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Dec 5, 2012 (4 years and 7 months ago)

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Federal Institute for Drugs
and Medical Devices

Clinical Trial Authorisation in Germany
for First-in-Man Trials with NCEs
Thomas Sudhop, MD
Presented by Christian Steffen, MD
Federal Institute for Drugs and Medical Devices (BfArM)
Germany
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The TeGenero Incident
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Trial Design

Mono-centre, double-blind, randomised first-in-man trail on
TGN1412

TGN1412: CD-28 “super-agonist” antibody

Trial population: 32 healthy volunteers in 4 cohorts

0.1 mg/kg, 0.5 mg/kg, 2 mg/kg, 5 mg/kg

First cohort: 8 subjects

6 TGN1412 0.1 mg/kg, 2 Placebo

Acute cytokine release syndrome in all six subjects treated with
TGN1412

Life-threatening

Requiring ICU treatment
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Clinical Course
Suntharalingam et al. NEJM 2006
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Suntharalingam et al.
NEJM 2006
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Schneider et al., NATURE BIOTECHNOLOGY
VOLUME 24 NUMBER 5 MAY 2006
NATURE BIOTECHNOLOGY
VOLUME 24 NUMBER 5 MAY 2006
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Cytokine Release
Suntharalingam et al. NEJM 2006
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Relevant Guidelines for Clinical Trials

Non-Clinical Safety Studies For The Conduct Of Human Clinical Trials For
Pharmaceuticals (ICH M3; CPMP/ICH/286/95)

Preclinical safety evaluation of biotechnology-derived pharmaceuticals (ICH S6;
CPMP/ICH/302/95)

The Non-clinical Evaluation of the Potential for delayed Ventricular
Repolarization (QT Interval Prolongation) by Human Pharmaceuticals (ICH S7B;
CPMP/ICH/423/02)

Safety pharmacology studies for human pharmaceuticals (ICH S7A;
CPMP/ICH/539/00)

Guideline for Good Clinical Practice (ICH E6; CPMP/ICH/135/95)

General Considerations for Clinical Trials (ICH E8; CPMP/ICH/291/95)

Guideline on Virus Safety Evaluation of Biotechnological Investigational
Medicinal Products – Draft (EMEA/CHMP/BWP/398498/2005-corr)

Guideline on the Requirements to the Chemical and Pharmaceutical Quality
Documentation concerning Investigational Medicinal Products in Clinical Trials
(CHMP/QWP/185401/2004
)

EUDRALEX- Vol. 10 – Clinical trials


more
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Regulatory Actions

March 23
rd
, 2006
TGN1412 incident at Northwick Park Hospital, London

April 2006
MHRA published interim actions on mABs

April 2006
Publication of the TGN1412 IMP dossier

May 2006
UK Expert Scientific Group on Phase One Clinical Trials
(ESGPOCT) founded

May 2006
German PEI published possible criteria for high-risk mABs

July 2006
ESGPOCT published interim report

July 2006
French AFSSAPS published concept paper

September 2006
BfArM drafted concept paper (internal use only)

November 2006
Final Report of the ESGPOCT

January 2007
EMEA announces CHMP-SWP Guideline

March 2007
CHMP-SWP Guideline published for public consultation
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Report of the Working Party on
Statistical Issues
in First-in-Man studies
Royal Statistical Society
March 2007
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How to improve current Practice?

First in man trial bear multiple risks due to limited data on the
IMP and the interaction of IMP and human body

Unfortunately this part of clinical development had virtually no
commonly accepted guidelines

A Guideline on
Requirements for First-in-Man Clinical Trials for
potential high-risk medicinal products
has been published now
for public consultation by the SWP of the EMEA

Both German competent authorities have been involved (PEI,
BfArM)
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First-in-man guideline
Definition of potential high-risk IMP

Quality aspects
Non-clinical requirements
Clinical requirements
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Risk Assessment by Risk Classes

