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Title: Folie%201


1
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
  • Workshop
  • Minimizing risk by
  • optimizing clinical trial design
  • and performance
  • Wolfgang Timmer, Sybille Baumann


2
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
  • Overview
  • Some general considerations about risk
  • General strategies of minimizing risk during the
    different phases of clinical development
  • Identification of the factors of risk The new
    EMEA Guideline
  • What is missing in the EMEA Guideline?
  • Other proposals
  • Further considerations on design features of
    clinical studies and the clinical environment
  • Personal view on particular issues
  • Discussion at any time during this talk


3
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
  • Multiplicity of risk categories in clinical drug
    development
  • Project development risk
  • Competitive risk
  • Device technology development risk
  • Market adoption risk
  • Management risk
  • Liquidity risk
  • Health-related risk of clinical investigational
    subjects(which is referred to in the following)


4
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
  • The quality of risks may vary during clinical
    development
  • Early clinical development, Phase I (strict
    sense)First-in-man trials in healthy subjects
  • Risk mainly related to unanticipated serious
    toxicity
  • Special trial designs in studies with healthy
    subjects
  • Risk may be related to special design features
    such as DDI studies, supratherapeutic doses in
    TQT trials, provocation models, etc.
  • Clinical efficacy studies, PoC, Phase II
  • Risk due to lack of efficacy Risk related to
    special features of the underlying or concomitant
    disease
  • Late-stage clinical development Phase III
  • dto. Rare side effects may become apparent in
    large-scale studies


5
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
  • There are different standards of risk awareness
  • Identification of high riskcompounds and
    adequate action
  • Thorough consideration of the demands of
    aparticular study or novel mechanism of action
    which mightnot be reflected by existing
    guidelines or by a published case report
  • Assurance of the standard quality of a clinical
    study or development programmeAdherence to GCP,
    ethical and legal requirements and applicable
    regulatory guidelines.Application of
    state-of-the-art study designs and
    implementation of quality standards that
    arecommonly accepted in the medical community.

Is the top of thepyramide still missing?

I
II
III
6
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
  • Strategies of minimizing risk depending on risk
    quality (I)
  • Early clinical development, Phase I (strict
    sense)First-in-man trials in healthy subjects
  • ? Improve the predictive value of preclinical
    models
  • ? Identify high-risk drugs and apply special
    safety procedures
  • ? Do not conduct the trial, if the drug is not
    safe !


7
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
  • Strategies of minimizing risk depending on risk
    quality (II)
  • Special trial designs in studies with healthy
    subjects
  • ? Dont conduct sophisticated studies too early
    during a clinical development programme
  • ? Some special studies may be needed to assess
    the risk of later trials in patients
  • ? If a very high supratherapeutic dose is
    suggested by the FDA for a TQT trial, dare to
    enter a scientific discussion on the suitable
    dose
  • ? Dont perform trials that are not essential
    for dossier submission at an early stage


8
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
  • Strategies of minimizing risk depending on risk
    quality (III)
  • Clinical efficacy studies, PoC, Phase II
  • ? Prospectively define clear Go / No Go
    Criteria, and dont proceed with project
    development, if the criteria are not met.
  • ? Use an adequate active comparator in trials
    with out-patients
  • ? Make use of drop out data and concomitant
    medication use to collect full information on
    clinical efficacy (which may also offer the
    chance to optimize the sample size)
  • ? Carefully consider an additional risk
    possibly related to interaction with the
    underlying disease, and perform additional
    methodological or safety trials, if applicable


9
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
  • Strategies of minimizing risk depending on risk
    quality (IV)
  • Late-stage clinical development Phase III
  • ? Base large-scale trials on results of
    adequate dose-range-finding study
  • ? Dont skip Phase II (!)
  • ? Give due consideration to rare side effects
    by on-line safety monitoring and adequate
    pharmacovigilance procedures


10
Minimising risk by optimising clinical trial
design AGAH Workshop 19 April 2008
Risk-benefit assessment Which kind of benefit
are we talking about ? a) benefit for the
individual b) possible later benefit for the
investigational subject ? medical community
? ? all studies in healthy subjects ? few
studies in patients ? all studies in
patients ? oncology trials ? orphan
indications ? diseases for which no
satisfactory treatment is available

