Ldb 145 geni mutanti_2014-11-12 alberti - mercato farmaceutico

Daniele Alberti, Oncology Medical Director Novartis Farma S.p.A., Origgio (VA) Biobang, Lecce, 12 novembre 2014

Production scale-up e mercato farmaceutico

Disclosures su potenziali conflitti di interesse

§ Dipendente Novartis da 32 anni

§ Oncology Medical Director Italia da 8 anni

§ Coordinatore Gruppo Ricerca Clinica Assobiotech da due mesi

§ Abito a Monza

Daniele Alberti – Biobang Lecce – 12 novembre 2014

Perchè sono qui con voi oggi?


Farmaceutica – la carta da giocare


La Vision di Novartis Oncology Region Europe

Be the leading company transforming science into

innovative solutions to cure cancer patients in Europe

Essere l’azienda leader che trasforma la ricerca in soluzioni innovative per la cura

dei pazienti oncologici in Europa

Assobiotec’s Vision

Transparent collaboration among Research Industry, Academy, Health Care Professionals and National and

Regional Institutions, focussing on Patients and, consequently, on Associations representing them.

Source:

D. Alber) -‐ Biotech Week -‐ Roma ISS 9-‐10-‐2014

Universities

Hospitals

Institutions Companies

Perchè siamo qui oggi?


Agenda

14.00 – 14.10 Introduzione e agenda

14.10 – 14.50 Strategia di sviluppo nuovi prodotti in indicazioni onco- ematologiche

14.50 - 15.10 Opportunità di rilancio: Clinical Trial Center (CTC), Reti Oncologiche ed Ematologiche e laboratori regionali

15.10 - 15.30 Discussione / Presentazione Lavori di gruppo

15.30 – 16.30 Lavori di gruppo

16.30 – 17.00 Feedback in plenaria dai Gruppi di lavoro

17.00 – 17.15 Conclusioni


Agenda









Chi è Novartis Oncology

§  Business Unit di Novartis Corporation

§  Creata per focalizzazione nell’innovazione in campo oncologico per i pazienti

§  Pioniere delle Target Therapy

§  Portafoglio di 12 prodotti e promettente pipeline

§  Market Leader in ematologia

§  2° impresa in onco-ematologia

§  Pur senza prodotti chemioterapici

«Revolutionary therapy with

Imatinib» (NCCN Guidelines)


Imatinib: i risultati ottenuti nei primi anni 2000 hanno condizionato il modello di sviluppo Novartis Oncology

CML Malattia

Trial ed Errore

Interferone Cytarabine Time in months

% in

CC

R

40%

Approccio empirico per la scoperta dei nuovi farmaci: l’era pre-Imatinib

Il cambio di paradigma - La prima terapia mirata di successo: CML e Imatinib

Malattia CML

Ove

rall

Surv

ival

0

20

40

60

80

100

0 12 24 36 48 60 72 84

IRIS: 6 year survival: 88%

Chronic phase CML

Time (months)

Ove

rall

Surv

ival

0

20

40

60

80

100

0 12 24 36 48 60 72 84

IRIS: 6 year survival: 88%

Chronic phase CML

Time (months)

Ricerca farmaceutica su base molecolare

Patogenesis


LGK974 Solid tumors

LCL161 Solid tumors

CGM097 Solid tumors

CFG920 Solid tumors

AEB071 Solid tumors

LGH447 Hemat. tumors

LDK378 ALK+ NSCLC3

BYL719 Solid tumors

LJM716 Solid tumors

LCI699 Cushing’s Syndrome

TKI258 Solid & Hemat. tumors

MEK162d NRAS Mutant Melanoma

BGJ398 Solid tumors

AUY922 Solid tumors

PKC412 AML4

MEK162 + LGX818 BRAF Mutant Melanoma

LGX818 BRAF Mutant Melanoma

LEE011c Breast Cancer

LDE225 Basal Cell Carcinoma

BKM120 Breast Cancer

LBH589* Multiple Myeloma

Signifor®LAR11 Acromegaly

Afinitor® HER2+ Breast Cancer 2nd/3rd

Line

Afinitor® HER2+ Breast Cancer 1st Line

Afinitor® DLBCL5

Afinitor® Non-functioning GI Lung NET6

CTL019a Leukemia

INC280b Solid tumors

Pan-DAC

CYP17

IAP

PI3K

porcupine

CDK4/6

Aldos

pan PIM

mTOR

MEK

CD19

Smo

HER3 FLT-3 Signifor®LAR11 Cushing’s somatostatin

PKC

HDM2/P53

c-MET

HSP90

PI3Kα

FGFR

mTOR

mTOR

mTOR

somatostatin

MEK+ B-RAF

PI3K

B-RAF

ALK

LDE225 Solid tumors

Smo

MEK162d Solid tumors

MEK

LEE011c Solid tumors

CDK4/6

LGX818 Solid tumors

B-RAF

NVS New Molecule

NVS New Indication

Tasigna CML Treatment Free Remission

LDE225 Medulloblastoma

PKC412 ASM9

Jakavi® e Polycythemia Vera

MEK162d LGSOC8

LDK378 ALK+Adv NSCLC3

(Chemo naïve,crizotinib naïve)

