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Regulatory Framework Leigh Shaw, Director . 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
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Regulatory Framework Leigh Shaw, Director
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
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
Key Issue – Phase 1 • Safety • Manufacturing • Pharmacology • Safety Pharmacology • Pharmacokinetics • Toxicology • Trial Design
Manufacturing • What the product is? • How do you make it? • What do you make it from? • How do you control it? • Is it stable?
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
Pharmacokinetics • In vitro metabolism • Plasma protein binding
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
Clinical • Study design • Starting dose/maximum dose • Dose escalation criteria • Safety monitoring/stopping criteria • Sentinel groups • Site facilities • Staff • Facilities, e.g. ICU
Weight of evidence/efficacy data • Demonstrate medical plausibility • Affects benefit side of risk:benefit assessment • In vitro and in vivo data
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?
Differences between small molecules and biologics • Manufacturing • Synthetic versus biological process • Use of animal ingredients • Cell bank testing • Variability of process • Comparability of batches
Differences between small molecules and biologics • Non-clinical • Species selection • Number ofspecies • Immunogenicity issues • Dose intervals • Selection of doses • Genotoxicity • Safety pharmacology
Differences between small molecules and biologics • Clinical • Patients versus volunteers • Starting dose selection • Immunogenicity
Differences between small molecules and biologics • Synthetic peptides (and oligonucleotides) • Hybrid between small molecule and biologic • Manufacturing: Small molecule • Non-clinical: Biologic • Clinical: Both
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
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
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
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
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
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?
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
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)
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
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
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)