Pre-marketing Clinical Trials Research Articles

The Consideration of Appropriate Surrogate Endpoint in Premarket Clinical Trials of Drug-Coated Balloon Catheter for the Treatment of Femoropopliteal Artery Stenosis.

Most clinical trials of drug-coated balloon (DCB) for the treatment of femoropopliteal artery stenosis chose 12-month primary patency rate (PPR) or 6-month late lumen loss (LLL) as the primary endpoint. It is still debatable whether 6-month LLL can be served as an appropriate surrogate endpoint for 12-month PPR. This study aimed to identify whether LLL can serve as an appropriate surrogate endpoint in peripheral DCB clinical trials, and shed light on the selection of primary outcome for subsequent confirmatory clinical trials of DCB in the treatment of femoropopliteal artery stenosis. The linear regression model was used to evaluate the correlation between 12-month PPR and 6-month LLL. Pooled standardized mean differences (SMDs) and relative gain between the DCB and plain old balloon angioplasty (POBA) group were computed to assess the consistency and surrogacy, using fixed or random effect model as appropriate. The coefficient of variation (CV) was calculated for both endpoints to compare their degree of variation overall and at study level. A total of 34 studies are eligible for this study. A significant negative linear correlation was found between 12-month PPR and 6-month LLL (R2=0.67, slope=-0.309, p=0.007). The SMD (DCB-POBA) of LLL and PPR was -0.76 (95% confidence interval [CI]: -0.98, -0.54), and 0.59 (95% CI: 0.46, 0.72) (p=0.18). The pooled relative gain of PPR (43%, 95% CI: 35%, 50%) was significantly lower than that of LLL (72%, 95% CI: 61%, 84%) (p<0.001). Coefficient of variation of LLL was larger than that of PPR overall in DCB and POBA groups. Although a significant moderate correlation was observed between 12-month PPR and 6-month LLL, PPR shows more conservative and robust than LLL, which may exaggerate clinical benefits. Late lumen loss should be used discreetly depending on different situations and clinical benefits for patients. This study addresses the critical issue of primary endpoint selection in clinical trials of drug-coated balloon for femoropopliteal artery stenosis. By elucidating the moderate correlation between 6-month late lumen loss (LLL) and 12-month primary patency rate (PPR), the findings underscore the limitations of LLL as a surrogate endpoint due to its variability and potential to overstate clinical benefits. The study advocates for the use of 12-month PPR as a more robust and conservative endpoint in pivotal trials, particularly for novel devices. These findings provide clinicians with a nuanced understanding of outcome measures, promoting evidence-based decision-making and regulatory alignment to ensure patient benefits in vascular interventions.

Discovering Severe Adverse Reactions From Pharmacokinetic Drug-Drug Interactions Through Literature Analysis and Electronic Health Record Verification.

While drug-drug interactions (DDIs) and their pharmacokinetic (PK) mechanisms are well-studied prior to drug approval, severe adverse drug reactions (SADRs) caused by DDIs often remain underrecognized due to limitations in pre-marketing clinical trials. To address this gap, our study utilized a literature database, applied natural language processing (NLP) techniques, and conducted multi-source electronic health record (EHR) validation to uncover underrecognized DDI-SADR signals that warrant further investigation. PubMed abstracts related to DDIs from January 1962 to December 2023 were retrieved. We utilized PubTator Central for Named Entity Recognition (NER) to identify drugs and SADRs and employed SciFive for Relation Extraction (RE) to extract DDI-SADR signals. The extracted signals were cross-referenced with the DrugBank database and validated using logistic regression, considering risk factors including patient demographics, drug usage, and comorbidities, based on EHRs from Vanderbilt University Medical Center (VUMC) and the All of Us research program. From 160,321 abstracts, we identified 111 DDI-SADR signals. Seventeen were statistically significant (13 by one EHR and 4 by both EHR databases), with 9 being previously not recorded in the DrugBank. These included methadone-ciprofloxacin-respiratory depression, oxycodone-fluvoxamine-clonus, tramadol-fluconazole-hallucination, simvastatin-fluconazole-rhabdomyolysis, ibrutinib-amiodarone-atrial fibrillation, fentanyl-diltiazem-delirium, clarithromycin-voriconazole-acute kidney injury, colchicine-cyclosporine-rhabdomyolysis, and methadone-voriconazole-arrhythmia (odds ratios (ORs) ranged from 1.9 to 35.83, with P-values ranging from < 0.001 to 0.017). Utilizing NLP to extract DDI-SADRs from Biomedical Literature and validating these findings through multiple-source EHRs represents a pioneering approach in pharmacovigilance. This method uncovers clinically relevant SADRs resulting from DDIs that were not evident in pre-marketing trials or the existing DDI knowledge base.