Smo

ALK

BCR-ABL

MEK

FLT-3

JAK

NVS New Formulation

1  Idiopathic thrombocytopenic purpura 2  Myelodysplastic syndrome/

Acute myeloid leukemia 3  Non-small cell lung cancer 4  Acute myeloid leukemia 5  Diffuse large B-cell lymphoma 6  Neuroendocrine tumors 7  Tuberous sclerosis complex 8  Low-grade serous ovarian cancer 9  Aggressive systemic mastocytosis 10 Chronic lymphocytic leukemia 11 Long-acting release 12 Severe aplastic anemia

a.  CTL019 (also known as CART-19) is licensed from the University of Pennsylvania (Penn) and subject to the agreement between Novartis and Penn

b.  INC280 (also known) as INCB028060) is licensed from Incyte Corp. c.  LEE011 was discovered in collaboration with Astex d.  MEK162 or ARRY-162 is licensed from Array BioPharma, Inc. e.  Jakavi (INC424) is licensed from Incyte for development and commercialization outside of the US

* LBH589 submitted in the US in March 2014

BKM120 Solid tumors

PI3K

Registration Trials Phase IIII or pivotal

Filed (In Registration)

Confirmatory Trials (Phase I/II) Exploratory Trials

Afinitor TSC7 Seizures

mTOR

Novartis Oncology pipeline is industry leading in small molecule targeted therapies...


Classical view: Classified based on location and treated with surgery, radiation, and chemotherapy

Cancers involving PI3K pathway: §  Pancreas (70%) §  Colon (35%) §  Bile duct (30%) §  Lung (20%)

§  Breast (45%) §  Glioblastoma multiform (70%) §  Endometrial (40%) §  Ovary (15%)

Lymphoma Leukemia

Lung Cancer

Skin Cancer

Gastric Cancer Colon Cancer

Spleen Cancer

Targeted inhibition of cancer pathways

Cancer treatment strategy: from WHERE? to WHAT?


Translational Medicine

Our approach is based on individualizing treatment in the clinic to op)mize outcomes

Following the science

§ Using pathways to deliver mechanism based therapeu)cs

Global Development § Rapidly bringing medicines to pa)ents globally

Transla7onal Medicine

§ Redefining the disease; iden)fy the right pa)ent popula)on

Capping Risk sharing

Commercial Solu7ons

§ Providing more than a medicine – tools & services to op)mize outcomes…


Cancer Cell Line Encyclopedia Reading “The Book of Cancer”

Gene Amplifications and Delections

Gene Expression

Gene Sequence: Mutations and Translocations

•  > 1000 cell lines •  Representation driven by unmet

medical need •  1300 compounds profiled

against 500 cell lines

Compound Profiling


Define the sensitivity for a specific compound

Amax

Com

poun

d

Cell line

Sensitive

Insensitive

uM

BYL719


-100 0 Amax

Com

poun

d

Cell line

Which compounds will work best in specific patients?

MKN45: MET-amplified gastric cancer


Response Prediction Biomarkers and Targeted Cancer Drug Development

Drives: §  Improved patient benefit because tumors are

uniquely dependent on the drug target

§  Increased probability of success by enriching studies for likely responders and excluding non-responders

§  Maximal benefits to payers with drugs used only in patients likely to benefit

§  Faster time to market with lower development cost through smaller studies with stronger signals


What is a companion diagnostics?

FROM “One Size Fits All”

TO “Personalized Medicine”

Saves life and money by using biomarkers to improve safety, effectiveness, and health outcome of patients via targeted risk stratification, prevention and tailored treatment approaches: The Right drug for the right patient at the right time and the right dose.

Moving from “One Size Fits All” to “Personalized Medicine” using diagnostic test methods (mostly in vitro diagnostic tests performed on patients derived specimens)


How to “personalize” Medicine?

The value of a companion diagnostics for intended use decisions: Use of genetic or other molecular biomarkers information to improve, safety, effectiveness and health outcome of patients via more effectively targeted risk stratification, prevention and tailored treatment management approaches

Risk stratification: §  Patients more or less likely to develop

disease / conditions

Inform treatment selection: §  Is it safe? §  Is it effective

Inform dosage: §  Slow metabolizers §  Rapid metabolizers §  Therapeutic drug monitoring (TDM)

Prognostic / Predictive test: §  Identify patients more likely to benefit from

standard of care (e.g. adjuvant chemotherapy)

Disease monitoring: §  Is it safe to continue therapy or should

therapy be switched?

