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Future of Regulatory Safety Assessments

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Drug Discovery and Evaluation: Methods in Clinical Pharmacology

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Abstract

Drug development contributes to improve health, duration, and quality of life. Lethal diseases have turned into chronic tolerable conditions, but medical need for many pathological processes continues. Concerns appear that in spite of extensive workload, success of pharmaceutical activity, and included facilitated access to novel drugs, may slow down. The preclinical testing via in vitro and animal experimentation reveals limitations to select the right promising candidates, most likely to be effective in humans and predict undesirable side effects early on.

Therefore, constant efforts are necessary to improve the strategies. Courage needs to be stimulated to leave traditional paths and find new and better ways. This “rethinking” process needs directions to focus on additional options: use of more in silico data, deeper insight via cell cultures or receptor studies, new methods to explore more intensively relevant mechanisms of diseases and pharmacodynamics, more comparative data from different animal models, which species really deliver signals relevant for patients; for this objective, disease models or implementation of human conditions into transgenic animals may be supportive. More rigorous randomized designs of preclinical studies and their blinded assessment may improve reproducible and therefore validated results.

In times of “big data” regulatory agencies, academic and industry researchers (possibly under political pressure) should feel obliged to stop selective publications (only positive effects) but create access also to options to learn from failures. The use of available knowledge (literature, experience, scientific advice) may limit the risks of reducing attrition rates and help to shorten timelines. Discussions with agencies have already facilitated a number of strategies. Examples are ICH guidelines M3 (allowing early access to new compounds for women of childbearing potential) or S 9 (reducing the preclinical development package for patients suffering from tumors).

The purpose of this chapter is to prompt openness and imagination to use new methods, more science, experience, and communication among researchers to the benefit of patients.

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References and Further Reading

  • Akhtar A (2015) The flaws and human harms of animal experimentation. Camb Q Healthc Ethics 24(4):407–419

    Article  Google Scholar 

  • Arlington S (2012) From vision to decision: pharma 2020. Price Waterhouse Coopers (PwC), London. Available at https://www.pwc.com/gx/en/pharma-life-sciences/pharma2020/assets/pwc-pharma-success-strategies.pdf. Accessed on 3 July 2017

    Google Scholar 

  • ARRIVE – Animal Research: Reporting of In Vivo Experiments. Available at https://www.nc3rs.org.uk/arrive-animal-research-reporting-vivo-experiments. Accessed on 3 July 2017

  • Arrowsmith J (2011) Trial watch: phase III and submission failures: 2007–2010. Nat Rev Drug Discov 10:87

    Article  CAS  Google Scholar 

  • Bailey J, Thew M, Balls M (2013) An analysis of the use of dogs in predicting human toxicology and drug safety. Altern Lab Anim 41(5):335–350

    CAS  PubMed  Google Scholar 

  • Bailey J, Thew M, Balls M (2014) An analysis of the use of animal models in predicting human toxicity and drug safety. Altern Lab Anim 42:181–199

    CAS  PubMed  Google Scholar 

  • Baumann A, Flagella K, Forster R, de Haan L, Kronenberg S, Locher M et al (2014) New challenches and opportunities in nonclinical safety testing of biologics. Regul Toxicol Pharmacol 69(2):226–233

    Article  CAS  Google Scholar 

  • Begley C, Ellis L (2012) Drug development: raise standards for preclinical cancer research. Nature 483:531–533

    Article  CAS  Google Scholar 

  • Bennani YL (2012) Drug discovery in the next decade: innovation needed ASAP. Drug Discov Today 16(17–18):779–792

    Google Scholar 

  • Bhatia SN, Ingberg DE (2014) Microfluidic organs-on-chips. Nat Biotechnol 32:760–772

    Article  CAS  Google Scholar 

  • Bluemel J (2012) Considerations for the use of nonhuman primates in nonclinical safety assessment. In: Weinbauer GF, Vogel F (eds) Challenges in nonhuman primate research in the 21st century, Waxman (2012). Charles River Publication Series, pp 59–70. ISBN 978-3-8309-2839-3