11
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
  • Reflection on risk management in clinical trials
  • A risk greater than minimal is not acceptable in
    a healthy volunteer trial.
  • However, the implicit risk of a clinical trial
    will never be zero.
  • Risk has to be minimized as far as possible.
  • This can be achieved by optimizing clinical trial
    design.
  • But there are more strategies to reduce risk,
    e.g., perform appropriate preclinical or clinical
    studies to support the trial, or first perform
    other investigations that may make clinical
    testing unnecessary (identify the critical path
    in project management).
  • Even a study which bears a minimal risk may not
    be acceptable, if there is neither a benefit for
    the individual subject, nor a chance for a later
    benefit for other patients.
  • Sponsors and investigators should implement
    strategies to early identify and re-assess risk
    during an ongoing clinical trial.
  • If the risk assessment changes during a clinical
    trial, adequate measures should be taken.


12
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
London, 19 July 2007 Doc. Ref.EMEA/CHMPSWP/28367/0
7
COMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN
USE(CHMP)

GUIDELINE ON STRATEGIES TO IDENTIFY AND MITIGATE
RISKS FOR FIRST-IN- HUMAN CLINICAL TRIALS WITH
INVESTIGATIONAL MEDICINAL PRODUCTS
DRAFT AGREED BY CHMP EXPERT GROUP 6 March
2007 ADOPTION BY CHMP FOR RELEASE FOR
CONSULTATION 22 March 2007 END OF CONSULTATION
(DEADLINE FOR COMMENTS) 23 May 2007 AGREED BY
CHMP EXPERT GROUP 4 July 2007 ADOPTION BY CHMP 19
July 2007 DATE FOR COMING INTO EFFECT 1 September
2007
KEYWORDS First-in-human, Phase I clinical trials,
identification of risk, non-clinical requirements
, animal models, MABEL, risk mitigation strategies
13
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
  • Scope of the Guideline
  • applies to all new chemical and biological
    investigational drugs except gene and cell
    therapy medicinal products
  • should be read in conjunction with the published
    EU guidelines
  • outlines factors of risk
  • covers non-clinical issues for consideration
  • covers design issues for first-in-man trials


14
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
  • Identification of the factors of risk
  • For some novel medicinal products, the
    non-clinical safety programme might not be
    sufficiently predictive of serious adverse
    reactions in man, and the non-clinical testing
    and the design of the first-in-human study
    requires special consideration.
  • Concerns may be derived from particular knowledge
    or lack thereof regarding
  • the mode of action,
  • the nature of the target, and/or
  • the relevance of animal models


15
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
  • Identification of the factors of risk
  • (1) The mode of action
  • Novelty and extent of knowledge of the supposed
    MOA, including
  • Nature and intensity (extent, amplification,
    duration, reversibility) of the effect on the
    target,
  • Effects on non-targets and subsequent
    mechanisms,
  • Type of the dose-response as measured in
    experimental systems linear vs. non-linear
    (e.g., plateauing, over-proportional
    increase, U-shaped, bell-shaped).
  • The following MOAs require special attention
  • Target is connected with multiple signalling
    pathways (pleiotropic effects),
  • There is a biological cascade or cytokine
    release which may lead to an amplification of
    the effect (e.g., in the immune system or blood
    coagulation system).


16
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
Identification of the factors of risk (1) The
mode of action Three data points are required to
describe a sigmoidal dose-response
curve There is a risk of misinterpreting the
data, if the dose-response curve is
non-sigmoidal. More titration steps are
needed to detect an atypical dose-response curve.

?
Effect
?
?
Log Dose
?
?
Effect
?
?
?
?
Log Dose
17
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
Identification of the factors of risk (1) The
mode of action If an effect is triggered by a
biological cascade or cytokine release, already
the effect of a low dose may be amplified, and
there may not be any safe dose at all.

Effect
CD3 or CD28 (super-) agonists might serve as an
example.
Toxic effects
Desired effect size
Log Dose
18
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
  • Identification of the factors of risk
  • (2) The nature of the target
  • Consider the extent of knowledge on the target,
    including
  • Structure,
  • Tissue distribution (including expression on
    cells of the immune system),
  • Disease specificity,
  • Regulation and level of expression,
  • Biological function (subsequent mechanisms
    should also be considered),
  • Polymorphisms of the target and their impact
    on pharmacological effects.