Improve or optimize clinical treatment pathways


21 | Portfolio Prioritisation| Portfolio Management| Aug 2010 | Business Use Only

Pathways under evaluation in NVS Oncology CTs in Italy


LGK974 Solid tumors

LCL161 Solid tumors

CGM097 Solid tumors

CFG920 Solid tumors

AEB071 Solid tumors


LDK378 ALK+ NSCLC3

BYL719 Solid tumors

LJM716 Solid tumors




BGJ398 Solid tumors

AUY922 Solid tumors

PKC412 AML4









Line


Afinitor® DLBCL5


CTL019a Leukemia


Pan-DAC

CYP17

IAP

PI3K

porcupine

CDK4/6

Aldos

pan PIM

mTOR

MEK

CD19

Smo


PKC

HDM2/P53

c-MET

HSP90

PI3Kα

FGFR

mTOR

mTOR

mTOR

somatostatin

MEK+ B-RAF

PI3K

B-RAF

ALK

LDE225 Solid tumors

Smo


MEK


CDK4/6

LGX818 Solid tumors

B-RAF

NVS New Molecule

NVS New Indication



PKC412 ASM9


MEK162d LGSOC8



Smo

ALK

BCR-ABL

MEK

FLT-3

JAK

NVS New Formulation






BKM120 Solid tumors

PI3K





mTOR



IGF1R

PIM kinase signaling in cancer

§  Promote cell survival and proliferation

§  Overexpressed primarily in hematologic malignancies

§  PIMs and AKT mediate cell survival through overlapping pathways

p110

RTK

PI3K p85

PIP2

PTEN

PIP3 PIP3

PDK AKT 308 473

Raptor

mTOR

GβL

p21CIP

BAD

T

T Rheb

survival

cell cycle

TSC2

TSC1

Pim1

Pim2

Pim3

4E-BP1

S6K/S6

translation

PIM expression


0.5 0

-0.5 -1

-1.5 -2

-2.5

Cell Line Encyclopedia: PIM inhibition most effective in myeloma and AML

0.5 0

-0.5 -1

-1.5 -2

-2.5

autonomic_ganglia biliary_tract bone breast central_nervous_system endometrium haematopoietic_and_lym kidney large_intestine liver lung oesophagus ovary pancreas pleura prostate skin soft_tissue stomach thyroid upper_aerodigestive_tract urinary_tract (Empty)

Log

Con

cent

ratio

n (µ

M) o

f GI5

0

AML ALL Burkitts T-NHL NHL Myeloma

CLL

CML


LGH447 Phase I in relapsed/refractory multiple myeloma

§ Heavily pre-treated patients with multiple chemotherapeutic agents and prior bone marrow transplants

§ 48 patients treated to date

Dose Expansion Relapsed or refractory

multiple myeloma

Dose escalation

Relapsed or refractory multiple myeloma

MTD/ RDE


LGH447 is active in relapsed/refractory myeloma

70 mg

150 mg

200 mg

250 mg

350 mg

500 mg

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

Treatment ongoing

VGPR PR SD PD Unknown

Duration of exposure (weeks) Daniele Alberti – Biobang Lecce – 12 novembre 2014

CDK4/6

LEE011, a CDK4/6 inhibitor, has broad potential in oncology

§  LEE011 inhibits CDK4/6-specific Rb phosphorylation, halting cell-cycle progression in G1

§  LEE011 blocks cell growth driven by most activated cancer genes

§  Preclinical data support multiple synergistic combinations within the NVS Oncology portfolio

§  LEE011 + PI3Ki + letrozole in ER+ breast cancer maybe superior to combinations that do not include PI3Ki

E2F

RAS

RAF

MEK

ERK

PI3K

AKT

mTOR

BKM120

Afinitor®

BYL719

BGJ398

LEE011

LJM716

EGF816

INC280

Jakavi®

Zykadia®

MEK162

LGX818

JAK

TSC

PTEN

Oncogenic proliferation and survival

HER2/3 FGFR EGFR MET ALK


Sequencing patients on MEK162 in NRAS mutant melanoma suggests combination with LEE011

Day 21 of Treatment

Cycle 1 Day 31

Baseline

CDKN2A/B

NRAS


LGK974 Solid tumors

LCL161 Solid tumors

CGM097 Solid tumors

CFG920 Solid tumors

AEB071 Solid tumors


LDK378 ALK+ NSCLC3

BYL719 Solid tumors

LJM716 Solid tumors




BGJ398 Solid tumors

AUY922 Solid tumors

PKC412 AML4









Line


Afinitor® DLBCL5


CTL019a Leukemia


Pan-DAC

CYP17

IAP

PI3K

porcupine

CDK4/6

Aldos

pan PIM

mTOR

MEK

CD19

Smo


PKC

HDM2/P53

c-MET

HSP90

PI3Kα

FGFR

mTOR

mTOR

mTOR

somatostatin

MEK+ B-RAF

PI3K

B-RAF

ALK

LDE225 Solid tumors

Smo


MEK


CDK4/6

LGX818 Solid tumors

B-RAF

NVS New Molecule

NVS New Indication



PKC412 ASM9


MEK162d LGSOC8



Smo

ALK

BCR-ABL

MEK

FLT-3

JAK

NVS New Formulation






BKM120 Solid tumors

PI3K





mTOR



How we view cancer today has changed dramatically The example of lung cancer :