Abstract 4136286: Safety Events with a Large-Bore Aspiration Thrombectomy Device for Pulmonary Embolism: An analysis of the U.S. Food and Drug Administration Manufacturer and User Facility Device Experiences from 2018 to 2024

Introduction: Large bore thrombectomy is increasingly used to treat acute PE. Post-market surveillance using the U.S. FDA Manufacturer and User Facility Device Experience (MAUDE) database may capture serious device adverse events (AE) not described in small pre-market clinical trials. We aim to analyze serious AE associated with use of the Inari Medical (Irvine, California) large bore thrombectomy system to treat PE. Methods: All MAUDE events between January 1, 2018 and May 1, 2024 involving PE treatment with Triever and Flowtriever devices were reviewed and categorized based on device type, incident year, and clinical event. Based on narrative description, AE were placed into categories of cardiac, pulmonary, device malfunction, anemia, and other. Results: A total of 58 AE reports representing 50 unique clinical episodes were included. MAUDE event types were death (n=32), injury (n=23) and malfunction (n=3), and the majority (45/58) involved the larger aspiration catheters (Table 1). Death occurred in 27 of 50 unique episodes. Cardiac injury (n=19) and pulmonary injury (n=18) were most common and included 25 serious perforations. Serious AEs are listed in Table 2. Device malfunction/improper use was rare (n=7) and was not associated with death. Paradoxical embolism was described causing stroke and coronary occlusion. 3 of 4 blood loss AEs occurred prior to 2021. Conclusion: This report includes the largest description of reported AEs with large bore aspiration thrombectomy systems used to treat PE. This report describes serious events, often associated with death, that are likely infrequent and were not detected in pivotal studies or registries. Understanding these AEs may guide future technique and device refinement, and the current findings demonstrate the importance of large post-approval studies.

Smaller is better? Compact vs. Conventional gamma camera for sentinel lymph node localization in patients with breast cancer.

Sentinel lymph node biopsy (SLNB) has been recognized as "the gold standard" for axillary staging in early breast cancer patients with clinically negative lymph nodes, resulting in significant morbidity decrease and quality of life improvement. This study aims to validate the performance of a newly developed handheld portable gamma camera (PGC) produced by Imagensys (Italy), in detecting and locating sentinel lymph nodes (SLNs) during the preoperative and intraoperative phases in breast cancer patients compared to conventional lymphoscintigraphy. Adult female patients with histologically confirmed breast cancer, candidates for surgery and SLNB, were prospectively enrolled in this open-label, pre-marketing clinical trial. All patients underwent pre- operative assessment using both the PGC and conventional lymphoscintigraphy. The performance of the two devices was compared using the Poisson regression model for incidence rate ratios (IRRs). The intrinsic sensitivity of the devices was compared using the Wilcoxon Ranked Sign Test. The utility of PGC during intra-operative procedures was also evaluated. The manoeuvrability of the devices was evaluated using operator-satisfaction questioner. Sixty-eight patients (median age 50 years, BMI 21.4) were enrolled, including two patients with bilateral breast cancer, who underwent SLNB on both axillae. The PGC demonstrated superior preoperative lymph node detection rate (IRR 8.01, 95% CI 6.11-10.50; p < 0.0001) and intrinsic device sensitivity (mean counts per second 409 ± 286 vs. 255 ± 1173 for conventional device, p = 0.0003) compared to the conventional gamma camera. Intra-operative assessment with PGC was performed in 62 patients and no additional lymph nodes were visualised. However, the conventional gamma camera demonstrated superior manoeuvrability (p < 0.0001). The PGC handheld gamma camera showed promising results for preoperative SLN assessment in patients with breast cancer. The limited manoeuvrability may be related to the operator's experience leading to higher inter-operator variability. Appropriate training and frequent use of nuclear medicine and surgical equipment could overcome this limitation.

