TIRS 2015 Day 4 Risk Assessment Harpur - American College of … 2015_Day 4_Risk... ·...
Transcript of TIRS 2015 Day 4 Risk Assessment Harpur - American College of … 2015_Day 4_Risk... ·...
Toxicology for Industrial and Regulatory Scientistsgy g y
Risk Assessment
Ernie Harpur PhD ATS FBTSErnie Harpur PhD ATS FBTSInstitute of Cellular Medicine
Newcastle UniversityNewcastle UniversityUK
Email: [email protected]
April 30th, 2015
Lecture Outline and Key MessagesLecture Outline and Key Messages
What is meant by Hazard, Risk, Risk (Safety) Evaluation and Risk Management in context of Drug Development?
(Acceptable) Risk versus Benefit? (Acceptable) Risk versus Benefit? Methodologies – what are the steps? It’s never too early to start and the process is continuous Plan ahead ground your safety plan in science monitor revise in the light Plan ahead, ground your safety plan in science, monitor, revise in the light
of new information,
It’s a team effort – each member (discipline) brings a different perspective – good communication is essential
Un-interpreted data are virtually worthless (except to raise alarm)
Mechanistic understanding can be extremely valuableg y All of the above underpins good decision making
Think ahead – The value of a study is only as good as its design
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Above all THINK
RA should be driven by science and logic and clearl and logic and clearly
communicated
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Key Message
Thinking ahead helps to avoid the unexpected
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Key MessagesKey Messages
If you don’t know where you are going, any path will take you there
Even if you do know your destination
h kyou have make good choices as to the route of getting hthere
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The best route is not necessarily theThe best route is not necessarily theThe best route is not necessarily the The best route is not necessarily the most obvious or directmost obvious or direct
A Few Definitions and Principles (1)
Hazard is the /id titsource/identity
of potential pharm
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A Few Definitions and Principles (2)
Risk is contextualcontextual
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A Few Definitions and Principles (3)
Risk is the probability (likelihood) that an adverse
outcome will occur in a person or group that is
exposed to a particular hazard. Mathematically,
the probability of harm lies between 0 and 1 but, inthe probability of harm lies between 0 and 1 but, in
reality, estimation of risk is at best semi-
quantitative limited by unknowns andquantitative, limited by unknowns and
uncertainties
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A Few Definitions and Principles (3)
Risk is the probability (likelihood) that an adverse
outcome will occur in a person or group that is
exposed to a particular hazard. Mathematically,
the probability of harm lies between 0 and 1 but, inthe probability of harm lies between 0 and 1 but, in
reality, estimation of risk is at best semi-
quantitative limited by unknowns andquantitative, limited by unknowns and
uncertainties
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A Few Definitions and Principles (4)
Risk assessment is the process used to estimate the likelihood that health will be affected adversely under alikelihood that health will be affected adversely under a specific set of conditionsRisk assessments are:Part science and part value judgmentp j gNever free of uncertainties and rely on Weight of EvidenceInherently conservativeUseful for decision-makingIterative as new data become informationIterative – as new data become information
Safety is the probability that harm will not occur under specified conditions; the state of being reasonably free from harm
1Safety α
Risk
conditions; the state of being reasonably free from harm
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Risk Management with objective of Risk MitigationRisk Mitigation
Process of identifying evaluating selectingProcess of identifying, evaluating, selecting, and implementing actions to reduce risk to human health and ecosystemsFocus on information derived from risk
assessment but, inevitably other factors -cultural, ethical, political, social, economic and technological - can play a role in the decision process
REMS = Risk Evaluation and Mitigation Strategy
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g gy
Nothing is totally safe There is always some risk* (concept of acceptable
risk – which is contextual)
Individuals have variable perception of risk and some are willing to engage in high risk activities (e.g. extreme sports, smoking)
However, where evaluation of the risk is in the hands of others, society has become intolerant of risk-taking, i.e. is risk averse
Risk assessment is not an exact science – industry and regulators often come to different conclusions based on evaluation of the same data
The regulators are the ultimate arbiters of what is acceptable risk
* Zero risk or 100% safety is not attainable
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Zero risk or 100% safety is not attainable
Degree of acceptable risk depends on a lot of things including potential benefitg p
Nature of the toxicological finding (genetic, carcinogenic reproductive etc) and extent to which it carcinogenic, reproductive etc) and extent to which it can be monitored
Nature of the disease being treated S lf li iti h i lif th t i Self-limiting vs chronic severe or life threatening
(e.g. cancer) Prevalence of disease and/or requiring unsupervised q g p
medication (e.g. asthma) Vulnerable populations (e.g. children) Presence of factors likely to enhance individual Presence of factors likely to enhance individual
variability (e.g. polymorphic metabolism) Unmet medical need vs availability of effective
t t t
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i.e. benefit/risk evaluationtreatments
Risk assessment (RA) ( )
Can be applied to almost any activity in lifeactivity in life.
Toxicologists are concerned mostly with chemical risks.