19
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
  • Identification of the factors of risk
  • (3) Relevance of animal species and models
  • The available animal species should be compared
    to humans, regarding
  • Structural homology of the target,
  • Target distribution,
  • Signal transduction pathways,
  • Nature of the pharmacological effects,
  • Metabolism and pharmacokinetic aspects.
  • Where animal models are perceived to be of
    questionable relevance,this should be considered
    as adding to the risk.


20
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
  • Relevance of animal species and models
  • An algorithm on how to deal with the
    uncertainty
  • A relevant model or surrogate exists, it is
    well-known and the method is validated. ? Use
    that appropriate model or surrogate.
  • A relevant model or surrogate exists, but it is
    not yet known. ? Search for appropriate model or
    surrogate.
  • A particular model or surrogate is of
    questionable relevance. ? Perform in-depth
    evaluation of its relevance, ? Search for other
    model or surrogate, ? Integrate information from
    in-vivo, ex-vivo and in-vitro studies.
  • A relevant model or surrogate does not exist.
  • ? Use of homologous proteins or transgenic
    animals expressing the human target may be
    the only choice. Be aware of the risk and take
    appropriate measures.
  • A model which is actually not relevant is
    regarded as relevant by mistake. ? This is the
    most dangerous case which must be avoided!

(I)

(IIa)
(IIb)

(IIc)
(III)
21
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
  • Unanticipated Serious Toxicity The TGN 1412
    Experience
  • The CD28-specific mAb TGN1412 rapidly caused a
    life-threatening cytokine- storm in all six
    healthy volunteers who received this superagonist
    .
  • Preclinical testing failed to predict toxicity
    in man.
  • Further studies were conducted by the NIBSC to
    develop improved tests for emerging
    immunomodulatory biologicals.
  • Novel in-vitro procedures have now been
    reported, in which TGN1412, immobilized in
    various ways, is presented to human white blood
    cells in a manner that stimulates the striking
    release of cytokines and lymphocyte
    proliferation that actually occurred in vivo in
    humans.
  • These novel procedures would have predicted the
    toxicity of TGN1412, but at the time when the
    Phase I study was released, these procedures were
    not known
  • The Journal of Immunology, 2007, 179 3325-3331
  • Cytokine Storm in the Phase I Trial of
    Monoclonal Antibody TGN1412 Better Understanding
    the Causes to Improve Preclinical Testing of
    Immunotherapeutics
  • Stebbings R, Findlay L, Edwards C, Eastwood D,
    Bird C, North D, Mistry Y, Dilger P, Liefooghe E,
    Cludts I,Fox B, Tarrant G, Robinson J, Meager T,
    Dolman C, Thorpe S, Bristow A, Wadhwa M, Thorpe
    R, Poole C


22
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
  • Unanticipated Serious Toxicity The TGN 1412
    Experience
  • TGN1412 is here shown to have the capabilityto
    evoke cytokine release and proliferation ofhuman
    CD4 lymphocytes only whenpresented to human
    PBMC using the effectivemethods identified in
    these studies.
  • The methods are immobilisation by dryingonto
    plates, binding to endothelial cells andcapture
    by immobilised anti Fc-antibody.
  • Robin Thorpe showed this slide on the occasion of
    the Conference Bioanalysis in Clinical Trials
    2008


23
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
  • Unanticipated Serious Toxicity The TGN 1412
    Experience
  • In contrast to man, Cynomolgus macaques given
    TGN1412 at any of the doses tested did not
    experience any gross adverse reaction.
  • Cynomolgus macaque lymphocytes do not undergo
    proliferation when stimulated with immobilised
    TGN1412, unless IL-2 or immobilised anti-monkey
    CD3 is added to cultures(i.e., it acts like a
    conventional anti-CD28 mAB).
  • TGN1412 is superagonistic for human PBMC, but not
    for Macaque PBMC.
  • Robin Thorpe showed this slide on the occasion of
    the Conference Bioanalysis in Clinical Trials
    2008


24
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
  • Unanticipated Serious Toxicity The TGN 1412
    Experience
  • (some of the) lessons learned
  • Due to the novelty of the mechanism of action,
    there was insufficient knowledge about the
    validity of the preclinical testing procedures.
  • The preclinical tests that were actually
    performed prior to human experimentation were not
    able to predict the toxicity in humans.
  • Concerns should have been derived from
    TGN1412s mode of action, the nature of the
    target, and the insufficient knowledge about the
    relevance of animal species and models.


