Title: Clinical Trial Authorisation in Germany for First-in-Man Trials with NCEs
1Clinical 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
2The TeGenero Incident
3Trial 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
4Clinical Course
Suntharalingam et al. NEJM 2006
5Suntharalingam et al. NEJM 2006
6NATURE BIOTECHNOLOGY VOLUME 24 NUMBER 5 MAY 2006
Schneider et al., NATURE BIOTECHNOLOGY VOLUME 24
NUMBER 5 MAY 2006
7Cytokine Release
Suntharalingam et al. NEJM 2006
8Relevant 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
9Regulatory 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
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11Report of the Working Party on Statistical Issues
in First-in-Man studies
Royal Statistical Society March 2007
12How 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)
13First-in-man guideline
Definition of potential high-risk IMP Quality
aspects Non-clinical requirements Clinical
requirements
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15Risk 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
16Definition of High-Risk IMPs
- Monoclonal Antibodies (mAb)
- The mAb employs a new mechanism of action
- The mAb addresses a target that lacks appropriate
animal models - The mAb comprise a new type of engineered
structural format
- NCEs
- 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 - 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 regulators perspective. Nature Biotechnology
200624493-6
17High-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
18Intermediate- / 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.
19High-Risk Trials Non-clinical DataPharmacodynami
cs
- 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
20High-Risk Trials Non-clinical DataPharmacokineti
cs
- 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
21Trial 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
22Starting 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
23How to obtain a safe starting Dose
- Classic approach NOAEL / safety factor (gt10)
- 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
24MABEL 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
25Dose 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)
26Dosing 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
27When 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 gt 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
28Dose 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
29Cohort 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
30Number 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 (62, 83, 103
)
31Staggered Administration Design (62)
Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 Day 10 Day 11
Dose 1 2A1P 4A1P
Dose 2 2A1P 4A1P
Dose 3 2A1P 4A1P
Dose 4 2A1P 4A1P
Dose 5 2A1P 4A1P
Dose 6 2A1P 4A1P
Dose 7 2A1P 4A1P
Dose 8 2A1P 4A1P
Dose 9 2A1P 4A1P
Dose 10 2A1P 4A1P
A Active medicinal product P Placebo A Active medicinal product P Placebo A Active medicinal product P Placebo A Active medicinal product P Placebo A Active medicinal product P Placebo A Active medicinal product P Placebo A Active medicinal product P Placebo A Active medicinal product P Placebo A Active medicinal product P Placebo A Active medicinal product P Placebo A Active medicinal product P Placebo A Active medicinal product P Placebo
For the next dosing day all relevant clinical and
safety data must be available and reviewed
32Time 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
33Trial 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.
34REPUBLIQUE 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.).
35Conclusion
- 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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