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Chemical risks of concern to T i l i t (1)Toxicologists (1)
(Where human exposure is unintended)(Where human exposure is unintended)
• Natural substances (e.g. fungal toxins) Industrial (e g solvents)Industrial (e g solvents) Industrial (e.g. solvents)Industrial (e.g. solvents)• Agro (e.g. pesticides - designed to kill selectively)• Food residues (e.g. growth promoters)• Food contaminants (e.g. from packaging materials)Environmental (e.g. ecological effects of manEnvironmental (e.g. ecological effects of man--made made
chemicals, including medicines)chemicals, including medicines)
Relevant in context of Drug DevelopmentRelevant in context of Drug Development
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gg
Chemical risks of concern to T i l i t (2)Toxicologists (2)
(Where human exposure is intentional)( p )
• Food additives (e.g. preservatives, colourants)• Chemical warfare agents• Chemical warfare agentsRecreational drugs (alternative use of alternative use of
therapeutic drugstherapeutic drugs or ‘designer’ drugs)MedicinesMedicinesMedicinesMedicines
Relevant in context of Drug DevelopmentRelevant in context of Drug Development
‘chemical’ = ‘compound’ = ‘molecule’ = ‘drug candidate’
drug/medicine
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g/
Small Molecules versus Biologicals
As you have heard there are many striking y y gdifferences in the approach to safety evaluation of potential Biotherapeutics (versus conventional small molecules) e gsmall molecules), e.g.Nature (and methods of evaluation) of the potential
hazardsEstimation of a safe starting dose in PhIThis talk focuses on Risk Assessment of small
molecules although some of the principles aremolecules, although some of the principles are also relevant to the special case of Biotherapeutics
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p
RA in Drug Development
RA in Drug Development has several facets, including:
• RA of occupational exposure during manufacture
• RA of alternative use (Drug Abuse LiabilityAssessment or DALA)
• RA f i t l i t• RA of environmental impact
This lecture is focused on: A t f th i k f d ff t i h t ki Assessment of the risk of adverse effects in humans taking new
medicines in clinical trials and for treatment of disease after marketing Includes risks associated with excipients, impurities, degradants as
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gwell as API (active pharmaceutical ingredient)
Is the key purpose of Pharmaceutical Toxicology
Key Components of RA
Hazard identification (inherent toxic t ti l)potential)
Hazard characterization (relationship to dose, exposure, metabolism, species differences, mechanism, reversibility etc)Evaluation of relevance for humans and
safety marginssa ety a g sMonitorability – biomarkers?
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Safety Evaluation of Medicines is aMulti Component ProcessMulti-Component Process
11 T t l tiT t l ti1.1. Target evaluationTarget evaluation
2.2. Hazard Identification andHazard Identification andCharacteri ationCharacteri ation
Predictive Predictive CharacterizationCharacterization
3.3. Evaluation of relevance for humansEvaluation of relevance for humansprocessprocess
4. Evaluation of risk versus benefit4. Evaluation of risk versus benefit-- concept of concept of acceptableacceptable riskriskpp pp
5. Clinical Safety Plan; Risk Mitigation Strategy5. Clinical Safety Plan; Risk Mitigation Strategy
6 Confirmation of safety through monitored6 Confirmation of safety through monitored
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6. Confirmation of safety through monitored 6. Confirmation of safety through monitored clinical useclinical use
RA is a continuum throughout Discovery g y
and Development
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Example of an Nonclinical Safety Program
Phase I/IIaLead Candidate
6 ‐10years
Preclinical Phase IIb Phase III Regul.
