dose levels. Conclusion: Our results suggest that safety or efficacy-driven post-marketing dose optimization studies were rarely successful in changing the label dose. Dose optimization could be more important for drugs with a steep exposure-safety relationship and a flat exposure-efficacy relationship. Citation Format: Pooneh Soltantabar, Hoi-Kei Lon, Kourosh Parivar, Diane Wang, Mohamed Elmeliegy. Optimizing benefit/risk in oncology: Review of post marketing dose optimization. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5063.

Radiofrequency Ablation Provides Rapid and Durable Pain Relief for the Palliative Treatment of Lytic Bone Metastases Independent of Radiation Therapy: Final Results from the OsteoCool Tumor Ablation Post-Market Study

PurposeThe OsteoCool Tumor Ablation Post-Market Study (OPuS One) was a prospective, multi-national, single-arm study to investigate safety and effectiveness of radiofrequency ablation (RFA) for palliation of painful lytic bone metastases with 12 months of follow-up. RFA has demonstrated effective palliation of osseous metastases in small clinical studies with short-term follow-up; however, a long-term assessment with robust subject numbers is lacking.Materials and MethodsProspective assessments were conducted at Baseline, 3 days, 1 week, and 1, 3, 6, and 12-months. Pain and quality of life were measured prior to RFA and postoperatively using the Brief Pain Inventory, European Quality of Life—5 Dimension, and European Organization for Research and Treatment of Cancer Care Quality of Life Questionnaire for palliative care. Radiation, chemotherapy and opioid usage, and related adverse events were collected.Results206 subjects were treated with RFA at 15 institutions in OPuS One. Worst pain, average pain, pain interference and quality of life significantly improved at all visits starting 3 days post-RFA and sustained to 12 months (P < 0.0001). Post hoc analysis found neither systemic chemotherapy nor local radiation therapy at the index site of RFA influenced worst pain, average pain, or pain interference. Six subjects had device/procedure-related adverse events.ConclusionRFA for lytic metastases provides rapid (within 3 days) and statistically significant pain and quality of life improvements with sustained long-term relief through 12 months and a high degree of safety, independent of radiation.Level of Evidence: 2b, Prospective, Non-Randomized, Post-Market studyThis journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Cervical Disc Arthroplasty vs Anterior Cervical Discectomy and Fusion at 10 Years: Results From a Prospective, Randomized Clinical Trial at 3 Sites

Over the past 20 years, multiple randomized controlled trials have shown cervical disc arthroplasty (CDA) to be safe and effective for treating 1- and 2-level degenerative disc disease (DDD). The purpose of this postmarket study is to compare 10-year outcomes between CDA and anterior cervical discectomy and fusion (ACDF) from a randomized study at 3 centers. This study was a continuation of a randomized, prospective, multicenter clinical trial comparing CDA with the Mobi-C cervical disc (Zimmer Biomet) vs ACDF. Following completion of the 7-year US Food and Drug Administration study, 10-year follow-up was obtained from consenting patients at 3 high-enrolling centers. The clinical and radiographic endpoints collected at 10 years included composite success, Neck Disability Index, neck and arm pain, short form-12, patient satisfaction, adjacent-segment pathology, major complications, and subsequent surgery. A total of 155 patients were enrolled (105 CDA; 50 ACDF). Follow-up was obtained from 78.1% of patients eligible after 7 years. At 10 years, CDA demonstrated superiority to ACDF. Composite success was 62.4% in CDA and 22.2% in ACDF (P < 0.0001). The cumulative risk of subsequent surgery at 10 years was 7.2% vs 25.5% (P = .001), and the risk of adjacent-level surgery was 3.1% vs 20.5% (P = .0005) in CDA vs ACDF, respectively. The progression to radiographically significant adjacent-segment pathology at 10 years was lower in CDA vs ACDF (12.9% vs 39.3%; P = 0.006). At 10 years, patient-reported outcomes and change from baseline were generally better in CDA patients. A higher percentage of CDA patients reported they were "very satisfied" at 10 years (98.7% vs 88.9%; P = 0.05). In this postmarket study, CDA was superior to ACDF for treating symptomatic cervical DDD. CDA was statistically superior to ACDF for clinical success, subsequent surgery, and neurologic success. Results through 10 years demonstrate that CDA continues to be a safe and effective surgical alternative to fusion. The results of this study support the long-term safety and effectiveness of cervical disc arthroplasty with the Mobi-C.

