TGN 1412 Welche Änderungen haben sich für die Erstanwendung am Menschen aus Sicht des BfArM ergeben?

TGN 1412

Welche Änderungen haben sich für die Erstanwendung am Menschen aus Sicht

des BfArM ergeben?

PD Dr. med. Thomas Sudhop Bundesinstitut für Arzneimittel

und Medizinprodukte, Bonn

Bundesinstitut für Arzneimittel und Medizinprodukte

IMP Risk Classes

ƒ Trials with “High Risk IMPs”

ƒ Trials with “Non-High Risk IMPs”

ƒ Intermediate risk IMPs

ƒ Low risk IMPs

High-Risk IMPs

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

ƒ Case-by-case decision based on knowledge or uncertainties

ƒ Mode of action

ƒ Nature of Target

ƒ Relevance of Non-Clinical models

Intermediate- / Low-Risk IMP

Intermediate-Risk IMPs

ƒ neither classified as high risk IMPs

ƒ nor as low risk IMPs Low-Risk IMP

ƒ 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

ƒ prior clinical trials did not exert any unforeseeable risk then a clinical

trial should be considered as a low risk trial.

Pharmacodynamics

ƒ Primary and secondary pharmacodynamics

ƒ in in vitro animal and human systems and

ƒ in vivo in one or more chosen animal models

ƒ including

ƒ receptor binding

ƒ receptor occupancy

ƒ duration of effect

ƒ dose-response

ƒ Appropriate titration necessary to detect possible U- or bell-

shaped dose response curves

Trials with High-Risk IMPs: Non-clinical Data

Pharmacokinetics

ƒ Standard ADME programme for all species used for in-vivo studies

ƒ Absorption, Distribution, Metabolism and Elimination

ƒ Exposure data at pharmacological doses from the

relevant animal models should be provided

Trial Population

ƒ Health status

ƒ Healthy volunteers or patients?

ƒ Primary purpose is to assess tolerability and PK not therapeutic benefit

ƒ No parallel inclusion of the same subjects in other trials

ƒ Definition of “healthy”

ƒ Patients: Effect of concomitant treatment

ƒ Gender

ƒ Women in ‘first in man’ trials?

ƒ Age range

ƒ Ethnics

Dose Regimen

ƒ First dose

ƒ Route of administration

ƒ Number of subjects per dose increment (cohort)

ƒ Number of subjects to be dosed at the same time

ƒ Time lag between dosing of the next subjects of

ƒ the same dose level (within cohort)

ƒ the next higher dose level (between cohorts)

ƒ Dose progression factor

ƒ When to stop (who and when)

How to obtain a safe starting Dose

ƒ Classic approach: NOAEL / Safety factor (>10)

ƒ Usually derived from doses rather than exposures

ƒ Allometric Methods according FDA Guidance

ƒ Human equivalent dose (HED) according FDA recommendations is usually calculated on animal NOAELs

ƒ PAD adjustment might be necessary

ƒ 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

Mabel Approach

ƒ Recommended for first-in-man trials with high-risk IMPs

ƒ MABEL: “Minimal anticipated biological effect level”

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

ƒ Receptor binding and receptor occupancy

ƒ Concentration/response data

ƒ Exposures at pharmacological doses in relevant species

ƒ MABEL should be calculated based on PK/PD modelling approach

ƒ Starting dose = MABEL dose / Safety factor

ƒ If NOAEL-HED dose is lower, use NOAEL-HED-derived dose

Dosing in High-risk Trials

ƒ Initial sequential dose administration design within each cohort

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

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

ƒ PK and PD data from the previous cohorts should be compared

to known non-clinical PK, PD and safety information

Number of subjects dosed simultaneously

ƒ Trials with high risk IMPs

ƒ not more than one subject

ƒ sequential administration design within each cohort

ƒ Trials with intermediate risk IMPs

ƒ not more than two subjects per new dose level at first

ƒ Staggered administration designs

ƒ suitable for several cohort sizes (6+2, 8+3, 10+3 …)

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

Time lag between administered Doses

ƒ High risk trials

ƒ Individually calculated, risk based lag time

ƒ Intermediate risk trials

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

ƒ t

-based approach

ƒ Adjustment might be necessary in case of observed events with late onset

Conclusion

ƒ BfArM changed the requirements for first-in-man trials

ƒ Additional requirements enhance trial subjects safety

ƒ Additional requirements shall enhance predictability of human results from non-clinical data

ƒ No stand-alone approach but concept is in line with the new

EMEA-SWP guideline on first-in-man trials with high-risk IMPs

Backup Folien

The Tegenero Incident

Trial Design

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

ƒ TGN1412: CD-28 “super-agonist” antibody

ƒ Trial population: 32 healthy volunteers in 4 cohorts

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

ƒ First cohort: 8 subjects

ƒ 6 TGN1412 0.1 mg/kg, 2 Placebo

ƒ Acute cytokine release syndrome in all six subjects treated with TGN1412

ƒ Life-threatening

ƒ Requiring ICU treatment

Clinical Course

Suntharalingam et al. NEJM 2006

Cytokine Release

Suntharalingam et al. NEJM 2006

Lessons needed to be learned from TGN1412

ƒ Sponsors / Pharmaceutical companies

ƒ CROs

ƒ Ethic Committees

ƒ Competent Authorities

ƒ Trial subjects

Relevant Guidelines for Clinical Trials

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

ƒ Preclinical safety evaluation of biotechnology-derived pharmaceuticals (ICH S6;

CPMP/ICH/302/95)

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

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

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

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

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

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

ƒ EUDRALEX- Vol. 10 – Clinical trials

ƒ … more

How to improve current practise?

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

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

ƒ 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

ƒ Both German competent authorities have been involved (PEI, BfArM)

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

When to stop

ƒ Common approach

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

ƒ Nevertheless MTD not needed to be assessed in every IMP

ƒ How to assess the MTD?

ƒ From MID (Minimum intolerated dose) to MTD

ƒ MTD => last dose level below MID

ƒ Who is responsible for the stopping decision?

ƒ Role of the investigator (physician)

ƒ All stopping procedures and responsibilities should be clearly explained in the

trial protocol

Dose Escalation

ƒ Standard procedure

ƒ Arithmetic or geometric increase

ƒ Relevant factors

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

ƒ Therapeutic range in non-clinical models

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

ƒ Potential pharmacodynamic effects (if any)

ƒ Potential toxic effects

ƒ …

Cohort Size

ƒ 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

ƒ Common standard is an A + P design

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

ƒ P = 2 to 4 subjects receiving placebo

Trial Centres for First-in-man Trials

ƒ High-risk Trials:

ƒ Appropriate clinical facilities

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

ƒ Immediate access to facilities for the treatment of medical

emergencies (such as cardiac emergencies, anaphylaxis, cytokine release syndrome, convulsions, hypotension),

ƒ ready availability of Intensive Care Unit facilities.