1. ENABLING AND PROMOTING EXCELLENCE IN THE HEALTHCARE REGULATORY PROFESSION TOPRA Nonclinical Development Module Non-clinical studies in drug development Kathryn Chapman, Head of Innovation and Translation, NC3Rs

2.  Ethical perspectives of animals in research  Areas in which animals are used in nonclinical drug development  The cost of animal experimentation and business drivers  Predictivity of animals in nonclinical studies  Alternatives to animals in nonclinical studies  Reducing animal use within current regulatory guidelines  Change to regulatory guidelines  The importance of case by case, scientifically-based decision making This presentation will cover:

3. Use of animals in research - Ethics

4.  Not black and white but.....  Where are you on the scale?  Common ground (1-9) is the 3Rs 012345678910  Anything goes  Pro-vivisectionist  Everything is tightly regulated  No need to do anything more  Animal research is not very useful  In vitro technologies can answer much more  On balance cost/benefit  Case by case  Some areas ok/some not  Nothing goes  Anti-vivisectionist Use of animals in research - Ethics

5. Focus on science – NC3Rs  Independent, scientific organisation  Established in 2004 by Government  Role is to support the UK science base through the application of the 3Rs  Budget ~£7 million per annum  Team of 20 staff  www.nc3rs.org.uk www.nc3rs.org.uk

6. Use of animals in research - background How many procedures were carried out in the UK in 2013? -Less than 1 million -1 to 5 million -Over 5 million What % of procedures are breeding of GM or HM animals? -25% -50% -75%

7. What proportion of procedures are for toxicological testing? - <10% -20% -30% What proportion of these are for regulatory purposes? -70% -80% -90% Use of animals in research - background

8. <1% procedures involve non- human primates

9.  Difficult decisions $$$$ ££££  Cost of animal studies vs cost of alternatives vs cost of delay  Range of costs (short-term rodent study up to non-human primate reproductive tox. study)  Alternatives can often be expensive  Biggest cost can be the RISK  Can lead to conservative study design, false sense of security and slow scientific progress  The cost of attrition – need to do something about current process...  Decreasing Phase 2 failure from 2 in every 3 drugs to “only” 1 in every 2 reduces cost per launch by $450 million (Paul et al., Nature Reviews Drug Discovery 9, 203 - 214 (2010)) Use of animals in research - business

10. Background: The causes of attrition in drug development Reference: Nature Reviews Drug Discovery: August 2013: p569

11.  Nonclinical animal studies often but do not always predict human response  Important to review animal studies > assuming they are telling us what we think they are  Assume we can always do better  Many new initiatives involving data-sharing, funding opportunities and regulatory change  E.g. Innovative Medicines Initiative, Horizon 20:20, Innovate UK/NC3Rs non- animal technologies (UK roadmap), NC3Rs working groups, EPAA, JRC, EPA, ABPI/EFPIA working groups, CRACK IT etc. etc. Use of animals in research – predictive capacity

12. Safety pharmacology models – predictive capacity  Animal models do not always translate  “Plausible preclinical correlates” used to examine Dizziness, Nausea, Pain, Fatigue  E.g. Fatigue – preclinical correlates: reduced home cage arousal, reduced activity, reduced handling reactivity

13. What are the alternatives?  Get more and better data from different more predictive animal studies  Use non-animal technologies

14. Use of the alternatives in practice?  Workshops with FDA, EMA, MHRA  E.g. Washington: A future vision for nonclinical protein-based biotherapeutic development  Case studies with unexpected and expected toxicity and assessment of whether new technologies could have predicted the outcome Workshop participants ≈ 60  10 FDA and EU regulators  Plus 6 past regulators  30 Pharma/Biotech industry  5 CRO industry  10 Experts in mechanistic toxicology and emerging technologies

15. Why a workshop?

16. Case study: anti-XX  Type of example the regulators do not usually see  Notch pathway involved in tumour angiogenesis  Anti-XX shows robust anti-tumour activity  Due to non-productive angiogenesis  Proliferative vascular neoplasms  Skin, lung, and heart lesions seen only in rats  Liver findings in mice, rats and cynos  Hepatic centrilobular to bridging sinusoidal dilation  Severity: rat > mouse > cyno  Decreased RBCs in rats and cynos  Severity: cyno > rat  Monitorable  Anti-XX and F(ab’) 2 ab fragment associated with toxicity  Different profiles across molecules and between species Anti-XX dose-related toxicities in rats and monkeys resulted in No-Go decision on IND