Real-world five-year outcomes of FlexyRap® cobalt-chromium rapamycin-eluting stents with biodegradable polymer in patients with de-novo coronary artery disease.

The use of biodegradable polymer drug-eluting stents (BP-DES) has been proven to minimize restenosis and stent thrombosis. The current post-marketing monitoring was observed at the 5-year clinical outcomes of individuals who had been treated with FlexyRap® DES in the real world. To assess the safety and effectiveness of FlexyRap® DES at the 5-year follow-up in real-world settings. Findings from a retrospective, multi-center, observational, post-market clinical follow-up study of patients treated with FlexyRap® DES for de novo coronary artery disease (CAD) were reported. During the 12-mo follow-up, the primary endpoint was target lesion failure, which was defined as the composite of cardiovascular death, target vessel myocardial infarction (TV-MI), and clinically driven target lesion revascularization. The data of 500 patients received with FlexyRap® DES was obtained at the completion of the surveillance timeline of 5-year. After the implantation of FlexyRap® DES, the device success rate was 100%. Adverse events that led to major bleeding, permanent disability, or death were not experienced in the patients. The major adverse cardiac event rate at 12-mo, 3-year, and 5-year follow-up was 1 (0.2%), 0 (0%), and 1 (0.2%) respectively with 0 (0%) cardiovascular death, 2 (0.4%) TV-MI, and 0 (0%) TLR compositely. Furthermore, late stent thrombosis was found in 2 (0.4%) patients at the follow-up of 12-mo, very late stent thrombosis was observed in 2 patients (0.4%) at 3-year follow-up. FlexyRap® DES was proved to be safe and efficacious in real-world patients with de novo CAD, indicating a lowered rate of cardiac events and stent thrombosis at 5-year follow-up.

12-Month clinical and radiographic outcomes of ViBone viable bone matrix in patients undergoing cervical and lumbar spinal fusion surgery

BackgroundTo investigate the clinical safety and efficacy of ViBone® Viable Bone Matrix (VBM), a next generation cellular bone matrix allograft that comprises all three essential bone-forming components: osteogenic, osteoinductive, and osteoconductive factors, and is optimized to enhance cell viability and bone formation.MethodsThis was a multi-center, prospective, post-market study evaluating the safety and efficacy of ViBone VBM in patients undergoing 1–3 level anterior cervical discectomy and fusion or lumbar interbody fusion surgery. Patients were evaluated at baseline, 6-month, and 12-month follow-up clinically and radiographically. Clinical assessment included Visual Analog Scale for pain (VAS-pain), the Neck Disability Index (NDI) for patients with cervical pathologies, and the Oswestry Disability Index (ODI) for patients with lumbar pathologies. Fusion success defined by an independent radiologist was determined radiographically by plain films.ResultsClinical outcomes evaluated with VAS-pain, NDI, and ODI scales were improved significantly at 6 and 12 months compared to baseline. All patients reached clinically significant improvements at 12 months. There were no adverse events or infections attributed to ViBone VBM. At 12 months, the fusion rate per patient was 88.1% in cervical and 97.6% in lumbar patients, while per-level fusion was 98.5% for cervical and 100% for lumbar segments.ConclusionsPatients undergoing cervical and lumbar spinal fusion implanted with ViBone VBM demonstrated favorable outcomes at 6 months and 12 months as measured by subjective clinical measures and radiographic fusion rates.Trial registration This study was registered as NCT03425682 on 1/29/2018.

