Non-clinical Safety Evaluation of Biotherapeutics – Challenges, Opportunities and new Insights

Blaich, Guenter; Baumann, Andreas; Kronenberg, Sven; Haan, Lolke de; Ulrich, Peter; Richter, Wolfgang; Tibbitts, Jay; Chivers, Simon; Tarcsa, Edit; Caldwell, Robert Granville; Crameri, Flavio

doi:10.1016/j.yrtph.2016.08.012

Cited by 15 publications

(8 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For CBMPs, the design of conventional toxicity studies, as applied in development of small molecule drugs or of other biological medicinal products and comprising repeat dose toxicity studies of increasing duration in accordance with the intended duration of clinical testing [ 9 – 11 ], is likely to be inappropriate. Instead of considering how to amend such study designs so that they may be applied to a particular cellular therapy, developers should consider the aim of such testing and how this can be achieved most optimally [ 12 – 14 ]. The primary aim is to give reasonable reassurance that use of the clinical CBMP as defined in the clinical protocol will be safe.…”

Section: Toxicitymentioning

confidence: 99%

Preclinical Development of Cell-Based Products: a European Regulatory Science Perspective

McBlane¹,

Phul²,

Sharpe

2018

Pharm Res

View full text Add to dashboard Cite

PurposeThis article describes preclinical development of cell-based medicinal products for European markets and discusses European regulatory mechanisms open to developers to aid successful product development. Cell-based medicinal products are diverse, including cells that are autologous or allogeneic, have been genetically modified, or not, or expanded ex vivo, and applied systemically or to an anatomical site different to that of their origin; comments applicable to one product may not be applicable to others, so bespoke development is needed, for all elements - quality, preclinical and clinical.MethodsAfter establishing how the product is produced, proof of potential for therapeutic efficacy, and then safety, of the product need to be determined. This includes understanding biodistribution, persistence and toxicity, including potential for malignant transformation. These elements need to be considered in the context of the intended clinical development.ResultsThis article describes regulatory mechanisms available to developers to support product development that aim to resolve scientific issues prior to marketing authorization application, to enable patients to have faster access to the product than would otherwise be the case.ConclusionsDevelopers are encouraged to be aware of both the scientific issues and regulatory mechanisms to ensure patients can be supplied with these products.

show abstract

Section: Toxicitymentioning

confidence: 99%

Preclinical Development of Cell-Based Products: a European Regulatory Science Perspective

McBlane¹,

Phul²,

Sharpe

2018

Pharm Res

View full text Add to dashboard Cite

show abstract

“…The nonhuman primate (NHP) is often the only species relevant for regulatory general toxicology studies, and therefore, single species toxicology programs are common. 7 Nevertheless, if a large molecule does demonstrate cross-reactivity with multiple species (including rodent), then toxicology testing using two species is required (examples in the paper by Sewell et al and Blaich et al 8 , 9 ). Provided the toxicity profile is identical in short-term toxicology studies, it is possible to justify assessment of chronic toxicity in a single species only (typically rodent), although there seems to be no published evidence to confirm that this scenario is being adopted.…”

Section: Why Do We Use Two Species In Regulatory Toxicology Studies?mentioning

confidence: 99%

“…The pharmaceutical and related industries are proactive in reviewing requirements, justifying the relevance of current testing strategies, and identifying opportunities for adoption of new or different approaches which may provide more predictive data and of course apply 3Rs principles to the use of animals. Other consortia have, or are actively considering, specific questions which align with and/or complement this project, including the predictivity of nonclinical to clinical (FIH) data, 13 predevelopment attrition of pharmaceuticals, 19 the appropriate use of animals for mAbs, 8 , 20 and other biotherapeutics development, 9 among others. Within this busy collaborative environment, it is realized that any new data analysis should not duplicate or replicate other initiatives but identify a unique topic/question or opportunities to supplement and expand the overall picture.…”