High Risk Trials

Difficult to express general guidance

Require a very special assessment

Non-High Risk Trials

Intermediate risk trials

Low risk trials
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Definition of High-Risk IMPs
Monoclonal Antibodies (mAb)*
1.
The mAb employs a new
mechanism of action
2.
The mAb addresses a target that
lacks appropriate animal models
3.
The mAb comprise a new type of
engineered structural format
NCEs
1.
The NCE is new in class and
employs a new mechanism of
action. It is reasonable to
consider that the mechanism of
action might fundamentally affect
clinical relevant important vital
systems such as the respiratory,
immune, cardiovascular,
gastrointestinal tract, CNS, and
other vital body systems
2.
The NCE is new in class and
addresses a target or pathway
that lacks relevant nonclinical
models.
*Schneider CK, Kalinke U, and Löwer J. TGN1412 - a regulator’s perspective. Nature Biotechnology 2006;24:493-6

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High-Risk IMPs

An IMP has to be considered as high-risk IMP when
there are concerns that serious ADRs may occur in
first-in-man trials

Case-by-case decision based on knowledge or
uncertainties

Mode of action

Nature of target

Relevance of non-clinical models
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Intermediate- / Low-Risk Trials
Intermediate-Risk Trials

neither classified as high risk trial

nor as low risk trial
Low-Risk Trials

IMP is member of a well known and well characterised class of
medicinal products or is second in class and the class has well
described pharmacological properties
and

prior clinical trials did not exert any unforeseeable risk then a
clinical trial should be considered as a low risk trial.
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High-Risk Trials: Non-clinical Data
Pharmacodynamics

Primary and secondary pharmacodynamics

in
in vitro
animal and human systems and

in vivo
in one or more chosen animal models

including

receptor binding

receptor occupancy

duration of effect

dose-response

Appropriate titration necessary to detect possible U-
or bell-shaped dose response curves
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High-Risk Trials: Non-clinical Data
Pharmacokinetics

Standard ADME program for all species used
for
in-vivo
studies

Absorption, Distribution, Metabolism and
Elimination

Exposure data at pharmacological doses from
the relevant animal models should be
provided
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Trial Population

Health status

Healthy volunteers or patients?

Primary purpose is to assess tolerability and PK not therapeutic benefit

No parallel inclusion of the same subjects in other trials

Definition of “healthy”

Patients: Effect of concomitant treatment

Gender

Women in ‘first in man’ trials?

Age range

Ethnics
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Starting Dose

Characteristics of an optimum and safe starting dose

It does not cause any clinical measurable effects

neither pharmacodynamic

nor toxic effects

dose prior MED / PAD (minimal effective dose,
pharmacologically active dose)

The next higher dose causes first pharmacological effects (if
detectable in healthy volunteers) without toxic effects

MED
Log dose
Effect
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How to obtain a safe starting Dose

Classic approach: NOAEL / safety factor (
>
10)

Usually derived from doses rather than exposures

NOEL, PAD (Pharmacologically active dose)

Allometric Methods according FDA Guidance

Human equivalent dose (HED) according FDA
recommendations is usually calculated on animal NO
A
ELs

PAD adjustment might be necessary

NOAEL-HED Approach: Combining NOAELs with
HED plus
safety factor
Guidance for industry and reviewers: Estimating the safe starting dose in clinical trials for therapeutics in adult healthy
volunteers, July 2005, http://www.fda.gov/CDER/guidance/5541fnl.pdf
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MABEL Approach

Recommended for high-risk first-in-man trials

MABEL: “Minimal anticipated biological effect level”

Based on all relevant in-vitro and in-vivo PK and PD data such as

Receptor binding and receptor occupancy

Concentration/response data

Exposures at pharmacological doses in relevant species

MABEL should be calculated based on PK/PD modelling approach

Starting dose = MABEL dose / Safety factor

If NOAEL-HED dose is lower, use NOAEL-HED-derived dose
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Dose Regimen

First dose

Route of administration

Number of subjects per dose increment (cohort)

Number of subjects to be dosed at the same time

Time lag between dosing of the next subjects of

the same dose level (within cohort)

the next higher dose level (between cohorts)

Dose progression factor

When to stop (who and when)
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Dosing in High-Risk Trials

Initial sequential dose administration design within each
cohort

Adequate period of observation between the
administration of each subject depending on estimated PK
and PD data

Before administration of the next cohort all results from all
subjects of the subsequent cohort(s) must be reviewed

PK and PD data from the previous cohorts should be
compared to known non-clinical PK, PD and safety
information
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When to stop

Common approach

From MED (minimum effective dose) to MTD (maximum tolerated dose)

Nevertheless MTD not needed to be assessed in every IMP

How to assess the MTD?