ProgramDISCOVERY DEVELOPMENT
Phase I/IIaIdentification Identification
Preclinical Phase IIb Phase IIIReview
GLP•Genetox Screening • Carcinogenicity• Pre‐ and Post‐Natal Tox•Non‐Standard Studies **
• Exploratory Safety Pharm• In vitro EmbryoTox Test
Internal decision Making
•Genetox Package• Safety Pharm Package
• Fertility Tox• Embryofetal Tox• Chronic Tox
GLPGLP•RF Tox
• Screening Repro Tox (if any)
* RF = Range‐Finding, • Safety Pharm Package• Short‐term Repeated‐dose Tox•RF Pregnant Rat / Rabbit *•Non‐Standard Studies **
•RF Carcinogenicity•Non‐Standard Studies **
g g,** Unplanned studies (e.g. safety
assessment of impurities, mechanistic studies)
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Internal and Regulatory decision Making
RA is a continuum throughout Discovery and Development (1)Development (1)
Prior to first administration to humans we can speak of Preclinical Risk AssessmentHowever, the context , “translation to humans”,
drives the processpBegins in Discovery with assessment of risks
inherent in the pharmacological targetContinues with selection of the candidate withContinues with selection of the candidate with
lowest risk (already a trade off with other properties associated with efficacy)Pre-clinical RA should incorporate all availablePre clinical RA should incorporate all available
information, including prior knowledge (any information on the pharmacological or chemical class available from the literature: this may include
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class available from the literature: this may include clinical information)
RA is a continuum throughout Discovery and Development (2)Development (2)
Risk assessment continuesRisk assessment continues throughout clinical development,
dd d f ll t j t itiaddressed formally at major transition points (key input to good decisions)It is the first step in the process of
developing a safety managementdeveloping a safety management programme with the objective of Risk Minimisation
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Minimisation
RA in Discovery and Development
Important always to think aheadImportant always to think aheadRemember the primary goal – to
mitigate riskmitigate risk Can influence timing Choice of model Study design – choice of endpoints (biomarkers) E er st d sho ld be seen as an Every study should be seen as an opportunity to generate information useful to decision making
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useful to decision making
Example of RA strategy in Discovery
Leadd ifi i
Candidated ifi i
Preclinical
DISCOVERY
Leadi i i
Target Identification IdentificationOptimizationSelection
•On‐target/Off‐target liability
•In silico analyses (other end points) •Genotoxicity Tier I (In silico +/‐ Ames II)•Cytotoxicity Tier I assaysC di l (i ili hERG)
•Genotoxicity Tier II (In silico, Ames II +/‐MNT vitro and follow‐up)
•Cytotoxicity Tier I assays (hepatocytes)
•Cardiovascular (in silico + hERG)
•Cytotoxicity Tier I assays (hepatocytes)•In vitro Embryotoxicity (or Zebra fish)•Cardiovascular (hERG, other ion channels if warranted)
•Toxicity Tier II functional assays (if warranted)
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•7 – 14 day exploratory rat study•Cardiovascular (in vitro + in vivo)•Repro tox screening (case‐by‐case)
Decision making can be aidedDecision making can be aided by a decision treey
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Genetox Evaluation and Decision Tree during Discovery: An Example
Discovery Phase Preclinical PhaseDevelopmentDecision
No structural alert:
y p
Standard battery of assays:•AMES• in vitro CA or MLA• in vivo MNT
AMES II
( + )
( ‐ )
GO( + )
( ‐ )
GOin vitro MNT
No structural alert: Do an Ames II for Development
Decision
Standard battery :• AMES( )
If no other compoundsIf other compounds
In silicofor prioritization
NO GOEvaluate other compounds ‐Chemical
• AMES• in vitro CA (notMLA)
in vivo MNT Additional studies:
• In vivo CA
Cautious Go with modified
( ‐ )
( + )
Exploratory In vivoMNT/CA
Structural alert: Do an Ames II
MNT = Micronucleus TestCA = Chromosome Aberration TestMLA = Mouse Lymphoma Test
NO GOOptimization • In vivo UDS
• Mechanistic studies: DNA interaction
Risk Assessment
FIHpackage
asap
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MLA = Mouse Lymphoma TestUDS = unscheduled DNA Synthesis FIH = First in Human
Embryofetal Tox Evaluation and Decision Tree during Discovery:An Example
Standard battery of studies:
Discovery Phase
( ‐ )In Vitro EmbryoTox1
Preclinical/clinical PhaseDevelopmentDecision
•EFT Rat / Rabbit ( + )
GOEmbryoTox
Is EFT a NoGo for the project?
If no other compoundsIf other compounds
yes NO
NO GOEvaluate other compounds If
Cautious Go with
( ‐ )
( + )
Exploratory EFT study in rodent Consider early EFT package
NO GO
compounds . If all positive,
perform in vivostudy with lead
Go with modified
FIHpackage
( + )
EFT: Embryofetal toxicityFIH = First In Human
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1 Oncologics and biologics should be evaluated on a case‐by‐case basis
The conduct of animal The conduct of animal studies is linked to the
phase of clinical studies is linked to the
phase of clinical pdevelopment
pdevelopment
Timely delivery of interpreted data from Timely delivery of interpreted data from animal studies is essential to enable rapid
clinical development
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pDependent on a reliable clinical plan
RESEARCH/DISCOVERYPRINCIPAL NON‐CLINICAL SAFETY STUDY
Selection ofdevelopment candidate
SAFETY STUDY REQUIREMENTS • Repeat dose tox: 14 days
• Genetic toxicity testing• Safety pharmacology candidate
(PRECLINICAL PHASE)
• Safety pharmacology
• Reproductive tox: fertility and embryo foetal development
First administration to humansPhase I
y p• Chronic tox; equivalent duration
• Reproductive tox: pre- and
DECISION POINTS IN CLINICALPhase IIa and IIb
postnatal development• Carcinogenicity studies
DECISION POINTS IN CLINICAL DEVELOPMENT (REGULATORY
HURDLES)
Phase IIa and IIb
Ph III
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Phase IIIMAMarketing Authorization