Source: Kantar Health, 22nd Annual Cancer Progress Conference, 2011


LDK378: Oral, Highly Selective ALK Inhibitor §  LDK378 is an orally available, selective, small molecule

inhibitor of ALK

§  ALK expression is highly restricted in adults and drugs with the potential to inhibit ALK may have a high therapeutic index1

§  EML4-ALK is a potent oncogenic driver in cellular and animal models, and inhibition of ALK has been found to induce apoptosis of EML4-ALK–containing cell lines in vitro and in vivo2,3

•  The EML4-ALK fusion gene has been identified in NSCLC with an estimated frequency of 11%. It has also been identified in breast and CRC tumors4-6

§  LDK378 has entered phase I investigation in patients with cancer harbouring an ALK gene translocation or overexpressing the ALK protein. It also is being evaluated in a Phase I study in combination with AUY933. Two phase II studies are ongoing evaluating it as a single agent in patients with NSCLC7

1. Pulford K et al. Blood. 1997;89(4):1394–1404. 2. Soda M, et al. Proc Nat Acad Sci USA. 2008;105(50):19893–97. 3. Koivunen J, et al. Clin Cancer Res . 2008;14:4275–83; 4. Soda M, et al. Nature 2007; 448(7153):561-566; 5. Horn L, et al. J Clin Oncol. 2009; 27(26): 4232-4235; 6. Lin E, et al. Mol Cancer Res. 2009; 7(9):1466-1476; 7. www.clinicaltrials.gov

CRC, colorectal cancer; NSCLC, non-small cell lung cancer

Compounds are investigational; there is no guarantee they will become commercially available. The safety and efficacy have not been established. Daniele Alberti – Biobang Lecce – 12 novembre 2014

Most ALK+ lung cancer patients respond to LDK378 – even after failing crizotinib

Baseline Daniele Alberti – Biobang Lecce – 12 novembre 2014

Typical response to LDK378

AQer 3.5 weeks Baseline


The LDK378/ceritinib/Zykadia story began just three years ago

§  March 2011 first patient treated

§  November 2012 FDA Breakthrough Therapy designation

§  December 2013 FDA filing

§  April 2014 APPROVED!!!!

37 months from FPFV to filing

Italy contributed with 2 centers and 13 pts in dose escalation/espansion


Jakavi – First Targeted Agent in Polycythemia Vera (PV): Pivotal Ph III study (RESPONSE) met primary & key secondary endpoints

0 5

10 15 20 25 30 35 40 45 50

Ruxolitinib (n=110)

BAT (n=112)

Patie

nts,

%

20.9% n=23 0.9%

n=1

95% CI, 13.7–29.7

P<0.0001

95% CI, 0.0–4.9

Primary Endpoint Absence of phlebotomy eligibility & ≥35% SV reduction at Week 32

0 5

10 15 20 25 30 35 40 45 50

Ruxolitinib (n=110)

BAT (n=112)

Patie

nts,

%

95% CI, 16.1–32.7

P=0.0028

23.6% n=26

8.9% n=10

BAT 95% CI, 4.4–15.8

Key Secondary Endpoint Complete Hematologic Remission (CHR) at Week 32

Robust evidence of clinically relevant benefit •  Study met its primary endpoint of phlebotomy independence and spleen response: HR 28.6

(P<0.0001); benefit consistent across all subgroups •  Markedly higher % of patients without phlebotomy at Week 32 (60% vs 20%) •  Markedly higher % of patients achieving CHR (24% vs 9%, P=0.0028) •  Markedly higher % of patients with symptom response •  Lower rate of thromboembolic AE (0.9% vs 5.4%) PV patients resistant to or intolerant of HU have a high unmet medical need with significant phlebotomy dependence, high symptom burden, and shorter OS


Tasigna for Patients with CML: Treatment-Free Remission Based on Sustained Complete Molecular Response

Path to Cure Strategy

Treatment Phase Consolidation Phase

Treatment-Free Remission (TFR)

≥3 years on Nilotinib BCR-ABL Monitoring

Nilotinib 1 year

sustain CMR4.5

CMR4.5 with ≥2 years Nilotinib

Treatment-Free Maintain ≤ MR3.0

De Novo Patients

ENEST-Freedom

≥3 years on Nilotinib BCR-ABL Monitoring

Nilotinib 1 year

sustain CMR4.5

CMR4.5 with ≥2 years Nilotinib

Treatment-Free Maintain ≤ MR4.0

Imatinib 2yrs not achieved

CMR4.5

ENESTop

SWITCH

Study period

Recruitment Status

Submission

2016

Enrollment completed

Enrollment Completed


Tasigna® in Combination with an Allosteric BCR-ABL Inhibitor Could Advance Treatment of CML