From MID (Minimum intolerated dose) to MTD

MTD => last dose level below MID

Who is responsible for the stopping decision?

Role of the investigator (physician)

All stopping procedures and responsibilities should be clearly explained
in the trial protocol
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Dose Escalation

Standard procedure

Arithmetic or geometric increase

Relevant factors

Steepness of the slope of dose/effect and dose/toxicity
relations

Therapeutic range in non-clinical models

Predictability (raw estimate) of the effects of the next dose
step

Potential pharmacodynamic effects (if any)

Potential toxic effects


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Cohort Size

With larger cohorts usually more precise data can be
obtained, but larger cohorts put more subjects at risk
and increase the costs of clinical development
programmes

Common standard is an A + P design

with A = 6 to 10 subjects receiving the active product and

P = 2 to 4 subjects receiving placebo
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Number of subjects dosed
simultaneously

High risk trials

not more than one subject

sequential administration design within each cohort

Intermediate risk trials

not more than two subjects per new dose level at first

Staggered administration designs

suitable for several cohort sizes (6+2, 8+3, 10+3 …)
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Staggered Administration Design (6+2)

Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Day 10
Day 11
Dose 1
2A+1P
4A+1P









Dose 2

2A+1P
4A+1P








Dose 3


2A+1P
4A+1P







Dose 4



2A+1P
4A+1P






Dose 5




2A+1P
4A+1P





Dose 6





2A+1P
4A+1P




Dose 7






2A+1P
4A+1P



Dose 8







2A+1P
4A+1P


Dose 9








2A+1P
4A+1P

Dose 10









2A+1P
4A+1P
A: Active medicinal product P: Placebo
For the next dosing day all relevant clinical and safety data must be available and reviewed
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Time Lag between administered Doses

High risk trials

Individually calculated, risk based lag time

Intermediate risk trials

Time lag between the first two subjects of each new dose level
should be based on appropriate nonclinical estimates

t
max
-based approach

Adjustment might be necessary in case of observed events with late
onset
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Trial Centres for First-in-man Trials

High-risk Trials:

Appropriate clinical facilities

Medical staff with appropriate level of training and expertise
and an understanding of the IMP, its target and mechanism
of action

Immediate access to facilities for the treatment of medical
emergencies (such as cardiac emergencies, anaphylaxis,
cytokine release syndrome, convulsions, hypotension),

ready availability of Intensive Care Unit facilities.
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Furthermore, without prejudging the terms and conditions governing the
approval of research centres, which will be defined by ”arrêté”,
it should be
pointed out that each research centre should have set up standard
operating procedures
enabling the centre to ensure, the safety of
volunteers, depending on the foreseeable risks associated with each drug
and/or each protocol. Hence, the foreseeable risks associated with each
clinical trial must be evaluated and, depending on this risk:

the roles of the pharmacologist and the resuscitator must be specified, and
the resuscitator and the appropriate medical service must be informed
beforehand.

the appropriate monitoring of subjects by medical and paramedical staff
must be organised (modalities, qualifications of personnel, round-the-clock
presence or not, care modalities, emergency procedures, etc.).

REPUBLIQUE FRANCAISE

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Conclusion

Protocol design
- no concomitant exposure to other IMPs

High risk trials
- sequential administration design
- non-sequential design has to be fully justified

Trial site
- conducted by medical staff with training and expertise
- immediate treatment of medical emergencies
- ready availability of Intensive Care Unit
- preferably single protocol and single site
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