Contract Research Organizations Research Articles

Rapid Steroid Withdrawal after Renal Transplantation Reduces Mortality: Five Year Follow-Up of a Randomized Controlled Trial (Harmony Study) Confirms Long Term Efficacy and Safety

Background: We previously reported excellent efficacy and improved safety aspects of rapid steroid withdrawal (RSWD) in the randomized controlled one year “Harmony” trial, in which 587 predominantly deceased-donor kidney transplant recipients were randomized either to basiliximab or rabbit ATG induction therapy and compared to standard immunosuppressive therapy consisting of basiliximab, low tacrolimus once daily, mycophenolate mofetil, and corticosteroids. Methods: Following the end of the original one-year study period, patients were asked to participate in the observational follow-up (FU) study examining most of the end points of the original study. Hereby, de novo incidences between year one and three as well as year three and five were assessed at the three-/five-year visits, respectively. Findings: Biopsy-proven acute rejection and death-censored graft survival rates remained low and independent of RSWD. RSWD was an independent positive factor for patient survival (adjusted hazard ratio 0·554, 95% confidence interval 0·314 to 0·976; p=0·041). Survival rate was increased with 89·4 % or 90·4 % in RSWD patients (basiliximab or rabbit ATG) compared to 84·7 % in control patients (p = 0·064). The reduced incidence of post-transplantation diabetes mellitus in RSWD patients during the original one-year study period was not compensated by later incidences during FU. Also, incidences of other important outcome parameters such as opportunistic infections, malignancies, cardiovascular morbidity/risk factors, donor specific antibody formation, or kidney function did not differ during FU period. Unexpectedly, patient incidences of bacterial infections requiring hospitalization was reduced in the rabbit ATG group. Interpretation: The Harmony FU trial confirms excellent efficacy and beneficial safety aspects of RSWD under modern immunosuppressive therapy. This is the first randomized study demonstrating increased patient survival in RSWD patients. The results shown here support that RSWD should become the new gold standard approach in an immunologically low-risk, elderly, and severely diseased population of Caucasian kidney transplant recipients. Trial Registration: Follow-up study DRK5786; Original trial NCT 00724022). Funding: The FU trial was designed and run by the first and last author who received financial support from Astellas Pharma GmbH and Sanofi (Investigator Initiated Trial (NCT 00724022, follow up study DRK5786). Neither of the funders had any role in data collection, data analysis, data interpretation, or writing of the manuscript. An independent contract research organization (Coordination Center for Clinical Studies of the Technical University of Dresden, Dresden, Germany) was responsible for data collection, monitoring and statistical analyses. Declaration of Interest: CH received grant support, consulting fees, and lecture fees from Astellas, Sanofi, Genzyme, Roche Pharma, Novartis, and Wyeth/Pfizer. CK received consulting fees and lecture fees from Astellas, Chiesi, Novartis, Sanofi-Genzyme. JWM received grant support, consulting fees, and lecture fees from Vifor, GSK, Novartis, Astra-Zeneca and Boehringer Ingelheim. OW has received research grants for clinical studies, speaker’s fees, honoraria and travel expenses from Amgen, Alexion, Astellas, Basilea, Biotest, Bristol-Myers Squibb, Correvio, Chiesi, Gilead, Hexal, Janssen, Dr. F. Kohler Chemie, MSD, Novartis, Roche, Pfizer, Sanofi, Takeda, TEVA and UCB. BB received grant support, consulting fees and lecture fees from Astellas, Bayer, Chiesi and Novartis. All other authors declare no competing interests. Ethical Approval: The study was approved by the institutional review boards of all sites participating in the follow-up period.

Direct Data Extraction and Exchange of Local Labs for Clinical Research Protocols: A Partnership with Sites, Biopharmaceutical Firms, and Clinical Research Organizations