Simultaneous binding of two inhibitors to BCR-ABL

§  ABL001 is a highly potent and selective allosteric inhibitor of BCR-ABL

§  ABL001 binds to BCR-ABL in combination with nilotinib or imatinib without cross-competition

Imatinib (ATP site)

Allosteric Inhibitor

Wild-type BCR-ABL protein

In preclinical model, ABL001/nilotinib combination appears to prevent emergence of resistance1

§  Combinations of the two inhibitors prevent emergence of resistance in a blast crisis CML xenograft model

§  Phase I study has been initiated

1 Novartis data on file Daniele Alberti – Biobang Lecce – 12 novembre 2014

CONCLUSIONS

§ Clonal heterogeneity is prevalent

§ Minor clones can be lethal

§ Mutuation profiling has potential to identify drug resistant clones and remission status in real time

§ Clinical Markers of drug response are emerging

§  IMiD: Cereblon, Ikaros, IRF4

§ Proteasome: IRE1, XBP1


Potential future applications

§ Diagnostic: Predictive biomarker for distinct disease subtype

§ Therapeutic: Different predicted response to epigenetic and/or tyrosine kinase inhibitors

§ Paradigm for other cancers: Does the order of acquisition matter in other cancers?


Our strategy is defined by patient selection, novel combinations and understanding resistance

Pathway analysis and drug sensitivity

Patient preselection with genetic and pathway biomarkers

Genetic analysis of responders and non-responders

New targets and combinations

Clinical trial design

Understanding resistance


Window of opportunity trials Rationale §  With many new targeted therapies, there are limitations in measuring response by

traditional methods, such as response rate defined by RECIST criteria, which may lead to erroneous conclusions about a drug’s benefit.

§  Evaluating molecular end points can be hindered by difficulties in procuring tumor tissue before and after drug administration and by heterogeneity in previous exposure to cancer therapies.

§  A method to circumvent this issue is to assess novel agents in pre-surgical (window-of-opportunity) trials. In this model, women with newly diagnosed breast cancer, for instance, receive a study drug between the diagnostic breast biopsy and planned surgical resection (typically 2-4 week period).

§  Goals of these trials include: •  Evaluation of target modulation after drug exposure •  Pharmacokinetic assessments of a potential anticancer agent •  Improve understanding of an agent’s biologic effect early in its development •  Validate markers that may predict subsets of patients who will/will not benefit •  Targeting select patients in subsequent clinical trials that are powered to detect

changes in clinical outcome

Kalinsky J Clin Oncol. 30(21):2573-5


FDA Guidance

§  The US Food and Drug Administration issued Guidance on “Exploratory Investigational New Drug Studies” in 2006 in which it was described that: •  Exploratory IND studies usually involve very limited human exposure and

have no therapeutic or diagnostic intent. Such studies can serve a number of useful goals. For example, an exploratory IND study can help sponsors 1.  Determine whether a mechanism of action defined in experimental

systems can also be observed in humans (e.g., a binding property or inhibition of an enzyme)

2.  Provide important information on pharmacokinetics (PK) 3.  Select the most promising lead product from a group of candidates

designed to interact with a particular therapeutic target in humans, based on PK or pharmacodynamic (PD) properties

§  An example of 3. also includes “window of opportunity pre-surgical trials”


Novartis’ Bayesian Phase I: External Outreach

§  Engaging Health Authorities and Gaining Acceptance •  Presented to FDA Biostatisticians and Oncologists at White Oak Campus

(Jun 2009) •  Commented on Draft FDA Adaptive Design Guidance (May 2010) •  Discussed with Japanese PMDA to gain acceptance to implement in several

Phase I studies (Jan 2009) •  Presentation to PMDA on Bayesian Statistics (Nov 2010)

§  Scientific Leadership •  Session #493 at Joint Statistical Meetings on Aug 5, 2009 (Discussant:

Michael Brave, FDA Oncologist) •  Roundtable #44 at 2010 FDA-Industry Workshop on Sept 21, 2010

(Discussant: Sue-Jane Wang, FDA Biostatistician) •  Phase I Design Workshop, New York, Oct 2009


Dose Escalation Study Challenges and design overview

Right Regimen? Right Recipients? Robustly? Rapidly?

Safely determine with limited sample size


CART: A Revolutionary Step in Developing an Individualized Therapy for Each Patient

§  Paradigm of cancer treatment is changing – immunotherapies and adoptive cell therapies present the next frontier after targeted therapies

§  CARTs allow for personalization of therapy to the individual patient’s cancer leading to their transformative benefit–risk profile

§  Long-term molecular remission in several patients suggests the potential CARTs to cure patients of their cancer

§  CARTs have the potential to revolutionize the treatment of many types of cancer across a wide range of targets

§  In contrast to checkpoint inhibitors, CARTs direct the immune system to kill cells with specific surface targets

Adoptive Cell Therapy

CART


Agenda









Il Trial Office o Trial Center Alcuni centri di ricerca clinica all’avanguardia si stanno orientando verso la creazione di Trial Office o Trial Centre.

