Contract Research Organizations Research Articles

Medical Writer Apprentice Programs: Who Has Them, What Are They Like, and Do We Need More? Survey Results From 2022

In 2022, the American Medical Writers Association established a taskforce to develop a survey to understand the current state of medical writer apprentice programs, and the desire for a standard framework to help guide the development of such programs. The survey was targeted to contributors who were actively responsible for leading and/or training and developing a medical writing team, and was administered by using SurveyMonkey. A total of 78 responses were received, with largest percentage of respondents primarily working in pharmaceutical/biotech/medical device companies (44%), followed by contract research organizations (CROs)/medical writing companies (23%) and medical writing consultancies (10%). The survey revealed that less than half (42%) of survey respondents’ companies currently have an established apprentice program, and that CROs (73%) and medical writing-specific consultancies (57%) were more likely to have apprentice programs than pharmaceutical/biotech/device companies (24%). The respondents also provided details about the goals, training styles, structures, and durations of existing programs. Importantly, regardless of whether or not respondents’ companies already have an apprentice program, the majority of respondents felt it would be useful to have a standard framework for an apprentice program either to refine existing programs or to develop a new program. As such, the AMWA Executives Advisory Council established an Apprenticeship Framework Working Group to develop a standard yet flexible framework for companies to use as an adaptable resource as they develop their own apprentice programs. The development of this framework is ongoing at the time of publication of this article.

Data transparency and demographic representation in approval packages of FDA-approved oncology drugs from 2012-2021.

1594 Background: Over the past decade, the U.S. Food and Drug Administration (FDA) has leveraged regulations and guidance documents to accelerate improvements in demographic reporting and encourage adequate representation of minorities in clinical trials. This cross-sectional study aims to assess the impact of these interventions by characterizing demographic data reporting and representation by sex, age, and racial and ethnic identity in pivotal trials supporting novel cancer therapeutics approved by the FDA from 2012 through 2021. Methods: Study demographic data were abstracted from FDA drug approval packages and US cancer population demographic data was abstracted from US Cancer Statistics. The percentages of trials reporting sex, age, racial and ethnic identity of participants in drug approval packages were calculated and participation to prevalence ratios (PPRs) were calculated by dividing the percentage of participants in each demographic by the percentage of the US cancer population in each group. PPRs were constructed for each pivotal trial by cancer type. Adequate representation was defined as PPR 0.8-1.2 and the proportion of trials which were adequately representative of each demographic was calculated and trended over time. Results: From 2012 through 2021, the FDA approved 118 cancer therapeutics, based on 131 pivotal trials. For drugs approved 2012-2016, the majority of associated pivotal trials reported participation based on sex (100% of trials), age (100%) and White (98%), Black (75%) or Asian (84%) racial identity, but not American Indian or Alaskan Native racial identity (18%) or Hispanic ethnic identity (41%). For drugs approved 2017-2021, there were no significant improvements in demographic data reporting, although there was a trend towards increased reporting on Hispanic ethnic identity from 2012-2016 (41%) to 2017-2021 (65%) (p= 0.06). For drugs approved 2012-2016, most pivotal trials adequately represented female participants (78% of trials) and participants identifying as White (87%), but few pivotal trials adequately represented older adults (7%), participants identifying as Black (11%), American Indian or Alaskan Native (0%), Asian (18%) or Hispanic (5%). Representation in pivotal trials did not significantly improve for any demographic for drugs approved 2017-2021 (p>0.05). Conclusions: This study found that the last decade’s efforts to improve demographic data transparency and representation in clinical trials have not yet borne fruit for novel cancer therapeutics. More consequential FDA regulations may be necessary. Beyond the FDA, demographic data transparency and adequate minority representation in oncology clinical trials is an all-stakeholder responsibility. A more just clinical trial infrastructure requires greater collaboration between the FDA, sponsors, enrollers, contract research organizations and cooperative groups.

OP16 The Importance of Clinical Research Organizations (CRO) in Clinical Research and Impact of COVID-19 Pandemic

OP16 The Importance of Clinical Research Organizations (CRO) in Clinical Research and Impact of COVID-19 Pandemic

A phase 1 dose escalation study of GCC19CART: A novel coupled CAR therapy for patients with metastatic colorectal cancer.