INTRODUCTION: Manual transcription of site clinical trial data into sponsor Electronic Data Capture (EDC) systems is labor intensive and error prone. Herein, we describe Direct Data Extraction (DDE) best practices identified by the Society for Clinical Data Management eSource Consortium that will enable other groups to implement DDE for their own clinical research efforts. OBJECTIVES: The primary objective of this study was to show the efficiency gains and return on investment for implementing DDE compared to traditional manual data entry methods. METHODS: A DDE Proof of Concept (PoC) at Memorial Sloan Kettering Cancer Center (MSK) and Yale University compared manual EDC transcription and DDE. Sites continued to manually transcribe data into Lilly’s EDC in parallel. Data entry timestamps were captured and analyzed for: 1) data latency, 2) transcription errors, 3) query rate, and 4) time and effort savings. Novartis tracked similar efficiency gains when implementing DDE with MSK in 2012, and National Cancer Center Hospital East (NCCE) in 2014. RESULTS: Compared to manual transcription, the Lilly-MSK-Yale DDE PoC decreased: data latency from 20.4 to 3.5 days; transcription errors from 6.7% to 0%; site effort by 8 hrs. per patient, per study; site queries by 2.5 queries per patient, per visit; and monitoring activity by 3 hrs. per patient per study. The NVS-MSK local lab DDE productivity analysis found that 20–24% of manually entered data were removed, and queries were reduced by approximately 50%. A similar productivity analysis between NVS and NCCE showed a 99% reduction in traditional data review activities by NVS, and a 96% reduction in queries to the site. CONCLUSION: DDE increased the productivity of an existing clinical trial data transfer process by decreasing data latency, transcription errors, and queries. It allows for the more efficient use of both sponsor, CRO, and site staff time and effort.

Selected Developments in Biotechnology Law and the Biotechnology Industry

Selected Developments in Biotechnology Law and the Biotechnology Industry

43017 Learning about Adaptive Capacity and Preparedness of CTSA Hubs

ABSTRACT IMPACT: This work will inform the ongoing development of adaptive capacity and preparedness of the CTSA Program and other clinical and translational research organizations in their quest of improving processes that drive outcomes and impacts, shaping effective programs and services, and strengthening their emergency readiness and sustainability. OBJECTIVES/GOALS: -Share the progress and preliminary findings of an ‘Adaptive Capacity and Preparedness of CTSA Hubs’ CTSA Working Group; -Improve our awareness and understanding of the efficient and effective changes helping CTSA hubs build robust capacity to address METHODS/STUDY POPULATION: A multi-case study including: - Triangulating multiple sources of information and mixed methods (survey/interviews of research administrators, researchers, evaluators, and other key stakeholders), literature review, document and M&E system information analysis, and expert review; - Describing CTSA hubs’ experiences as related to research implementation, translation, and support during the time of emergency; - Administering a comprehensive survey of the CTSAs addressing their challenges, lessons learned, and practices that work in various program components/areas. Data collection includes aggregate and cross-sectional data, with representation based on CTSA size, maturity, and population density. RESULTS/ANTICIPATED RESULTS: The described approach shows sound promise to investigate and share strategies and best practices for building adaptive capacity and preparedness of CTSAs -- across various scientific sectors, translational research spectrum, and the goals outlined by NCATS for the CTSA program. The anticipated results of this research will include the identified/shared innovative solutions and lessons learned for this rapidly emerging, high-priority clinical and translational science issue. ‘High-quality lessons learned’ are those that represent principles extrapolated from multiple sources and triangulated to increase transferability to new contexts and situations. DISCUSSION/SIGNIFICANCE OF FINDINGS: The project provides useful knowledge and tools to research organizations and stakeholders across multiple disciplines -- for mitigating the impact of the COVID-19 disaster via effective adjusting programs, practices, and processes, and building capacity for future successful, ‘emergency ready and responsive’ research and training.

2020 White Paper on Recent Issues in Bioanalysis: Vaccine Assay Validation, qPCR Assay Validation, QC for CAR-T Flow Cytometry, NAb Assay Harmonization and ELISpot Validation ( Part 3 –Recommendations on Immunogenicity Assay Strategies, NAb Assays, Biosimilars and FDA/EMA Immunogenicity Guidance/Guideline, Gene & Cell Therapy and Vaccine Assays)

The 14th edition of the Workshop on Recent Issues in Bioanalysis (14th WRIB) was held virtually on June 15-29, 2020 with an attendance of over 1000 representatives from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations, and regulatory agencies worldwide. The 14th WRIB included three Main Workshops, seven Specialized Workshops that together spanned 11 days in order to allow exhaustive and thorough coverage of all major issues in bioanalysis, biomarkers, immunogenicity, gene therapy and vaccine. Moreover, a comprehensive vaccine assays track; an enhanced cytometry track and updated Industry/Regulators consensus on BMV of biotherapeutics by LCMS were special features in 2020. As in previous years, this year's WRIB continued to gather a wide diversity of international industry opinion leaders and regulatory authority experts working on both small and large molecules to facilitate sharing and discussions focused on improving quality, increasing regulatory compliance and achieving scientific excellence on bioanalytical issues. This 2020 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop and is aimed to provide the Global Bioanalytical Community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2020 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 3) covers the recommendations on Vaccine, Gene/Cell Therapy, NAb Harmonization and Immunogenicity). Part 1 (Innovation in Small Molecules, Hybrid LBA/LCMS & Regulated Bioanalysis), Part 2A (BAV, PK LBA, Flow Cytometry Validation and Cytometry Innovation) and Part 2B (Regulatory Input) are published in volume 13 of Bioanalysis, issues 4 and 5 (2020), respectively.