Impact of Balya Protex Powder on Fatigue Levels in Patients with Diabetes Mellitus Adhering to the Ayurveda-Based Comprehensive Diabetic Care Program

Chronic fatigue in diabetic patients can be the outcome of protein deficiency. Plant based protein is closer to nature and bodily acceptable, hence we chose to assess plant-based protein “Balya Protex Powder” over whey protein. A prospective, multicentre, post-market study was conducted in India. Patients with a diagnosis of diabetes mellitus aged 18 years and above were included in this study. All patients adhered to the Comprehensive Diabetic Care (CDC) Program. Comparative data of change in fatigue score was collected retrospectively from type 2 diabetes mellitus patients assigned a low carbohydrate low calorie diet for 90 days. A total of 101 patients were included in this study, 50 patients consumed the Balya Protex Powder whilst 51 did not consume the Balya Protex powder whilst adhering to the CDC program. Weight of the patients decreased by 7.92% and 5.52% in the Balya Protex Powder consumption and Balya Protex Powder non-consumption group, respectively. Body mass index decreased by 5.93% and 5.18% in the Balya Protex Powder consumption and Balya Protex Powder non-consumption group, respectively. Abdomen girth decreased by 8.39% and 4.67% in the Balya Protex Powder consumption and Balya Protex Powder non-consumption group, respectively. Weakness grade decreased by 83.69% and 47.61% in the Balya Protex Powder consumption and Balya Protex Powder non-consumption group, respectively. All patients showed significant reduction in glycated hemoglobin (HbA1c) levels, however patients in the subgroup who were taking 30 gm of Balya Protex Powder daily showed 50% greater reduction in chronic fatigue score. It can be concluded that Balya Protex Powder consumption leads to good glycemic control with reduced fatigue in diabetic patients whilst adhering to the CDC program.

Revisiting Latex Gloves in Healthcare - A Post-Market Clinical Study

Sterile Surgical Gloves are worn to prevent contamination of the patient during invasive procedures and they help prevent surgical site infections and reduce the risk of exposure to blood and body fluid pathogens for the healthcare worker. The purpose of the study was to evaluate the safety and performance of Sterile Latex Surgical Gloves- Powdered and Powder Free, Sterile Latex Gynaecological Gloves- Powdered and Powder Free. Overall, 976 subjects participated in the study, out of which sterile latex surgical gloves were used by the users in 288 cases. Sterile latex surgical gloves powder free was used by users in 291 cases. Sterile Latex Gynaecological Gloves Powdered were used by users in 201 cases and Sterile Latex Gynaecological Gloves Powder Free was used in196 cases. From the clinical safety parameter analysis, sterile latex surgical gloves were safe to use and none of the users reported safety-related issues. The overall rating given by the user for product performance was excellent for all the products. All the users agreed that the product is meeting the product quality. The overall rating given by the user for product satisfaction is Excellent. None of the users have reported any undesirable events. Keywords: gloves, latex, allergy, healthcare workers

Remimazolam Compared to Propofol During Hysteroscopy: A Safety and Efficacy Analysis.

Propofol is the main drug used to induce sedation for endoscopic procedures, and few drugs had shaken its dominant clinical use for a decade until the development of remimazolam. Remimazolam has been demonstrated to perform well in post-marketing studies on sedation for colonoscopy or other procedures requiring short periods of sedation. This study aimed to establish whether remimazolam was effective and safe for inducing sedation for hysteroscopy. One hundred patients who were scheduled to undergo hysteroscopy were randomly assigned to receive induction with remimazolam or propofol. A dose of 0.25mg/kg remimazolam was administered. Propofol was started at 2-2.5mg/kg. Before remimazolam or propofol induction, 1μg/kg fentanyl was infused. Hemodynamic parameters, vital signs, and bispectral index (BIS) values were measured and adverse events recorded to evaluate safety. We comprehensively evaluated the efficacy and safety of the two drugs by the success rate of induction, fluctuation of vital signs, depth of anesthesia, adverse reactions, recovery time, and other indicators. Information on 83 patients was successfully recorded and carefully documented. The success rate of sedation in the remimazolam group (groupR) was 93%, which was lower than for the propofol group (groupP) (100%), but there was no statistically significant difference between the two groups. The incidence of adverse reactions in groupR (7.5%) was significantly lower than that in groupP (67.4%), and the results were statistically significant (P < 0.01). The fluctuation of vital signs in groupP was more severe after induction, especially in patients with cardiovascular diseases. Remimazolam avoids the injection pain produced by propofol sedation, has a better pre-sedation experience, had the advantage of stable hemodynamics after injection compared to propofol, and a lower respiratory depression rate in the study patients.

