Global Regulatory Perspective workshop International society for cell therapies

GRP – Paris April 23, 2014

Sergio Fracchia Regulatory Affairs

Overview

Current scenario for expedited programs

Accelerated access in EU

Conditional Marketing application

Exception circumstance

Accelerated assessment

ATMPs:

Regulatory framework

Ideal products for new regulatory approaches to licensing?

The future: towards a staggered approach - adaptive licensing

A potential case study: Conditional Marketing Authorization for a cell

therapy MP for haematological malignancies

Expedited programs to MA in EU and USA

EU USA

Conditional Marketing Application Breakthrough therapy

Exceptional circumstances Accelerated Assessment

Accelerated assessemnt Fast track

Priority review

Applicability framework

Emergency situations

Unmet medical need

Serious, life threatening disease

Marketing authorization granted under specific obligations

Conditional Marketing Application (CMA)

Legal basis:

EC 726/2004: Regulation for centralized procedure - Art. 14(7)

EC 507/2006: Regulation on CMA

EMA/509951/2006: Scientific Application and practical arrangements for

CMA

Conditions for Application

Indication for a life-threatening or seriously debilitating disease

Used in emergency situation

Orphan drug designation

Conditional Marketing Application (CMA)

Conditions for granting

Positive risk/benefit balance from (on-going) confirmatory RCT

Comprehensive non-clinical and quality data

Adequate definition of the safety profile

Obligation to complete on-going studies in definite time frame

Outline of remaining efficacy and safety question

Study synopsis

Fulfilment of unmet medical need

Critical review of available methods

Quantitative evaluation

Practical arrangements

Request submitted in Module 1.5

Day 120 LoQ

Yearly renewable following request 6 months prior expiry date to EMA

90 day assessment procedure

Exceptional Circumstances

Legal basis:

EC 726/2004: Regulation for centralized procedure - Art 14(8),

EMEA/357981/2005: Guideline on procedures for granting

Conditions for application: inability to provide comprehensive information

Efficacy and safety data due to rarity of indication

To present state of scientific knowledge

Contrary to medical ethics

Conditions for granting

Normally not lead to “full” marketing authorization

Administered only under medical supervision

Practical arrangements

Request submitted in Module 1.5

Day 120 LoQ

Annual re-assessment of benefit/risk profile

Differences beetween CMA and EC

Conditional Marketing Application Exeptional circumstances

Positive risk assesment benefit based on scientific data,

pending confirmation No comprehensive data provided

One year authorization, renewable Annual re-assessement procedure

Full authorization upon pending studies completion Not lead to full authorization

The EU scenario – some statistics

2009 2010 2011 2012

NAS 29/43 (67%) 17/22 (77%) 23/30 (77%) 32/39 (82%)

CMA 1/1 (100%) 4/4 (100%) 3/3 (100%) 4/4 (100%)

Exceptional 6/7 (85%) 2/2 (100%) 2/2 (100%) 1/1 (100%)

AA 0 2 3 1

ATMPs – legislative framework

Common rules for pharmaceutical manufacturing, development, and marketing

Medicinal Products

Community Code Dir. 2001/83/EC

Medicinal Products

Centralised procedure Reg. (EC) 726/2004

Clinical Trials 2001/20/EC

GMP 2003/94/EC

Variations 1084/2003/EC 1085/2003/EC

Tissues/Cells/Blood 2004/23/EC 2006/86/EC 2006/17/EC 2002/98/EC

‘Annex I’ 2003/63/EC

ATMP Regulation 1394/2007/EC EC/688/2009

‘Annex I’ 2009/120/EC

Scientific Guidelines Quality

Pre-clinical Clinical

Scientific advice Certification & Classification

Follow up, Post Authorization &

Risk management ERA RBD

Suitabilty of ATMPs for expedited development programs

ATMPs definitions:

Orphan indication

New active substances

High unmet medical need

Life-threatening diseases

Clinical trials

Conducted in accordance with 2001/20 EC

Extended timelines for efficacy endpoint assessment

Non-conventional design

Electronic registries for on-going monitoring

Marketing application

Centralized procedure applies for ATMPs

Randomized phase III clinical trial

ATMPs currently on the market or in approval phase

Product Holder Approval Therapeutic area Post-Mkt Comm

Chondrocelect Tigenix 05/10/2009 Cartilage disease NA

MACI (R) Genzyme 27/06/2013 Fractures, Cartilage NA

Provenge (R) Dendreon UK 03/10/2013 Prostatic Neoplasms Registry establishment

Results of on-going clinical trial

clinical study for distant metastasis

Glybera (E) UniQure 25/10/2012 Hyperlipoproteinemia

Type (E)