    Google Scholar 

  • Bode G, Van der Laan JW (2016) Paradigm change in cancerogenicity, Presentation: German Pharm-Tox Summit, Berlin, 29-02 to 03-03-2016, Berlin, ACS Publications, pubs.acs.org./crt, Symposium 19

    Google Scholar 

  • Bode G, Clausing P, Gervais F, Loegsted J, Luft J, Nogues V, Sims J et al (2010) The utility of the minipig as an animal model in regulatory toxicology. J Pharmacol Toxicol Methods 62(3):196–220

    Article  CAS  Google Scholar 

  • Bussiere JL, Martin P, Horner M, Couch J, Flaherty M, Andrews L, Beyer J, Horvath C (2009) Alternative strategies for toxicity testing of species-specific biopharmaceuticals. Int J Toxicol 28(3):230–253

    Article  CAS  Google Scholar 

  • CAMARADES: Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies. Available at http://www.dcn.ed.ac.uk/camarades/. Accessed 3 July 2017

  • Casty F, Wieman M (2013) Drug development in the 21st century. The synergy of public, private, and international collaboration. Ther Innov Regul Sci 47(3):375–383

    Article  Google Scholar 

  • Cavagnaro J, Lima BS (2015) Regulatory acceptance of animal models of disease to support clinical trials of medicines and advanced therapy medicinal products. Eur J Pharmacol 759:51–62

    Article  CAS  Google Scholar 

  • Chalmers I, Glasziou P (2009) Avoidable waste in the production and reporting of research evidence. Lancet 374:86–89

    Article  Google Scholar 

  • Chapman KL, Pullen N, Andrews L, Ragan I (2010) The future of non-human primate use in mAb development. Drug Discov Today 15:235–242

    Article  CAS  Google Scholar 

  • Chapman K, Andrews L, Bajramovic JJ, Baldrick P et al (2012) The design of chronic toxicology studies of monoclonal antibodies: implications for the reduction in use of non-human primate. Regul Toxicol Pharmacol 62:347–354

    Article  CAS  Google Scholar 

  • Chapman KL, Holzgrefe H, Black LE, Brown M, Chellman G, Copeman C, Couch J et al (2013) Pharmaceutical toxicology: designing studies to reduce animal use, while maximizing human translation. Regul Toxicol Pharmacol 66:88–103

    Article  CAS  Google Scholar 

  • Cherkasov A, Muratov E, Fourches D, Varnek A, Baskin I, Cronin M et al (2014) QSAR modeling: where have you been? Where are you going to? J Med Chem 57(12):4977–5010

    Article  CAS  Google Scholar 

  • Clarke J, Hurst C, Martin P, Vahle J, Ponce R, Mounho B, Heidel S, Andrews L, Reynolds T, Cavagnaro J (2008) Duration of chronic toxicity studies for biotechnology-derived pharmaceuticals: is 6 months still appropriate? Regul Toxicol Pharmacol 50:2–22

    Article  CAS  Google Scholar 

  • Tufts center for study of drug development (CSDD) (2015) Outlook 2015. Available at: http://csdd.tufts.edu/files/uploads/Outlook-2015.pdf. Accessed 5 Feb 2017

  • Davis PR, Head E (2014) Prevention approaches in a preclinical canine model of Alzheimer’s disease: benefits and challenges. Front Pharmacol 5:47

    Article  Google Scholar 

  • Denayer T, Stöhr T, van Roy M (2014) Animal models in translational medicine: validation and prediction. New Horiz Transl Med 2:5–11

    Google Scholar 

  • DiMasi J, Kim J, Getz K (2014) The impact of collaborative and risk-sharing innovation approaches on clinical and regulatory cycle times. Ther Innov Regul Sci 48(4):482–487

    Article  Google Scholar 

  • DiMasi J, Grabowski H, Hansen R (2016) Innovation in the pharmaceutical industry: new estimates of R&D costs. J Health Econ 47:20–33

    Article  Google Scholar 

  • Directive 65/65/EEC of 26 January 1965 on the approximation of provisions laid down by Law, Regulation or Administrative Action relating to proprietary medicinal products. Off J Eur Union 22, 09/02/1965, pp 369–373