3547 Background: GCC19CART, the first clinical candidate from the CoupledCAR solid tumor platform, is designed to overcome the limitations of conventional CAR T-cells in solid tumor malignancies by pairing solid tumor CAR T-cells with CD19 targeting CAR T-cells to amplify the proliferation and activation of the solid tumor CAR T component. GCC19CART targets guanylate cyclase-C (GCC), which is expressed in the metastatic lesions of 70%-80% of subjects with colorectal cancers and largely restricted to the intestinal tract. A Phase 1 investigator-initiated clinical trial is underway in China for patients with relapsed or refractory metastatic colorectal cancer who have received at least 2 prior lines of therapy. As of a data cutoff on Jan 28, 2023 21 subjects have been enrolled in 2 dose escalation groups at 5 hospitals in China. Methods: Subjects are screened for GCC expression by immunohistochemistry. Eligible subjects undergo leukapheresis, a single dose of lymphodepleting chemotherapy (fludarabine 30mg/m2 and cyclophosphamide 300mg/m2) 3 days prior to infusion, and then administration of a single infusion of GCC19CART at one of two preassigned doses: 1x106 or 2x106 CAR T-cells/kg. All responses were confirmed by an independent third-party imaging contract research organization. Results: 13 subjects have been enrolled to dose level 1 (1x106 cells/kg) and 8 subjects have been enrolled to dose level 2 (2x106 cells/kg). The most common adverse events were cytokine release syndrome (CRS) in 21/21 subjects (Grade 1 19/21 (90.48%) or Grade 2 2/21 (9.52%)) and diarrhea in 21/21 subjects (Grade 1 6/21 (28.57%) Grade 2 5/21 (23.81%) Grade 3 9/21 (42.86%) or Grade 4 1/21 (4.76%)). All patients with grade 3 and higher side effects were well managed. Immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in 2/21 (9.52%) subjects at Grade 3 or 4 and resolved with corticosteroids. The combined overall response rate (ORR) for both dose levels was 28.6% (6/21). For dose level 1, overall response rate (ORR) was 15.4% (2/13). Two subjects demonstrated a partial response (PR) while 3 additional subjects had partial metabolic response (PMR) on PET/CT with stable disease (SD) or progressive disease (PD) per RECIST 1.1. For dose level 2, The ORR was 50% (4/8). 4 subjects demonstrated a PR and 2 additional subjects had PMR on PET/CT with SD per RECIST 1.1.The median PFS was 1.9 months in the dose 1 group and 6.3 months in the dose 2 group. The median overall survival was 13.3 months in the dose 1 group and 18.3 months in the dose 2 group. Conclusions: Preliminary results demonstrate that GCC19CART has meaningful dose-dependent clinical activity and an acceptable safety profile in relapsed or refractory metastatic colorectal cancer. This trial is ongoing and updated data will be presented. A Phase 1 trial of GCC19CART in the US has opened for accrual and is expected to enroll patients in mid-2022. Clinical trial information: ChiCTR2000040645 .

Operational Challenges of an Asia-Pacific Academic Oncology Clinical Trial.

The Asia-Pacific (APAC) region is a major focus for multinational clinical trials, although its cultural, linguistic, economic, and regulatory diversity pose significant challenges for trial conduct, particularly for academic clinical trials. We describe our experience running the investigator-initiated phase III randomized, fully accrued, Aspirin for Dukes C and high-risk Dukes B Colorectal cancer trial (ASCOLT, ClinicalTrials.gov identifier: NCT00565708, N = 1,587), studying the benefit of aspirin in resected high-risk colorectal cancer. ASCOLT opened in 2008 and is the first large academic adjuvant trial fully conducted in the APAC region. Centrally coordinated by the Trial Management Team at the National Cancer Centre Singapore, it has involved 74 sites across 12 APAC countries/regions, including five middle-income countries. Challenges encountered included regulatory complexity, communication and logistical barriers, limited funding and resources, disparate experience and infrastructure across sites, recruitment holds because of changes in local laws, patient attrition, and disruptions caused by the COVID-19 pandemic. Over 100 contracts and 49 ethics board reviews were required, contributing to a lengthy prestudy preparation time of 2 years and start-up times of approximately 6 months per site. Some of the mitigating actions included engaging local cooperative groups (eg, the Australasian Gastro-Intestinal Trials Group in Australia and New Zealand) and seven contract research organizations to manage sites, regular communication with the central team, transition to electronic data management, and a centralized drug-dispensing system. To ensure an efficient and patient-centered clinical trials environment in the APAC region and sustained growth, we suggest coordinated approaches to harmonize regulatory processes, APAC academic oncology trials consortia to streamline processes and provide governance, and ongoing commitment from governments, funding agents, and industry.