25
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
  • Section 4.4 of the EMEA Guideline Clinical
    Aspects
  • Key aspects of the trial should be designed to
    mitigate risk factors
  • Study population
  • Trial sites
  • First dose
  • Route and rate of aministration
  • Number of subjects per dose increment
  • Interval between dosing of subjects within the
    same cohort
  • Dose escalation increments
  • Transition to next dose cohort
  • Stopping rules
  • Allocations of responsibilities for decisions
    with respect to dosing


26
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
  • Subject for discussion
  • What should have been put more clearly in the
    EMEA Guideline?
  • The speakers personal opinion is the following
  • Clear recommendations concerning specific design
    features of first-in-human studies are missing,
    e.g., guidelines regarding group size, staggering
    of subgroups, dosing intervals, etc.
  • The Guidance should dare to mention the term
    high risk medicinal products.
  • Some mechanisms of actions or substance classes
    should be named which are per definitionem at
    high risk.
  • When is a frontrunner (Pilotproband)
    mandatory?
  • The Guideline should clearly name some
    proceedings which are forbidden.
  • A discussion on the interpretation of the NOAEL /
    MID may be helpfulNot only the dose, but also
    the quality of the observed events is
    important(e.g., target organ toxicity vs.
    unspecific side effects)


27
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
  • Further published EU Guidelines
  • Non-clinical aspects
  • 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 Repolarisation(QT Interval
    Prolongation) By Human Pharmaceuticals (ICH S7B),
    CPMP/ICH/423/02,
  • Safety Pharmacology Studies For Human
    Pharmaceuticals (ICHS7A), CPMP/ICH/539/00,
  • Toxicokinetics The Assessment Of Systemic
    Exposure In Toxicity Studies (ICH S3A),
    CPMP/ICH/384/95,
  • Position Paper On The Non-clinical Safety Studies
    To Support Clinical Trials With A Single
    Microdose (CPMP/SWP/2599/02).
  • Clinical aspects
  • Guideline For Good Clinical Practice (ICH E6),
    CPMP/ICH/135/95,
  • General Considerations For Clinical Trials (ICH
    E8), CPMP/ICH/291/95,
  • EUDRALEX Volume 10 Clinical Trials. In
    particular Chapter I Application and
    Application Form, and Chapter II Monitoring and
    Pharmacovigilance.


28
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
  • ICH Guideline E8, General Considerations for
    Clinical Trials
  • This is a very general guideline which is not
    intended to give special advice on how to deal
    with high-risk compounds.
  • However, that guideline may be helpful to
    optimize clinical trials designin light of the
    fact that it describes accepted principles in the
    conduct of clinical trials and overall
    development strategy.
  • The guideline integrates several aspects and
    gives many references to important ICH guidelines
    and topics.
  • It does also mention some special circumstances
    which are safety-relevant,
  • e.g. - appropriate timing of particular
    studies, - how to deal with cases of pregnancy
    during a clinical trial, - criteria of subject
    selection which are subject to the clinical phase.


29
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
  • Design features of First-in-Man Trials
    Prerequisites
  • Consider all preclinical data (pharmacology,
    toxicology, pharmacokinetics)
  • Make sure all required preclinical tests have
    been conducted(Note that additional preclinical
    investigations may be required prior to human
    experimentation, if certain critical issues were
    identified)
  • Properly identify the initial dose / Select
    adequate dose steps
  • Consider possible class effects
  • Identify possible high-risk substances, and, if
    necessary, take additional measures to minimize
    risk and take care of the subjects safety
  • ? Consider the novelty of the MOA, the nature of
    the target, and the extent of knowledge about
    the relevance and validity of the preclinical
    testing procedures.
  • ? Is the biological effect reversible?
  • ? Could a particular adverse effect be
    adequately monitored?
  • ? In case of an intoxication, would a causal
    treatment be available?


30
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
  • Estimating the maximum safe starting dose
  • FDA Guidance for Industry
  • Determine NOAELs mg/kg in toxicity studies in
    appropriate species,
  • Convert each animal NOAEL to Human Equivalent
    Dose (HED) based on body surface area,
  • Select lowest HED, or HED from most appropriate
    species,
  • Choose safety factor (normally 10),
  • Divide HED by that factor,
  • ? Maximum Recommended Starting Dose (MRSD)
  • Consider lowering the MRSD based on
    Pharmacologically Active Dose (PAD) (converted to
    HED, if it is from an in vivo study)


31
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
  • When should an increased safety factor (gt 10) be
    applied?
  • Steep dose-response curve
  • Severe toxicities
  • Nonmonitorable toxicity
  • Unexplained mortality in animal studies
  • Toxicities without advance warning
  • Irreversible toxicity
  • Variable bioavailability
  • Non-linear pharmacokinetics
  • Inadequate dose-response data
  • Novel targets
  • Animal models with limited relevance
  • Anything else?