2020 White Paper on Recent Issues in Bioanalysis: BAV Guidance, CLSI H62, Biotherapeutics Stability, Parallelism Testing, CyTOF and Regulatory Feedback(Part 2A - Recommendations on Biotherapeutics Stability, PK LBA Regulated Bioanalysis, Biomarkers Assays, Cytometry Validation & Innovation Part 2B - Regulatory Agencies' Inputs on Bioanalysis, Biomarkers, Immunogenicity, Gene & Cell Therapy and Vaccine).

The 14th edition of the Workshop on Recent Issues in Bioanalysis (14th WRIB) was held virtually on June 15-29, 2020 with an attendance of over 1000 representatives from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations, and regulatory agencies worldwide. The 14th WRIB included three Main Workshops, seven Specialized Workshops that together spanned 11 days in order to allow exhaustive and thorough coverage of all major issues in bioanalysis, biomarkers, immunogenicity, gene therapy and vaccine. Moreover, a comprehensive vaccine assays track; an enhanced cytometry track and updated Industry/Regulators consensus on BMV of biotherapeutics by LCMS were special features in 2020. As in previous years, this year's WRIB continued to gather a wide diversity of international industry opinion leaders and regulatory authority experts working on both small and large molecules to facilitate sharing and discussions focused on improving quality, increasing regulatory compliance and achieving scientific excellence on bioanalytical issues. This 2020 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop, and is aimed to provide the Global Bioanalytical Community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2020 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication covers the recommendations on (Part 2A) BAV, PK LBA, Flow Cytometry Validation and Cytometry Innovation and (Part 2B) Regulatory Input. Part 1 (Innovation in Small Molecules, Hybrid LBA/LCMS & Regulated Bioanalysis), Part 3 (Vaccine, Gene/Cell Therapy, NAb Harmonization and Immunogenicity) are published in volume 13 of Bioanalysis, issues 4, and 6 (2021), respectively.

2020 White Paper on Recent Issues in Bioanalysis: BMV of Hybrid Assays, Acoustic MS, HRMS, Data Integrity, Endogenous Compounds, Microsampling and Microbiome (Part 1 - Recommendations on Industry/Regulators Consensus on BMV of Biotherapeutics by LCMS, Advanced Application in Hybrid Assays, Regulatory Challenges in Mass Spec, Innovation in Small Molecules, Peptides and Oligos).

The 14th edition of the Workshop on Recent Issues in Bioanalysis (14th WRIB) was held virtually on June 15-29, 2020 with an attendance of over 1000 representatives from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations, and regulatory agencies worldwide. The 14th WRIB included three Main Workshops, seven Specialized Workshops that together spanned 11days in order to allow exhaustive and thorough coverage of all major issues in bioanalysis, biomarkers, immunogenicity, gene therapy, cell therapy and vaccine. Moreover, a comprehensive vaccine assays track; an enhanced cytometry track and updated Industry/Regulators consensus on BMV of biotherapeutics by Mass Spectrometry (hybrid assays, LCMS and HRMS) were special features in 2020. As in previous years, this year's WRIB continued to gather a wide diversity of international industry opinion leaders and regulatory authority experts working on both small and large molecules to facilitate sharing and discussions focused on improving quality, increasing regulatory compliance and achieving scientific excellence on bioanalytical issues. This 2020 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop and is aimed to provide the Global Bioanalytical Community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2020 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication covers the recommendations on (Part 1) Hybrid Assays, Innovation in Small Molecules, & Regulated Bioanalysis. Part 2A (BAV, PK LBA, Flow Cytometry Validation and Cytometry Innovation), Part 2B (Regulatory Input) and Part 3 (Vaccine, Gene/Cell Therapy, NAb Harmonization and Immunogenicity) are published in volume 13 of Bioanalysis, issues 5, and 6 (2021), respectively.