The study of awareness of ukrainian clinical research professionals in gcp

Aim. To assess whether Ukrainian clinical research professionals’ self-assessment of their GCP knowledge matches their actual (tested) GCP knowledge; to assess actual GCP knowledge in populations with different experience level, role in clinical trials, and number of attended GCP trainings; to assess whether short-term GCP trainings suffice for adequate professional level in GCP domain.
 Materials and methods. We developed a questionnaire which consisted of the following parts: demographic data, self-assessment of core competencies, tests on the basic issues of ICH GCP and assessment of the necessity for additional training. Data were analysed by using of description statistical methods and Kruskal-Wallis, Chi-square, Fisher exact test, and Mann-Whitney tests. Statistical analyses were performed using Statistica StatSoft software, Version 8.0 (StatSoft Power Solution Inc.).
 Results. We received 216 questionnaires with answers; some questionnaires were not fully completed and did not have answers to key questions of the study. Therefore, in the analysis, we included only 186 properly done questionnaires.
 Conclusions. Respondents' self-assessment of their competence level in GCP properly matches the test results. 
 Experience level did not substantially influence GCP knowledge. Regardless of experience level, the respondents demonstrated a low level of knowledge for the questions "randomization purpose according to ICH GCP" and "monitoring purposes according to ICH GCP". Both the group with high self-perceived competence and the group with low self-perceived competence demonstrated the level of knowledge above 70% for all other questions. 
 Respondents of the group, which brought together representatives of the regulatory authority, research ethics committees and contract research organizations had slightly better results than other clinical research professionals.
 The number of trainings attended did not affect the quality of knowledge demonstrated by respondents. Thus, an in-depth long-term academic training for clinical research professionals is warranted and is a possible topic for future research.
 Key words: clinical research competence domains; good clinical practice; clinical research professionals; professional development; self-assessment; clinical trials

P19-derived neuronal cells express H1, H2, and H3 histamine receptors: a biopharmaceutical approach to evaluate antihistamine agents

Histamine is a biogenic amine implicated in various biological and pathological processes. Convenient cellular models are needed to screen and develop new antihistamine agents. This report aimed to characterize the response of neurons differentiated from mouse P19 embryonal carcinoma cells to histamine treatment, and to investigate the modulation of this response by antihistamine drugs, vegetal diamine oxidase, and catalase. The exposure of P19 neurons to histamine reduced cell viability to 65% maximally. This effect involves specific histamine receptors, since it was prevented by treatment with desloratadine and cimetidine, respectively, H1 and H2 antagonists, but not by the H3 antagonist ciproxifan. RT-PCR analysis showed that P19 neurons express H1 and H2 receptors, and the H3 receptor, although it seemed not involved in the histamine effect on these cells. The H4 receptor was not expressed. H1 and H2 antagonists as well as vegetal diamine oxidase diminished the intracellular Ca2+ mobilization triggered by histamine. The treatment with vegetal diamine oxidase or catalase protected against mortality and a significant reduction of H2O2 level, generated from the cells under the histamine action, was found upon treatments with desloratadine, cimetidine, vegetal diamine oxidase, or catalase. Overall, the results indicate the expression of functional histamine receptors and open the possibility of using P19 neurons as model system to study the roles of histamine and related drugs in neuronal pathogenesis. This model is less expensive to operate and can be easily implemented by current laboratories of analysis and by Contract Research Organizations.

Best practice considerations for nonclinical in vivo cardiovascular telemetry studies in non-rodent species: Delivering high quality QTc data to support ICH E14/S7B Q&As

The ICH E14/S7B Questions and Answers (Q&As) guideline introduces the concept of a “double negative” nonclinical scenario (negative hERG assay and negative in vivo QTc study) to demonstrate that a drug does not produce a clinically relevant QT prolongation (i.e., no QT liability). This nonclinical “double negative” data package, along with negative Phase 1 clinical QTc data, may be sufficient to substitute for a clinical Thorough QT (TQT) study in some specific cases. While standalone GLP in vivo cardiovascular studies in non-rodent species are standard practice during nonclinical drug development for small molecule programs, a variety of approaches to the design, conduct, analysis and interpretation are utilized across pharmaceutical companies and contract research organizations (CROs) that may, in some cases, negatively impact the stringent sensitivity needed to fulfill the new Q&As. Subject matter experts from both Pharma and CROs have collaborated to recommend best practices for more robust nonclinical cardiovascular telemetry studies in non-rodent species, with input from clinical and regulatory experts. The aim was to increase consistency and harmonization across the industry and to ensure delivery of high quality nonclinical QTc data to meet the proposed sensitivities defined within the revised ICH E14/S7B Q&As guideline (Q&As 5.1 and 6.1). The detailed best practice recommendations presented here cover the design and execution of the safety pharmacology cardiovascular study, including optimal methods for acquiring, analyzing, reporting, and interpreting the resulting QTc and pharmacokinetic data to allow for direct comparison to clinical exposures and assessment of safety margin for QTc prolongation.

Performance Evaluation of SARS-CoV-2 Viral Transport Medium Produced by Bangladesh Reference Institute for Chemical Measurements.