Relative importance of animal studies to Safety Evaluation
PRE‐
CLINICAL
CLINICAL
DEVELOPMENT
MARKETED
PRODUCT
PHASE IVPHASE I‐III PHASE IV
Human Use
( )
Relative Importance of Findings in Animal gStudies
( )
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First Administration to Humans
Approval to market
Risk Assessment is a Multidisciplinary Effort
RA used to be conducted prior to submission of an application for marketing authorisation Still a requirement (provision of REMS – Risk Evaluation and Mitigation Strategy)
Now recognised that this should begin much earlier -before FIH: evaluation of risk should drive the development and implementation of a Clinical Safetydevelopment and implementation of a Clinical Safety Plan Begins with determination of a safe starting dose and dose escalation strategy in
Ph I C i i h h i f f i i d i ll h f li i l Continues with choice of safety monitoring during all phases of clinical
development
Good communication is important as is mutual respect for individual roles and contributionsfor individual roles and contributionsToxicologists should be proactive in presenting
information (implies interpretation of the data) as early as possible but avoiding premature communication
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as possible but avoiding premature communication causing unnecessary alarm (a fine line)
Core of a Safety Evaluation ProgrammeConduct of a well defined
and standardised series of studies*
Rodent and Range of dose levels, Extensive range ofnon-rodent speciesappropriate routes of
administrationmeasurements
Definition of toxicity and estimation of safety ratios
Evaluation of risk for humans
* Does not preclude integration of additional science‐driven endpoints, for example to provide mechanistic insight or evaluate a biomarker
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for example to provide mechanistic insight or evaluate a biomarker
Study Design is KEY
Core Study Designs: Facilitate preparation of individual study protocols Help to ensure uniform standards Diminish the risk of non compliance with worldwide Diminish the risk of non-compliance with worldwide
regulatory requirements
B tBut
Should be modified to satisfy scientific needs
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Concept of Safety Ratio (based on Exposure)Concept of Safety Ratio (based on Exposure)Concept of Safety Ratio (based on Exposure) Concept of Safety Ratio (based on Exposure) is still at the core of a is still at the core of a
Quantitative Risk AssessmentQuantitative Risk AssessmentQua a e s ssess eQua a e s ssess e
S f R iExposure at NOAEL in most sensitive animal species
Safety Ratio =p p
Exposure in human at therapeutic dose
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Interpretation of Relevance of Findings
Extrapolation Across Species - Uncertainty FactorsFactors
HUMAN VARIABILITYSPECIES DIFFERENCES
Default UF =10 Default UF =10
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Helps determine what magnitude of Safety Ratio is acceptable
How can we improve the assessment ofHow can we improve the assessment ofHow can we improve the assessment of How can we improve the assessment of the risk of an adverse effect being the risk of an adverse effect being
manifest in humans?manifest in humans?manifest in humans?manifest in humans?
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We need to fully understand the nature of the toxic effect:-effect:-
characterise in detail characterise in detail
study the relationship to metabolism and plasma concentrationsplasma concentrations
are there species differences?
is the effect reversible?
h t th h i ? what are the mechanisms?
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Evolution of the ScientificEvolution of the ScientificEvolution of the ScientificEvolution of the Scientificand Regulatory and Regulatory Climate Climate ––
A t f M h iA t f M h i b db dAcceptance of MechanismAcceptance of Mechanism--based based decision Makingdecision Makingdecision Makingdecision Making
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In the Beginning In the Beginning -- Default Default Options in Options in RARAg gg g pp
Defined as the option chosen on the basis of Defined as the option chosen on the basis of l i tifi k l d d i k tl i tifi k l d d i k tgeneral scientific knowledge and risk assessment general scientific knowledge and risk assessment
policy that appears to be the best choice in the policy that appears to be the best choice in the absence of data to the contrary.absence of data to the contrary.absence of data to the contrary.absence of data to the contrary.
Example:Example: the assumption that humans are at least the assumption that humans are at least iti t t i ff t th t itiiti t t i ff t th t itias sensitive to toxic effects as the most sensitive as sensitive to toxic effects as the most sensitive
responding animal species.responding animal species.
Since default options are intentionally selected to be Since default options are intentionally selected to be conservative, they are more likely to overestimate conservative, they are more likely to overestimate
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than to underestimate risk to human health.than to underestimate risk to human health.
Science and Judgement in Risk AssessmentScience and Judgement in Risk Assessment
““As scientific knowledge increases, the science policy As scientific knowledge increases, the science policy choices made by the agency and Congress should choices made by the agency and Congress should have less impact on regulatory decisionhave less impact on regulatory decision--making.making.
Better data andBetter data and increased understanding of biological increased understanding of biological mechanismsmechanisms should enable risk assessments that are should enable risk assessments that are less dependent on conservative default assumptionsless dependent on conservative default assumptionsless dependent on conservative default assumptions less dependent on conservative default assumptions and more accurate as predictions of human risk.”and more accurate as predictions of human risk.”