Effectiveness and economic impact of Dupilumab in asthma: a population-based cohort study

RationaleSevere asthma is burdened by relevant socio-economic and clinical impact. Randomized controlled trials on Dupilumab showed efficacy and a good safety profile, but post-market studies are needed.ObjectivesTo evaluate the impact of Dupilumab on (i) the use of anti-asthmatic drugs, including oral corticosteroids (OCS), (ii) the rates of asthma exacerbation-related hospital admissions, and (iii) the healthcare costs in patients with asthma.MethodsData were retrieved from Healthcare Utilization database of Lombardy region (Italy). We compared healthcare resources use between the 6 months after Dupilumab initiation (“post-intervention period”) and (i) the 6 months before Dupilumab initiation (“wash-out period”) and (ii) the corresponding 6 months of the prior year (“pre-intervention period”).Main resultsIn a cohort of 176 patients, Dupilumab significantly reduced anti-asthmatic drugs use (including OCS and short-acting β2-agonists, inhaled corticosteroids (ICS)/long-acting β2-agonists and ICS alone) when comparing the “pre-intervention” to the “post-intervention” period. When considering hospital admissions, we observed a not statistically or marginally significant reduction between both periods before Dupilumab and the post-intervention period. Six-months discontinuation rate was 8%. Overall healthcare costs had a tenfold increase between the “pre-intervention” and “post-intervention” period, which was mainly led by the biologic drug cost. Conversely, expenditures connected to hospital admissions did not change.ConclusionsOur real-world investigation suggests that Dupilumab reduced anti-asthmatic drugs use, including OCS, in comparison to a corresponding period in the prior year. However, long-term healthcare sustainability remains an open issue.

The First Live-Cell Based Product in The Iranian Drug List; ReColorCell®.

Vitiligo is an autoimmune skin disorder that can significantly affect the quality of life in patients. However, current treatment strategies such as phototherapy, topical glucocorticosteroids, or systemic immunosuppressants can be helpful in vitiligo management, and treatments for disease stability which is the main challenge in vitiligo management. Novel therapeutic modalities have made promising advances in this regard. Molecular targeted therapy to target Janus-activated kinase (JAK) such as Tofacitinib and Ruxolitinib in addition to the cell-based treatments are innovative therapeutic options, which are recently used for vitiligo treatment. Transplantation of non-cultured melanocytes-keratinocytes have been studied in Iran and phase one data published in 2010 on 10 patients that continued on 300 patients as phase three in 2018. Cell Tech Pharmed™ Co. registered and applied this cell-based product, ReColorCell®, as a GMP certified by Iranian Food and Drug Administration (IR-FDA). On 11th December 2021, ReColorCell® officially registered as the first cell-based product in the Iranian drug list (IDL). Currently, the post-market study of this product is ongoing.

Omadacycline in treating community-based infections: a review and expert perspective

ABSTRACT Introduction Omadacycline is approved for the treatment of community-acquired bacterial pneumonia (CABP) and acute bacterial skin and soft tissue infection (ABSSSI). The integration of newer agents into clinical use involves understanding the nuances of clinical decision-making. This review will provide an in-depth focus on omadacycline in clinical practice. Areas covered Literature review of omadacycline utilizing PubMed was performed to provide a comprehensive evaluation of omadacycline pharmacology, microbiology, registrational Phase 3 clinical trials, and post-marketing clinical studies. In addition, the immunomodulatory and other attributes of tetracycline class of antibiotics, of which omadacycline is a member, are reviewed, introducing the concept of antibiotic selection with attention to the bacterial pathogen and human host relationship. Expert opinion Omadacycline builds upon the favorable attributes of tetracycline antibiotics and provides very reliable empiric coverage for both Staphylococcus aureus and Streptococcus spp. Clinicians require a more robust understanding of antibiotics, including omadacycline, in order to optimize patient outcomes, streamline care, and reduce medical costs.