A viral transport medium (VTM) was developed following the Centers for Disease Control and Prevention, USA (US-CDC) standard operating procedure (SOP) DSR-052-05 with necessary improvisation and was used for storing coronavirus disease 2019 (COVID-19) swab specimens. Considering Bangladesh's supply chain and storage conditions, improvisation was essential for extending sample storage time while retaining efficiency. In-house VTM was produced using Hank's balanced salt solution (HBSS) supplemented with 1% bovine serum albumin V (BSA), 0.5 µg /mL of gentamicin sulfate, and 100 µg/mL of fluconazole. The produced VTM composition, quality, sterility, specificity, and efficiency were verified in-house and through an independent contract research organization (CRO). An accelerated stability study projected that under the recommended temperature (4 °C), it would remain stable for four months and preserve samples for over a month. The real-time reverse transcriptase-polymerase chain reaction (rRT-PCR) test detected the targeted N gene and ORF1ab gene from the VTM stored samples. Our VTM is equally as effective as the Sansure Biotech VTM in keeping SARS-CoV-2 RNA specimens detectable in rRT-PCR (100% sensitivity and specificity in random and blinded samples). In conclusion, the BRiCM VTM will make the battle against pandemics easier by effectively collecting and storing nasopharyngeal and oropharyngeal swabs for COVID-19 detection.

Evaluation of Cellular Immune Response to Adeno-Associated Virus-Based Gene Therapy.

The number of approved or investigational late phase viral vector gene therapies (GTx) has been rapidly growing. The adeno-associated virus vector (AAV) technology continues to be the most used GTx platform of choice. The presence of pre-existing anti-AAV immunity has been firmly established and is broadly viewed as a potential deterrent for successful AAV transduction with a possibility of negative impact on clinical efficacy and a connection to adverse events. Recommendations for the evaluation of humoral, including neutralizing and total antibody based, anti-AAV immune response have been presented elsewhere. This manuscript aims to cover considerations related to the assessment of anti-AAV cellular immune response, including review of correlations between humoral and cellular responses, potential value of cellular immunogenicity assessment, and commonly used analytical methodologies and parameters critical for monitoring assay performance. This manuscript was authored by a group of scientists involved in GTx development who represent several pharma and contract research organizations. It is our intent to provide recommendations and guidance to the industry sponsors, academic laboratories, and regulatory agencies working on AAV-based GTx viral vector modalities with the goal of achieving a more consistent approach to anti-AAV cellular immune response assessment.

Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial

Patients with acute myeloid leukaemia (AML) positive for internal tandem duplication (ITD) mutations of FLT3 have poor outcomes. Quizartinib, an oral, highly potent, selective, type 2 FLT3 inhibitor, plus chemotherapy showed antitumour activity with an acceptable safety profile in patients with FLT3-ITD-positive newly diagnosed AML. The aim of the study was to compare the effect of quizartinib versus placebo on overall survival in patients with FLT3-ITD-positive newly diagnosed AML aged 18-75 years. We conducted a randomised, double-blind, placebo-controlled, phase 3 trial comparing quizartinib and placebo in combination with chemotherapy in induction and consolidation, followed by quizartinib or placebo single-agent continuation, in patients with FLT3-ITD-positive newly diagnosed AML at 193 hospitals and clinics in 26 countries in Europe; North America; and Asia, Australia, and South America. Patients aged 18-75 years were eligible. Patients were randomly assigned (1:1) to the quizartinib group or the placebo group by an independent biostatistician through an interactive web and voice response system, stratified by region, age, and white blood cell count at diagnosis. Patients, investigators, funders, and contract research organisations were masked to treatments assigned. Induction therapy comprised a standard 7 + 3 induction regimen of cytarabine 100 mg/m2 per day (or 200 mg/m2 per day allowed if institutional or local standard) by continuous intravenous infusion from day 1 to day 7 and anthracycline (daunorubicin 60 mg/m2 per day or idarubicin 12 mg/m2 per day) by intravenous infusion on days 1, 2, and 3, then quizartinib 40 mg orally or placebo once per day, starting on day 8, for 14 days. Patients with complete remission or complete remission with incomplete neutrophil or platelet recovery received standard consolidation with high-dose cytarabine plus quizartinib (40 mg per day orally) or placebo, allogeneic haematopoietic cell transplantation (allo-HCT), or both as consolidation therapy, followed by continuation of single-agent quizartinib or placebo for up to 3 years. The primary outcome was overall survival, defined as time from randomisation until death from any cause and assessed in the intention-to-treat population. Safety was evaluated in all patients who received at least one dose of quizartinib or placebo. This study is registered with ClinicalTrials.gov (NCT02668653). Between Sept 27, 2016, and Aug 14, 2019, 3468 patients with AML were screened and 539 patients (294 [55%] male patients and 245 [45%] female patients) with FLT3-ITD-positive AML were included and randomly assigned to the quizartinib group (n=268) or placebo group (n=271). 148 (55%) of 268 patients in the quizartinib group and 168 (62%) of 271 patients in the placebo group discontinued the study, primarily because of death (133 [90%] of 148 in the quizartinib group vs 158 [94%] of 168 in the placebo group) or withdrawal of consent (13 [9%] of 148 in the quizartinib group vs 9 [5%] of 168 in the placebo group). Median age was 56 years (range 20-75, IQR 46·0-65·0). At a median follow-up of 39·2 months (IQR 31·9-45·8), median overall survival was 31·9 months (95% CI 21·0-not estimable) for quizartinib versus 15·1 months (13·2-26·2) for placebo (hazard ratio 0·78, 95% CI 0·62-0·98, p=0·032). Similar proportions of patients in the quizartinib and placebo groups had at least one adverse event (264 [100%] of 265 in the quizartinib group and 265 [99%] of 268 in the placebo group) and one grade 3 or higher adverse event (244 [92%] of 265 in the quizartinib group and 240 [90%] of 268 in the placebo group). The most common grade 3 or 4 adverse events were febrile neutropenia, hypokalaemia, and pneumonia in both groups and neutropenia in the quizartinib group. The addition of quizartinib to standard chemotherapy with or without allo-HCT, followed by continuation monotherapy for up to 3 years, resulted in improved overall survival in adults aged 18-75 years with FLT3-ITD-positive newly diagnosed AML. Based on the results from the QuANTUM-First trial, quizartinib provides a new, effective, and generally well tolerated treatment option for adult patients with FLT3-ITD-positive newly diagnosed AML. Daiichi Sankyo.

