Chiara Cremolini

University of Pisa

Azienda Ospedaliero-Universitaria Pisana

How to Crystalize Your Ideas on Clinical Research:

The Art of Designing and Conducting a Clinical Trial

ESMO World Congress on Gastrointestinal Cancer

Barcelona, 5th July 2019

Disclosure

Recognize the gap!

Starting points

THE IDEA

Challenge your idea

1. Novelty

Challenge your idea

2. How does it fit in the frame of the current cinical practice?

Challenge your idea

3. Which are the future perspectives in the field?

Starting points

THE IDEA

THE STUDY POPULATION

Overall population of affected pts Study population

Study population

Translation of trial results back to clinical practice

Overall population of affected pts Study population

Translation of trial results back to clinical practice

Overall population of affected pts Study population

Very dangerous risks in the era of targeted agents

1) To miss efficacious drugs because we do not get to catch

“signs of efficacy” in not properly designed trials in

unselected populations

2) Not to identify the “best” target population for a certain

drug

Starting points

THE IDEA

THE STUDY POPULATION

THE DESIGN

Recommended Dose

PHASE 1 PHASE 3PHASE 2 PHASE 4

Activity and Safety

Efficacy

Post-marketing info

Drugs’ development - traditional paradigm

Recommended Dose

PHASE 1 – 1b PHASE 3 PHASE 4

Efficacy

Post-marketing info

Drugs’ development - new scenarios

Expansion cohort

Safety info and signals of activity

Recommended Dose

PHASE 1 PHASE 2 PHASE 4

Activity and Safety Post-marketing infoRobust magnitude of benefit

Strong biologic rationale and backgroundRare conditions

Drugs’ development - new scenarios

Larotrectinib – accelerated approval

Drilon et al, NEJM 2018

• Histology Independent

• Patients are randomised to

receive a Rx matched to BM

• Compartimentalised: Each

cohort can be randomised

(ideally) or not

• Further definitive trial

required???

“New” designs

Catenacci et al, Mol Oncol ‘15

Basket design

• Histology dependent

• Patients are randomised to

receive a Rx matched to BM

• Compartimentalised: Each

cohort can be randomised

(ideally) or not

• Further definitive trial

required???

“New” designs

Umbrella design

Catenacci et al, Mol Oncol ‘15

Recommended Dose

PHASE 1 PHASE 3PHASE 2 PHASE 4

Activity and Safety

Efficacy

Post-marketing info

Drugs’ development - traditional paradigm

Reasons behind choices

Is a comparator arm needed / useful ?

No

The null hypothesis is based on historical data

SINGLE-ARM PHASE II

PHASE II RANDOM

(pick the winner)

COMPARATIVE PHASE III

Yes

PHASE II RANDOM

(comparative)

No comparison between arms allowed

Increasing

level

of e

vid

ence

22

By F.Perrone e M. Di Maio

23

24

25

26

27

By F.Perrone e M. Di Maio

Patients light up the differences

More patients → more power

Starting points

THE IDEA

THE STUDY POPULATION

THE DESIGN

THE ENDPOINT

The value of endpoints

CLINICAL VALUE

• Relevance in the

therapeutic route of

affected patients

METHODOLOGICAL VALUE

• Surrogacy

• Reproducibility

• Comparability

DO NOT RENOUNCE TO UNCONVENTIONAL, BUT CLINICALLY

SOUND ENDPOINTS EXPECIALLY IN EXPLORATORY SETTINGS

The art of conducting a clinical trial

NETWORKING!

Especially now, in the era of

disease fragmentation

The art of conducting a clinical trial

Know a little bit of…

Data management

Data interpretation

Statistics

Ethical requirements

Regulatory aspects

Financial issues

Take home messages

1. Be ambitious and look at the future

1. Make your study part of a story

2. Networking is the keyword for a successful study

3. Be pragmatic and take care of all the aspects of the study

Thank you!