Immune Checkpoint Inhibitors-Associated Thrombosis: Incidence, Risk Factors and Management.

Immune checkpoint inhibitors (ICIs) target programmed cell death (PD) 1 receptor and its ligand PD-L1, and have become an integral part of treatment regimens in many cancers including lung cancer, renal cell carcinoma, melanoma, and more. Cancer is associated with a significantly increased risk of venous thromboembolism compared to non-cancer patients, and the risks increase further with anticancer therapies including ICIs. Cancer-associated thrombosis can lead to hospitalizations, delayed cancer treatment, and mortality. While thrombosis was not reported as a major complication in initial clinical trials leading to the approval of ICIs, emerging evidence from post-marketing studies revealed concerning risks of thrombosis in patients receiving ICIs. However, results remained heterogenous given differences in study designs and populations. Recent studies also showed that C-reactive protein dynamics might be an easily accessible biomarker for thrombosis and disease response in this population. In addition, early findings indicated that a commonly used anticoagulant for cancer-associated thrombosis, factor Xa inhibitors, might have potential synergistic antitumor effects when combined with ICIs. Herein we will review the current literature on the incidence, risk factors, and management of thrombosis in patients with cancer receiving ICIs. We aim to provide valuable information for clinicians in managing these patients.

Injection Site Reactions Before and After Intramuscular Injection Technique Revision: A Postmarketing Analysis of NALDEBAIN® From 2017 to 2022.

The NALDEBAIN® has been available since 2017, and high incidence of injection reactions in the phase 3 study has been reported. Since the first year in the market, the injection site reactions were still the majority of adverse drug reactions (ADRs) in pharmacovigilance reports. The new intramuscular (IM) instruction and package was introduced in the middle of 2018. In this retrospective study, we analyzed the pharmacovigilance data and published postmarketing studies to investigate the impact of IM injection-related reactions in Taiwan between the period of 2017-2022. Individual case safety reports (ICSRs) and ADRs were classified by system organ class and preferred term. The reporting rate of ICSRs was used to evaluate the impact of the new IM instruction and package. A total of 37 ICSRs were identified from pharmacovigilance reports. Among them, 51% of IM injection-related reactions were reported after one single dose of NALDEBAIN administration. The reporting rate of IM injection-related reactions in pharmacovigilance data dropped from 125.00 to 3.56 per ten thousand exposures after IM instruction and package revision in 2018. In addition, the percentage of IM injection-related reactions also reduced in postmarketing studies from 27.5% to 4.5%. There were no serious IM injection-related reactions found in the pharmacovigilance and postmarketing dataset. Injection site reactions were common after intramuscularly administered oil-based agents during the first year which is later markedly reduced by changing the length of the needle and injection education.

Safety of concomitant administration of inactivated hepatitis A vaccine with other vaccines in children under 16years old in post-marketing surveillance.

Concomitant administration refers to the receipt of two or more vaccines during a single healthcare encounter, which is an efficient way to increase vaccination coverage in children. However, the post-marketing safety studies of concomitant administration are scarce. Inactivated hepatitis A vaccine (Healive®) has been used widely in China and other countries for more than a decade. We aimed to explore the safety of Healive® co-administered with other vaccines compared to Healive® alone in children under 16years old. We retrieved Adverse Events Following Immunization (AEFI) cases and vaccination doses of Healive® during 2020-2021 in Shanghai, China. The AEFI cases were divided into concomitant administration group and Healive® alone group. We used administrative data on vaccine doses as denominators to calculate and compare crude reporting rates between groups. We also compared baseline gender and age distribution, clinical diagnoses, and time interval from vaccination to onset of symptoms between groups. A total 319,247 doses of inactivated hepatitis A vaccine (Healive®) were used and 1,020 AEFI cases (319.50 per million doses) associated with Healive® were reported during 2020-2021 in Shanghai. There were 259,346 doses concomitantly administered with other vaccines and 830 AEFI cases (320.04 per million doses) were reported. There were 59,901 doses of Healive® that vaccinated alone, with 190 AEFI cases (317.19 per million doses). There was only one case with serious AEFI in concomitant administration group, with a rate of 0.39 per million doses. Reported rates of AEFI cases were similar between groups in general (p>0.05). Concomitant administration of inactivated hepatitis A vaccine (Healive®) with other vaccines has a similar safe profile as Healive® alone.