A global federated real-world data and analytics platform for research.

This article describes a scalable, performant, sustainable global network of electronic health record data for biomedical and clinical research. TriNetX has created a technology platform characterized by a conservative security and governance model that facilitates collaboration and cooperation between industry participants, such as pharmaceutical companies and contract research organizations, and academic and community-based healthcare organizations (HCOs). HCOs participate on the network in return for access to a suite of analytics capabilities, large networks of de-identified data, and more sponsored trial opportunities. Industry participants provide the financial resources to support, expand, and improve the technology platform in return for access to network data, which provides increased efficiencies in clinical trial design and deployment. TriNetX is a growing global network, expanding from 55 HCOs and 7 countries in 2017 to over 220 HCOs and 30 countries in 2022. Over 19000 sponsored clinical trial opportunities have been initiated through the TriNetX network. There have been over 350 peer-reviewed scientific publications based on the network's data. The continued growth of the TriNetX network and its yield of clinical trial collaborations and published studies indicates that this academic-industry structure is a safe, proven, sustainable path for building and maintaining research-centric data networks.

Pharmacovigilance analysis of the Vigibase on neonatal withdrawal syndrome following in utero exposure to antidepressants

IntroductionEvidence on neonatal withdrawal syndrome following antidepressant intrauterine exposure is limited, particularly for antidepressants other than selective serotonin reuptake inhibitors (SSRIs).ObjectivesTo ascertain whether maternal antidepressant treatment may be associated with withdrawal syndrome in neonates, investigating the comparative reporting between individual antidepressants and classes.MethodsWe performed a case/non-case pharmacovigilance study, searching reports of withdrawal syndrome in newborns in the VigiBase, the WHO database of suspected adverse drug reactions. Disproportionality analysis was performed, estimating reporting odds ratio (ROR) and the Bayesian information component (IC). Antidepressants were compared to all other medications, to methadone, and within each class of antidepressants (SSRIs, tricyclics (TCA) and other antidepressants). Antidepressants were ranked in terms of clinical priority, based on a semiquantitative score.ResultsWe retrieved 406 reports of neonatal withdrawal syndrome in 379 neonates related to 15 antidepressants. Compared to all other drugs, disproportionate reporting was detected for antidepressants altogether (ROR: 6.18, 95%CI:5.45-7.01), for TCAs (10.55, 95%CI:8.02-13.88), other antidepressants (ROR: 5.90, 95%CI:4.74-7.36) and SSRIs (ROR: 4.68, 95%CI:4.04-5.42). All antidepressants showed a significant disproportionality, apart from bupropion (figure 1). We did not find any disproportionate reporting for any antidepressant compared to methadone. The clinical priority ranking showed moderate clinical priority for all antidepressants, with the exception four, that had a weak one (figure 1). Most frequently reported symptoms were respiratory symptoms (n=106), irritability/agitation (n=75), tremor (n=52) and feeding problems (n=40).Image:ConclusionsExposure to antidepressants in utero is associated with moderate signals of disproportionate reporting for neonatal withdrawal syndrome for most antidepressants. Clinicians should pay extra attention to neonates with antidepressant-treated mothers.Disclosure of InterestC. Gastaldon: None Declared, E. Arzenton : None Declared, E. Raschi: None Declared, O. Spigset: None Declared, D. Papola: None Declared, G. Ostuzzi: None Declared, U. Moretti: None Declared, G. Trifirò Grant / Research support from: he was the scientific director of a Master program on pharmacovigilance, pharmacoepidemiology and real-world evidence which has received non-conditional grant from various pharmaceutical companies; he coordinated a pharmacoepidemiology team at the University of Messina until Oct 2020, which has received funding for conducting observational studies from various pharmaceutical companies (Boehringer Ingelheim, Daichii Sankyo, PTC Pharmaceuticals). He is also scientific coordinator of the academic spin-off “INSPIRE srl” which has received funding for conducting observational studies from contract research organizations (RTI Health Solutions, Pharmo Institute N.V.)., Consultant of: has served in the last three years on advisory boards/seminars funded by SANOFI, Eli Lilly, AstraZeneca, Abbvie, Servier, Mylan, Gilead, Amgen, Speakers bureau of: has served in the last three years on advisory boards/seminars funded by SANOFI, Eli Lilly, AstraZeneca, Abbvie, Servier, Mylan, Gilead, Amgen, C. Barbui: None Declared, G. Schoretsanitis Consultant of: Dr. Schoretsanitis has served as a consultant for HLS Therapeutics and Thermo Fisher Scientific.