    Google Scholar 

  • Directive 2001/82/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to veterinary medicinal products. Off J Eur Union L 311, 28/11/2001, pp 1–66

    Google Scholar 

  • Directive 2010/63/EU of the European Parliament and of the Council of 22 September 2010 on the protection of animals used for scientific purposes. Off J Eur Union L276, 20/10/2010, pp 33–79

    Google Scholar 

  • Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use. Off J Eur Union L 311, 28/11/2001, pp 37–128

    Google Scholar 

  • Doke SK, Dhawale SC (2015) Alternatives to animal testing: a review. Saudi Pharm J 23(3):223–229

    Article  Google Scholar 

  • Egan KJ, Vesterinen HM, Beglopoulos V, Sena ES, Macleod MR (2016) From a mouse: systematic analysis reveals limitations of experiments testing interventions in Alzheimer’s disease mouse models. Evid-Based Preclin Med 3(1):12–23

    Article  Google Scholar 

  • EMA (2008) Note for guidance on non-clinical safety studies for the conduct of human clinical trials and marketing authorisation for pharmaceuticals. CPMP/ICH/286/95

    Google Scholar 

  • EMA (2010) Guideline on repeated dose toxicity. CPMP/SWP/1042/99 Rev 1 Corr

    Google Scholar 

  • EMA (2012) Guideline on similar biological medicinal products containing monoclonal antibodies – non-clinical and clinical issues. EMA/CHMP/BMWP/403543/2010

    Google Scholar 

  • EMA (2014) Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. EMEA/CHMP/BMWP/42832/2005 Rev1

    Google Scholar 

  • EMA (2016a) Guideline on the principles of regulatory acceptance of 3R (replacement, reduction, refinement) testing approaches. EMA/CHMP/CVMP/JEG-3Rs/450091/2012

    Google Scholar 

  • EMA (2016b) Reflection paper providing an overview of the current regulatory testing requirements for medicinal products for human use and opportunities for implementation of the 3R (EMA/CHMP/CVMP/JEG3Rs-3Rs/742466/2015) – published for consultation

    Google Scholar 

  • EMA (2016c) Reflection paper providing an overview of the current regulatory testing requirements for veterinary medicinal products and opportunities for implementation of the 3Rs (EMA/CHMP/CVMP/JEG-3Rs/164002/2016) – published for consultation

    Google Scholar 

  • EMA (2017a) Guideline on strategies to identify and mitigate risks for first-in-human clinical trials with investigational medicinal products (EMEA/CHMP/SWP/28367/07 Rev. 1

    Google Scholar 

  • EMA (2017b) Reflection paper on statistical methodology for the comparative assessment of quality attributes in drug development (EMA/CHMP/138502/2017) – published for consultation

    Google Scholar 

  • EURL ECVAM (2017) Homepage of the European Commission, The European Union Reference Laboratory for alternatives to animal testing (EURL-ECVAM). Available at https://eurl-ecvam.jrc.ec.europa.eu/. Accessed 1 Sept 2017

  • European Commission 2013: Report from the Commission to the Council and the European Parliament: seventh report on the statistics on the number of animals used for experimental and other scientific purposes in the member states of the European Union, SEC(2010) 1107, 15pp. European Commission, Brussels. Available at: http://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:52013DC0859&from=EN. Accessed 13 Jan 2017

  • European Commission (2016) Animals used for scientific purposes. Available at http://ec.europa.eu/environment/chemicals/lab_animals/3r/acceptance_en.htm. Accessed 4 July 2017

  • Evens R (2016) Pharma success in product development – does biotechnology change the paradigm in product development and attrition. AAPS J 18:281

    Article  CAS  Google Scholar 

  • Everitt JI (2015) The future of preclinical animal models in pharmaceutical discovery and development: a need to bring in cerebro to the in vivo discussions. Toxicol Pathol 43:70–77

    Article  Google Scholar 

  • FDA (2004) Innovation or stagnation: challenge and opportunity on the critical path to new medical products. In: Challenges and Opportunities Report US Department of Health and Human Services. Available at: https://www.fda.gov/downloads/scienceresearch/specialtopics/criticalpathinitiative/criticalpathopportunitiesreports/ucm113411.pdf. Accessed 13 Sept 2017