Supportive care for animals on toxicology studies: An industrial best practices survey conducted by the IQ 3Rs TPS CRO Outreach Working Group

Contract Research Organizations (CROs) conducting toxicology studies on behalf of biopharmaceutical sponsors and others routinely provide supportive care for animals to minimize pain and distress on studies. A large number of guidance documents govern the care of experimental animals, however there is currently no uniform approach on the communication between sponsor and their CRO partners in providing a standard definition of and strategies for administering supportive care in toxicity studies. This survey was conducted by the CRO Outreach Working Group (WG), a part of the 3Rs Translational and Predictive Sciences (TPS) Leadership Group of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ Consortium), to better understand the provision of supportive care on nonclinical studies. The survey aimed to define supportive care strategies, identify alternatives to supportive care, and understand regulatory feedback and implications about supportive care decisions. The survey was distributed to members of the 3Rs Leadership Group of the IQ Consortium and several CRO partners, representing 35 organizations as potential respondents. The results of the survey from 13 respondents provided positive feedback that helped in highlighting the existing best practices for supportive care. Areas of enhancements identified included greater consistency in the inclusion of sponsor veterinarians on project teams for externalized studies, the timing of initiation of supportive care, and increased sharing of regulatory outcomes. Suggested best practices include creating a plan of action for veterinary care prior to study start, and enhancing information sharing regarding expected toxicities from previous study findings. Improved communication regarding supportive care will pave the way for enhanced 3Rs initiatives, refining the existing animal care paradigm and helping to ensure the most ethical toxicology study designs.

Recommendations to Streamline and Standardize Clinical Trial Site Feasibility Assessments: An ASCO Research Statement.

Feasibility assessments (FAs) are important to establish site capabilities to conduct clinical trials and their suitability for specific trials. However, current FA methods used by biotechnology and pharmaceutical (biotech-pharma) trial sponsors and contract research organizations (CROs) are costly, inefficient, unnecessarily burdensome, and resource intensive. These methods delay trial start-up, act as a barrier to site participation, and ultimately reduce timely patient access to clinical trials and novel treatments. An ASCO Task Force was convened to assess the specific burdens and challenges with FAs and to develop recommendations to improve their efficiencies and effectiveness. Stakeholders (including trial sites, biotech-pharma sponsors, and CROs) provided insights into challenges and offered solutions through two surveys and an in-person meeting. The Task Force used the feedback to formulate consensus recommendations to improve FAs for oncology clinical trials. Three key recommendations were identified for application across all biotech-pharma sponsored trials: (1) implement a streamlined and uniform FA process across trials and sponsors; (2) minimize and standardize questions; and (3) leverage technology to centralize FAs, facilitate communications, and reduce redundancies. There is an urgency to improve the current FA process, which is costly, inconsistent, inefficient, labor intensive, and of uncertain effectiveness. All stakeholders stand to benefit from implementing these recommendations, which aim to minimize burdens and ensure that more trial sites and patients have timely access to oncology clinical trials. To have meaningful impact, adoption and consistent execution of these recommendations across all trials, sponsors, CROs, and sites are essential.

Animal metrics: Tracking contributions of new approach methods to reduced animal use.

Many companies and global regulatory programs have expressed the intent to move away from in vivo animal testing to new approach methods (NAMs) as part of product safety assessments. NAMs, which include non-animal approaches for testing and assessment – from computer-based modeling to in chemico or in vitro models – allow faster data gener­ation with potentially greater relevance to humans while avoiding animal use. To monitor progress implementing NAMs, each organization first must define what is in scope, starting with the definition of “animal” (e.g., mammals, vertebrates) and applicable studies (e.g., animals used for “in-house” experiments, at contract research organizations, as part of envi­ronmental monitoring). Next, organizations must establish baseline animal use, including defined rules for inclusion/ exclusion of animals that ensure consistency in future assessments. Lastly, organizations must establish metrics for animal savings based on the utility of NAM data. This paper presents one approach to establish “animal use” metrics in a toxi­cology program at The Dow Chemical Company. The premise of our program is that most NAM information has value for animal savings, but the value depends on how data are used (e.g., research and development, screening, or regulatory requirements) and the level of certainty for internal decision-making. This manuscript provides metrics on the impact of NAMs, allowing a quantitative assessment of animal use numbers over time, accountability for resources spent on NAM development, and identification of areas where NAM development is still needed. This approach can be refined for use at other organizations.