Section: Compounds For Review and Process Plansmentioning

confidence: 99%

Reviewing the Utility of Two Species in General Toxicology Related to Drug Development

et al. 2018

Self Cite

View full text Add to dashboard Cite

As part of the safety assessment of new drugs, the use of two species (a rodent and a nonrodent) for regulatory toxicology studies is the typical approach taken for small molecules. For biologics, species selection is dictated by pharmacological relevance, and single species toxicology packages (typically using the nonhuman primate) are common. The UK National Centre for the Replacement, Refinement, and Reduction of Animals in Research and the Association of the British Pharmaceutical Industry are collaborating on a project to review the utility of two species in regulatory toxicology studies, with the aim to explore whether there are wider circumstances when data from a single species could be sufficient to enable safe progression in humans. An international working group consisting of 37 representatives from pharmaceutical and biotechnology companies, contract research organizations, academia, and regulatory bodies is coordinating a large-scale data sharing exercise to examine the potential for changes in current practice to reduce the number of species used for nonclinical safety testing at different stages of development. The challenge will be to determine whether two species toxicology adds significant value or whether in some instances data from a single species are sufficient (across a broader range of molecules than is currently the case) without compromising human safety.

show abstract

“…In addition to the annual general membership meeting in the United States, an annual BioSafe meeting is held in Europe. [1][2][3][4][5] The eighth Annual BioSafe European General Membership meeting was hosted by Novartis on October 30 to 31, 2018, in Basel, Switzerland. The attendees were from the biopharmaceutical industry, small biotech companies, and contract research organizations (CROs) from Europe and United States, representing various disciplines including pharmacology, toxicology and pathology, pharmacokinetics (PK), and bioanalytics.…”

Section: Introductionmentioning

confidence: 99%

“…4. Draft guideline for ex vivo gene-modified cells is open for comments (prolonged comment window July 31, 2019, due to EMA move to Amsterdam).…”

mentioning

confidence: 99%

Nonclinical Development of Biologics: Integrating Safety, Pharmacokinetics, and Pharmacodynamics to Create Smarter and More Flexible Nonclinical Safety Programs Optimizing Animal Use

Hey

Baumann²,

Kronenberg

et al. 2021

Int J Toxicol

Self Cite

View full text Add to dashboard Cite

Safety assessment of biological drugs has its challenges due to the multiple new different modalities, for example, antibody-drug conjugates, bispecifics, nanobodies, fusion proteins and advanced therapy medicinal products (ATMPs), their different pharmacokinetic and pharmacodynamic properties, and their ability to trigger immunogenicity and toxicity. In the public and in the pharmaceutical industry, there is a strong and general desire to reduce the number of animals used in research and development of drugs and in particular reducing the use of nonhuman primates. Important discussions and activities are ongoing investigating the smarter designs of early research and dose range finding studies, reuse of animals, and replacing animal experiments with in vitro studies. Other important challenges include absence of a relevant species and design of studies and developing genetically modified animals for special investigative toxicology studies. Then, the learnings and challenges from the development of the first ATMPs are available providing valuable insights in the development path for these new potentially transformative treatments. Finally, development of strategies for assessment of immunogenicity and prediction of translation of immunogenicity and associated findings to the clinic. On this, the eighth meeting for the European BioSafe members, these challenges served as the basis for the presentations and discussions during the meeting. This article serves as the workshop report reviewing the presentations and discussions at the meeting.

show abstract

Non-clinical Safety Evaluation of Biotherapeutics – Challenges, Opportunities and new Insights

Cited by 15 publications

References 42 publications

Preclinical Development of Cell-Based Products: a European Regulatory Science Perspective

Preclinical Development of Cell-Based Products: a European Regulatory Science Perspective

Reviewing the Utility of Two Species in General Toxicology Related to Drug Development

Nonclinical Development of Biologics: Integrating Safety, Pharmacokinetics, and Pharmacodynamics to Create Smarter and More Flexible Nonclinical Safety Programs Optimizing Animal Use

Contact Info

Product

Resources

About