  • Friedrich A, Olejniczak K (2011) Evaluation of carcinogenicity studies of medicinal product for human use authorized via the European centralized procedure (1995–2009). Regul Toxicol Pharmacol 60:225–248

    Article  CAS  Google Scholar 

  • Ganderup NC, Harvey W, Mortensen JT, Harrouk W (2012) The minipig as nonrodent species in toxicology – where are we now? Int J Toxicol 31(6):507–528

    Article  Google Scholar 

  • Getz K (2011) Transforming legacy R&D through open innovation. Monit 4(3):16–21

    Google Scholar 

  • Getz KA, Kaitin KI (2015) Why is the pharmaceutical and biotechnology industry struggling? In: Schüler P, Buckley B (eds) 2015: re-engineering clinical trials. Best practices for streamlining the development process. Academic Press/Elsevier. ISBN: 9780124202467

    Google Scholar 

  • Glasziou P (2014) The role of open access in reducing waste in medical research. PLoS Med 11:e1001651

    Article  Google Scholar 

  • Greaves P, Williams A, Eve M (2004) First dose of potential new medicines to humans: how animals help. Nat Rev Drug Discov 3:226–236

    Article  CAS  Google Scholar 

  • Greek R, Hansen LA (2013) The strengths and limits of animal models as illustrated by the discovery and development of antibacterials. Biol Syst 2:109

    Article  Google Scholar 

  • Green SB (2015) Can animal data translate to innovations necessary for a new era of patient-centred and individualised healthcare? Bias in preclinical animal research. BMC Med Ethics 16:53

    Article  Google Scholar 

  • Groenink L, Folkerts G, Schuurman HJ (2015) Editorial, special issue on translational value of animal models. Eur J Pharmacol 759:1–2

    Article  CAS  Google Scholar 

  • Gulin JE, Rocco DM, García-Bournissen F (2015) Quality of reporting and adherence to ARRIVE guidelines in animal studies for Chagas disease preclinical drug research: a systematic review. PLoS Negl Trop Dis 9(11):e0004194

    Article  Google Scholar 

  • Hay M, Thomas DW, Craighead JL, Economides C, Rosenthal J (2014) Clinical development success rates for investigational drugs. Nat Biotechnol 32:40–51

    Article  CAS  Google Scholar 

  • Hester RE, Harrison M, Illing P (2006) General overview of the safety evaluation of chemicals. In: Hester RE, Harrison M (eds) Alternatives to animal testing. RSC Publishing. ISBN 978-0-85404-211-1

    Google Scholar 

  • Heywood R (1981) Target organ toxicity. Toxicol Lett 8:349–358

    Article  CAS  Google Scholar 

  • Hirano E, Knutsen RH, Sugitani H, Ciliberto CH, Mecham RP (2007) Functional rescue of elastin insufficiency in mice by the human elastin gene: implications for mouse models of human disease. Circ Res 101(5):523–531

    Article  CAS  Google Scholar 

  • Horn J, de Haan RJ, Vermeulen M, Luiten PGM, Limburg M (2001) Nimodipine in animal model experiments of focal cerebral ischemia: a systematic review. Stroke 32:2433–2438

    Article  CAS  Google Scholar 

  • ICH guideline S3A: Note for guidance on toxicokinetics: the assessment of systemic exposure in toxicity studies. Oct 1994

    Google Scholar 

  • ICH guideline S1A: Need for carcinogenicity studies of pharmaceuticals. Nov 1995

    Google Scholar 

  • ICH guideline S1B: Testing for carcinogenicity of pharmaceuticals. July 1997

    Google Scholar 

  • ICH guideline S 7 B: The nonclinical evaluation of the potential for delayed ventricular repolarization (QT interval prolongation) by human pharmaceuticals. May 2005

    Google Scholar 

  • ICH guideline S1C(R2): Dose selection for carcinogenicity studies of pharmaceuticals. March 2008