Di cosa si tratta?

Si tratta di una organizzazione che ha lo scopo di supportare e coordinare la conduzione e la gestione della ricerca clinica presso il centro e in centri sperimentali afferenti, supportare gli sperimentatori nel garantire l’aderenza alle Good Clinical Practices (GCP) nello studio di nuovi farmaci e dispositivi, e offrire servizi di Contract Research Organization (CRO) accademica alle aziende farmaceutiche.


Il «ciclo di vita» di una ricerca clinica

Pianificazione

• Stesura del protocollo e della documentazione a supporto • Selezione dei fornitori (lab centralizzati, logistica farmaco, data management, CRO, ecc.) • Analisi di fattibilità e selezione dei centri • Definizione del team di studio e relative attività di formazione • Definizione delle tempistiche dello studio

Avvio e Conduzione

• Ottenimento delle autorizzazioni regolatorie e etico-amministrative • Attivazione centri • Arruolamento • Monitoraggio e data management

Chiusura Analisi e report finale

• Completamento delle attività di cleaning e chiusura del database • Analisi statistica • Chiusura dei centri • Conclusioni cliniche in base ai risultati dell’analisi statistica • Stesura del report clinico statistico integrato ed eventuali pubblicazioni • Sottomissione alle autorità regolatorie


Protocollo e proposta lista centri

FEASIBILITY VISIT

ATTIVITA’ PRE-TRIAL

VISITA DI INIZIO STUDIO

VISITE DI MONITORAGGIO

VISITA DI CLOSE-OUT

Approvazione regolatoria, etica e aministrativa

Ready to Go e Drug Clearance FPFV LPLV LPFV

Cleaning - DBLock

Tappe principali nell’esecuzione di uno studio Tappe principali nell’esecuzione di uno studio


Il valore aggiunto del Trial Center nell’attivazione del centro

§  Preparazione della documentazione per sottomissione ad AIFA* (Autorità Competente) e ai CE •  Segnalazione allo Sponsor della documentazione necessaria per la

prevalutazione dello studio •  Preparazione della documentazione aggiuntiva per la pre-valutazione dello

studio

§  Sottomissione al CE coordinatore e ai CE dei Centri satellite e AIFA* •  Valutazione in parallelo a AIFA*/ISS/Centro Coordinatore •  Interazione con il CE al fine di ottenere tempestivamente il verbale

* per studi di fase I, AIFA si avvale dell’Ufficio Sperimentazioni Cliniche di ISS per la valutazione

1. supporto attività di Trial Start Up


§ Gestione pratiche amministrative (delibera, convenzione economica) con centro sperimentale • Finalizzazione degli accordi economici prima della seduta di

prevalutazione • Supporto nell’approvazione della bozza di convenzione dopo la

seduta del CE • Supporto nella raccolta delle firme della convenzione e della delibera

2. supporto nella gestione contrattuale

3. supporto nella raccolta dei documenti per l’attivazione del centro §  Raccolta tempestiva e precoce dei documenti

necessari al team di monitoraggio per l’apertura del centro e l’invio del farmaco

Il valore aggiunto del Trial Center nell’attivazione del centro


Prima della visita del paziente: organizzazione e preparazione delle visite dei pazienti

§  contatti con gli specialisti, §  preparazione di kit di laboratorio, §  Identificazione del farmaco da assegnare ai pazienti §  consensi previsti dallo studio o documenti a supporto della visita

del paziente §  Gestione del farmaco

Durante la visita del paziente

§  Supporto al team dello studio nella gestione appropriata della visita e delle valutazioni (gestione dei kit di laboratorio, questionari e diari paziente, appuntamenti con gli specialisti...)

§  compilazione della drug accountability e supporto al team medico per la verifica della compliance

Il valore aggiunto del Trial Office: la gestione operativa dello studio


Dopo la visita del paziente §  Inserimento tempestivo dei dati in CRF e

risposta alla queries §  Invio tempestivo dei campioni al laboratorio

centrale §  Invio tempestivo degli ECG e delle immagini

radiologiche al vendor §  Visite di monitoraggio e interazione continua

con i team di monitoraggio §  Interazione con i team locali e internazionali

dello sponsor e i vendors

Il valore aggiunto del Trial Office: la gestione operativa dello studio

Per gli studi di fase I ma non solo §  Partecipazione a teleconferenze di aggiornamento dello studio

(es Dose Escalation Meeting per gli studi di fase I) §  SIV o training di protocollo in TC con il clinical team §  Contatti con il clinical team per discutere problematiche

specifiche dei pazienti §  Identificazione e gestione delle DLT §  Disponibilità 24 ore/24