Using Stakeholder Focus Groups to Refine the Care of Pigs used in Research.

Research organizations should be proactive in regularly evaluating and refining their animal care and use programs in order to advance animal welfare and minimize distress. Pigs are often used in research, but few empirical studies have examined optimal husbandry and research use practices for pigs in a research environment. We developed the Pig Welfare Working Group (PWWG) to address the need for more formal guidelines on the management and use of pigs in research. The PWWG was a stakeholder focus group whose goal was to identify challenges and opportunities relevant to improving animal welfare through collaboration, knowledge sharing, and inclusive decision-making. Through consensus building, the PWWG developed 12 recommendations for behavioral management, housing, research procedures, transportation, and rehoming programs. The recommendations were rolled out across the contract research organization, business units, sites, and countries. Follow up will be conducted regularly to assess welfare, monitor progress toward implementing the recommendations, and recognize and reward participants making changes at their site.

Time for implementation of local observational studies.

To the Editor The importance of improving clinical research is a consensual topic. Observational studies represent a practical approach to measuring real-world outcomes and responding to health policy directives by their descriptive nature and hypothesis generators. Thus, in the era of evidence-based medicine, the prompt approval of these studies would benefit their implementation and data collection. This pilot study evaluated the approval times for eight observational studies in the fields of hematology, psychiatry, oncology, and immunology, in 43 Portuguese hospitals, between 2018 and 2021. Study objectives range from effectiveness, outcomes measurements, quality-of-life research, or patient pathway analyses. We considered 112 records corresponding to submissions to ethics committees (EC) and approval requests to administration boards. A descriptive analysis of the approval times was performed. The mean time to obtain EC authorization was 67 days (SD = 55; median = 46.5; 6–253), and the time for financial contracts' approval was 71 days (SD = 56; median = 53; 1–226). In 10% of the cases, the time to EC authorization was higher than 165 days, and financial contracts' approval surpassed 148 days. The mean time to final approval was 118 days (SD = 62; median = 99; 41–276). Among the considered records, 29% were approved in less than 30 days (6–29), 27% in less than 60 days (32–54), and 44% in more than 60 days (62–253). There were no differences between approval times in public vs private hospitals or central vs secondary hospitals. Still, university hospitals had a significantly longer median time for EC authorization (94 days vs 42 days in non-university hospitals, P = 0.008, calculated using the Mann-Whitney U test) (Fig. 1). While the increased approval times might either be a direct consequence of the hospitals' high internal flow or be due to the need to clarify submission-related issues raised by the hospitals, remarkably, the submissions approval rate is 100%.Figure 1.: Time comparison until EC opinion between private vs public hospitals (A), non-university vs university hospitals (B), and central hospitals vs others (local, IPOs, and islands: Madeira and Azores; C).A similar scenario was observed by Eichler et al, who analyzed the necessary time for institutional review boards to approve noninterventional studies in Germany and found that university hospitals needed more than three times the days that state medical chambers required (72.4 vs 20.3 days, respectively).1 Another analysis that described the differences in the processes to obtain EC approval for one study in 16 European/European-affiliated countries showed that time from application until first national approval ranged from less than a week (in Greece and the Netherlands) to more than 300 days (in Portugal).2 Although preliminary, these results suggest high heterogeneity among hospitals, highlighting the need to adopt improved strategies to standardize procedures across sites. Simultaneously, stakeholders involved in clinical studies (sponsors, clinical research organizations, investigators, and regulatory agencies) should implement preventive methods to meliorate EC authorization time and financial contracts' approval process. Study limitations include the small number of observations and the fact that some submissions coincided with the COVID-19 pandemic, which may have interfered with the usual procedures and times. Contributors G.M.C.R. and M.J.S. were responsible for the conceptualization, investigation, data curation, and editing. A.R.J. was responsible for the conceptualization and editing. A.P.F. performed data curation and editing. A.M. was responsible for the conceptualization, methodology, and initial draft preparation. M.S. was responsible for the conceptualization, supervision, formal analysis, and review. Financial support and sponsorship This research was sponsored by the pharmaceutical laboratory Janssen-Cilag.