    Google Scholar 

  • ICH guideline M3(R2): Non-clinical safety studies for the conduct of human clinical trials and marketing authorisation for pharmaceuticals. June 2009

    Google Scholar 

  • ICH Guideline S2(R1): Guidance on genotoxicity testing and data interpretation for pharmaceuticals intended for human use. Nov 2011

    Google Scholar 

  • ICH guideline S3B Pharmacokinetics: guidance for repeated dose tissue distribution studies. Oct 1994

    Google Scholar 

  • ICH Guideline S5(R2): Detection of toxicity to reproduction for medicinal products & toxicity to male fertility. June 1993

    Google Scholar 

  • ICH guideline S6 (R1): Preclinical safety evaluation of biotechnology-derived pharmaceuticals. June 2011

    Google Scholar 

  • ICH guideline S7A: Safety pharmacology studies for human pharmaceuticals. Nov 2000

    Google Scholar 

  • ICH guideline S9: Nonclinical evaluation for anticancer pharmaceuticals. Oct 2009

    Google Scholar 

  • Kaitin K, DiMasi J (2011) Pharmaceutical innovation in the 21st century: new drug approvals in the first decade 2000–2009. Clin Pharm Therap 89(2):183–188

    Article  CAS  Google Scholar 

  • Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG (2010) Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol 8:e1000412

    Article  Google Scholar 

  • Kimmelman J, Anderson JA (2012) Should preclinical studies be registered? Nat Biotechnol 30(6):488–489

    Article  CAS  Google Scholar 

  • Kola I, Landis J (2004) Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov 3:711–715

    Article  CAS  Google Scholar 

  • Kooijman M (2013) Why animal studies are still being used in drug development. Altern Lab Anim 41(6):79–81

    Google Scholar 

  • Kooijman M, van Meer P, Moors E, Schellekens H (2012) Thirty years of preclinical safety evaluation of biopharmaceuticals: did scientific progress lead to appropriate regulatory guidance? Expert Opin Drug Saf 11(5):797–801

    Article  Google Scholar 

  • Korevaar DA, Hooft L, Ter Riet G (2011) Systematic reviews and meta-analyses of preclinical studies: publication bias in laboratory animal experiments. Lab Anim 45:225–230

    Article  CAS  Google Scholar 

  • Lamberti M, Mathias A, Myles J, Howe D, Getz K (2012) Evaluating the impact of patient recruitment and retention practices. Drug Inf J 46(5):573–580

    Article  Google Scholar 

  • Landis SC, Amara SG, Asadullah K, Austin CP, Blumenstein R, Bradley EW, Crystal RG et al (2012) A call for transparent reporting to optimize the predictive value of preclinical research. Nature 490:187–191

    Article  CAS  Google Scholar 

  • Langley G, Austin CP, Balapure AK, Birnbaum LS, Bucher JR, Fentem J, Fitzpatrick SC et al (2015) Lessons from toxicology: developing a 21st-century paradigm for medical research. Environ Health Perspect 123:A268–A272

    Article  CAS  Google Scholar 

  • Lee GS, Lee KY, Choi KC, Ryu YH, Paik SG, Oh GT, Jeung EB (2007) Phenotype of a calbindin-D9k gene knockout is compensated for by the induction of other calcium transporter genes in a mouse model. J Bone Miner Res 22(12):1968–1978

    Article  CAS  Google Scholar 

  • Liebsch M, Grune B, Seiler A, Butzke D, Oelgeschläger M et al (2011) Alternatives to animal testing: current status and future perspectives. Arch Toxicol 85(8):841–858

    Article  CAS  Google Scholar 

  • Macleod M (2011) Why animal research need to improve. Nature 477:511

    Article  Google Scholar 

  • Macleod MR, O’Collins T, Howells DW, Donnan GA (2004) Pooling of animal experimental data reveals influence of study design and publication bias. Stroke 35:1203–1208

    Article  Google Scholar 

  • Matthews R (2008) Medical progress depends on animal models – doesn’t it? J R Soc Med 101(2):95–98

    Article  Google Scholar 

  • Mella JR, Chiswick EL, King E, Remick DG (2014) Location, location, location: cytokine concentrations are dependent on blood sampling site. Shock 42:337–342