Ma non dimentichiamo... §  Completamento dei training richiesti §  Conservazione e mantenimento della

documentazione di studio §  Revisione della documentazione di studio

§  Protocolli e emendamenti §  Manuali §  Comunicazioni dello sponsor §  Comunicazioni di safety (es IB e SUSAR)

§  Allineamento dello staff del centro §  Contatti con il Comitato Etico §  Contatti con i vendor §  Conservazione del farmaco durante lo studio

Il valore aggiunto del Trial Center: la gestione operativa dello studio


Si stanno introducendo ormai da qualche tempo nuovi paradigmi di monitoraggio, quindi il monitoraggio cosiddetto on-site viene sostituito o alternato al cosiddetto monitoraggio remoto

Questi nuovi paradigmi di monitoraggio sfruttano le tecnologie oggi disponibili e permettono l’accesso remoto e in tempo reale, ai dati degli studi clinici (eCRF web-based, EMR –Electronic Medical Records)

Il valore aggiunto del Trial Center: il monitoraggio da remoto


Monitoraggio dello studio: cosa sta cambiando


Il monitoraggio da remoto si affianca quindi alle tradizionali attività di monitoraggio dei CRA effettuate “on-site“ (al Centro):

•  Il CRA può monitorare i dati dello studio da remoto tramite un accesso diretto al database clinico

•  I dati vengono rivisti da remoto, in "tempo reale", e vengono valutati per completezza, qualità e coerenza

• Contatti regolari con il centro via telefono, e-mail e visite “on-site” permettono di assicurare qualità e disponibilità dei dati in eCRF

• Le visite “on-site” presso il centro sono programmate in funzione dell’arruolamento dei pazienti e della qualità dei dati valutata durante il monitoraggio remoto

L’inserimento tempestivo dei dati da parte del centro è il prerequisito essenziale per l’effettuazione del

monitoraggio remoto da parte del CRA

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Contenuto & obiettivi progetto

Ø  Realizzazione cluster biotecnologico della REL per l'implementazione dell'analisi genomica e lo sviluppo di trattamenti innovativi nelle neoplasie ematologiche

Ø  Implementazione di sistemi diagnostici/prognostici Ø  Creazione piattaforma bioinformatica Ø  Realizzazione REL Clinical Trial Unit Ø  Valorizzazione capitale umano e integrazione di

giovani ricercatori

Un esempio: Bando Regione Lombardia – Fondazione Cariplo


Risultati attesi in numeri

Ø  L’aiuto finalizzato alla realizzazione di REL Clinical Trial Unit, consentirà un aumento delle dimensioni del progetto pari al 25% (in termini assoluti 400.000 euro), con un incremento contestuale del numero di persone assegnate ad attività di RSI (con un investimento in termini assoluti di 240.000 euro).

Ø  In termini quantitativi ci aspettiamo che attraverso la realizzazione di REL Clinical Trial Unit, rispetto agli indicatori di attività del progetto, vi sia un aumento del 20% del numero di studi clinici realizzati con farmaci a bersaglio molecolare.


Tempistica

q  Sett 2013: sottomissione progetto al bando Cariplo-Regione Lombardia

q  Dic 2013: conferma ammissione

q  Feb 2014: •  incontro con Dr. Della Porta per definire step di

attivazione progetto •  procedure amministrative da seguire

q  Ongoing: •  Realizzazione progetto •  Rendicontazione


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Some suggestions for Clinical Research regarding the“Sistema Paese”

•  University – professional training/educa7on:

–  MDs & biotechnologists à clinical research

–  Data manager –  Research Nurses

•  Hospitals/University – take advantage of clinical research:

–  Clinical Trial Centers –  Dedicated human resourses –  Integrated mul)disciplinary

approach: clinical medicine, imaging, pathological anatomy, labs

–  Administra)ons facilita)ng authorizing processes

–  Coordinated & Aligned Ethical Commi[ees

•  Elimina7on of “Ins7tu7onal Silos” and ra7onaliza7on of rules in order to facilitate inves7ments in clincal research:

–  Ministry of Health –  AIFA –  ISS –  Regions –  Assurance Companies –  Privacy Authority –  Tax Benefits

•  Pharmaceu7cal / Biotec Companies: –  Willingness to invest in Italy –  Recognize contribu)on of Italian

Centers of Excellence –  Partnership with local, regional and

na)onal organiza)ons –  A[en)on to Pa)ents’ Associa)ons 62



10,5%

La sperimentazione clinica dei medicinali in Italia

D. Alberti - Nuovi farmaci- AIL Ferrara 31-5-2014 64

Clinical Trials Novartis Oncology Italy (planned, running & ongoing – 12 November 2014)

NVS 135 (81%)

IIT 31 (19%)

Hemato 51

Onco 115

Number of clinical trials


Impact analysis Law 8 November 2012 n°189 Significant increase in average .me of total authoriza.on, leading to a loss of compe..vity on interna.onal level and to using company risorses dedicated to clinical trials for burocra.c work


Some state-of –the-art Clinical Research Centers are creating Trial Offices or Trial Centers.

