Www.gf-associates.co.uk Regulatory Framework Leigh Shaw, Director

www.gf-associates.co.uk

Regulatory FrameworkLeigh Shaw, Director

http://www.gf-associates.co.uk/


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




• Non-clinical– Species selection– Number of species– Immunogenicity issues– Dose intervals– Selection of doses– Genotoxicity– Safety pharmacology




• Clinical– Patients versus volunteers– Starting dose selection– Immunogenicity




• 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



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 2 Assessment – 10d

Possible clock stop – 10d Low Int’ trials, 20d others

Possible clock stop – 10d

Decision – 10d

Report

- 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

Decision – 10d

Concerned MS: Part 1

Part 2 Assessment

Part 2 Assessment

Decision – 10d

Q’sClock 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

EU US

Reduced regulatory fees Reduced regulatory fees

10 year market exclusivity 7 year market exclusivity

Assistance from EMA Assistance 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-approvalMAA/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-IND EoP2/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 £10m euro

Micro <10 £2m euro £2m 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)


Documents

Www.gf-associates.co.uk Regulatory Framework Leigh Shaw, Director