17. Use of the alternatives in practice?  Set up an expert sub-group to:  Provide a training set of biologics  Advise on a set of technologies relevant to biologics to be tested  Engage the UK regenerative medicine research community  Workshop at Stevenage Bioscience Catalyst in collaboration with Innovate UK and the regenerative medicine hubs to ‘trouble-shoot’ industry case studies  Provide resource for SMEs and larger biotechnology/pharma companies to research and develop technologies  Innovate UK/NC3Rs/MRC/EPSRC/BBSRC Non-Animal Technologies competition - £6million to be invested in 2015

18. Use of the alternatives in practice – regulatory perspective  Major challenge with ‘validation’

19. Use of the alternatives in practice – regulatory perspective  Major challenge with ‘validation’

20.  Should we be increasing the use of alternative approaches for scientific and business reasons?  What are your thoughts on how we could accelerate this while ensuring human safety?  Who do we need to engage and how? Question slide

21. Scientific question and regulatory requirement  Is the pharmacological or toxicological effect we see in our animal studies reversible or not?  Need to assess this on at least one study and at least one dose study (not necessarily prior to first in man) How is this being done currently?  Often by inclusion of recovery animals on all studies  Often by inclusion of recovery animals on more than one dose group (biologicals>small molecules)  Case by case and scientific rationale? Reducing animal use within current regulatory guidelines – use of recovery animals

22.  Are recovery animals always needed? Are they needed as often as they are used?  When, why, how?  259 studies, 137 compounds, 22 companies Reducing animal use within current regulatory guidelines – use of recovery animals

23.  Are recovery animals used by regulators prior to FIM clinical trials to make decisions?  Are recovery animals used to make go/no go decisions within companies?  Are there opportunities for the number of recovery animals be reduced? Reducing animal use within current regulatory guidelines – use of recovery animals prior to FIM

24. Use of recovery animals: Data 1 Biologicals  Recovery animals were included on all studies for 85% compounds Small molecules  Recovery animals were included on all studies for 65% compounds Biologicals Small molecules

25. Use of recovery animals: Data 2 Biologicals  Recovery animals were included on > 1 dose group for 70% compounds Small molecules  Recovery animals were included on >1 dose group for 28% compounds

26. Use of recovery animals: Data 3

27. Use of recovery animals: Data 4

28. Rationale for inclusion of recovery animals? Biologicals:

29. The Impact  Reduction of up to 66% with thoughtful inclusion of recovery animals/study design  Could save money as well as animals

30. Change to regulatory guidance - Biosimilars  ‘Generic’ protein and antibody-based drugs  Cheaper and affordable therapies for cancer and immune diseases  Global markets  Companies need to show that the new product is ‘similar’ to the original so-called biosimilar  Non-human primates often the only relevant species

31. Global Status # Companie s # Biosimilars Company locations Phase 369China, India, Mexico, S. Korea, Switzerland Phase 211Israel Phase 133Germany, S. Korea, US Preclinical2259Brazil, Canada, China, Hungary, India, Japan, Russia, S. Korea, Spain, Switzerland, US Totals3072 Biosimilar mAbs in the pipeline are increasing (Updated March 14, 2012) Change to regulatory guidance - Biosimilars

32. Biosimilar development – are we being driven by science? Typical study design for a mAb biosimilar (comparative tox study) Often clinical data from other countries at this point.....

33. EMEA guidance suggests in vitro only

34.  UK NC3Rs and MHRA have set up a biosimilar working group (May 2014)  12 companies from UK, Europe, US, Korea, Japan, Russia, India, Canada  4 regulatory bodies (national and international)  Shared data, experience and reviewed practice from 26 products  Shared experiences and reviewed current practice  No company had experience of in vitro data alone being accepted for a biosimilar mAb  This is even when the same in vitro assays as for the original product were used and there were no differences detected  Survey from companies showed that in vivo studies that were not deemed scientifically necessary were often conducted and NHP use could have been reduced (to <20 animals) Biosimilar development – how can we inform change?