An external quality assessment feasibility study; cross laboratory comparison of haemagglutination inhibition assay and microneutralization assay performance for seasonal influenza serology testing: A FLUCOP study.

External Quality Assessment (EQA) schemes are designed to provide a snapshot of laboratory proficiency, identifying issues and providing feedback to improve laboratory performance and inter-laboratory agreement in testing. Currently there are no international EQA schemes for seasonal influenza serology testing. Here we present a feasibility study for conducting an EQA scheme for influenza serology methods. We invited participant laboratories from industry, contract research organizations (CROs), academia and public health institutions who regularly conduct hemagglutination inhibition (HAI) and microneutralization (MN) assays and have an interest in serology standardization. In total 16 laboratories returned data including 19 data sets for HAI assays and 9 data sets for MN assays. Within run analysis demonstrated good laboratory performance for HAI, with intrinsically higher levels of intra-assay variation for MN assays. Between run analysis showed laboratory and strain specific issues, particularly with B strains for HAI, whilst MN testing was consistently good across labs and strains. Inter-laboratory variability was higher for MN assays than HAI, however both assays showed a significant reduction in inter-laboratory variation when a human sera pool is used as a standard for normalization. This study has received positive feedback from participants, highlighting the benefit such an EQA scheme would have on improving laboratory performance, reducing inter laboratory variation and raising awareness of both harmonized protocol use and the benefit of biological standards for seasonal influenza serology testing.

Safety, tolerability, and efficacy of zavegepant 10 mg nasal spray for the acute treatment of migraine in the USA: a phase 3, double-blind, randomised, placebo-controlled multicentre trial

Intranasal formulations can provide treatment options for people with migraine in whom oral drugs are ineffective, slow-acting, or intolerable because of nausea and vomiting. Zavegepant, an intranasally administered small molecule calcitonin gene-related peptide (CGRP) receptor antagonist, was previously assessed in a phase 2/3 trial. This phase 3 trial aimed to compare the efficacy, tolerability, safety, and timecourse of response for zavegepant nasal spray with placebo in the acute treatment of migraine. This double-blind, randomised, placebo-controlled, multicentre phase 3 trial, conducted at 90 academic medical centres, headache clinics, and independent research facilities in the USA, recruited adults (aged ≥18 years) with a history of two to eight moderate or severe migraine attacks per month. Participants were randomly assigned (1:1) to zavegepant 10 mg nasal spray or matching placebo and self-treated a single migraine attack of moderate or severe pain intensity. Randomisation was stratified by the use or non-use of preventive medication. Study centre personnel entered eligible participants into the study using an interactive web response system that was operated and managed by an independent contract research organisation. All participants, investigators, and the funder were masked to group assignment. The coprimary endpoints, freedom from pain and freedom from the most bothersome symptom at 2 h after the treatment dose, were assessed in all randomly assigned participants who took the study medication, had a migraine attack of moderate or severe pain intensity at baseline, and provided at least one evaluable post-baseline efficacy datapoint. Safety was analysed in all randomly assigned participants who received at least one dose. The study is registered with ClinicalTrials.gov, number NCT04571060, and is closed to accrual. Between Oct 27, 2020, and Aug 20, 2021, 1978 participants were recruited and assessed for eligibility. 1405 participants were eligible (703 were assigned to zavegepant and 702 to placebo), and 1269 were included in the efficacy analysis set (623 in the zavegepant group and 646 in the placebo group). 2 h after the treatment dose, more participants in the zavegepant group than in the placebo group had pain freedom (147 [24%] of 623 participants vs 96 [15%] of 646 participants, risk difference 8·8 percentage points, 95% CI 4·5-13·1; p<0·0001) and freedom from their most bothersome symptom (247 [40%] vs 201 [31%], risk difference 8·7 percentage points, 3·4-13·9; p=0·0012). The most common adverse events in either treatment group (≥2%) were dysgeusia (129 [21%] of 629 in the zavegepant group vs 31 [5%] of 653 in the placebo group), nasal discomfort (23 [4%] vs five [1%]), and nausea (20 [3%] vs seven [1%]). No signal of hepatotoxicity due to zavegepant was identified. Zavegepant 10 mg nasal spray was efficacious in the acute treatment of migraine, with favourable tolerability and safety profiles. Additional trials are needed to establish the long-term safety and consistency of effect across attacks. Biohaven Pharmaceuticals.

