scholarly journals Perspectives From the 12th Annual Minipig Research Forum: Early Inclusion of the Minipig in Safety Assessment Species Selection Should be the Standard Approach

2019 ◽  
Vol 47 (7) ◽  
pp. 891-895 ◽  
Author(s):  
Keith Jones ◽  
Joanna Harding ◽  
Andy Makin ◽  
Pramila Singh ◽  
Björn Jacobsen ◽  
...  
Keyword(s):  
Drug Development ◽  
Small Molecules ◽  
Biomedical Research ◽  
Safety Assessment ◽  
Scientific Data ◽  
Species Selection ◽  
Selection Strategy ◽  
Early Screening ◽  
Development Stages ◽  
Regulatory Guidelines

Over the last decade, the minipig has been established as a species which can be used in biomedical research, including drug development safety assessment. There are no mandatory regulatory guidelines regarding species selection strategy for safety assessment; hence, choice is at the discretion of companies responsible for drug development. A survey of member companies by IQ DruSafe (2016) highlighted inconsistent and low use of the minipig. At the 12th Annual Minipig Research Forum in 2018, presentations and a workshop examined current practices and considered if the minipig could be utilized more from earliest drug development stages. Despite the agreed utility of scientific data and validity of the minipig, especially for small molecules, each company has its own approach in nonrodent species selection, without consistent rationale. The overall objective should be to ensure the most appropriate species is selected and is scientifically based, with the minipig systematically included from early screening stages.

scholarly journals Qualification of translational safety biomarkers

2021 ◽  
pp. 153537022110021
Author(s):  
John-Michael Sauer ◽  
Amy C Porter
Keyword(s):  
Skeletal Muscle ◽  
Drug Development ◽  
Vascular Injury ◽  
Validation Studies ◽  
Safety Assessment ◽  
Regulatory Agencies ◽  
Development Studies ◽  
Clinical Validation ◽  
Development Tools ◽  
Important Drug

Safety biomarkers are important drug development tools, both preclinically and clinically. It is a straightforward process to correlate the performance of nonclinical safety biomarkers with histopathology, and ideally, the biomarker is useful in all species commonly used in safety assessment. In clinical validation studies, where histopathology is not feasible, safety biomarkers are compared to the response of standard biomarkers and/or to clinical adjudication. Worldwide, regulatory agencies have put in place processes to qualify biomarkers to provide confidence in the manner of use and interpretation of biomarker data in drug development studies. This paper describes currently qualified safety biomarkers which can be utilized to monitor for nephrotoxicity and cardiotoxicity and ongoing projects to qualify safety biomarkers for liver, skeletal muscle, and vascular injury. In many cases, the development and use of these critical drug development tools is dependent upon partnerships and the precompetitive sharing of data to support qualification efforts.

Aggregate Safety Assessment Planning for the Drug Development Life-Cycle

2021 ◽  
Author(s):  
Barbara A. Hendrickson ◽  
William Wang ◽  
Greg Ball ◽  
Dimitri Bennett ◽  
Amit Bhattacharyya ◽  
...  
Keyword(s):  
Life Cycle ◽  
Drug Development ◽  
Safety Assessment ◽  
Development Life Cycle

Phase 1 Clinical Trials of Small Molecules: Evolution and State of the Art

2021 ◽  
Vol 16 ◽  
Author(s):  
John J. Sramek ◽  
Michael F. Murphy ◽  
Sherilyn Adcock ◽  
Jeffrey G. Stark ◽  
Neal R. Cutler
Keyword(s):  
Clinical Trials ◽  
Drug Development ◽  
Healthy Volunteers ◽  
Small Molecules ◽  
Phase 1 ◽  
Dose Range ◽  
Pharmacodynamic Modeling ◽  
Inpatient Setting ◽  
Conducting Phase ◽  
Safe Dose

Background: Phase 1 studies comprise the first exposure of a promising new chemical entity in healthy volunteers or, when appropriate, in patients. To assure a solid foundation for subsequent drug development, this first step must carefully assess the safety and tolerance of a new compound, and often provide some indication of potential effect, so that a safe dose or dose range can be confidently selected for the initial Phase 2 efficacy study in the target patient population. Methods: This review was based on a literature search using both Google Scholar and PubMed, dated back to 1970, using search terms including “healthy volunteers”, “Phase 1”, and “normal volunteers” , and also based on the authors’ own experience conducting Phase 1 clinical trials. This paper reviews the history of Phase 1 studies of small molecules and their rapid evolution, focusing on the critical single and multiple dose studies, their designs, methodology, use of pharmacokinetic and pharmacodynamic modeling, application of potentially helpful biomarkers, study stopping criteria, and novel study designs. Results: We advocate for determining the safe dose range of a new compound by conducting careful dose escalation in a well-staffed inpatient setting, defining the maximally tolerated dose (MTD) by reaching the minimally intolerated dose (MID). The dose immediately below the MID is then defined as the MTD. This is best accomplished by using appropriately screened patients for the target indication, as patients in many CNS indications often tolerate doses differently than healthy non-patients. Biomarkers for safety and pharmacodynamic measures can also assist in further defining a safe and potentially effective dose range for subsequent clinical trial phases. Conclusion: Phase 1 studies can yield critical insights to the pharmacology of a new compound in man and offer perhaps the only development period in which the dose range can be safely and thoroughly explored. Phase 1 studies often contain multiple endpoint objectives, the reconciliation of which can present a dilemma for drug developers and study investigators alike, but which can crucially determine whether a compound can survive to the next step in the drug development process.

