Clinical Trial Authorisation in Germany for First-in-Man Trials with NCEs

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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

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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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NATURE BIOTECHNOLOGY VOLUME 24 NUMBER 5 MAY 2006
Schneider et al., 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 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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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)
• 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
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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 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

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High-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

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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

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How 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
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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 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

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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 (62, 83, 103
  )

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Staggered 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
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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
• tmax-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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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.).

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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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