Efficiency in the CRO industry, 2010-2019

Outsourcing to Contract Research Organizations (CROs) has become a widespread practice by pharmaceutical and biotechnological firms seeking to reduce risks and costs associated to the development of new products. This paper analyzes empirically the efficiency of the CROs industry by looking at a sample of firms operating in Europe over the years 2010-2019. We compute efficiency scores of the firms in the sample by means of DEA non- parametric techniques. Basic results suggest that the sector achieves large levels of average efficiency, amounting to 0.716. Average efficiency increases over time in the time horizon considered. A second stage Tobit estimation implies that big firms exhibit higher levels of efficiency than medium size and small firms because large sizes facilitate the use of state-of-the-art technology for data collection and analysis and the accession to stable commercial alliances. Efficiency is also positively correlated with sound human resource and financial managements, and with a moderate size of the fixed assets held by the firm. These results suggest that more merges and acquisitions are expected in this sector in the near future.

Cytokine-Storm-Induced Coagulopathy In Critical COVID-19 and Septic Shock Patients: Head-to-Head Comparison

Background: A cytokine-storm-induced coagulopathy has been described in both critical COVID-19 and septic shock. Improving the understanding of the critical COVID-19 pathophysiology could help in finding new therapeutic targets already explored in the treatment of septic shock. Methods: This prospective observational was conducted between February 1, 2019, and June 1, 2020. Consecutive adult patients admitted to ICU for critical COVID-19 with acute respiratory distress syndrome (ARDS) (n=22), septic shock (n=48) and matched control patients (n=48) were enrolled. A between-group comparison of lung histopathology, clinical characteristics and outcomes and key plasmatic soluble biomarkers of inflammation and coagulopathy was performed. Findings: The histopathological findings showed microthrombi with NETosis in both COVID-19- and septic shock-related ARDS. In the prospective cohort, the critical COVID-19 patients exhibited a prolonged ICU length-of-stay, less organ failure, no sepsis-induced coagulopathy, a higher level of soluble tissue factor (106±57 versus 60±28pg/mL for septic shock, pInterpretation: Critical COVID-19 exhibits a prolonged disease course but less organ failure compared to septic shock. At ICU admission, COVID-19 is characterized by a lymphocytic immune response and distinct coagulopathy with less platelet or coagulation factor consumption, and fibrinolysis alterations. Clinical Trial Registration Details: NCT04107402.Funding Information: Fondation Saint-Luc (Brussels, Belgium) and QUALIblood s.a.Declaration of Interests: The Division of Cardiology at Cliniques universitaires Saint-Luc, Belgium, has received unrestricted research grants from AstraZeneca (Belgium). J.D. is the CEO and founder of QUALIblood s.a., a Belgian Contract Research Organization. The remaining authors declare no competing interests.Ethics Approval Statement: The ethics committee approved the study protocol, and all patients signed their informed consent (B403201938590, NCT04107402). Protocol amendment was done to include COVID-19 patients in the ongoing study.

Correlation analysis of the proportion of monocytic myeloid-derived suppressor cells in colorectal cancer patients.

Monocytic myeloid-derived suppressor cells (mMDSCs) are a class of immunosuppressive immune cells with prognostic value in many solid tumors. It is reported that the proportion of mMDSCs in the peripheral blood can be a predictive marker for response to cancer immunotherapy. In this study, we performed a correlation analysis of the proportion of mMDSCs in freshly-drawn peripheral blood, levels of plasma proteins, and demographic factors in colorectal cancer (CRC) patients, to find factors that could be used to predict mMDSC proportions. Freshly-drawn mMDSCs were measured using flow cytometry on peripheral blood mononuclear cells (PBMCs) from healthy donors (n = 24) and CRC patients (n = 78). The plasma concentrations of 29 different cytokines, chemokines, growth factors, and enzymes were measured using a multiplex assay or enzyme-linked immunosorbent assay. Correlation analysis to find mMDSC-associated factors was conducted using univariate and multivariate models. In univariate correlation analysis, there were no plasma proteins that were associated with mMDSC proportions in CRC patients. In multivariate analysis, considering all variables including age, sex, and plasma proteins, levels of inducible nitric acid synthase (iNOS) (p = 0.013) and platelet-derived growth factor (PDGF)-BB (p = 0.035) were associated with mMDSC proportion in PBMCs (mMDSC proportion [%] = 0.2929 - 0.2389 * PDGF-BB + 0.3582 * iNOS) (p < 0.005, r = 0.32). Measuring the plasma concentrations of iNOS and PDGF-BB may be useful in predicting the proportion of mMDSCs in CRC patients' peripheral blood. Further research is required to establish and validate these predictive factors. Data registration Patient data were registered in an anonymization system at Tsukuba Clinical Research & Development Organization (T-CReDO).