    Article  CAS  Google Scholar 

  • Michelson Prize & Grants (2014) The quality assurance toolkit. Available at http://www.michelsonprizeandgrants.org/resources/qa-toolkit. Accessed 29 Aug 2017

  • Morgan SJ, Elangbam CS, Berens S, Janovitz E, Vitsky A, Zabka T, Conour L (2013) Use of animal models of human disease for nonclinical safety assessment of novel pharmaceuticals. Toxicol Pathol 41(3):508–518

    Article  Google Scholar 

  • National Research Council [US] Institute for Laboratory Animal Research 2011: Guidance for the Description of Animal Research in Scientific Publications

    Google Scholar 

  • NIH, National Human Genome Research Institute (2009) Knockout mice. Available at: https://www.genome.gov/12514551/. Accessed 2 Aug 2017

  • NTP (2017) https://ntp.niehs.nih.gov/pubhealth/evalatm/test-method-evaluations/acute-systemic-tox/in-vitro-validation/index.html

  • Nuffield Council on Bioethics (2005) The ethics of research involving animals. Available at: https://nuffieldbioethics.org/wp-content/uploads/The-ethics-of-research-involving-animals-full-report.pdf. Accessed 12 Sept 2017

  • OECD (2015) Guidance document on revisions to OECD genetic toxicology test guidelines. Available at https://www.oecd.org/chemicalsafety/testing/Genetic%20Toxicology%20Guidance%20Document%20Aug%2031%202015.pdf

  • Olson H, Betton G, Robinson D, Thomas K, Monro A, Kolaja G, Lilly P, Sanders J et al (2000) Concordance of the toxicity of pharmaceuticals in humans and in animals. Regul Toxicol Pharmacol 32(1):56–67

    Article  CAS  Google Scholar 

  • Paul S, Mytelka D, Dunwiddie C, Persinger C, Munos B, Lindborg S, Schacht A (2010) How to improve R&D productivity: the pharmaceutical industry’s grand challenge. Nat Rev Drug Discov 9:203–214

    Article  CAS  Google Scholar 

  • Perrin S (2014) Preclinical research: make mouse studies work. Nature 507:7493

    Article  Google Scholar 

  • PhRMA (Pharmaceutical Research and Manufacturers of America) 2015: 2015 biopharmaceutical research industry profile. Available at: http://www.phrma.org/sites/default/files/pdf/2015_phrma_profile.pdf. Accessed 4 Feb 2017

  • Pound P, Ebrahim S, Sandercock P, Bracken MB, Roberts I (2004) Where is the evidence that animal research benefits humans? BMJ 328(7438):514–517

    Article  Google Scholar 

  • Prinz F, Schlange T, Asadullah K (2011) Believe it or not: how much can we rely on published data on potential drug targets? Nat Rev Drug Discov 10(9):712

    Article  CAS  Google Scholar 

  • Prot J, Leclerc E (2012) The current status of alternatives to animal testing and predictive toxicology methods using liver microfluidic biochips. Ann Biomed Eng 40(6):1228–1243

    Article  Google Scholar 

  • Pwc (PricewaterhouseCoopers) 2012: Pharma 2020: The vision. Which path will you take? Available at: http://www.pwc.com/gx/en/industries/pharmaceuticals-life-sciences/pharma-2020/pharma-2020-vision-path.html. Accessed 4 Feb 2017

  • Research Quality Association (2008) Guidelines for quality in non-regulated scientific research. Available at: http://www.therqa.com/publications/booklets/guidelines-quality-non-regulated-scientific-research/. Accessed 29 Aug 2017

  • Ritskes-Hoitinga M, Leenaars M, Avey M, Rovers M, Scholten R (2014) Systematic reviews of preclinical animal studies can make significant contributions to health care and more transparent translational medicine[editorial]. Cochrane Database Syst Rev (3). https://doi.org/10.1002/14651858.ED000078

  • Rowell JL, McCarthy DO, Alvarez CE (2012) Dog models of naturally occurring cancer. Trends Mol Med 17(7):380–388