Real-World Use of Semaglutide for Weight Management: Patient Characteristics and Dose Titration-A Danish Cohort Study.

To determine patient characteristics and dose titration patterns of real-world Wegovy (semaglutide) users. We used a population-based cohort study including Danish adults who filled Wegovy prescriptions from 12 December 2022 to 31 December 2023. Outcomes were patient characteristics, prescriber type, and dose titration patterns. We identified 110,748 individuals (median age 49 years; 70% female) filling 773,708 prescriptions for Wegovy. General practitioners initiated treatment in 86%. Common comorbidities included hypertension (30%), dyslipidemia (17%), and arthrosis (17%). Only 13% reached the maximum dose of 2.4 mg by their fifth prescription, while 5.7% stopped after the first prescription. Few users (10%) followed recommended dose increases every 4 weeks. Overall, 25% filled at least one prescription of 2.4 mg, while 33-48% continued with the 1.0-mg dosage from the fourth prescription onward. Real-world Wegovy users generally resembled trial participants, but few follow the dose titration schemes tested in premarket clinical trials.

The consideration of appropriate surrogate endpoint in premarket clinical trials of drug coated balloon catheter for the treatment of femoropopliteal artery stenosis

The consideration of appropriate surrogate endpoint in premarket clinical trials of drug coated balloon catheter for the treatment of femoropopliteal artery stenosis

An Evaluation of Novel Oncology Approvals with a PMR/C for Assessing Data in Racial and Ethnic Populations Underrepresented in Premarket Clinical Trials.

Clinical trials supporting oncology drug approvals frequently underrepresent diverse racial and ethnic populations. Recent policies have focused on ensuring premarket clinical trials are more inclusive and representative of racial and ethnic diversity in the general U.S. population or intended patient population; however, recent U.S. Food and Drug Administration (FDA) guidance on postmarketing approaches to collecting data in underrepresented populations demonstrates that, in certain circumstances, postmarketing requirements and/or commitments (PMR/Cs) may be issued to conduct more representative studies if there are remaining questions about safety or efficacy. This analysis demonstrates that prior to 2020, no drugs had PMR/Cs to further characterize use in a more representative population, and in the last 3 years, more than half of novel oncology approvals have had such a PMR/C (21/40, 53%). In addition, this analysis helps to identify characteristics, such as single-arm pivotal trial design, U.S. enrollment, and results of safety subgroup analyses based on race and ethnicity, that may contribute to decisions to issue a PMR/C to conduct a study that is more representative of the racial and ethnic diversity of the U.S. or intended patient population. These results can inform efforts to improve premarket clinical trials to ensure they are representative and able to characterize use in any patient who may need the drug.