Conducting dermatology clinical trials during the COVID-19 pandemic

The clinical trials industry faces a number of challenges during the evolving coronavirus disease 2019 (COVID-19) pandemic, for example, site closures, mandatory self-isolation, travel restrictions, interruptions to delivery of investigational product, or staff or participants becoming infected with severe acute respiratory syndrome coronavirus 2. These challenges can pose difficulties in adhering to visit schedules, performing laboratory testing, conducting protocol-specified procedures, and administration of investigational product. As a result, clinical trial sites, contract research organizations, and sponsors have had to act swiftly to ensure that trial patients are safe and systems are in place for continuing trials. Protocols should also be amended to reflect changes and approved by an ethics board. The authors provide practical considerations and recommendations for dermatology clinical trial operations during the COVID-19 pandemic.

Nab-paclitaxel plus gemcitabine versus nab-paclitaxel plus gemcitabine followed by FOLFIRINOX induction chemotherapy in locally advanced pancreatic cancer (NEOLAP-AIO-PAK-0113): a multicentre, randomised, phase 2 trial

The optimal preoperative treatment for locally advanced pancreatic cancer is unknown. We aimed to compare the efficacy and safety of nab-paclitaxel plus gemcitabine with nab-paclitaxel plus gemcitabine followed by fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) as multidrug induction chemotherapy regimens in locally advanced pancreatic cancer. In this open-label, multicentre, randomised phase 2 study, done at 28 centres in Germany, eligible patients were adults (aged 18-75 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1 and histologically or cytologically confirmed, treatment-naive locally advanced pancreatic adenocarcinoma, as determined by local multidisciplinary team review. After two cycles of nab-paclitaxel 125 mg/m2 plus gemcitabine 1000 mg/m2 (administered intravenously on days 1, 8, and 15 of each 28-day cycle), patients without progressive disease or unacceptable adverse events were randomly assigned (1:1) to receive either two additional cycles of nab-paclitaxel plus gemcitabine (nab-paclitaxel plus gemcitabine group) or four cycles of sequential FOLFIRINOX (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, irinotecan 180 mg/m2, fluorouracil 400 mg/m2 by intravenous bolus followed by a continuous intravenous infusion of 2400 mg/m2 for 46 h on day 1 of each 14-day cycle; sequential FOLFIRINOX group). Randomisation was done by the clinical research organisation on request of the trial centre using a permuted block design (block size 2 and 4). Patients, investigators, and study team members were not masked to treatment allocation. The primary endpoint was surgical conversion rate (complete macroscopic tumour resection) in the randomised population by intention-to-treat analysis, which was assessed by surgical exploration in all patients with at least stable disease after completion of induction chemotherapy. This trial is registered with ClinicalTrials.gov, NCT02125136. Between Nov 18, 2014, and April 27, 2018, 168 patients were registered and 130 were randomly assigned to either the nab-paclitaxel plus gemcitabine group (64 patients) or the sequential FOLFIRINOX group (66 patients). Surgical exploration after completed induction chemotherapy was done in 40 (63%) of 64 patients in the nab-paclitaxel plus gemcitabine group and 42 (64%) of 66 patients in the sequential FOLFIRINOX group. 23 patients in the nab-paclitaxel plus gemcitabine group and 29 in the sequential FOLFIRINOX group had complete macroscopic tumour resection, yielding a surgical conversion rate of 35·9% (95% CI 24·3-48·9) in the nab-paclitaxel plus gemcitabine group and 43·9% (31·7-56·7) in the sequential FOLFIRINOX group (odds ratio 0·72 [95% CI 0·35-1·45]; p=0·38). At a median follow-up of 24·9 months (95% CI 21·8-27·6), median overall survival was 18·5 months (95% CI 14·4-21·5) in the nab-paclitaxel plus gemcitabine group and 20·7 months (13·9-28·7) in the sequential FOLFIRINOX group (hazard ratio 0·86 [95% CI 0·55-1·36]; p=0·53). All other secondary efficacy endpoints, such as investigator-assessed progression-free survival, radiographic response rate, CA 19-9 response rate, and R0 resection rate, were not significantly different between the two treatment groups except for improved histopathological downstaging in evaluable resection specimens from the sequential FOLFIRINOX group (ypT1/2 stage: 20 [69%] of 29 patients in the sequential FOLFIRINOX group vs four [17%] of 23 patients in the nab-paclitaxel plus gemcitabine group, p=0·0003; ypN0 stage: 15 [52%] of 29 patients in the sequential FOLFIRINOX group vs four [17%] of 23 patients in the nab-paclitaxel plus gemcitabine group, p=0·02). Grade 3 or higher treatment-emergent adverse events during induction chemotherapy occurred in 35 (55%) of 64 patients in nab-paclitaxel plus gemcitabine group and in 35 (53%) of 66 patients in the sequential FOLFIRINOX group. The most common of which were neutropenia (18 [28%] in nab-paclitaxel plus gemcitabine group, 16 [24%] in the sequential FOLFIRINOX group), nausea and vomiting (two [3%] in nab-paclitaxel plus gemcitabine group, eight [12%] in the sequential FOLFIRINOX group), and bile duct obstruction with cholangitis (six [9%] in nab-paclitaxel plus gemcitabine group, seven [11%] in the sequential FOLFIRINOX group). No deaths were caused by treatment-related adverse events during the induction chemotherapy phase. Our findings suggest that nab-paclitaxel plus gemcitabine is similarly active and safe as nab-paclitaxel plus gemcitabine followed by FOLFIRINOX as multidrug induction chemotherapy regimens for locally advanced pancreatic cancer. Although conversion to resectability was achieved in about a third of patients, additional evidence is required to determine whether this translates into improved overall survival. Celgene.

