Regulatory Framework Leigh Shaw, Director

1. Regulatory Framework Leigh Shaw, Director

2. Overview • What is needed for a successful IND (or CTA)? • Weight of evidence/efficacy data • Phase I volunteer vs. patients • Differences between small molecules and biologics • Orphan drug designation • Scientific advice – types, timing, consequences • Financial incentives for SMEs/virtual biotech

3. What is needed for a successful IND (or CTA)? “Companies assume their products are safe and efficacious. Regulators assume that products are not safe and not efficacious.” CAT member during ITF meeting, 2011

4. Key Issue – Phase 1 • Safety • Manufacturing • Pharmacology • Safety Pharmacology • Pharmacokinetics • Toxicology • Trial Design

5. Manufacturing • What the product is? • How do you make it? • What do you make it from? • How do you control it? • Is it stable?

6. Pharmacology • What does the product do/how does it do it? • In vitro/In vivo studies • Does it do anything else? • Secondary pharmacology • Safety Pharmacology: What does the product do to the major organ systems? • CNS, Respiration, Cardiovascular

7. Pharmacokinetics • In vitro metabolism • Plasma protein binding

8. Toxicology • Repeat dose toxicity • choice/number of species, dose route, duration, toxicokinetics, dose levels • Genetic toxicity • single dose study: bacterial test • multiple dose study: chromosomal damage in mammalian cells

9. Clinical • Study design • Starting dose/maximum dose • Dose escalation criteria • Safety monitoring/stopping criteria • Sentinel groups • Site facilities • Staff • Facilities, e.g. ICU

10. Weight of evidence/efficacy data • Demonstrate medical plausibility • Affects benefit side of risk:benefit assessment • In vitro and in vivo data

11. Phase I volunteer vs. patients • Control over choosing the subject population – age, health status • Ease of access to relevant subjects • Controlled setting and facilities • Characteristics/risks of the product – gene therapies, cytotoxics • Ability to detect PD effects/biomarkers • Start study with volunteers then move to mild patients?

12. Differences between small molecules and biologics • Manufacturing • Synthetic versus biological process • Use of animal ingredients • Cell bank testing • Variability of process • Comparability of batches

13. Differences between small molecules and biologics • Non-clinical • Species selection • Number ofspecies • Immunogenicity issues • Dose intervals • Selection of doses • Genotoxicity • Safety pharmacology

14. Differences between small molecules and biologics • Clinical • Patients versus volunteers • Starting dose selection • Immunogenicity

15. Differences between small molecules and biologics • Synthetic peptides (and oligonucleotides) • Hybrid between small molecule and biologic • Manufacturing: Small molecule • Non-clinical: Biologic • Clinical: Both

16. INDs - the process Possible teleconference to discuss potential clinical hold issues • Approved • or • Clinical hold Up to 30 day review time at FDA Compile data and apply to FDA

17. CTA – The Future • “The Clinical Trials Directive is arguably the most criticised piece of legislation in the Union acquis on medicines.” • EC Impact Analysis on the Directive

18. The new legislation • It is a Regulation • Single EU portal • Single dossier and single submission • Faster approval times for ‘low-interventional trials’ • Shorter authorisation time for multi-state clinical trials • Entry into force 2014; Application from 2016

19. The new process – single MS Possible clock stop – 10d Low Int’ trials, 20d others Report Apply through Portal Validation – 6d Part 1 Assessment – 25d (10 Low Int’ trials;30d for ATMP) Decision – 10d Part 2 Assessment – 10d • Approved • Conditions • Not approved Possible clock stop – 10d

20. The new process – multi MS Assessment – 25d Part 1 (10d Low Int’ trials;30d for ATMP); 10d Part 2 Apply through Portal < 41 DAYS Decision – 10d Part 2 Assessment Validation – 6d Reporting MS: Part 1 Report to CMS and Sponsor Decision – 10d Concerned MS: Part 1 Part 2 Assessment Q’s Clock stop – 10d Low Int’ trials;20d rest RMS 5d < 66 DAYS

21. The new process – issues • Compatibility of MS IT systems • Extra documentation for some countries • No distinction of EC/CA approval – so up to MS to organise EC, fit with site approvals? • Workloads for Reporting MS’ • Will flexibility in timings for responding to questions be lost?

22. Orphan drug designation • Products intended for treatment of rare diseases • prevalence of <5 in 10,000 in the EU, <200,000 in the US • OR • Without incentives, unlikely that marketing would generate sufficient return to justify investment

23. Orphan drug designation - Incentives

24. Scientific advice – types, timing National (FDA, MHRA etc) or centralised (EMA) Scientific Advice pre-IND EoP2/SPA pre-NDA/MAA New indications/switch applications Phase 3 Post-approval Phase 2 Phase 1 MAA/NDA Informal meeting/ regulatory advice (ITF, pre-pre-IND) Certification of quality and non-clinical data (CAT) Joint HTA meetings Classification as ATMP (CAT)

25. Scientific advice – consequences • Provide • Questions and company position • Enough background to answer the questions • Consider • Jurisdiction • Type of product • Stage of development • Not binding, but…. • Advice remains on file • Need robust justification for not following

26. Financial incentives for SMEs/ virtual biotech • Must have < 250 staff and either annual turnover  50m euro, or annual balance sheet  43m euro or or or or

27. Financial incentives for SMEs/ virtual biotech • Fee discounts/deferrals: • 90% reduction in scientific advice fees • 90% reduction in fees for inspections • Deferred fees for MAA application • Free workshops/training with EMA • Free administrative and procedural assistance • Free translations for your product information into all EU languages • Various national provisions and fee easements (e.g. MHRA offer option to pay 25% of fees upfront and remainder when MAA approved)