PD-L1 expression in ovarian clear cell carcinoma using the 22C3 pharmDx assay

BackgroundOvarian clear cell carcinoma (OCCC), well known for its chemoresistance to platinum-based chemotherapy, exhibited a good response in clinical trials of anti–PD-1/PD-L1 inhibitors. By assessing PD-L1 expression, we sought to determine the potential therapeutic benefit of PD-1/PD-L1 inhibitors in OCCC.Methods and resultsThe retrospective study included 152 individuals with OCCC between 2019 and 2022 at Peking Union Medical College Hospital. Paired tumors of primary versus recurrent lesions (17 pairs from 15 patients) or primary versus metastatic lesions (11 pairs from 9 patients) were also included. The 22C3 pharmDx assay and whole sections were used for PD-L1 immunohistochemical staining. Pathologists with experience in premarket clinical trials evaluated PD-L1 expression based on various diagnostic criteria (TPS 1%, CPS 1, or CPS 10). The number and percentage of positive PD-L1 cases were 34 (22.4%, TPS ≥ 1%) and 59 (38.8%, CPS ≥ 1), respectively. Thirty-three (21.7%) of the cases had high PD-L1 expression (CPS ≥ 10). Half of the platinum-resistant patients (11/22) were PD-L1 positive (CPS ≥ 1). In addition, positive PD-L1 expression (CPS ≥ 1) was related to clinicopathological characteristics that represented a worse prognosis, such as advanced stages, lymph node metastasis, and distant metastasis (p = 0.032, p < 0.001 and p = 0.003, separately). PD-L1 was expressed equally or more in the recurrent lesion compared with its matched primary lesion.ConclusionsIn conclusion, anti–PD-1/PD-L1 inhibitors are a promising therapeutic choice for OCCC. For evaluation of PD-L1 expression, CPS is more recommended than TPS. Evaluation of recurrent lesion was still suitable and predictive when the primary tumor tissue was not available. Distant metastatic lesions can serve as alternative samples for PD-L1 evaluation, while usage of lymphatic metastatic lesions is not recommended.

A pharmacovigilance study of drug-reduced male semen quality based on the Food and Drug Administration adverse event reporting system database.

Real-world big data studies on drug-reduced male semen quality are few and far between, with most studies based on animal trials, small scale retrospective studies, or a limited number of pre-market clinical trials. This study aimed to identify culprit drugs that reduced male semen quality based on the United States Food and Drug Administration adverse event reporting system. The Medical Dictionary for Regulatory Activities preferred terms and standardized Medical Dictionary for Regulatory Activities queries were used to define reduced male semen quality. Adverse events related to drug-reduced male semen quality were then analyzed by disproportionality analysis using the United States Food and Drug Administration adverse event reporting system data between 2004 and 2023. At the preferred term level, 59 drugs with risk signals were detected to be associated with drug-reduced male semen quality, with the three most frequently reported second-level Anatomical Therapeutic Chemical groups being antineoplastic agents (n=16, 27.12%), psychoanaleptics (n=9, 15.25%), and psycholeptics (n=6, 10.17%). At the standardized Medical Dictionary for Regulatory Activities queries level, the five drugs with the greatest number of cases were finasteride (845 cases, IC025=7.72), dutasteride (163 cases, IC025=7.22), tamsulosin (148 cases, IC025=5.99), testosterone (101 cases, IC025=4.08), and valproic acid (54 cases, IC025=2.44). Additionally, clinical information about drug-reduced male semen quality is absent from the Summary of Product Characteristics of 41 drugs in our study. Using the United States Food and Drug Administration adverse event reporting system database, we offer a list of drugs with risk signals for reducing male semen quality. In the future, there is still a need for more studies on drugs whose effects on male semen quality are not fully understood.

Respiratory Syncytial Virus Vaccines: Analysis of Pre-Marketing Clinical Trials for Immunogenicity in the Population over 50 Years of Age.

