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
Federal Institute for Drugs
and Medical Devices
The TeGenero Incident
Federal Institute for Drugs
and Medical Devices
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
Federal Institute for Drugs
and Medical Devices
Clinical Course
Suntharalingam et al. NEJM 2006
Federal Institute for Drugs
and Medical Devices
Suntharalingam et al.
NEJM 2006
Federal Institute for Drugs
and Medical Devices
NATURE BIOTECHNOLOGY VOLUME 24 NUMBER 5 MAY 2006
Schneider et al., NATURE BIOTECHNOLOGY VOLUME 24 NUMBER 5 MAY 2006
Federal Institute for Drugs
and Medical Devices
Cytokine Release
Suntharalingam et al. NEJM 2006
Federal Institute for Drugs
and Medical Devices
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
Federal Institute for Drugs
and Medical Devices
Regulatory Actions
•
March 23rd, 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
Federal Institute for Drugs
and Medical Devices
Report of the Working Party on
Statistical Issues
in First-in-Man studies
Royal Statistical Society
March 2007
Federal Institute for Drugs
and Medical Devices
Federal Institute for Drugs
and Medical Devices
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)
Definition of potential high-risk IMP
Quality aspects
Non-clinicalFirst-in-man
requirements guideline
Clinical requirements
Federal Institute for Drugs
and Medical Devices
Federal Institute for Drugs
and Medical Devices
Federal Institute for Drugs
and Medical Devices
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
Federal Institute for Drugs
and Medical Devices
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
Federal Institute for Drugs
and Medical Devices
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
Federal Institute for Drugs
and Medical Devices
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.
Federal Institute for Drugs
and Medical Devices
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 Uor bell-shaped dose response curves
Federal Institute for Drugs
and Medical Devices
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
Federal Institute for Drugs
and Medical Devices
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
Federal Institute for Drugs
and Medical Devices
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
Effect
• MED
Log dose
Federal Institute for Drugs
and Medical Devices
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 NOAELs
– 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
Federal Institute for Drugs
and Medical Devices
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
Federal Institute for Drugs
and Medical Devices
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)
Federal Institute for Drugs
and Medical Devices
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
Federal Institute for Drugs
and Medical Devices
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
Federal Institute for Drugs
and Medical Devices
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
– …
Federal Institute for Drugs
and Medical Devices
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
Federal Institute for Drugs
and Medical Devices
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 …)
Federal Institute for Drugs
and Medical Devices
Staggered Administration Design (6+2)
Dose 1
Dose 2
Day 1
Day 2
2A+1P
4A+1P
2A+1P
Dose 3
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Day 11
4A+1P
2A+1P
Dose 4
4A+1P
2A+1P
Dose 5
4A+1P
2A+1P
Dose 6
4A+1P
2A+1P
Dose 7
4A+1P
2A+1P
Dose 8
4A+1P
2A+1P
Dose 9
4A+1P
2A+1P
Dose 10
A: Active medicinal product
Day 10
4A+1P
2A+1P
P: Placebo
For the next dosing day all relevant clinical and safety data must be available and reviewed
4A+1P
Federal Institute for Drugs
and Medical Devices
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
• tmax-based approach
• Adjustment might be necessary in case of observed events with late
onset
Federal Institute for Drugs
and Medical Devices
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.
Federal Institute for Drugs
and Medical Devices
REPUBLIQUE FRANCAISE
•
•
•
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.).
Federal Institute for Drugs
and Medical Devices
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
Federal Institute for Drugs
and Medical Devices