35.  For all products at least one in vivo study was carried out  75% non-human primate, 25% rat  Most (14/26) are 4 weeks in duration with some single dose studies and durations up to 26 weeks  Most NHP studies are 3M+3F/dose but some are up to 5M+5F  Most rodent studies are 10M+10F/dose but some are up to 15M+15F (Range: 3-15)  For 3 products a DART study had been requested in non- human primates Summary of the in vivo studies

36. Biosimilar development – how can we inform change? Reasoning for in vivo studies fell into the following categories Highest common denominator (regulator geography) US/EMA meetings not timely CTA acceptance in global trials Investor acceptance Check box For the courtroom Unexpected off-target toxicity (no examples of this but was cited as a reason would be argued as scientific)  All companies agree in vitro studies are more sensitive to pick up differences than in vivo  All companies agree that where in vivo studies may add value a minimised study design (n=20) would suffice  All companies had carried out or were asked to carry out in vivo studies that they did not consider to add scientific value  One company was asked to carry out an NHP and a rodent study with the biosimilar when the clinical molecule had not been tested in these species (relevant in chimp and human only)  Do we need to use as many non-human primates as we currently are?

37.  Reopen and input into WHO guidance  National practice and guidelines  Global harmonisation  Recommendations include: - in vitro only - minimised in vivo  Clarify the scientific reason for the studies: they are not to assess safety but to detect differences between products Change to regulatory guidance - Biosimilars

38. Project Approach Impact on regulations and practice Abuse potential  Literature review on self-administration studies comparing the rat and the non-human primate  Presentations to international regulatory authorities (EMA, FDA)  Recommendations included in the revision of the international regulatory guidance (ICH M3) Biotherapeutics  Cross-company data sharing on nonclinical study design  Peer-reviewed publications  Six international workshops (three in the US)  Recommendations included in the revision of the international regulatory guidance (ICH S6)  Recommendations implemented by companies reducing non-human primate use from 144 to 64 per drug Acute toxicity  Cross-company data sharing on acute toxicity studies  Peer-reviewed publications demonstrating that acute toxicity studies had no value  Two workshops with the pharmaceutical industry and international regulators from Europe, Japan and the US  International regulatory change (ICH M3) to remove the requirement for acute toxicity studies  Recommendations implemented by companies  Up to 100 rodents per drug no longer used  78% reduction in the number of clinical trial applications which include data from acute toxicity studies between 2007 and 2014 Change to regulatory guidance

39. Acute toxicology studies are: BECAUSE  Other studies routinely carried out in drug development are more informative  Extremely limited with regard to the parameters examined  Not, in practice, used in setting doses for other animal studies  Do not provide information on the nature of toxic effects  Not, in practice, used to set doses in the first human clinical trial

40. Do animal studies always add value? Do acute toxicity studies add value in drug development?  No for First In Man clinical trials  No for overdose  ICH M3 and Q&A changed  NC3Rs was a catalyst for change Refs: 1. Robinson, S., et al. (2008). Regul Toxicol Pharmacol 50, 345-352. 2. Robinson, S., and Chapman, K. (2009). Regul Toxicol Pharmacol 55, 110. 3. Chapman, K., et al (2010). Regul Toxicol Pharmacol 58, 354-359. 2013 8% 2014 16% Impact:  Regulatory change (ICH M3)  In 2014 only 8% of clinical trial applications included acute toxicity data

41.  Use of the 3Rs supports and promotes good science and business  Resist the tick box approach – regulatory flexibility  Build cross-company relationships and share best practice  Stimulate new thinking and development of novel technologies  Enable non-competitive data-sharing across companies and sectors  Make use of the EMA safe harbour  Increase regulatory interaction The importance of case-by-case decision making covered in this presentation

42. QUESTIONS?

43. Acknowledgements: All the companies involved in NC3Rs activities and individuals who freely give up their time to work on these initiatives NC3Rs: Fiona Sewell Cathy Vickers MHRA: Akosua Adjei David Jones Contact details Name: Kathryn Chapman Tel: 020 7611 2233 Email: kathryn.chapman@nc3rs.org.uk