1994 R t* f itt f th N ti l A d f1994 R t* f itt f th N ti l A d f1994 Report* of a committee of the National Academy of 1994 Report* of a committee of the National Academy of Sciences/National Research Council (Requested by US EPA)Sciences/National Research Council (Requested by US EPA)
*Risk Assessment of Hazardous Air Pollutants*Risk Assessment of Hazardous Air Pollutants
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The Essential Value of Understanding The Essential Value of Understanding Mechanisms is not aMechanisms is not a recentrecent conceptconceptMechanisms is not a Mechanisms is not a recent recent conceptconcept
“Only if mechanisms are understood is it possible to “Only if mechanisms are understood is it possible to extrapolate toxicity measurements across species extrapolate toxicity measurements across species and from the large doses used in experimental and from the large doses used in experimental animals to the exposures experienced by man.”animals to the exposures experienced by man.”
* From the conclusions of Study Group Report: Long* From the conclusions of Study Group Report: Long--term term Toxic Effects. The Royal SocietyToxic Effects. The Royal Society (1978)(1978)
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Benefit of Mechanistic Information inDrug DevelopmentDrug Development
Retrospective Review of 17 Compounds Withdrawn from DevelopmentRetrospective Review of 17 Compounds Withdrawn from Development
Factors confirming the decision to terminate development in 13 casesFactors confirming the decision to terminate development in 13 casesFactors confirming the decision to terminate development in 13 casesFactors confirming the decision to terminate development in 13 cases
1.1. No, or very low, safety margin (Tox Dose/Ther Dose)No, or very low, safety margin (Tox Dose/Ther Dose)
2.2. Lack of understanding of the mechanism of toxicity or its relevance for Lack of understanding of the mechanism of toxicity or its relevance for manman
3.3. Clear indication the lesion has relevance for manClear indication the lesion has relevance for man
Decision to terminate development questioned in 4 casesDecision to terminate development questioned in 4 casesDecision to terminate development questioned in 4 casesDecision to terminate development questioned in 4 cases
Knowledge, current at the time of retrospective review, (i.e. a better Knowledge, current at the time of retrospective review, (i.e. a better understanding of the lesion) might have led to a decision to continue understanding of the lesion) might have led to a decision to continue development if available at the time.development if available at the time.
R. Brimblecombe (1990) The Importance of Retrospective Comparisons. In: AnimalR. Brimblecombe (1990) The Importance of Retrospective Comparisons. In: AnimalToxicity Studies: Their Relevance for Man Proceedings of a CMR SymposiumToxicity Studies: Their Relevance for Man Proceedings of a CMR Symposium
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Toxicity Studies: Their Relevance for Man. Proceedings of a CMR Symposium.Toxicity Studies: Their Relevance for Man. Proceedings of a CMR Symposium.
MechanismMechanism--based risk Assessment of Chemicalsbased risk Assessment of Chemicals
Rapid development and application of the science Rapid development and application of the science of using mechanistic data in chemical risk of using mechanistic data in chemical risk assessment in recent yearsassessment in recent years
Growing consensus in the scientific/regulatory Growing consensus in the scientific/regulatory community of the value of incorporating community of the value of incorporating mechanistic data into risk assessmentsmechanistic data into risk assessmentsmechanistic data into risk assessmentsmechanistic data into risk assessments
Regulatory acceptance has been demonstratedRegulatory acceptance has been demonstrated(e g(e g globulin)globulin)(e.g. (e.g. 2u2u--globulin)globulin)
Emphasis has been on assessment of Emphasis has been on assessment of i i i ki i i k
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carcinogenic riskcarcinogenic risk
What is Meant by the Study of Mechanisms?
In In the context of drug developmentthe context of drug development
Understanding enough of theUnderstanding enough of the mechanism (or mode)mechanism (or mode) ofof Understanding enough of the Understanding enough of the mechanism (or mode) mechanism (or mode) of of toxic action to explain or predict species differences toxic action to explain or predict species differences and confidently assess the risk for humans.and confidently assess the risk for humans.
Our understanding is never complete.Our understanding is never complete.