32
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
  • The Minimal Anticipated Biological Effective Dose
    (MABEL)
  • The MABEL is the anticipated dose level leading
    to a minimal biologic effect in humans.
  • For high-risk compounds, the MABEL approach is
    recommended.
  • The following information should be considered
    (acc. to EMEA Guideline)- target binding and
    receptor occupancy studies in vitro in target
    cells from human and the relevant animal
    species,- concentration-response curves in vitro
    in target cells from human and the
    relevant animal species, and dose/exposure-respon
    se in vivo in the relevant animal
    species,- PK/PD modelling, whereever possible.
  • A safety factor may be applied for the
    calculation of the first dose in human from
    MABEL.
  • The safety factor should take into account
    criteria of risk.
  • When the methods of calculation (NOAEL, MABEL)
    give different estimations of the first dose in
    man, the lowest value should be used.


33
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
  • Design features of First-in-Man Trials
    Infrastructure
  • Sufficient and qualified staff must be available.
  • Technical equipment and remedies for the
    treatment of emergency situations must be
    available.
  • Physicians and study nurses must be trained in
    emergency procedures.
  • It is recommended that an anesthesiologist or a
    physician who has practical experience in the
    treatment of emergencies is available at the
    site.
  • The night following the day when study drug was
    administered, a physician should stay on the ward
    and be on duty next door to the volunteers.
  • A risk management plan must be available.
  • An emergency call system should be installed in
    the phase I unit.
  • The phase I unit should be located in reasonable
    proximity of a clinic with an intensive care
    unit.
  • Volunteers should never stay alone. Single rooms
    should be avoided.


34
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
  • Design features of First-in-Man Trials
    Infrastructure
  • Emergency equipment


35
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
  • Design features of First-in-Man Trials
    Infrastructure
  • Emergency call system


36
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
  • Insertion for discussion clinical environment
    of FIM trials
  • Far-reaching recommendations on the clinical
    environment for first-in-man studies are given in
    this report
  • Expert Scientific Group on Phase One Clinical
    Trials Final Report
  • Author Gordon W. Duff (chairman)
  • Publisher http//www.tsoshop.co.uk
  • This particular Expert Scientific Group was
    established following the very serious adverse
    reactions that occurred in the first-in-man
    clinical trial of TGN1412 in March 2006.
  • The Expert Scientific Group has set out 22
    recommendations that should increase the safety
    of volunteers in future clinical trials.
  • Published 6th December 2006
  • Extent ca. 700p.
  • ISBN 10 0117037222, 13 9780117037229
  • Price 125.00


37
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
  • Insertion for discussion clinical environment
    of FIM trials
  • Expert Scientific Group on Phase One Clinical
    Trials Final Report
  • Recommendation No. 20
  • First-in-man studies of higher risk medicines
    should always be conducted in an appropriate
    clinical environment supervised by staff with
    appropriate levels of training and expertise,
    with immediate access to facilities for the
    treatment and stabilisation in an acute
    emergency, and with pre-arranged contingency
    availability of ITU facilities in reasonable
    proximity.
  • At present, that maximum recommendation is not
    common practice.
  • Note that that recommendation does only refer to
    higher risk medicines,not to first-in-man trials
    in general.


38
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
  • Design features of First-in-Man Trials
    Study conduct (I)
  • 8 subjects per dose level 6 on active compound,
    2 on placebo
  • If an investigational compound belongs to a novel
    substance class, it may be advisable, or even
    mandatory, to treat no more than 4 subjects on
    the same day.
  • For the first cohort of the first dose group, the
    period of time between two subsequent
    administrations should not be shorter than 20
    minutes.When the drug is given p.o., an even
    longer distance may be appropriate taking into
    account the rate of absorption (tmax).
  • A full evaluation of the results of each dose
    group must be perfomed prior to proceeding to the
    next higher dose step
  • ? evaluation of safety and tolerability based on
    individual subject data listings and summary
    listings, if appropriate, and? evaluation of
    pharmacodynamic data or surrogates which may
    provide hints on clinical efficacy, and?
    evaluation of the plasma levels of the drug and
    relevant metabolites (on-line pharmacokinetics).