Symptom-level effects of SSRIs in depression studies in a large-scale study programme: efficacy, effects of baseline severity, impact on suicidality, and more

Abstract Conclusions about the efficacy of antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs), in clinical trials have generally been based on analyses of total sum scores on psychometric rating scales, mainly the Hamilton Depression Rating Scale (HDRS). However, this rating scale has several drawbacks, such as multidimensionality and a tendency of several items to pick up side-effects. Therefore, analyses that only rely on global drug treatment effects on the HDRS and similar scales risk misrepresenting important properties of any drugs investigated. This presentation concerns the findings of a research project investigating item-level effects of SSRIs in treating depression in a material encompassing 8262 patients having participated in pre- and post-marketing industry-sponsored studies concering paroxetine, sertraline or citalopram. This has been a fruitful endeavour, having resulted in numerous research papers. Though our main focus at the outset was to investigate if a comparatively low efficacy of SSRIs in clinical trials was an artefact related to the use of HDRS sum scores as the main outcome (which was indeed the case), we have also used this material to investigate a number of other important questions relating to the influence of SSRIs on the various symptoms experienced by patients with depression. Major findings discussed in the presentation include: i) confirmation of early (but not widely known) reports that SSRIs significantly reduce core depression symptoms already after a week of treatment ii) strong evidence for SSRIs being equally effective in treating core depressive symptoms in mild as well as severe depression, earlier reported differences apparently being explained by differences in terms of effects (and prevalence) of non-core symptoms iii) SSRIs do not seem to exacerbate suicidality as measured by the relevant item of the HDRS scale - indeed, both average scores as well as likelihood of worsening are significantly reduced already at week 1. The implications of these, and other, findings are discussed in relation to both the role of SSRIs in the clinic as well as pre-clinical research into e.g. the mode of action of these drugs. Disclosure of Interest None Declared

15-Year Post-Market Clinical Follow-up Study of 1,828 Ceramic (Zirconia) Implants in Humans.

Purpose: To evaluate the 15-year survival rate of zirconia (Y-TZP) implants with a roughened acid-etched surface in a retrospective post-market clinical follow-up (PMCF) study. Materials and Methods: One-piece ceramic implants (CeraRoot) with a roughened acid-etched surface (ICE) were used. Six different implant shapes/sizes were used in this study. Either a standard or flapless surgical approach was used for implant placement. Simultaneous bone augmentation or sinus elevation was performed when bone height or width was deficient. Definitive zirconia restorations were placed after 2 months or later if the Periotest value was > -3. The implants were followed up for up to 15 years. Results: A total of 1,828 implants were placed in 771 patients with a mean age of 51.18 years. The overall implant survival rate after 15 years of follow-up was 98.69%. Conclusion: From this long-term investigation, it can be concluded that CeraRoot ceramic implants showed a 15-year long-term clinical performance with a survival rate of 98.69% under the described protocol, without significant differences between the six implant shapes/sizes.