Reliance on “weight of evidence”Reliance on “weight of evidence”
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Risk Assessment – The pieces of the Jigsaw Puzzle
NOAEL andNOAEL and
ConcentrationConcentrationresponseresponsel ti hil ti hi
Adverse effectAdverse effectin animals and/orin animals and/or
safety marginsafety margin relationshipsrelationshipsin animals and/orin animals and/orhumanshumans
AnatomicalAnatomicaland clinicaland clinical
Past experiencePast experiencewith relatedwith related and clinicaland clinical
pathologypathologywith relatedwith relatedcompoundscompounds
SeriousnessSeriousnessand/orand/or
reversibility ofreversibility ofeffecteffect Availability ofAvailability ofSpeciesSpecies
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effecteffect Availability ofAvailability ofbiomarkerbiomarker
SpeciesSpeciesdifferences in effectdifferences in effect
Mechanistic data can, on occasion, help complete the puzzle
d
Concentrationresponse
Adverse effectin animals
NOAEL andsafety margin
responserelationships
a a sand/or humans
MECHANISMSPast experiencewith relatedcompounds
Anatomicaland clinicalpathology
SpeciesSeriousness
and/or Availability of
compounds p gy
Speciesdifferences
and/orreversibility of
effect
Availability ofbiomarker
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Mechanisms
Timecourse of Species difference inTimecourse ofpathogenesis
Reversibility
Species difference inanatomy, physiology
and biochemistry
Exposure and
M l l
Biochemicaleffects
ppharmacokinetics
Induction/inhibitionof cyt P450’s
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MolecularTarget
Metabolism/Chemical reactivity
The Incorporation of Mechanistic Information in the RiskThe Incorporation of Mechanistic Information in the RiskAssessment Process in Drug DevelopmentAssessment Process in Drug Developmentg pg p
Adverse effect detected inanimal or clinical study
Characterize lesion asfully as possible Significance is
adequatelyd t d
Significance isuncertain
Relate to Metabolismand/or Exposure
understood
Propose mechanistichypothesis
Draw on existing
knowledge(lit t )
Understand mechanism anddefine species differences
ASSESS RISKFOR HUMANS
(literature)
Conduct studies totest hypothesis define species differences FOR HUMANStest hypothesis
Results
Revisehypothesis
Stop Development Risk Acceptable?YES
NO
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ResultsInconsistent
with hypothesis
Identify newlead candidate orredesign molecule
ContinueDevelopment
YES
Mechanistic Understanding and Human RiskMechanistic Understanding and Human RiskAssessmentAssessmentAssessmentAssessment
What constitutes adequate evidence to support a What constitutes adequate evidence to support a mechanistic hypothesis must be decided on a case-by-case basis and changes with time.
Thus, existing knowledge and experience with other compounds can be valuable in formulating a p gmechanistic hypothesis and in human risk assessment.
Ultimately good clinical studies (guided by mechanistic Ultimately good clinical studies (guided by mechanistic understanding) are required to demonstrate that relevant toxic changes do not occur in patients.
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Example of the use of Example of the use of M h i ti D t t tM h i ti D t t tMechanistic Data to support Mechanistic Data to support
Risk Evaluation in Clinical Risk Evaluation in Clinical DevelopmentDevelopment
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Example : Compound XExample : Compound X
Animal findings pointed to a serious pathologyAnimal findings pointed to a serious pathology with potential relevance for humansClinical studies on holdNeeded information to provide confidence that
the risk for humans was lowCharacterization of the mechanism provided
reassuring data that humans would be much less vulnerable than animals AND a relevantless vulnerable than animals AND a relevant (mechanism-based) biomarker
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Toxicology FindingsToxicology Findings
Time- and dose-dependent pathology in the rat and, to a much lesser extent, the monkey:visceral lesions comprising multi-organ infiltration of
macrophages ith characteristicall distended c toplasmmacrophages with characteristically distended cytoplasm
brain lesions - degenerative and reactive changes including PAS positive inclusions in neurons, gliosis, infiltration with microglial cells and (rat only) perivascular PAS positive enlarged macrophages
P th l i t k d bl tPathologist remarked resemblance to pathology of Gaucher’s disease.
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Gaucher’s diseaseGaucher’s disease
Lipid storage disease - sphingolipidosis - caused by deficiency of the enzyme glucosylceramidase
Deficiency leads to accumulation of substrate - Deficiency leads to accumulation of substrate glucosylceramide - in macrophages of the RE system, primarily liver, spleen and bone marrow
CNS involvement in some cases (Gaucher types II & III); lesions in the brain attributed to accumulation of glucosylsphingosine, a cytotoxic substrate
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Hypothetical Biochemical Mechanism of Hypothetical Biochemical Mechanism of ToxicityToxicity
Glycosphingolipid Ceramide Sphingosine
ToxicityToxicity
Glycosphingolipid Ceramide Sphingosinecatabolism
Glucosylceramide Glucosylsphingosine
GlucosylceramidaseCpd X Cpd XCeramide Sphingosine
Cpd Cpd X
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Glucosylceramidase (GCase) InhibitionGlucosylceramidase (GCase) Inhibition
Confirmed that administration of Cpd X caused inhibition of GCase in rat and monkey Evident after a single dose up to 80 90% depending on Evident after a single dose - up to 80-90% depending on
dose, tissue and species Maintained during chronic administration Reversible within 1 month Reversible within ~1 month Seen in all animal species tested (rat, mouse, hamster,
dog, monkey); some differences in magnitude and dose responsedose-response
Slide 58ACT—Toxicology for Industrial Regulatory Scientists
GCase Inhibition and Lesions in Rat BrainGCase Inhibition and Lesions in Rat Brain
100%250
150
200tiv
ityo
tein
/hr)
33%100
150
Sp
ecifi
c A
co
se/m
g p
ro
23% 22% 19% 19%50
Mea
n S
nm
ol g
luco
00 0.3 1 3 10 30
(
Brain lesions - - - - + ++Cpd x (mg/kg/day)
Slide 59ACT—Toxicology for Industrial Regulatory Scientists
Brain lesions + ++
Modified Hypothesis for Mechanism of ToxicityModified Hypothesis for Mechanism of Toxicity
Glucosylceramidase inhibition Substrate accumulation Lesions
glucosylceramidase inhibition - does not cause toxicity per se but is the essential first step
hi h t i itwhich triggers it.
substrate accumulation - gradual process, d di id l GC ti itdepending on residual GCase activity, synthesis rates etc.
l i d l h “ iti l l l” f lesions - develop when “critical level” of substrate is reached - glucosylceramide in viscera, glucosylsphingosine in brain.
