![Page 2: Www.gf-associates.co.uk Regulatory Framework Leigh Shaw, Director](https://reader036.vdocuments.us/reader036/viewer/2022062417/551ba32455034675548b4737/html5/thumbnails/2.jpg)
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
![Page 3: Www.gf-associates.co.uk Regulatory Framework Leigh Shaw, Director](https://reader036.vdocuments.us/reader036/viewer/2022062417/551ba32455034675548b4737/html5/thumbnails/3.jpg)
www.gf-associates.co.uk
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
![Page 4: Www.gf-associates.co.uk Regulatory Framework Leigh Shaw, Director](https://reader036.vdocuments.us/reader036/viewer/2022062417/551ba32455034675548b4737/html5/thumbnails/4.jpg)
www.gf-associates.co.uk
Key Issue – Phase 1
• Safety– Manufacturing– Pharmacology– Safety Pharmacology– Pharmacokinetics– Toxicology– Trial Design
![Page 5: Www.gf-associates.co.uk Regulatory Framework Leigh Shaw, Director](https://reader036.vdocuments.us/reader036/viewer/2022062417/551ba32455034675548b4737/html5/thumbnails/5.jpg)
www.gf-associates.co.uk
Manufacturing
• What the product is?
• How do you make it?
• What do you make it from?
• How do you control it?
• Is it stable?
![Page 6: Www.gf-associates.co.uk Regulatory Framework Leigh Shaw, Director](https://reader036.vdocuments.us/reader036/viewer/2022062417/551ba32455034675548b4737/html5/thumbnails/6.jpg)
www.gf-associates.co.uk
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
![Page 7: Www.gf-associates.co.uk Regulatory Framework Leigh Shaw, Director](https://reader036.vdocuments.us/reader036/viewer/2022062417/551ba32455034675548b4737/html5/thumbnails/7.jpg)
www.gf-associates.co.uk
Pharmacokinetics
• In vitro metabolism
• Plasma protein binding
![Page 8: Www.gf-associates.co.uk Regulatory Framework Leigh Shaw, Director](https://reader036.vdocuments.us/reader036/viewer/2022062417/551ba32455034675548b4737/html5/thumbnails/8.jpg)
www.gf-associates.co.uk
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
![Page 9: Www.gf-associates.co.uk Regulatory Framework Leigh Shaw, Director](https://reader036.vdocuments.us/reader036/viewer/2022062417/551ba32455034675548b4737/html5/thumbnails/9.jpg)
www.gf-associates.co.uk
Clinical
• Study design– Starting dose/maximum dose– Dose escalation criteria– Safety monitoring/stopping criteria– Sentinel groups
• Site facilities– Staff– Facilities, e.g. ICU
![Page 10: Www.gf-associates.co.uk Regulatory Framework Leigh Shaw, Director](https://reader036.vdocuments.us/reader036/viewer/2022062417/551ba32455034675548b4737/html5/thumbnails/10.jpg)
www.gf-associates.co.uk
Weight of evidence/efficacy data
• Demonstrate medical plausibility
• Affects benefit side of risk:benefit assessment
• In vitro and in vivo data
![Page 11: Www.gf-associates.co.uk Regulatory Framework Leigh Shaw, Director](https://reader036.vdocuments.us/reader036/viewer/2022062417/551ba32455034675548b4737/html5/thumbnails/11.jpg)
www.gf-associates.co.uk
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?