Immunosenescence refers to age-related alterations in immune system function affecting both the humoral and cellular arm of immunity. Understanding immunosenescence and its impact on the vaccination of older adults is essential since primary vaccine responses in older individuals can fail to generate complete protection, especially vaccines targeting infections with increased incidence among the elderly, such as the respiratory syncytial virus. Here, we review clinical trials of both candidate and approved vaccines against respiratory syncytial virus (RSV) that include adults aged ≥50 years, with an emphasis on the evaluation of immunogenicity parameters. Currently, there are 10 vaccine candidates and 2 vaccines approved for the prevention of RSV in the older adult population. The number of registered clinical trials for this age group amounts to 42. Our preliminary evaluation of published results and interim analyses of RSV vaccine clinical trials indicates efficacy in older adult participants, demonstrating immunity levels that closely resemble those of younger adult participants.

The Appropriateness of Medical Devices Is Strongly Influenced by Sex and Gender.

Until now, research has been performed mainly in men, with a low recruitment of women; consequentially, biological, physiological, and physio-pathological mechanisms are less understood in women. Obviously, without data obtained on women, it is impossible to apply the results of research appropriately to women. This issue also applies to medical devices (MDs), and numerous problems linked to scarce pre-market research and clinical trials on MDs were evidenced after their introduction to the market. Globally, some MDs are less efficient in women than in men and sometimes MDs are less safe for women than men, although recently there has been a small but significant decrease in the sex and gender gap. As an example, cardiac resynchronization defibrillators seem to produce more beneficial effects in women than in men. It is also important to remember that MDs can impact the health of healthcare providers and this could occur in a sex- and gender-dependent manner. Recently, MDs' complexity is rising, and to ensure their appropriate use they must have a sex-gender-sensitive approach. Unfortunately, the majority of physicians, healthcare providers, and developers of MDs still believe that the human population is only constituted by men. Therefore, to overcome the gender gap, a real collaboration between the inventors of MDs, health researchers, and health providers should be established to test MDs in female and male tissues, animals, and women.

Effectiveness of BNT162b2 Vaccine Against Omicron-SARS-CoV-2 Subvariants in Children 5-11 Years of Age in Quebec, Canada, January 2022 to January 2023.

In premarketing clinical trials conducted before Omicron emergence, BNT162b2 vaccine efficacy against COVID-19 was 90% in children. We conducted postmarketing evaluation of 1- and 2-dose vaccine effectiveness (VE) against Omicron BA.1, BA.2 and BA.4/5 subvariants in 5- to 11-year olds. We estimated VE against SARS-CoV-2 infection using a test-negative design. Specimens collected between January 9, 2022, and January 7, 2023, from children 5-11 years old in Quebec, Canada, and tested by nucleic acid amplification test were eligible. We estimated VE by time since last vaccine dose, interval between doses and by period of Omicron subvariant predominance. A total of 48,826 NAATs were included in overall analysis. From 14-55 to 56-385 days postvaccination, 2-dose VE against symptomatic infection decreased from 68% (95% CI, 62-74) to 25% (95% CI, 11-36). Two-dose VE with restriction to specimens collected from acute care hospitals (emergency rooms or wards) did not decline but was stable at ~40%. VE against symptomatic infection remained comparable at any interval between doses but increased with longer interval among children tested in acute care settings, from 18% (95% CI, -17 to 44) with 21- to 55-day interval to 69% (95% CI, 43-86) with ≥84-day interval. Two-dose VE against symptomatic infection dropped from 70% (95% CI, 63-76) during BA.1, to 32% (95% CI, 13-47) with BA.2 and to nonprotective during BA.4/5 dominance. In children 5-11 years of age, VE against symptomatic infection was stable at any interval between doses but decreased with time since the last dose and against more divergent omicron subvariants.

Real-world efficacy and tolerability of fremanezumab in adults with chronic migraine: a 3-month, single-center, prospective, observational study.