Slide 60ACT—Toxicology for Industrial Regulatory Scientists
Brain Lesions and Brain GS in RatBrain Lesions and Brain GS in Rat
600
400
500
phin
gosin
e ul
atio
nnt
rols)
200
300
Gluc
osyls
pac
cum
u(%
Con
0
100
0 0.3 1 3 10 30
Brain lesions - - - - + ++Cpd x (mg/kg/day)
Slide 61ACT—Toxicology for Industrial Regulatory Scientists
Implications for HumansImplications for Humans
Are humans likely to be a susceptible species?role of metabolism in inhibition
andandinter-species differences in
metabolismmetabolism…..
Slide 62ACT—Toxicology for Industrial Regulatory Scientists
Metabolism and GCase InhibitionMetabolism and GCase Inhibition
Cpd X undergoes extensive metabolism
Inhibition of GCase requires metabolism demonstrated usingdemonstrated usingliver microsomes +/- NADPHcultured hepatocytes +/- inhibitor of Cpd X metabolism
Which metabolite is responsible for inhibition? Are there species differences i it f ti ?in its formation?
Slide 63ACT—Toxicology for Industrial Regulatory Scientists
Identification of Cpd X Metabolite Involved in Identification of Cpd X Metabolite Involved in Glucosylceramidase InhibitionGlucosylceramidase InhibitionGlucosylceramidase InhibitionGlucosylceramidase Inhibition
NCF3
SR57746 OH
OH
OH
OH
O
RCpd X
NCF3
Conduritol B-Epoxide
Potent and specific inhibitor of glucosylceramidase
OH
RIntermediary
Epoxide
N
O
R
NCF3
OH
NCF3 OH
OH
OHTetrol Derivative(s)
NCF3
OH
OR R R
Dihydrodiol Derivative Intermediaryepoxide
Slide 64ACT—Toxicology for Industrial Regulatory Scientists
OHOH OH
OHOHOH
epoxide
Glucosylceramidase Inhibition by Cpd X and Glucosylceramidase Inhibition by Cpd X and Pro imal Metabolite in Hepatic MicrosomesPro imal Metabolite in Hepatic MicrosomesProximal Metabolite in Hepatic MicrosomesProximal Metabolite in Hepatic Microsomes
d 1 Dihydrodiol2IC50 (µM)
Cpd X1 DihydrodiolMetabolite
S-D Rat > 30 3.8
Monkey > 30 19.7
Human > 30 92.3
1 Highest conc. Tested = 30M
2 Hi h t T t d 100M
Slide 65ACT—Toxicology for Industrial Regulatory Scientists
2 Highest conc. Tested = 100M
Inter-species variability in metabolic pathways
Cpd XDihydrodiolmetabolite Dihydrodiol
epoxideepoxide
SpragueSprague--Dawley Dawley RatRat
Glucuronide
MonkeyMonkeyGlucuronide
Inactive metabolite
HumanHumanGlucuronide
Inactive metabolite
Slide 66ACT—Toxicology for Industrial Regulatory Scientists
Glucuronide
Inhibition of GCase by Cpd X in Cultured Inhibition of GCase by Cpd X in Cultured HepatocytesHepatocytes
Human
HepatocytesHepatocytes
80
100
ITY
ntro
l)
Monkey
60
AC
TIV
Ive
to C
on
20
40
GC
ase
(Rel
ativ
Sprague-Dawley Rat
0
20
0.001 0.01 0.1 1 10 100
Slide 67ACT—Toxicology for Industrial Regulatory Scientists
Cpd X(µM)
Conclusion on Mechanism
Proposed Gaucher mechanism of toxicity strongly p y g ysupported by substrate accumulation studies in brain (and liver)
Inhibition of GCase is the essential first step for lesion developmentGCase activity is a mechanistically relevant biomarker
Measure in clinical trials to assess human susceptibility
Lymphocytes present an accessible and relevant tissueLymphocytes present an accessible and relevant tissue
No inhibition of GCase in patients in clinical trials
Slide 68ACT—Toxicology for Industrial Regulatory Scientists
Human Lymphocyte Human Lymphocyte
10
GlucosylceramidaseGlucosylceramidase
789
10
ctiv
ity
Placebo (n=11)
1 mg SR57746A (n=8)Cpd X
3456
mid
ase
Ac
/mg/
hr) 2mg SR57746A (n=11)Cpd X
-1012
cosy
lcer
am(n
mol
/
-3-2
Glu
c
Change from Baseline (6 months)
Slide 69ACT—Toxicology for Industrial Regulatory Scientists
Benefits of the Application Benefits of the Application of Mechanistic of Mechanistic Toxicology inToxicology in Drug DevelopmentDrug DevelopmentToxicology in Toxicology in Drug DevelopmentDrug Development
Continued development of molecules Reassurance of safety through increased understanding of i ifi f l i b i f i diff isignificance of lesions, basis of species differences in response
etc……………or
