The safety, efficacy and regulatory triangle in drug development: Impact for animal models and the use of animals

Meer, Peter J.K. van; Graham, Melanie L.; Schuurman, Henk Jan

doi:10.1016/j.ejphar.2015.02.055

Cited by 47 publications

(32 citation statements)

References 79 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The detour test was also used to study the effect of viral infection [58] and early life stress on cognition in monkeys [59]. Substitution of rodents for primates would be beneficial from the ethical point of view and this is especially important because of the currently advocated 3Rs principle (replacement, reduction and refinement of animal use) [60]. Furthermore, experiments performed in mice enable researchers to study the effect of genetic manipulations on cognitive performance and the interaction between genes and drugs.…”

Section: Discussionmentioning

confidence: 99%

Detour Behavior of Mice Trained with Transparent, Semitransparent and Opaque Barriers

Juszczak

Miller

2016

PLoS ONE

View full text Add to dashboard Cite

Detour tasks are commonly used to study problem solving skills and inhibitory control in canids and primates. However, there is no comparable detour test designed for rodents despite its significance for studying the development of executive skills. Furthermore, mice offer research opportunities that are not currently possible to achieve when primates are used. Therefore, the aim of the study was to translate the classic detour task to mice and to compare obtained data with key findings obtained previously in other mammals. The experiment was performed with V-shaped barriers and was based on the water escape paradigm. The study showed that an apparently simple task requiring mice to move around a small barrier constituted in fact a challenge that was strongly affected by the visibility of the target. The most difficult task involved a completely transparent barrier, which forced the mice to resolve a conflict between vision and tactile perception. The performance depended both on the inhibitory skills and on previous experiences. Additionally, all mice displayed a preference for one side of the barrier and most of them relied on the egocentric strategy. Obtained results show for the first time that the behavior of mice subjected to the detour task is comparable to the behavior of other mammals tested previously with free-standing barriers. This detailed characterization of the detour behavior of mice constitutes the first step toward the substitution of rodents for primates in laboratory experiments employing the detour task.

show abstract

Section: Discussionmentioning

confidence: 99%

Detour Behavior of Mice Trained with Transparent, Semitransparent and Opaque Barriers

Juszczak

Miller

2016

PLoS ONE

View full text Add to dashboard Cite

show abstract

“…[27]]. However, the use of animal models is increasingly subject of discussion, also in the scientific community addressing the translational value of studies in animals [86,87]. Essentially, this discussion is not intending to abolish studies in animal models, but rather asks the question what can be studied in a given model testing a distinct (cell-based) medicinal product, and how this relates to a clinical condition.…”

Section: Module 4; Nonclinical Studiesmentioning

confidence: 98%

“…Noteworthy, regulatory authorities are increasingly inclined to accept data from combined efficacy-safety studies in preclinical testing of CBMPs [87]. This acceptance avoids the conduct of (costly) toxicity/tolerability studies, and has the advantage that the balance between safety, tolerability and efficacy of a given product can be assessed in one single study.…”

Section: Module 4; Nonclinical Studiesmentioning

confidence: 98%

“…This acceptance avoids the conduct of (costly) toxicity/tolerability studies, and has the advantage that the balance between safety, tolerability and efficacy of a given product can be assessed in one single study. Evidently, since safety is now part of the primary endpoint parameters, a higher level of data quality than in conventional efficacy studies is required: this does not mean that such studies which are often performed in an academic setting need to be compliant with principles of good laboratory practice (GLP), but rather a proper data quality management system should be in place, as outlined in further detail elsewhere [87].…”

Section: Module 4; Nonclinical Studiesmentioning

confidence: 99%

See 1 more Smart Citation

Regulatory aspects of clinical xenotransplantation

Schuurman¹

2015

International Journal of Surgery

Self Cite

View full text Add to dashboard Cite

Xenotransplantation attracted interest from regulatory authorities, particularly after the demonstration of pig-to-human transmission of porcine endogenous retrovirus (1996). This added to the risk of a product, resulting in a Guidance of the US Food and Drug Administration (2003). This addresses the full flow chart in product manufacturing, starting with the designated pathogen-free status of the source animal; and special aspects regarding the recipient like informed consent and monitoring for infectious pathogens. Also archiving of records from the donor and recipient, as well as storage of samples is described. The European Medicines Agency issued a Guideline on xenogeneic cell therapy products (2009). Cell-based medicinal products are subject to specific regulations and directives, which apply also to xenogeneic products: the xenotransplant guidances/guidelines are an addition to these regulations. Noteworthy, acellular products like heart valves and decellularized cornea are not considered a cell therapy product, but rather a medical device with its own regulation. WHO issued relevant documents, especially about safety, and the International Xenotransplantation Association published consensus documents, a.o., addressing preclinical efficacy requirements before entering clinical trials. This manuscript presents an overview of the regulatory framework, with special focus on cell therapy products necause these are expected to reach the market first (i.e., pancreatic islets, hepatocytes and cellularized cornea); major illustrations are from the European situation. Albeit being complex, the regulation of xenotransplant products does not form a block in product development, but rather supports the introduction of efficacious and safe products to meet the medical need.

show abstract

“…Transgenic pigs are increasingly offered as models for human disease in the field of neurology (Alzheimer's and Huntington's), ophthalmology (macular dystrophy), cardiovascular, metabolic (liver, diabetes), respiratory (cystic fibrosis), cancer, or immunodeficiency (Aigner et al 2013;Kemter et al 2012). Improvement in animal models for human safety assessment will be a major challenge in drug development, and this also applies to models that have been thought to be unsurmountable like the NHP model, which is considered the only relevant species for safety testing of recombinant proteins or monoclonal antibodies and that have demonstrated limited value and predictivity of patients (Van Meer, Graham, and Schuurman 2015).…”

mentioning

confidence: 99%

The Use of Minipig in Drug Discovery and Development

Heining

Ruysschaert

2015

Toxicol Pathol

View full text Add to dashboard Cite

The pig was introduced more than 20 years ago in drug development following attempts of finding a species that shares better homology with human than the dog, based on biophysiological parameters. However, miniaturization, standardized breeding, and health status control were required before the pig could find a broader than niche application in pharmaceutical industry. During the years of experience with minipigs in pharmaceutical research and the science evolving rapidly, the selection of a nonrodent animal species for preclinical safety testing became primarily driven by pharmacological (target expression homologous function), pharmacokinetic, and biophysiological considerations. This offered a broad field of application for the minipig, besides the wellestablished use in dermal projects in all areas of drug development but also in novel approaches including genetically modified animals. In this article, we look at recent approaches and requirements in the optimal selection of a nonrodent model in pharmaceutical development and critically ask how good a choice the minipig offers for the scientist, how did the testing environment evolve, and what are the key requirements for a broader use of the minipig compared to the other well-established nonrodent species like dog or monkey.

show abstract

The safety, efficacy and regulatory triangle in drug development: Impact for animal models and the use of animals

Cited by 47 publications

References 79 publications

Detour Behavior of Mice Trained with Transparent, Semitransparent and Opaque Barriers

Detour Behavior of Mice Trained with Transparent, Semitransparent and Opaque Barriers

Regulatory aspects of clinical xenotransplantation

The Use of Minipig in Drug Discovery and Development

Contact Info

Product

Resources

About