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 of species –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 Compile data and apply to FDA Up to 30 day review time at FDA Possible teleconference to discuss potential clinical hold issues -Approved or -Clinical hold -Approved or -Clinical hold

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 Validation – 6d Apply through Portal Part 1 Assessment – 25d (10 Low Int’ trials;30d for ATMP) Part 1 Assessment – 25d (10 Low Int’ trials;30d for ATMP) Part 2 Assessment – 10d Possible clock stop – 10d Low Int’ trials, 20d others Possible clock stop – 10d Low Int’ trials, 20d others Possible clock stop – 10d Decision – 10d Report -Approved -Conditions -Not approved -Approved -Conditions -Not approved

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

Orphan drug designation - Incentives EUUS Reduced regulatory fees 10 year market exclusivity7 year market exclusivity Assistance from EMAAssistance from OOPD Automatic access to centralised system for marketing authorisation Clinical investigation tax credits Orphan products grant funding

Scientific advice – types, timing Phase 1 Phase 2 Phase 3 Post-approval MAA/ NDA Informal meeting/ regulatory advice (ITF, pre- pre-IND) National (FDA, MHRA etc) or centralised (EMA) Scientific Advice Certification of quality and non-clinical data (CAT) Classification as ATMP (CAT) pre-INDEoP2/SPApre- NDA/MAA Joint HTA meetings New indications/switch applications

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 Enterprise category Headcount: Annual Work Unit (AWU) Annual turnover Annual balance sheet total Medium-sized<250  50m euro 43m euro Small<50  10m euro Micro<10  2m euro 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)