Organization to support and coordinate:

§  Implementation and managing of Clinical Research in the site as well as in afferent sites

§  Support researchers in respecting Good Clinical Practices (GCP) while studying new drugs and devices,

§  Offer accademical Contract Research Organization (CRO) services to pharmaceutical / biotech companies.

Clinical Trial Office / Trial Center


The RTC is a tax benefit on R&D costs according to current legislation and directly deducted from

operational costs

68 Daniele Alberti – Biobang Lecce – 12 novembre 2014

Efficienza autorizzativa studi clinici in Italia

Daniele Alberti- Incontro ISS 23-6-2014

Regione

Delta data di submission AC e CE - data ultima autorizzazione (ricevimento contratto) in mesi

Lazio 5,7 Toscana 3,5 Marche 6,3 Umbria 5,2 Abruzzo 5,6 Molise 6,1 Puglia 5,7 Campania 6,8 Basilicata 8,7 Calabria 6,2 Sicilia 6,2 Sardegna 5,5 Valle D'Aosta 8,2 Piemonte 5,3 Liguria 6,7 Lombardia 5,1 Veneto 6,2 Friuli - Venezia Giulia 6,5 Trentino - Alto Adige 6,3 Emilia - Romagna 6

0 2 4 6 8 10

Lazio Toscana Marche Umbria

Abruzzo Molise Puglia

Campania Basilicata Calabria

Sicilia Sardegna

Valle D'Aosta Piemonte

Liguria Lombardia

Veneto Friuli - Venezia Giulia Trentino - Alto Adige

Emilia - Romagna



Clinical Trials Novartis Oncology Italy – REGIONE PUGLIA (planned, runnging & ongoing – 12 November 2014)

Hemato 10

Onco 7

Number of clinical trials


10,2% 3,5% 1,2% Puglia vs TOT Italia

Investimenti BU Oncologia in Puglia nel 2014

97%

3% 2014

Investimenti da convenzione BU onco Italia

Investimenti da convenzione BU onco Puglia


Investimenti & cost avoidance della BU Oncologia Italia vs Puglia

€ 7,503,947

€ 9,330,870 € 8,037,865

€ 220,169 € 297,140 € 228,582

€ 13,246,425

€ 16,893,687

€ 11,732,010

€ 480,422 € 657,038 € 436,751

2012 2013 2014

Investimenti da convenzione BU onco Italia Investimenti da convenzione BU onco Puglia Cost Avoidance BU Onco Italia Cost Avoidance BU Onco Puglia


Partnerships – Working Together to develop new / more effective Advanced Therapy Medicinal Products

§  Medicines are one of the key cornerstones in the multimodality treatment of cancer

§  Targeted therapies & ATMPs represent a major step towards more effective cancer care in the future

§  The fight against cancer relies on commitment from all relevant stakeholders working in partnership with open dialogue

§  The political/regulatory framework should work to ensure all cancer patients in Italy have access to the highest attainable standard of cancer care

§  The whole Italian system needs to work more effectively and efficiently. This can only be achieved through cooperation among all stakeholder groups

73 Daniele Alberti – Biobang Lecce – 12 novembre 2014

Q&As

Grazie per l’attenzione


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Lavori di Gruppo

q 3-4 Gruppi q Argomenti proposti q Fattibilità Clinical Trial Center in Puglia q Proposte di Formazione finalizzate a impiego permanente in CTC q Bandi / Application con Partnership Pubblico-Privato q Venture Capital da Big Pharma

q Materiale q 1 slide riassuntiva progetto q 1 slide SWOT analysis

q Tempo 1 h: discussione, decisioni, proposte

q 3’ per condivisione in plenaria


Proposte Progetto

q  Scopo

q  Razionale

q  Metodi

q  Risultati Attesi

q  Tempi di conduzione

q  Stima Risorse Umane e Budget richiesti dal Progetto

q  Break-even point: tempo necessario per il ritorno degli investimenti richiesti dalprogetto


SWOT ANALYSIS

STRENGHTS WEAKNESSES

Descrivere brevemente (max 4 punti) i punti di forza del progetto

INDICARE IN QUESTA SEDE SE NON SONO STATE PREIDENTIFICATE OBIEZIONI ISTITUZIONI

Descrivere brevemente (max 4 punti) le problematiche del progetto o che potrebbero impattare sull a sua approvazione / implementazione

OPPORTUNITY THREATS

Descrivere brevemente (max 4 punti) le opportunità che il progetto potrebbe fornire chi lo propone, Regione, Università, Istituzioni, Pazienti

Descrivere brevemente (max 4 punti) i rischi che il protogretto potrebbe arrecare chi lo propone, Regione, Università, Istituzioni, Pazienti

Team 1 - proposte


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Presentations & Public Speaking

Ldb 145 geni mutanti_2014-11-12 alberti - mercato farmaceutico