Title: Folie%201
1Minimizing 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
2Minimizing 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
3Minimizing 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)
4Minimizing 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
5Minimizing 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
6Minimizing 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 !
7Minimizing 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
8Minimizing 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
9Minimizing 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
10Minimising 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
11Minimizing 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.
12Minimizing 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
13Minimizing 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
14Minimizing 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
15Minimizing 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).
16Minimizing 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
17Minimizing 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
18Minimizing 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.
19Minimizing 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.
20Minimizing 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)
21Minimizing 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
22Minimizing 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
23Minimizing 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
24Minimizing 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.
25Minimizing 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
26Minimizing 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)
27Minimizing 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.
28Minimizing 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.
29Minimizing 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?
30Minimizing 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)
31Minimizing 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?
32Minimizing 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.
33Minimizing 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.
34Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
- Design features of First-in-Man Trials
Infrastructure - Emergency equipment
35Minimizing risk by optimizing clinical trial
design AGAH Workshop 19 April 2008
- Design features of First-in-Man Trials
Infrastructure - Emergency call system
36Minimizing 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
37Minimizing 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.
38Minimizing 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).
39Minimizing 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
40Minimizing 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.
41Minimizing 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.
42Minimizing 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.
43Minimizing 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.
44Minimizing 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.
45Minimizing 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.
46Minimizing 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.
47Minimizing 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.
48Minimizing 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.
49Minimizing 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).
50Minimizing 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.