Molecular Survival Strategies of Organisms: HSP and Small Molecules for Diagnostics and Drug Development

2015 ◽  
pp. 323-344 ◽  
Author(s):  
Andreas Kirschning ◽  
Johanna-Gabriela Walter ◽  
Frank Stahl ◽  
Emilia Schax ◽  
Thomas Scheper ◽  
...  
Keyword(s):  
Drug Development ◽  
Small Molecules ◽  
Survival Strategies

Kidney Safety Assessment: Current Practices in Drug Development

2019 ◽  
Vol 39 (2) ◽  
pp. 120-131 ◽  
Author(s):  
Sean P. Troth ◽  
Frank Simutis ◽  
Gary S. Friedman ◽  
Susan Todd ◽  
Frank D. Sistare
Keyword(s):  
Drug Development ◽  
Safety Assessment ◽  
Current Practices

scholarly journals Reducing attrition in drug development: Smart loading pre-clinical safety assessment

2014 ◽  
Vol 229 ◽  
pp. S167
Author(s):  
Stefan Kavanagh ◽  
Howard Mellor ◽  
Christopher Pollard ◽  
Sally Robinson ◽  
Stefan Platz ◽  
...  
Keyword(s):  
Drug Development ◽  
Safety Assessment ◽  
Clinical Safety

scholarly journals A high throughput live transparent animal bioassay to identify non-toxic small molecules or genes that regulate vertebrate fat metabolism for obesity drug development

2008 ◽  
Vol 5 (1) ◽  
pp. 23 ◽  
Author(s):  
Kevin S Jones ◽  
Alexander P Alimov ◽  
Horacio L Rilo ◽  
Ronald J Jandacek ◽  
Laura A Woollett ◽  
...  
Keyword(s):  
Drug Development ◽  
Small Molecules ◽  
High Throughput ◽  
Fat Metabolism ◽  
Or Genes

scholarly journals Screening and selection strategy for the establishment of biosimilar to trastuzumab-expressing CHO-K1 cell lines

2020 ◽  
Author(s):  
Thailín Lao-González ◽  
Alexi Bueno Soler ◽  
Arnelys Duran Hernandez ◽  
Katya Sosa Aguiar ◽  
Luis Eduardo Hinojosa Puerta ◽  
...  
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Culture Media ◽  
Screening Strategy ◽  
Culture Conditions ◽  
Host Cells ◽  
Selection Strategy ◽  
Cell Line Development ◽  
Early Screening ◽  
Gene Optimization

Abstract The high prices of biopharmaceuticals or biologics used in the treatment of many diseases limit the access of patients to these novel therapies. One example is the monoclonal antibody trastuzumab, successfully used for breast cancer treatment. An economic alternative is the generation of biosimilars to these expensive biopharmaceuticals. Since antibody therapies may require large doses over a long period of time, robust platforms and strategies for cell line development are essential for the generation of recombinant cell lines with higher levels of expression. Here, we obtained trastuzumab-expressing CHO-K1 cells through a screening and selection strategy that combined the use of host cells pre-adapted to protein-free media and suspension culture and lentiviral vectors. The results demonstrated that the early screening strategy obtained recombinant CHO-K1 cell populations with higher enrichment of IgG-expressing cells. Moreover, the measurement of intracellular heavy chain polypeptide by flow cytometry was a useful metric to characterize the homogeneity of cell population, and our results suggest this could be used to predict the expression levels of monoclonal antibodies in early stages of cell line development. Additionally, we propose an approach using 25cm2 T-flasks in suspension and shaking culture conditions as a screening tool to identify high producing cell lines. Finally, trastuzumab-expressing CHO-K1 clones were generated and characterized by batch culture, and preliminary results related to HER2-recognition capacity were successful. Further optimization of elements such as gene optimization, vector selection, type of amplification/selection system, cell culture media composition, in combination with this strategy will allow obtaining high producing clones.

scholarly journals Lost in Translation - Bridging the preclinical and clinical worlds concepts, Examples, Successes, and Failures in Translational Medicine

2019 ◽  
Author(s):  
Attila A Seyhan
Keyword(s):  
Drug Development ◽  
Biomedical Research ◽  
Development Process ◽  
Public Funding ◽  
Human Studies ◽  
Attrition Rate ◽  
Drug Development Process ◽  
Preclinical Research ◽  
Attrition Rates ◽  
Research Findings

The biopharmaceutical companies involved in developing drugs for human diseases are facing considerable challenges, both politically and fiscally. There is growing pressure from the general public, funding agencies, and the policymakers for scientists and industry to improve drug development process, better bridge basic and translational human studies, and ultimately improve the process of the development of more effective, safer, and less costly drugs.The crisis involving the scale of the reproducibility and translatability of preclinical research to human studies and high attrition rate of drug development process is widely recognized both in academia and industry. Despite all this, the high attrition rates of drug development and the magnitude of the reproducibility and translatability problems with the preclinical research findings to human studies remain a fact.Recent reports in literature also suggest that many published research findings in preclinical research are misleading, not as robust as they claim, or cannot be reproduced and hence cannot be translated to human studies. The reasons are complex and challenging. Potential culprits range from the complexity of modern biomedical research to the limitations of tools, the trivial methodological differences, to poor experimental designs, inappropriate data analysis, misuse of statistics, the poor predictability of animal results in humans, as well as training and perverse incentives in academia.There are many reports suggesting solutions to overcome these roadblocks in biomedical research. However, how scientists, researchers, and the biopharmaceutical industry deal with this problem depends on the understanding of the root causes of the problem and the strategies and approaches to solving this problem to improve biomedical research.The purpose of this article is to conduct a thorough literature review to evaluate the nature of some of the problems leading to high attrition rates of drug development and to provide some suggestion to overcome the obstacles that impede the drug development process.

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