39
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
Flow Chart of an ascending-dose trial with
staggered subgroups (excerpt)
Date Dose Group 1 1st subgroup Dose Group 1 2nd subgroup Dose Group 2 1st subgroup Dose Group 2 2nd subgroup
01 Saturday
02 Sunday Admission (evening)
03 Monday Dosing of N4
04 Tuesday Admission (evening) Information of subjects Information of subjects
05 Wednesday Dosing of N4
06 Thursday Discharge Screening examination
07 Friday Start of bioanalytics
08 Saturday Discharge
09 Sunday
10 Monday Start of bioanalytics Screening examination
11 Tuesday
12 Wednesday
13 Thursday Results of Online PK available Results of Online PK available
14 Friday Dose Escalation Meeting (or TC) Dose Escalation Meeting (or TC)
15 Saturday
16 Sunday Admission (evening)
17 Monday Dosing of N4
18 Tuesday Admission (evening)
19 Wednesday Dosing of N4
20 Thursday Discharge
21 Friday Start of bioanalytics
22 Saturday Discharge
23 Sunday
24 Monday Start of bioanalytics

40
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
  • Design features of First-in-Man Trials
    Study conduct (II)
  • Allocation of responsibilities
  • The results of each dose cohort are discussed in
    a conference by
  • The Principal Investigator (Hauptprüfer, LKP
    acc. to 4 AMG),
  • Other Investigators who were present on the study
    day,
  • Other experts of the trial site, e.g., the
    pharmacokineticist (if applicable),
  • The sponsors experts, e.g., the sponsors
    responsible medical officer,the clinical trial
    monitor, the sponsors pharmacokineticist, etc.
  • The conference will come to a consensus
    conclusion which will be documented.
  • Note The ultimate medical responsibility for the
    subjects well-being is up to the investigator.
  • Interim results will be forwarded to the BfArM /
    EC, if
  • ... requested,
  • ... any alarming findings became apparent which
    may alter the formerly favourable risk-benefit
    assessment.


41
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
  • Design features of First-in-Man Trials
    Study conduct (III)
  • Stopping criteria
  • Stopping criteria should be pre-defined in the
    protocol.
  • It is important to differentiate the following
  • Individual stopping criteria (usually not
    applicable to SD studies)
  • Stopping criteria referring to progression to
    the next dose cohort
  • Stopping criteria referring to termination of
    the trial, even within a dose cohort
  • General stopping criteria should always be given
    in the protocol (such as more than 1/3 of
    subjects of a dose cohort experiencing
    drug-related SAEs ).
  • Specific stopping criteria are particular events
    that are given in the protocol based on the
    knowledge of non-clinical data or class effects.


42
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
  • Design features of First-in-Man Trials
    Study conduct (IV)
  • In special cases, it may be appropriate to dose
    only one (1) volunteer on a
  • particular study day Pilotproband,
    frontrunner
  • if the investigational drug is considered a
    high-risk drug
  • if a possible adverse effect, that could
    reasonably be expected by the drugs mechanism
    of action, may only become apparent with a delay
  • if any safety results of the ongoing study
    already give reasons for concern
  • if an alarming adverse effect observed in an
    animal toxicology study might not necessarily be
    species-specific, and if that effect, in case it
    occurred in humans,
  • might not be reversible, or, if a causal
    treatment was not available, or, if the AE
    could possibly be life-threatening.


43
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
  • Design features of multiple-dose (MD)
    First-in-Man Trials (I)
  • The design of the MD study should be based on the
    results of the SD trial.
  • If certain critical issues have been identified
    in the SD trial, additional monitoring procedures
    should be included as a consequence.
  • The number of dose groups is below the number of
    dose groups in theSD trial.
  • The number of subjects per dose level is usually
    higher as compared to theSD trial e.g., 12
    subjects per dose level 9 on active compound, 3
    on placebo.


44
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
  • Design features of multiple-dose (MD)
    First-in-Man Trials (II)
  • The highest dose level of the MD trial should be
    below the MTD identified inthe SD trial, taking
    into account the higher exposure in steady state.
  • The period of time between two subsequent
    administrations can be reduced,if sufficient
    information has been obtained from the SD study.
  • However, consider the risk of sensitization after
    repeated administration which might not have
    become obvious during the SD trial.
  • As always, a full evaluation of the results of
    each dose group must be perfomed prior to
    proceeding to the next higher dose step.