Following the promising pre-marketing placebo-controlled randomized clinical trials of fremanezumab, post-marketing studies are necessary to verify efficacy and tolerability in various real-world settings. The present study assessed real-world efficacy and safety of fremanezumab. A 3-month, single-center, prospective, observation study of adults with chronic migraine who were treated with monthly subcutaneous injections of 225 mg fremanezumab in Denmark. The primary outcome was defined as proportion of patients who achieved ≥30% reduction in monthly migraine days (MMDs) from baseline to weeks 9-12. Among secondary outcomes were ≥50 and ≥75% responder rates and the proportion of patients reporting adverse events. A total of 91 patients with chronic migraine were enrolled and received at least one dose of fremanezumab of whom 89 patients (98%) completed the 3-months treatment period. At baseline, the mean (SD) number of monthly headache days was 24.3 ± 5.8 and mean number of MMDs was 18.5 ± 7.4. The number of patients who achieved ≥30% reduction in MMDs from baseline to weeks 9-12 was 58 (65%), while 45 (51%) and 21 (24%) had ≥50 and 75% reduction in MMD, respectively. Twenty-one patients (23%) reported adverse event, in which the most common were constipation (4.4%), fatigue (4.4%) and dizziness (3.3%). No serious adverse events were reported. In adult chronic migraine patients with previous failure of conventional oral migraine preventives, fremanezumab was found to be effective and well-tolerated.

Bridging the gap: FDA diversity-related postmarketing requirements.

e13608 Background: Historically, pre-market clinical trials have lacked enrollment of racial and ethnic minority patients that represent the population intended to be treated with the approved drug in the US. The Food and Drug Administration (FDA) has several programs and initiatives designed to enhance diversity in oncology clinical trials, such as the Oncology Center of Excellence’s (OCE) Project Equity, FDA Guidance documents, and submission of Diversity Plans from industry. Under the code of federal regulations and/or statute, the FDA can issue post-marketing requirements (PMR) to fulfill accelerated approval requirements for confirmatory studies; for assessing safety signals; or for conducting dedicated studies in pediatric patients. FDA may also issue post-marketing commitments (PMC) to generate additional clinical evidence. PMRs and PMCs have been used to obtain additional information on under-represented populations. The objectives of this analysis were to identify oncology PMRs/PMCs issued with a specific focus on racial and ethnic minority populations and examine the trend over the 10-year period. Methods: We searched FDA’s publicly available database of PMR/PMCs, inclusive of drugs and biologic products, and internal agency databases for PMR/PMCs issued between 2012-2022. The PMR/PMC search was further narrowed down by keywords to capture all PMRs/PMCs relevant to races and ethnicity. The PMRs/PMCs were then manually reviewed for duplication and applicability to malignant indications. Results: In a 10-year period, 34 PMR/PMCs focused on race and ethnicity were issued across 461 oncology approvals (initial marketing approvals = 164, new indications = 297). Twenty-two were issued with the initial marketing approval and 12 with supplemental efficacy approvals. All PMR/PMCs were issued in the last 3 years (2019-2022). PMCs accounted for 55.9% (n = 19) and PMRs 44.1% (n = 15). Nine of the 15 PMRs requesting additional information on underrepresented populations were included with the accelerated approval PMRs. Six of the 34 PMR/PMCs were issued to obtain additional PK or dosing information in the underrepresented population. The most common PMR/PMC indications issued were lymphoma (n = 13, 38.2%), multiple myeloma (n = 8, 23.5%), and non-small cell lung cancer (n = 4, 11.8%). Although PMR/PMCs that mentioned a specific race were limited, African American/Black (n = 8) and Asian (n = 1) were occasionally identified. All studies identified in this analysis are ongoing except for one, for which the product was withdrawn. Conclusions: Our analysis highlights the trend and increased emphasis on race and ethnicity in post approval oncology studies. While progress has been made to promote studies that are representative of the US population through these PMRs/PMCs, diversity plans, and FDA guidance over the course of the past 10 years, more efforts are needed to better enhance diversity in clinical trials moving forward.

Combining evidence from clinical trials in conditional or accelerated approval.