Abstract OT1-12-04: MRO PMS study - Intraoperative Specimen Magnetic Resonance Imaging System for Intraoperative Margin Assessment for Invasive Breast Cancer Using the ClearCoast™ System in Breast Conserving Surgery

Abstract Background Re-operation for involved margins in breast conserving surgery is associated with worse cosmetic outcome, increased medical costs, and patient anxiety. Therefore, obtaining negative margins during primary BCS is essential. In our prior non-interventional study, published in October 2021 (Thill M et al., J Surg Oncol 2021) the re-operation rate would have been reduced by 83% for invasive carcinoma, from 10% to 2%, and 50% for DCIS, from 30% to 15% re-operations, if results had not been blinded for the surgeon. The results suggested a potential reduction of the re-operation rate by up to 80% for patients undergoing BCS. Aim of the study Aim of our current study is to evaluate the interventional performance of the ClearCoast™ system (ClearCut Medical, Ltd.) in assessing surgical margins for IBC in breast conserving surgery (BCS) and reducing the re-excision rates. Material and Methods The ClearCoast™ system utilizes a diffusion-weighted-imaging (DWI) protocol to create 2D surface maps showing T2*, a MR parameter related to the tissue’s apparent diffusion coefficient (ADC), with a depth penetration of 1mm. ADC is a highly accurate differentiator for irregular versus normal tissue. From May 2021 till to date a prospective, non- blinded post marketing study (N=93), evaluating the performance of the ClearCoast™ system is currently ongoing in the Breast Centre at the AGAPLESION MARKUS KRANKENHAUS, Frankfurt, Germany. After standard evaluation with ultrasound and/or X-ray with or without wire or clip marking, the specimens are intraoperatively scanned with the ClearCoast™ system, and positive margins will lead to a direct re-resection by decision of the surgeon applying a simple T2* threshold to flag irregular tissue. The final histopathology results will be compared with the scan results on a margin per margin bases. In addition, the rates of recurrent surgery of the interventional group will be compared with those of a historical group on the bases of matched pairs. Primary endpoint of the study is the re-excision rates in both the interventional and the historical standard of care group. To date, 64 patients are enrolled in the trial, therefore, results of the trial may be presented at the SABCS 2022. Citation Format: Marc Thill, Katharina Kelling, Viviane van Haasteren, Tina Schnitzbauer, Petia Kiene, Anna Levin, Eyal Kolka, Zachi Peles, Sebastian Aulmann. MRO PMS study - Intraoperative Specimen Magnetic Resonance Imaging System for Intraoperative Margin Assessment for Invasive Breast Cancer Using the ClearCoast™ System in Breast Conserving Surgery [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-12-04.

Clinical Impact of Standardized TAVR Technique and Care Pathway: Insights From the Optimize PRO Study

BackgroundProcedural success and clinical outcomes after transcatheter aortic valve replacement (TAVR) have improved, but residual aortic regurgitation (AR) and new permanent pacemaker implantation (PPI) rates remain variable because of a lack of uniform periprocedural management and implantation. ObjectivesThe Optimize PRO study evaluates valve performance and procedural outcomes using an “optimized” TAVR care pathway and the cusp overlap technique (COT) in patients receiving the Evolut PRO/PRO+ (Medtronic) self-expanding valves. MethodsOptimize PRO, a nonrandomized, prospective, postmarket study conducted in the United States, Canada, Europe, Middle East, and Australia, is enrolling patients with severe symptomatic aortic stenosis and no pre-existing pacemaker. Sites follow a standardized TAVR care pathway, including early discharge and a conduction disturbance management algorithm, and transfemoral deployment using the COT. ResultsA total of 400 attempted implants from the United States and Canada comprised the main cohort of this second interim analysis. The mean age was 78.7 ± 6.6 years, and the mean Society of Thoracic Surgeons predictive risk of mortality was 3.0 ± 2.4. The median length of stay was 1 day. There were no instances of moderate or severe AR at discharge. At 30 days, all-cause mortality or stroke was 3.8%, all-cause mortality was 0.8%, disabling stroke was 0.7%, hospital readmission was 10.1%, and cardiovascular rehospitalization was 6.1%. The new PPI rate was 9.8%, 5.8% with 4-step COT compliance. In the multivariable model, right bundle branch block and the depth of the implant increased the risk of PPI, whereas using the 4-step COT lowered 30-day PPI. ConclusionsThe use of the TAVR care pathway and COT resulted in favorable clinical outcomes with no moderate or severe AR and low PPI rates at 30 days while facilitating early discharge and reproducible outcomes across various sites and operators. (Optimize PRO; NCT04091048)