Registry establishment

Improve viral safety

Assay validation

New clinical study on 12 patients

Product Applicant Application Therapeutic area

Heparesc Cytonet Gmbh Jan 2014 Alimentary tract and metabolism products

Holoclar Chiesi April 2013 Ophtalmology

Zalmoxis MolMed March 2014 Haematologic malignancies

Adaptive licencing

Iterative, stepwise learning, evolutionary

Earlier market access based on combination RCT and observational data

(patient registries)

Post-evaluation safety and efficacy studies (PASS & PAESS) as condition of

marketing authorization (EC 2010/80 and EC 1235/2010)

Binary knowledge of a drug

Dichotomy pre and post licensing the magic moment

gatekeeper enablers Adapted from Hans-Georg Eichler, EMA, 2012

Adaptive licencing

Evolution or revolution?

The concept builds on the already existing procedures

▪ CMA

▪ RMP

▪ PV legislation

Broader vision as applicable to most of new products

Prospectively planned adaptive approach to drug licensing

Comprehensive development and licensing plan agreement

One size not fit all

Adaptive licencing

Current scenario Adaptive licensing

# treated patients grows rapidly after licence # treated patients grows slowly

No contribution to evidence generation Patient experience contribute to knowledge building

Adapted from Hans-Georg Eichler, Nature , 2012 91:426

Adaptive licencing – Challanges and conclusions

Lowering standard for market access

Communication of uncertainty

Education of stakeholders

Loss of equipose in post-authorization studies

Ethical issue in conduction of post-authorization RCT

Regulators still have issue on the point

Change / enlargement indication for the on-going clinical trial

Industry commitment to complete / perform post-authorization studies

Different reward structures and incentives

Patents / exclusivity period start from the initial authorization

Carefully controlled prescription system

No off-label use

MM-TK therapeutic approach

MM-TK clinical, manufacturing and regulatory development

TK007 - Phase I/II TK007 - Phase I/II Extension TK008 - Phase III

MP Formulation

change

Vector process scale up

DS process changes Changes for DS manufacturing

OD EU PA EMA OD USA CTA CTA Conditional

MAA PA EMA

EoP II

meeting PA EMA IND

2002 2003 2004 2005 2007 2008

CAT

Advice

2009 2011 2012 2014

MM-TK regulatory history

Year Regulatory step

2002 Phase I/II clinical trial (TK007) approval in Italy

2003 Orphan Drug designation in Europe (EU/3/03/168)

2004 Protocol Assistance for the design of the Phase III protocol

2005 Orphan Drug designation in USA

Amendment approval for change of MP formulation

2007 Protocol Assistance follow up for manufacturing changes and the Phase III study design

2008 Phase III clinical trial approval in Italy

2009 Product classification procedure to EMA

2011

Phase III clinical trial approval in USA (IND #14637)

Phase III clinical trial approval in Greece, Spain, Germany and The Netherlands

PreIND / End of Phase II meeting at FDA (CBER)

Scientific/Protocol Advice procedure

2012 Phase III clinical trial approval in Belgium and France

2013

Phase III clinical trial approval in Israel

ITF meeting on product suitability for conditional marketing authorization

PIP submission on August 2013 – expected final outcome from PDCO on February 2014

MAA Pre-submission meeting

MM-TK as candidate for CMA

OD designation in 2003

Indication: hr AML and ALL

DFS (2-years):

▪ 29-23% in remission

▪ 1-7% in relapse

Un-met medical need

HSCT from a fully matched donor

~50% of patients candidate to HSCT

miss a fully matched donor

MM-TK enables haplo-HCST

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

ALL AML CML Linfoma Talas MM

CBU Unrelated donor no donor found

Benefit risk assessment

EBMT1 Aversa2 Mheta3 Luznik4 Kasamon5 Ph I/II6

Patient # 266 104 201 68 185 30

Median age 35 33 23 46 50 49

Engraftment 91% 93% 98% 87% 84% 77%

TRM 50%

36-66%

36%

37-44% 51% 15% 15%

17%

12-20%

Relapse 30%

24-40% 25% 31% 58% 50% 10%

DFS (1-5

years) 30% - <10%

38%

16-51% 18% 26% 35% 43%

GvHD a/c 10 /14% 7 / 8% 13 / 15% 34% 31 / 15% 30-3%

OS n.d. n.d. 19%

30-13% 36% n.d. 47%

1) Ciceri F Blood 20008 , 112:3574 2): Aversa F – JCO 2005, 23 (15):3447 3) Mheta J. BMT 2004, 33:389

4) Luznik L, Biol BMT 2008, 14:641 5) Kasamon 2010, 16:482 6) Ciceri F Lancet Oncol 2009, 10:489