From First Drug Design Over Pre-Clinical Data Into First in Human Studies

PHASE 1 STUDIES:

FROM FIRST DRUG DESIGN OVER PRE-CLINICAL

DATA INTO FIRST IN HUMAN STUDIES

Patricia de Cock

2 SGS BIOPHARMA DAY – OCTOBER 25, 2016

LET’S TAKE A STEP BACK IN HISTORY


TODAY…

GMP

GLP

GDP


ACTUALLY…

Environment has changed a lot and is now highly regulated

The bio/pharmaceutical market is now:

Global

Very competitive

Complex R&D

“…er” : bigger, safer, quicker etc

BUT

Motivation and intention of companies did not change

Ideas still need to be executed, new medicines still need to come to

the market


IMPORTANCE OF PHASE 1 (FIH)

Usually in healthy subjects or patients (who are not expected to benefit

from the IMP!)

Answers to some very crucial questions:

Is the IMP safe in humans?

What does the body do to the IMP? (pharmacokinetics)?

What does the IMP to do the body? (pharmacodynamics)?

Might the IMP work in patients?

Phase 1 is the gateway between scientific

research and clinical medicine


FIH AND SUBSEQUENT TRIALS: TREND

TOWARDS THE FIRST “BUNDLE” OF STUDIES

Primary objectives of phase 1:

Safety and tolerability

Pharmacokinetics

Pharmacodynamics

Subsequent studies

Effect of potential influencers: food, gender, age, genetic differences

Relationship dose and PD (for example by measuring specific biomarkers)

Interaction studies

Distribution of IMP (radiolabeled IMP)

Specific effects (cardio – respiratory)

Body constitution/BMI

Specific targets (skin – csf – cervix – lungs)

Trend to bundle it into the first study


FROM IDEA UP TO STUDY PROPOSAL

Risk and safety assesment

All aspects of the IMP need to be known (IB – preclinical information): class,

MOA, toxicity, potency…

Specific procedures to be performed

Specific populations

High risk IMP

NCE versus a Biological

…

Risk management

Prediction and prevention of possible side effects

Extra safety measurements (extra visits, labs, telemetry, spirometry…)

Antidote if applicable

SAE procedure

Access to emergency setting – 24/7 physician on call – guard function in WE


FROM IDEA UP TO STUDY PROPOSAL

Defining the correct dose

Get familiar with NOAEL (No Observed Adverse Events level)

NOAEL convertion to the human equivalent dose (HED)

Selection of the HED of the most appropriate species

Apply a safety factor (at least a 10 fold) to get the Maximum Recommended

starting Dose (MRSD)

Adjust the MRSD to the predicted IMP action

Dose escalation

SAD to MAD

Safety meetings

Stopping rules


FROM STUDY PROPOSAL TO EXECUTION

Recruitment of the right volunteers

Information

Screening – ICF

IMP administration


FROM STUDY CONDUCTION TO DATA

COLLECTION

All steps of study executed

No unexpected findings, no SAE, no protocol amendements

Data base closed

Data collection

Clinical Study Report

Abstract

… up to the next phase…


BUT WHAT HAPPENS IF…

…. there is an SAE?

…. there are elevated lab tests?

…. the PI seems to be unblinded?

…. there is an unexpected finding?

…. PK data are not a good reflection of the predicted values?

…. a genetic profile seems to influence absorption?

…. an allergic reaction occurs?

…. there is a need for extra examininations during execution?

…. there is a need for a specialist advice?

… etc


BUT WHAT HAPPENS IF AN SAE OCCURS?

Study with a biological agent

First phase SAD – second phase MAD

First phase:

• First cohorts no problem

• Higher dose: quite severe reactions (no SAE) with elevated CRP en

muscle pain/shivering

Second phase:

• First cohort no problem

• Second cohort an SAE occured

Study implemented with amendement and no further problems

occured


BUT WHAT HAPPENS

IF AN UNEXPECTED FINDING OCCURS?

Study with a NME.

First phase SAD – second phase MAD

First phase:

• First two cohorts no problem

• Safety meeting: “GO” from the PI for dose escalation

• Third cohort no problems but non expected PK finding: longer halflife

than expected and significant active metabolite with very long halflife

Second phase:

• Implemented but with other doses and other design/other dose

escalation steps

Study implemented with amendement and no further problems

occured


WHAT HAPPENS IN CASE

THE PI SEEMS NOT BLIND ANYMORE?

Several studies with several agents.

PD findings that are seen in the lab values (glycemic lowering agent… anti

coagulants…)

Reactions that are very specific (shivering, CRP, target molecules…)

• Analysis of the problem: what is the impact on the judgement? What is the impacy

on data integrity?

• Solutions are divers: if predicted an open label can be considered. If unpredicted:

extra physician to judge specific values, evaluation of AEs before lab results are

available…

Inherent for phase 1 FIH research: after all it is the first time a product is

given to a human body…


TAKE HOME MESSAGES

Phase 1 = bridging scientific data to clinical practice

Phase 1 = mostly the first time in humans

Phase 1 = expect the unexpected and be prepared

Good execution needs partnership between company and

dedicated PI/study staff

The solution to unexpected problems lies in a continous dialogue

and thorough

investigation


Life Sciences Patricia DE COCK

Head of Investigators CPU

Clinical Pharmacology Unit Antwerpen

Lange Beeldekensstraat 267

B - 2060 Antwerpen

Belgium

phone: +32 3 217 2565

mail: [email protected]

THANK YOU FOR YOUR ATTENTION

+ 41 22 739 9548

+ 1 866 SGS 5003

+ 65 637 90 111

+ 33 1 53 78 18 79

+ 1 877 677 2667

+ 33 1 41 24 87 87

https://www.linkedin.com/company/sgs-life-sciences


QUESTIONS ?

From First Drug Design Over Pre-Clinical Data Into First in Human Studies

Health & Medicine

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