Galapagos to sell CRO arm to Selvita

The Belgian biotech firm Galapagos has agreed to sell its contract research organization (CRO) Fidelta to the Polish CRO Selvita for about $38 million. Based in Croatia, Fidelta employs more than 150 chemists and other scientists who provide discovery services to drug industry customers. Galapagos sold its other CROs, BioFocus and Argenta, to Charles River Laboratories in 2014.

C212: An R Package for the Detection of Safety Signals in Clinical Trials Using Body-Systems (System Organ Classes)

Safety in clinical trials may be characterised by the incidence or occurrence of adverse events. The statistical analysis of this data is complicated by the large number of adverse events recorded, with low event rates, small effect sizes and low power all contributing to the difficulty in determining a robust safety profile for a treatment during the trial process. In addition to end of trial analyses, a number of interim analyses may take place at different time points during the trial lifecycle. These offer the additional statistical challenge of testing accumulating data, with possibly differing recruitment rates on trial arms contributing to a lack of balance in the data. Adverse events are typically defined by medical dictionaries, which provide a common reference terminology for use in and between clinical trials. There are a number of medical dictionaries in current use, all of which provide similar services. One such dictionary is MedDRA (Medical Dictionary for Regulatory Activities), which was developed by the ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) and is widely used by regulatory bodies, clinical research organisations (CROs), and pharmaceutical companies. WHO-ART (World Health Organisation Adverse Reaction Terminology) is a similar dictionary maintained by the Uppsala Monitoring Centre for the World Health Organisation Collaborating Centre for International Drug Monitoring. MedDRA and WHO-ART have a similar hierarchical structure consisting of System Organ Classes (SOC) and various grouping and descriptor terms. The MedDRA hierarchical structure consists of five levels: System Organ Class (SOC), High Level Group Terms (HLGT), High Level Terms (HLT), Preferred Terms (PT), and Lower Level Terms (LLT). The PT is a single medical description of a symptom or observation while the LLT is how a patient or data recorder would describe a symptom or observation. Each LLT belongs to one PT and, in general, data will be recorded at the LLT level but reported at the PT level (the adverse event). As of 2020 there are 27 SOCs and over 80,000 LLTs. The grouping of adverse events by SOC (or body-system) provides for possible relationships between the adverse events within a SOC. One consequence of this is the possibility that, for treatments which may affect a particular SOC, there may be raised rates for a number of adverse events within that SOC. A number of methods have recently been proposed to address the statistical issues in adverse event analysis by using these groupings of adverse events by body-system or SOC, taking into account the additional information provided by these relationships to increase the power of detecting real adverse event effects. These methods, Hochberg, 1995; Hu et al., 2010; Matthews, 2006; Mehrotra & Adewale, 2012; Yekutieli, 2008), and Bayesian modelling approaches (Amy Xia et al., 2011; Berry & Berry, 2004; Carragher, 2017b), are implemented in the R package c212.

Sustainability Challenges and Opportunities in Oligonucleotide Manufacturing.