![Page 12: Www.gf-associates.co.uk Regulatory Framework Leigh Shaw, Director](https://reader036.vdocuments.us/reader036/viewer/2022062417/551ba32455034675548b4737/html5/thumbnails/12.jpg)
www.gf-associates.co.uk
Differences between small molecules and biologics
• Manufacturing– Synthetic versus biological process– Use of animal ingredients– Cell bank testing– Variability of process– Comparability of batches
![Page 13: Www.gf-associates.co.uk Regulatory Framework Leigh Shaw, Director](https://reader036.vdocuments.us/reader036/viewer/2022062417/551ba32455034675548b4737/html5/thumbnails/13.jpg)
www.gf-associates.co.uk
Differences between small molecules and biologics
• Non-clinical– Species selection– Number of species– Immunogenicity issues– Dose intervals– Selection of doses– Genotoxicity– Safety pharmacology
![Page 14: Www.gf-associates.co.uk Regulatory Framework Leigh Shaw, Director](https://reader036.vdocuments.us/reader036/viewer/2022062417/551ba32455034675548b4737/html5/thumbnails/14.jpg)
www.gf-associates.co.uk
Differences between small molecules and biologics
• Clinical– Patients versus volunteers– Starting dose selection– Immunogenicity
![Page 15: Www.gf-associates.co.uk Regulatory Framework Leigh Shaw, Director](https://reader036.vdocuments.us/reader036/viewer/2022062417/551ba32455034675548b4737/html5/thumbnails/15.jpg)
www.gf-associates.co.uk
Differences between small molecules and biologics
• Synthetic peptides (and oligonucleotides)– Hybrid between small molecule and biologic– Manufacturing: Small molecule– Non-clinical: Biologic– Clinical: Both
![Page 16: Www.gf-associates.co.uk Regulatory Framework Leigh Shaw, Director](https://reader036.vdocuments.us/reader036/viewer/2022062417/551ba32455034675548b4737/html5/thumbnails/16.jpg)
www.gf-associates.co.uk
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
![Page 17: Www.gf-associates.co.uk Regulatory Framework Leigh Shaw, Director](https://reader036.vdocuments.us/reader036/viewer/2022062417/551ba32455034675548b4737/html5/thumbnails/17.jpg)
www.gf-associates.co.uk
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
![Page 18: Www.gf-associates.co.uk Regulatory Framework Leigh Shaw, Director](https://reader036.vdocuments.us/reader036/viewer/2022062417/551ba32455034675548b4737/html5/thumbnails/18.jpg)
www.gf-associates.co.uk
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
![Page 19: Www.gf-associates.co.uk Regulatory Framework Leigh Shaw, Director](https://reader036.vdocuments.us/reader036/viewer/2022062417/551ba32455034675548b4737/html5/thumbnails/19.jpg)
www.gf-associates.co.uk
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
![Page 20: Www.gf-associates.co.uk Regulatory Framework Leigh Shaw, Director](https://reader036.vdocuments.us/reader036/viewer/2022062417/551ba32455034675548b4737/html5/thumbnails/20.jpg)
www.gf-associates.co.uk
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
![Page 21: Www.gf-associates.co.uk Regulatory Framework Leigh Shaw, Director](https://reader036.vdocuments.us/reader036/viewer/2022062417/551ba32455034675548b4737/html5/thumbnails/21.jpg)
www.gf-associates.co.uk
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?
![Page 22: Www.gf-associates.co.uk Regulatory Framework Leigh Shaw, Director](https://reader036.vdocuments.us/reader036/viewer/2022062417/551ba32455034675548b4737/html5/thumbnails/22.jpg)
www.gf-associates.co.uk
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
![Page 23: Www.gf-associates.co.uk Regulatory Framework Leigh Shaw, Director](https://reader036.vdocuments.us/reader036/viewer/2022062417/551ba32455034675548b4737/html5/thumbnails/23.jpg)
www.gf-associates.co.uk
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
![Page 24: Www.gf-associates.co.uk Regulatory Framework Leigh Shaw, Director](https://reader036.vdocuments.us/reader036/viewer/2022062417/551ba32455034675548b4737/html5/thumbnails/24.jpg)
www.gf-associates.co.uk
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
![Page 25: Www.gf-associates.co.uk Regulatory Framework Leigh Shaw, Director](https://reader036.vdocuments.us/reader036/viewer/2022062417/551ba32455034675548b4737/html5/thumbnails/25.jpg)
www.gf-associates.co.uk
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
![Page 26: Www.gf-associates.co.uk Regulatory Framework Leigh Shaw, Director](https://reader036.vdocuments.us/reader036/viewer/2022062417/551ba32455034675548b4737/html5/thumbnails/26.jpg)
www.gf-associates.co.uk
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
![Page 27: Www.gf-associates.co.uk Regulatory Framework Leigh Shaw, Director](https://reader036.vdocuments.us/reader036/viewer/2022062417/551ba32455034675548b4737/html5/thumbnails/27.jpg)
www.gf-associates.co.uk
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)