Conditional (European Medicines Agency) or accelerated (U.S. Food and Drug Administration) approval of drugs allows earlier access to promising new treatments that address unmet medical needs. Certain post-marketing requirements must typically be met in order to obtain full approval, such as conducting a new post-market clinical trial. We study the applicability of the recently developed harmonic mean -test to this conditional or accelerated approval framework. The proposed approach can be used both to support the design of the post-market trial and the analysis of the combined evidence provided by both trials. Other methods considered are the two-trials rule, Fisher's criterion and Stouffer's method. In contrast to some of the traditional methods, the harmonic mean -test always requires a post-market clinical trial. If the -value from the pre-market clinical trial is , a smaller sample size for the post-market clinical trial is needed than with the two-trials rule. For illustration, we apply the harmonic mean -test to a drug which received conditional (and later full) market licensing by the EMA. A simulation study is conducted to study the operating characteristics of the harmonic mean -test and two-trials rule in more detail. We finally investigate the applicability of these two methods to compute the power at interim of an ongoing post-market trial. These results are expected to aid in the design and assessment of the required post-market studies in terms of the level of evidence required for full approval.

Surgical treatment of heart failure in China: towards the era of artificial heart

The number of patients with heart failure in China is large, and the proportion of patients with end-stage heart failure continues to increase. The clinical effect of guideline-directed medications therapy for end-stage heart failure is poor. Heart transplantation is the most effective treatment for end-stage heart failure. But it is faced with many limitations such as the shortage of donors. In recent years, the research and development of artificial heart in China has made great progress. Three devices have been approved by the National Medical Products Administration for marketing, and another one is undergoing pre-marketing clinical trial. Since 2017, more than 200 cases of ventricular assist device implantation have been carried out in more than 34 hospitals in China. Among them, 70 patients in Fuwai Hospital, Chinese Academy of Medical Sciences had a 2-year survival rate of 90%. The first patient has survived more than 5 years with the device. More efforts should be put into the training of standardized technical team and quality control. Further research should be carried out in the aspects of pulsatile blood flow pump, fully implanted cable-free device, and improved biomaterial with better blood compatibility.

Pattern of cutaneous adverse drug reactions in an adverse drug monitoring center at a tertiary care hospital in Kerala

Background: Pre-marketing clinical trials can filter only about 50% of the drug reaction. Hence, to prevent the morbidity and mortality due to severe cutaneous reactions early detection, evaluation and monitoring of adverse drug reaction (ADR) especially cutaneous ADR (CADR) are mandatory. Hence, it is imperative that we update our knowledge of the precise nature of ADR which will prevent the reactions as well as to find the offending drug. Aim and Objectives: The aim of the study was to evaluate the pattern of CADR, the suspected drugs and to perform the causality assessment using WHO casualty assessment scale. Materials and Methods: A retrospective descriptive study was done using the data reported to ADR monitoring center in the Department of Pharmacology by the health-care professionals. Suspected CADR was diagnosed by the consultants concerned. The CADRs collected were categorized according to their morphology into maculopapupar rash (MPR), fixed drug eruptions (FDE), urticaria, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The causality assessment was done using WHO Causality assessment scale. Results: The mean age was 47.20 + 22.31. The most common CADR reported was Urticaria 65.5% followed MPR 23%, FDE 8.8%, and Steven Johnsons Syndrome 2.2%. Anti-microbial drugs were the most frequent cause of the adverse reactions with Amoxicillin clavulinic acid combination being the most frequent suspected drug producing CADR (13.3%). The WHO causality assessment for majority of CADR was Possible (73.5%). Conclusion: Clinical Patterns of CADRs in this set up have some minor variations when compared to studies done across India. Amoxicillin clavulinic acid is the most common suspected drug in this study which was not frequently reported in other ADR monitoring centers.