    Article  Google Scholar 

  • Russell WM, Burch RL (1959) The principles of humane experimental technique. Methuen, London. ISBN 9780900767784

    Google Scholar 

  • Sandercock P, Roberts I (2002) Systematic reviews of animal experiments. Lancet 360(9333):586

    Article  Google Scholar 

  • Scannel J, Blanckley A, Boldon H, Warrington B (2012) Diagnosing the decline in pharmaceutical R&D efficiency. Nat Rev Drug Discov 11:191–200

    Article  Google Scholar 

  • Schein PS, Davis RD, Carter S, Newman J, Schein DR, Rall DP (1970) The evaluation of anticancer drugs in dogs and monkeys for the prediction of qualitative toxicities in man. Clin Pharmacol Ther 11:3–40

    Article  CAS  Google Scholar 

  • SCHER (The Scientific Committee on Health and Environmental, The European Commission) (2009) Opinion on “The need for non-human primates in biomedical research, production and testing of products and devices”. Available at: http://ec.europa.eu/health/scientific_committees/opinions_layman/en/non-human-primates/l-3/2-research-safety-testing.htm#0p0. Accessed 7 Aug 2017

  • Schueler P, Buckley B (eds) (2014) Re-engineering clinical trials: best practices for streamlining the development process. Academic Press. ISBN-10: 0124202462

    Google Scholar 

  • Scott S, Kranz JE, Cole J, Lincecum JM, Thompson K, Kelly N et al (2008) Design, power, and interpretation of studies in the standard murine model of ALS. Amyotroph Lateral Scler 9:4–15

    Article  CAS  Google Scholar 

  • Sena E, van der Worp B, Howells D, Macleod M (2007) How can we improve the pre-clinical development of drugs for stroke? Trends Neurosci 30(9):433–439

    Article  CAS  Google Scholar 

  • Sena ES, van der Worp HB, Bath PM, Howells DW, Macleod MR (2010) Publication bias in reports of animal stroke studies leads to major overstatement of efficacy. PLoS Biol 8:e1000344

    Article  Google Scholar 

  • STAIR (Stroke Therapy Academic Industry Roundtable) (1999) Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke 30:2752–2758

    Article  Google Scholar 

  • Swaim LD, Taylor HW, Jersey GC (1985) The effects of handling techniques on serum ALT in mice. J Appl Toxicol 5:160–162

    Article  CAS  Google Scholar 

  • Taylor K, Gordon N, Langley G, Higgins W (2008) Estimates for worldwide laboratory animal use in 2005. Altern Lab Anim 36:327–342

    CAS  PubMed  Google Scholar 

  • Te Koppele J, Witkamp R (2008) Use of animal models of disease in the preclinical safety evaluation of biopharmaceuticals. In: Cavagnaro JA (ed) Preclinical safety evaluation of biopharmaceuticals: a science-based approach to facilitating clinical trials. Wiley, pp 293–308. ISBN: 978-0-470-10884-0

    Google Scholar 

  • Teelmann K, Hohbach C, Lehmann H (1986) Preclinical safety testing of species specific proteins produced with recombinant DNA-techniques. An attempt to transfer current experience into future testing strategies. Arch Toxicol 59:195–200

    Article  CAS  Google Scholar 

  • Ter Riet G, Korevaar DA, Leenaars M, Sterk PJ, VanNoorden CJF, Bouter LM, Lutter R, Elferink RPO, Hooft L (2012) Publication bias in laboratory animal research: a survey on magnitude, drivers, consequences and potential solutions. PLoS One 7:e43404

    Article  Google Scholar 

  • Tiwari A (2014) Microdosing: a new approach to clinical drug development. Available at: https://de.slideshare.net/drashutoshtiwari/microdosing-phase-0-studies. Accessed on 22 Sept 2017

  • Tsilidis KK, Panagiotou OA, Sena ES, Aretouli E, Evangelou E, Howells DW, Salman RA, Macleod MR, Ioannidis JPA (2013) Evaluation of excess significance bias in animal studies of neurological diseases. PLoS One 11:e1001609