Declining Enrolment and Other Challenges in IBD Clinical Trials: Causes and Potential Solutions.

Rates of enrolment in clinical trials in inflammatory bowel disease [IBD] have decreased dramatically in recent years. This has led to delays, increased costs and failures to develop novel treatments. The aim of this work is to describe the current bottlenecks of IBD clinical trial enrolment and propose solutions. A taskforce comprising experienced IBD clinical trialists from academic centres and pharmaceutical companies involved in IBD clinical research predefined the four following levels: [1] study design, [2] investigative centre, [3] physician and [4] patient. At each level, the taskforce collectively explored the reasons for declining enrolment rates and generated an inventory of potential solutions. The main reasons identified included the overall increased demands for trials, the high screen failure rates, particularly in Crohn's disease, partly due to the lack of correlation between clinical and endoscopic activity, and the use of complicated endoscopic scoring systems not reflective of the totality of inflammation. In addition, complex trial protocols with restrictive eligibility criteria, increasing burden of procedures and administrative tasks enhance the need for qualified resources in study coordination. At the physician level, lack of dedicated time and training is crucial. From the patients' perspective, long washout periods from previous medications and protocol requirements not reflecting clinical practice, such as prolonged steroid management and placebo exposures, limit their participation in clinical trials. This joint effort is proposed as the basis for profound clinical trial transformation triggered by investigative centres, contract research organizations, sponsors and regulatory agencies.

Impact of the reporting source on Platelet Inhibition and Treatment Outcomes (PLATO) trial deaths.

Platelet Inhibition and Clinical Outcomes (PLATO) was a multicenter, randomized double-blind trial assessing efficacy and safety of ticagrelor versus clopidogrel in patients with acute coronary syndrome. The reported mortality benefit of ticagrelor in the PLATO trial has been challenged for over decade, and never confirmed in later trials. To compare if there were any differences when deaths were reported to the FDAby the sponsors or by independent Contract Research Organizations (CRO). We obtained the complete PLATO deaths dataset reported to the FDA and revealed that some events were inaccurately reported favoring ticagrelor. The entire FDA list contains precisely detailed 938 PLATO deaths. The CRO reported outcomes from the USA, Russia, Georgia, and most of Ukraine, while sites in 39 other countries were controlled by the trial sponsors. We compared vascular- (code "11"), non-vascular- (code "12"), and unknown (code "97") deaths triaged by the reporting source. Overall, most PLATO deaths were vascular (n=677), less non-vascular (n=159) andunexpectedly many of "other" (n=7) or "unknown" (n=95) origin reported either by sponsors (n=807) or CRO (n=131). The trial sponsors reported more clopidogrel deaths from vascular (313 vs.239), non-vascular (86 vs.58) and unknown (53 vs. 26) causes.In contrast, CRO-monitored sites reported significantly (72 vs. 53; p<0.01) more ticagrelordeaths than after clopidogrel from vascular (51 vs.39), non-vascular (8 vs.7) and unknown (10 vs. 4) causes. Deaths were reported differently by sponsors and CRO within the same trial. Since some deaths were misreported by PLATO sponsors, only the CRO data seems mostly reliable. Among all countries, the CRO - reported PLATO-USA outcomes represent the largest and most realistic dataset of realistic evidence suggesting ticagrelor inferiority to clopidogrel for all primary endpoint components including vascular death.

Using innovative tools for in vitro absorption, distribution, metabolism and excretion studies to efficiently and effectively support drug development.

Drug development is a complicated and lengthy process requiring a significant amount of intellectual and capital input, as well as extensive collaborations among various organizations and institutions. Contract research organizations play important roles at some or even all stages of the drug development process. To provide better service in in vitro drug absorption, disposition, metabolism and excretion studies, maintain data accuracy and promote work efficiency, we developed an integrated information system termed the 'Drug Metabolism Information System', and it is being used routinely by our drug metabolism department. The Drug Metabolism Information System assists scientists with assay design, data analysis and report drafting and thus reduces human error.