CASE REPORT STUDIES OF ADVERSE EFFECTS POST COVID-19 VACCINATION: A NARRATIVE REVIEW

The accelerated Covid-19 vaccines’ emergency use authorization raises many questions regarding the safety and effectiveness of the vaccine due to the short duration of the pre-marketing clinical trial phase. In terms of vaccine safety, longer studies are needed, especially to see if there are long-term effects or unusual effects that were not detected during pre-marketing clinical trials. This study aims to summarize and assess the adverse reactions that occur after the administration of the Covid-19 vaccine that has obtained approval for emergency use. The search for case reports was carried out in the PubMed database with the keyword "case report on post covid-19 vaccination". Screening for duplication and assessment of each study was also carried out. The case findings obtained were then grouped based on patient demographics, type of vaccine, post-vaccination effects, medical interventions, and end results. There were 118 case reports of adverse effects after the Covid-19 vaccination. The most widely used type of vaccine was mRNA vaccine (76 cases; 64.41%) and the least was inactivated virus vaccine (3 cases; 2.54%). The most reported cases were those affecting the cardiovascular/circulatory/lymphatic system (42 cases; 35.59%) and the least were those affecting the respiratory system (1 case; 0.85%). A total of 89 cases were resolved (89 cases; 75.42%), 4 cases (3.39%) with disability and 2 cases (1.69%) of death were reported. The medical interventions used were mostly inflammatory response-related interventions.

Real-World Safety Profile of Biologics Used in Rheumatology: A Six-Year Observational Pharmacovigilance Study in the Calabria Region.

Background: The introduction of biological agents into the clinical armamentarium has modified the management of moderate-severe inflammatory arthritis (IA). However, these drugs can lead to serious adverse events (SAEs) and unpredictable adverse events (AEs) that are difficult to detect in pre-marketing clinical trials. This pharmacovigilance project aimed to study the AEs associated with biologics use in rheumatology. Methods: The current investigation is a multicenter, prospective, observational cohort study based on the Calabria Biologics Pharmacovigilance Program. Patients treated with one biologic agent from January 2016 to January 2022 were enrolled. Results: Overall, 729 (86.3%) of a total of 872 patients did not develop AEs or SAEs, whereas 143 (16.4%) patients experienced at least one AE, of which 16 (1.8%) had at least one SAE. The most common AEs were administration site conditions followed by gastrointestinal, nervous system and skin disorders. We reported a total of 173 switches and 156 swaps. Switches mainly occurred for inefficacy (136; 77.7%), whereas only 39 (22.3%) were due to the onset of an AE. Primary/secondary failure was the most frequent reason for swaps (124, 79%), while AEs onset led to 33 (21%) swaps. Conclusions: This study supports the validity of our program in monitoring and detecting AEs in the rheumatological area, confirming the positive beneficial/risk ratio of biologics.

Inclusion of women in FDA-regulated premarket clinical trials: A call for innovative and recommended action

Women were historically excluded from clinical trials. Despite numerous guidance and policy, we are still seeing this exclusion throughout the research pipeline more than 40 years later. The progress that has been made to include women in clinical trials and to report data disaggregated by sex continues to be limited due to multiple factors. In this paper, we aim to review some of the current FDA funding, policies, and practice in regard to inclusion of biological sex and sociocultural gender variables. This paper provides some recommendations and actionable policies to ensure that women as well as men can benefit from the updated biomedical research and clinical trials designed to take these variables into account. Strong regulations and mandates should be in place to direct pharmaceutical companies and industry toward the inclusion of women in biomedical research instead of a series of guidelines and recommendations that have not led to sufficient progress. Additionally, regulatory agencies should be completely independent in their decision-making process. Provision of Food and Drug Administration (FDA) funding by industry user fee for instance, might compromise FDA's impartiality in the approval process. Finally, better oversight is needed by the FDA for the labeling of drugs. FDA has made a significant contribution to the progress that has been made to this date, however, some of the current action plans including the Drug Trial Snapshots need to be refined to be more responsive to the current needs.