Earlier, informed decision to terminate development of
Improved choice of drug candidates Mechanism based models (in vitro/in vivo) of target organ toxicity
molecules which exhibit significant toxicity of relevanceto humans
Mechanism based models (in vitro/in vivo) of target organ toxicityfor rapid screening
Enhanced design of molecules Improved basis for SAR and molecular design
Enhanced design of clinical protocols (e.g. availability of relevant biomarkers)
Slide 70ACT—Toxicology for Industrial Regulatory Scientists
of relevant biomarkers) Improved quality of regulatory submissions
IMPROVING RISK ASSESSMENT FOR HUMANSIMPROVING RISK ASSESSMENT FOR HUMANS
Looking to the future
Slide 71ACT—Toxicology for Industrial Regulatory Scientists
Scientific Approach to Risk Assessment –Back to the FutureBack to the Future
SAFETYSEVALUATION
• Rational process
• Apply good science
• Scientific logic is paramount
• Challenge the conventional
Extend knowledge
• Challenge the conventional
IMPROVING RISKASSESSMENT FOR
MAN
of mechanisms
Exploit innovativetechniques
Slide 72ACT—Toxicology for Industrial Regulatory Scientists
MANTrain and develop toxicologists
The future is here – to the extent that iwe want to use it
Incorporate innovative approaches that capitalize upon novel technologies and approaches
T i t i t i t b l i Transcriptomics, proteomics, metabolomics High content screening Pathway analysisy y Predictive computational models Novel cell types and Transgenic animals Non in asi e imaging Non-invasive imaging Novel biomarkers
Slide 73ACT—Toxicology for Industrial Regulatory Scientists
Additional Reading
Reviews
Pritchard, JF et al (2003) Making better Drugs: Decision gates in Non-Clinical Drug Development. Nat Rev Drug Disc, 2, 542-553
Guth, BD (2007) Preclinical Cardiovascular Risk Assessment in modern Drug Development. Tox Sci, 97, 4-20
Kramer, JA et al (2007) The Application of Discovery Toxicology and Pathology towards the Design of safer Pharmaceutical Lead Candidates Nat Rev Drugtowards the Design of safer Pharmaceutical Lead Candidates. Nat Rev Drug Disc, 6, 636-649
Stevens, JL and Baker, TK (2009) The Future of Drug Safety Testing: Expanding the View and Narrowing the Focus. Drug Discovery Today, 14, 162-167.
Merlot, C (2010) Computational Toxicology – a Tool for early Safety Evaluation. Drug Discovery Today, 15, 16-22.
Slide 74ACT—Toxicology for Industrial Regulatory Scientists
Additional Reading
Application of genomics in drug safety assessment
MacGregor, JT (2003) The Future of Regulatory Toxicology: Impact of the g ( ) g y gy pBiotechnology Revolution. Tox Sci, 75,236-248
Cohen, S (2004) Risk Assessment in the Genomic Era. Tox Path, 32(Suppl. 1), 3-8
Mayne, JT et al (2006) Informed Toxicity Assessment in Drug Discovery: Systems-based Toxicology. Curr Opin Drug Disc Dev, 9, 75-83
Ryan, TP et al (2008) Strategic Applications of Toxicogenomics in early Drug Discovery. Curr Opin Pharmacol, 8, 654-660
Slide 75ACT—Toxicology for Industrial Regulatory Scientists
Additional Reading
The use of mechanistic information
Stevens, JL (2006) Future of Toxicology – Mechanisms of Toxicity and Drug Safety: Where do we go from here? Chem Res Tox, 19, 1393-1401
Guengerich FP (2011) Mechanisms of Drug Toxicity and Relevance toGuengerich, FP (2011) Mechanisms of Drug Toxicity and Relevance to Pharmaceutical development. Drug Metab Pharmacokinet, 26, 3-14
Toxicity Testing in the 21st CenturyToxicity Testing in the 21 Century
MacDonald, JS and Robertson, RT (2009) Toxicity Testing in the 21st Century: A View from the Pharmaceutical Industry. Tox Sci, 110, 40-46
Throckmorton, DC (2009) Regulatory Perspective on the Integration of Preclinical and Clinical Safety Data. Presentation at HESI meeting. http://www.hesiglobal.org/files/public/Of%20Interest/ILSIHESI2009Throckmorton.pdf
Slide 76ACT—Toxicology for Industrial Regulatory Scientists
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