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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. The TeGenero Incident. Trial Design.

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clinical trial authorisation in germany for first in man trials with nces

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)


trial design
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
clinical course
Clinical Course

Suntharalingam et al. NEJM 2006




cytokine release
Cytokine Release

Suntharalingam et al. NEJM 2006

relevant guidelines for clinical trials
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
regulatory actions
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

Report of the Working Party on Statistical Issues

in First-in-Man studies

Royal Statistical Society

March 2007

how to improve current practice
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)
first in man guideline

Definition of potential high-risk IMP

Quality aspects

Non-clinical requirements

Clinical requirements

First-in-man guideline
risk assessment by risk classes
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
definition 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


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.

Definition of High-Risk IMPs

*Schneider CK, Kalinke U, and Löwer J. TGN1412 - a regulator’s perspective. Nature Biotechnology 2006;24:493-6

high risk imps
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
intermediate low risk trials
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.
high risk trials non clinical data pharmacodynamics
High-Risk Trials: Non-clinical DataPharmacodynamics
  • 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
high risk trials non clinical data pharmacokinetics
High-Risk Trials: Non-clinical DataPharmacokinetics
  • 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
trial population
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
starting dose


Log dose

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
how to obtain a safe starting dose
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,

mabel approach
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
dose regimen
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)
dosing in high risk trials
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
when to stop
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
dose escalation
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
cohort size
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
number of subjects dosed simultaneously
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 …)
staggered administration design 6 2
Staggered Administration Design (6+2)

For the next dosing day all relevant clinical and safety data must be available and reviewed

time lag between administered doses
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
trial centres for first in man trials
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.


  • 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.).
  • 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