45
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
  • Discussion Combined Study Protocols (Food
    Effect SD MD)
  • PROs
    CONs
  • Combination offood effect and SD part Early
    investigation of food effect may
    be Methodological problems
  • useful to quantify a possible food Food effect
    cannot be investigated right at the
  • interaction which might affect subject
    safety. beginning acc. to a crossover design
    because
  • repeated administration would not be justified
  • Early identification of the recommended at that
    stage.
  • clinical treatment regimen is useful to mimick
  • the clinical setting in safety studies.
  • Combination ofSD part and MD part Sponsors may
    wish to combine the SD study The MD part contains
    a decision matrix and
  • and the MD study in one protocol to safe several
    dosing options.
  • some time. This does not improve clarity and
    transparence.
  • Safety procedures and timing of measurements
    may no longer be appropriate in light of the
    results
  • obtained in the SD study.
  • Any changes of the procedures in the MD part
    which are not reflected by the options given in
    the protocol would require submission of a
    protocol amendment.
  • The study as a whole (!) can only start when
    the tox data supporting the MD part are
    available.


46
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
  • Minimizing risk during clinical trials in healthy
    subjects
  • (Phase I programme, extended definition) some
    aspects
  • Make sure an adequate washout period has been
    observed since the subjects last trial
    participation. The use of a central volunteers
    data base is advisable.
  • Perform a drug screen and (in females) a
    pregnancy test at each admission to the study
    site.
  • Give due consideration to the use of adequate
    contraception methods.
  • Consider all available data and
    state-of-the-art study design ( efficient
    knowledge management). Seek advice of competent
    authorities, if needed.
  • If supra-therapeutic doses are requested for
    special studies by regulatory authorities,
    up-titration may be appropriate.
  • If a different galenical formulation will be
    administered during the programme via a different
    mode of administration, e.g., to test
    bioavailability, perform an adequately designed
    pilot study to investigate safety and
    tolerability.


47
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
  • Minimizing risk during clinical efficacy trials
    some aspects (I)
  • Consider possible differences in ADME between
    healthy subjects and (some) patients. Investigate
    the pharmacokinetics in patients with hepatic or
    renal impairment, if accumulation is to be
    expected. Adjust doses, if necessary.
  • Consider concomitant therapy. Conduct adequate
    DDI trials in healthy subjects.
  • A thorough dose-range-finding study should be
    conducted in clinical Phase II before a high
    number of patients will be exposed in large-scale
    trials.
  • The sample size should be appropriate for test
    and control groups. Bear in mind that the ratio
    active drug placebo does not necessarily need
    to be 11.


48
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
  • Minimizing risk during clinical efficacy trials
    some aspects (II)
  • Consider an active comparator to avoid putting
    the patients at risk due to lack of efficacy.
    Allow concomitant rescue medication use, if
    appropriate.
  • The sample size calculation of large-scale
    confirmatory trials (e.g., Ph.III) should be
    based on the results of exploratory trials (e.g.,
    Ph.II).
  • The sample size of a first clinical PoC-trial
    should be high enough to detect a clear signal
    and generate further hypotheses, however, a
    PoC-trial should not be powered like a
    confirmatory trial based on a desired product
    profile.


49
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
  • Summary of some points
  • Different risk categories exist.
  • Among other factors, risk depends on the
    knowledge that is already available.
  • Risk may vary during the clinical development
    programme.
  • In first-in-human trials, risk is mainly related
    to unanticipated toxicity.
  • The basic procedure to minimize risk is the
    permanent assurance of the standard quality of a
    clinical study or development programme
    adherence to ethical, legal and regulatory
    requirements, and state-of-the art trial
    design.
  • But there may be special demands of a particular
    study or development programme which must be
    identified by consideration of the background
    story, i.e., by thinking, and thorough review of
    the available data.
  • Identifying risk is not enough - Adequate
    measures must be taken.
  • In some ways, guidelines should be more precise
    (personal opinion).


50
Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
Regulatory authorities

Clinical investigational subjects
Investigator or Sponsor
unexpected toxicity ?
may harm the clinical investigational subjects
unexpected toxicity which may be predictable when
all hints are considered
H2O
may harm sponsors, investigators and regulators
Risk is derived from the early italian vocable
ris(i)co which denotes the cliff which must be
circumnavigated.
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