With a renewed and growing interest in therapeutic oligonucleotides across the pharmaceutical industry, pressure is increasing on drug developers to take more seriously the sustainability ramifications of this modality. With 12 oligonucleotide drugs reaching the market to date and hundreds more in clinical trials and preclinical development, the current state of the art in oligonucleotide production poses a waste and cost burden to manufacturers. Legacy technologies make use of large volumes of hazardous reagents and solvents, as well as energy-intensive processes in synthesis, purification, and isolation. In 2016, the American Chemical Society (ACS) Green Chemistry Institute Pharmaceutical Roundtable (GCIPR) identified the development of greener processes for oligonucleotide Active Pharmaceutical Ingredients (APIs) as a critical unmet need. As a result, the Roundtable formed a focus team with the remit of identifying green chemistry and engineering improvements that would make oligonucleotide production more sustainable. In this Perspective, we summarize the present challenges in oligonucleotide synthesis, purification, and isolation; highlight potential solutions; and encourage synergies between academia; contract research, development and manufacturing organizations; and the pharmaceutical industry. A critical part of our assessment includes Process Mass Intensity (PMI) data from multiple companies to provide preliminary baseline metrics for current oligonucleotide manufacturing processes.

Creating and sustaining collaborative multi-institutional industry site visit programs: a toolkit

Background: As more early career scientists enter into diverse career pathways, visiting local companies or organizations can support their exploration of these paths. As an efficient way to facilitate this, we developed a collaborative regional site visit program: the Enhancing Local Industry Transitions through Exploration (ELITE) Consortium. Consortium members arrange half-day visits to local industry sites, thus providing companies and trainees the opportunity to meet and identify potential professional and career opportunities. Three different training institutions worked cooperatively in the development and maintenance of the program. The ELITE Consortium was developed with eight phased steps; guidelines and operating procedures were created for each of these steps and are provided along with sample materials for institutions interested in building similar programs. Methods: Prior to fully developing the program, trainee interests were evaluated via questionnaire. During program implementation and thereafter, program directors tracked attendance and collected career outcome data from publicly available sources to identify first job positions after training. Regression analyses and chi-squared analyses were used to examine site visit matches and career outcome data. Results: Analyses suggest a positive impact of site visits on postdoctoral and graduate trainees’ career outcomes at companies or institutions that match a similar sector (e.g., for-profit) and type (e.g., biotech, pharmaceutical, contract research organization). Despite a small sample size, evidence suggests an especially positive impact on trainees who organize site visits to companies compared with those who simply participate. Conclusions: The ELITE Consortium was successful in helping trainees explore and identify a multitude of career paths. Trainees attained employment either directly or in related companies and institutions visited by ELITE participants. The joint, three-institution, flexible nature of the ELITE Consortium positively impacts the program’s sustainability and reach. The toolkit provided here will help other institutions to replicate and adapt the program with minimal effort.

A joint industry-sponsored data monitoring committee model for observational, retrospective drug safety studies in the real-world setting.

PurposeTo share better practice in establishing data monitoring committees (DMCs) for observational, retrospective safety studies with joint‐industry sponsorship.MethodsA DMC model was created to monitor data from an observational, retrospective, post‐authorization safety study investigating risk of medullary thyroid cancer in patients treated with long‐acting glucagon‐like peptide‐1 receptor agonists (LA GLP‐1RAs) (NCT01511393). Sponsors reviewed regulatory guidelines, best practice and sponsors' standard operation procedures on DMCs. Discussions were held within the four‐member consortium, assessing applicability to observational, retrospective, real‐world studies. A DMC charter was drafted based on a sponsor‐proposed, adapted DMC model. Thereafter, a kick‐off meeting between sponsors and DMC members was held to receive DMC input and finalize the charter.ResultsDue to this study's observational, retrospective nature, assuring participant safety – central for traditional explanatory clinical trial models – was not applicable to our DMC model. The overall strategy and key indication for our real‐world model included preserving study integrity and credibility. Therefore, DMC member independence and their contribution of expert knowledge were essential. To ensure between‐sponsor data confidentiality, all study committees/corporations and sponsors, besides the DMC, received blinded data only (adapted to refer to data blinding that revealed the specific marketed LA GLP‐1RA/sponsor). Communication and blinding/unblinding of these data were facilitated by the contract research organization, which also provided crucial operational oversight.ConclusionsTo our knowledge, we have established the first DMC model for joint industry‐sponsored, observational, retrospective safety studies. This model could serve as a precedent for others performing similar post‐marketing, joint industry‐sponsored pharmacovigilance activities.