    Article  CAS  Google Scholar 

  • Van Aerts LA, De Smet K, Reichmann G, van der Laan JW, Schneider CK (2014) Biosimilars entering the clinic without animal studies: a paradigm shift in the European Union. MAbs 6(5):1155–1162

    Article  Google Scholar 

  • van der Worp HB, de Haan P, Morrema E, Kalkman CJ (2005) Methodological quality of animal studies on neuroprotection in focal cerebral ischaemia. J Neurol 252:1108–1114

    Article  Google Scholar 

  • Van Luijk J, Bakker B, Rovers MM, Ritskes-Hoitinga M, de Vries RB, Leenaars M (2014) Systematic reviews of animal studies; missing link in translational research? PLoS One 9:e89981

    Article  Google Scholar 

  • Van Meer P (2013) The scientific value of non-clinical animal studies in drug development. PhD thesis, Utrecht University

    Google Scholar 

  • Van Meer P, Gispen-de Wied C, Moors E, Schellekens H (2012) The ability of animal studies to detect serious post marketing adverse events is limited. Regul Toxicol Pharmacol 64(3):345–349

    Article  Google Scholar 

  • Van Meer PJ, Kooijman M, van der Laan JW, Moors EH, Schellekens H (2013) The value of non-human primates in the development of monoclonal antibodies. Nat Biotechnol 31(10):882–883

    Article  Google Scholar 

  • Van Meer PJK, Graham ML, Schuurman HJ (2015) The safety, efficacy and regulatory triangle in drug development: impact for animal models and the use of animals. Eur J Pharmacol 759:3–13

    Article  Google Scholar 

  • Vesterinen HM, Sena ES, Egan KJ, Hirst TC, Churolov L, Currie GL, Antonic A, Howells DW, Macleod MR (2014) Meta-analysis of data from animal studies: a practical guide. J Neurosci Methods 221:92–102

    Article  CAS  Google Scholar 

  • Weaver ML, Blak Grossi A, Schützsack J, Parish J et al (2016) Vehicle systems and excipients used in minipig drug development studies. Toxicol Pathol 44(3):367–372

    Article  CAS  Google Scholar 

  • WHO (World Health Organization) (2006) Handbook: quality practices in basic biomedical research. Available at: http://www.who.int/tdr/publications/training-guideline-publications/handbook-quality-practices-biomedical-research/en/. Accessed 29 Oct 2017

  • Zbinden G (1987) Biotechnology products intended for human use, toxicological targets and research strategies. Prog Clin Biol Res 235:143–159

    CAS  PubMed  Google Scholar 

  • Zheng Y, Tesar DB, Benincosa L, Birnböck H (2012) Minipig as a potential translatable model for monoclonal antibody pharmacokinetics after intravenous and subcutaneous administration. MAbs 4(2):243–255

    Article  Google Scholar 

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Authors and Affiliations

  1. Institute of Pharmacology and Toxicology, University Medical Center, Goettingen, Germany

    Gerd Bode

  2. The University of Bonn/German Society for Regulatory Affairs, Bonn, Germany

    Petra Starck-Lantova

Authors
  1. Gerd Bode
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  2. Petra Starck-Lantova
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Correspondence to Gerd Bode .

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Editors and Affiliations

  1. CorDynamics , Dieburg, Germany

    Franz J. Hock

  2. CorDynamics , Chicago, IL, USA

    Michael R. Gralinski

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Bode, G., Starck-Lantova, P. (2019). Future of Regulatory Safety Assessments. In: Hock, F., Gralinski, M. (eds) Drug Discovery and Evaluation: Methods in Clinical Pharmacology. Springer, Cham. https://doi.org/10.1007/978-3-319-56637-5_71-2

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  • DOI: https://doi.org/10.1007/978-3-319-56637-5_71-2

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  • Print ISBN: 978-3-319-56637-5

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  1. Latest

    Future of Regulatory Safety Assessments
    Published:
    26 September 2018

    DOI: https://doi.org/10.1007/978-3-319-56637-5_71-2

  2. Original

    Future of Regulatory Safety Assessments
    Published:
    10 August 2018

    DOI: https://doi.org/10.1007/978-3-319-56637-5_71-1

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