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Why, how, and when to think about safety assessment during drug
development
Donna Lee, PhD, DABT Safety Assessment UCSC April 29th, 2014
© 2008, Genentech
• Why we care about toxicology: A brief history and the origin of our current approaches
• Key drivers of the nonclinical toxicology evaluation strategy
• Differences between small and large molecules that impact toxicology evaluations
• How toxicity data is used in decision-making at all stages of drug discovery and development
Today’s Agenda
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Applications of Toxicology
Environmental: impact of pollutants on environment/
ecosystems
Food: safety of addi5ves, freedom from contaminants
Clinical: treatment of poisoning in humans
Occupa4onal: Workplace exposure hazards
Agricultural: effects of pes5cides, fer5lizers on
workers
Forensic: legal applica5ons eg. iden5fica5on of chemical causing death/injury or property damage
Pharmaceu4cal: effects of drugs on
pa5ents
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How History Has Influenced Toxicology
• How do xenobiotics interact with living systems and impact normal function?
• What exposure levels are safe?
Science of Toxicology: the study of the adverse effects of xenobiotics (chemicals, drugs, poisons, etc.)
“All things are poison and nothing is without poison, only the dose permits something not to be poisonous”
Paracelsus (1493-1541)
Or, there is no such thing as a totally safe drug
Understanding this “Dose-Effect Relationship” forms the philosophical basis for all toxicity evaluations
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§ Current US regulatory framework for pharmaceutical drug evaluation is based on 1938 and 1962 laws; ~70 years old:
– Pre-marketing demonstration of safety
– Substantial evidence required of drug efficacy
§ We have a responsibility to patients and to global regulatory agencies to ensure that the drugs we intend for human use are safe
§ Toxicology evaluations can also help to advance our understanding of the biology of the molecule
How History Has Influenced Toxicology
Elixir Sulfanilamide
Poisoning in 1938
Thalidomide Birth Defects In 1962
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What is the End Game for Toxicology Evaluations?
What Are Examples of Major “Focus Areas” for Nonclinical Toxicology? " Do Not Want to Treat for One Disease and Cause Another
§ i.e. severe or irreversible changes to normal organ function of a non-intended target
" Do Not Want to Cause Cancer
" Do Not Want to Cause Birth Defects, Fetal Deaths or alter Ability to have Children
Our Goal:
• Identify a drug with an acceptable safety profile in humans that is appropriate for the intended population (e.g. therapeutic indication)
How Does Nonclinical Toxicology Enable this Goal? • Identify hazards → Characterize potential risks to humans (translation of nonclinical studies) • Guide clinical trial design
§ Starting Dose § Dosing Duration § Monitoring § Use in Special Populations (WOCBP and Pediatrics) § Inform the Label
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“On-Target” aka ‘exaggerated pharmacology’ = the undesired effect is due to pharmacological engagement of the intended molecular target “Off-Target” = the undesired effect is due to pharmacological engagement of an unintended molecular target Off-Target toxicity of large molecules is due largely to:
– Cross-reactivity with non-target proteins (generally rare!) – Occasional concerns over excipients in formulation
Off-Target toxicity of small molecules is due largely to: – Physical attributes: molecular weight, pH, acid-ionization constant (pKa),
solubility, boiling & melting points, lipophilicity (cLogP)
– Structural attributes: chemical interactions (e.g. thiophenes, anilines, basic amines, & acids)
– Processing and Elimination (ADME): tissue or cellular accumulation, generation of reactive metabolites, excipients required for oral absorption
On-Target Versus Off-Target Toxicity
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Toxicology Supports the Entire Drug Development Cycle Slide 8 5/5/14
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There is Extensive Safety Testing of New Drugs before and During Clinical Trials in Humans: Timing is Important!
IND Filing
Ph I start Ph II Ph III NDA Filing Post
Approval
FIH Non-GLP Lead
Optimization of lead or BU:
On-target & Off-target effects
LSR ED GO ESR
In vitro and In vivo Investigational or exploratory studies
Non-GLP rodent and non-rodent
pilot dose ranging studiess
GLP repeat dose
(Duration & Dose to
Support Phase 1)
Genotoxicity*
GLP Safety Pharmacology assessments
(hERG IC50), in vivo telemetry, etc
Reprotox (teratogenicity, fertililty, postnatal)*
Subchronic Dosing
(eg 3 mos)*
Chronic Dosing
(eg 6+ mos)
Carcinogenicity
Impurity Qualification (as part of other studies)
Special Studies:
Immunotox
Phototoxicity
Animal Studies Must Precede Human Dosing
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How Do Safety Scientists Approach Non-Clinical Safety Assessment?
Identification of Potential Hazards
Assessment of Translatable Risk to Humans
Weighing of the Risk to Benefit
Use of Non-Clinical Surrogate Models (in silico, in vitro, in vivo)
Building Weight-of-Evidence: data, experience, knowledge
• Type of Toxicity (Severity, Monitorability, Reversibility) • Degree of Unmet Medical Need (competition) • Therapeutic Indication • Target Population • Length of Treatment
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How Do We Typically Use Our Models to Build WOE?
We interpret the data from these model to use for rational decision-making
A Great Place to Work
In vivo studies
Investigation or Characterization Using in vitro/ex vivo/ in vivo models
Verify with In vivo studies
Advance with characterized risk
Stop Inform Back Up
Develop counter screen
±
Rank Scaffolds Select Lead
In vitro In silico modeling
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Drug Development Heavily Regulated through HA Guidelines
Preclinical Models Limitations
ü All models are imperfect ü Safety models tend to be biased toward conservatism ü Some models predict clinical
outcomes better than others
Despite all of the caveats: § Animal tox profiles are most physiologically relevant and required by Health Authorities (i.e. FDA, EMEA) to approve clinical programs § Other models (in silico, in vitro) are used for internal decision-making and WOE building
*3R’s = Reduce, Refine, Replace
Regulatory guidances establish requirements for hazard identification and risk assessment
In silico
In vitro In vivo
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ICH S6 and S6(R1): Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals (1997, 2011)
Slide 13 5/5/14
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ICH S9: Nonclinical Evaluation for Anti-Cancer Pharmaceuticals (EU 2009, US 2010)
Slide 14 5/5/14
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Regulatory Requirements of Non-clinical Safety Assessment
Identify and evaluate potential risks to humans – Target organs, dose-response relationship, and mechanism of toxicity
• Related to molecular entity, mechanism of action, target expression? • Expected and/or manageable versus unexpected or unmonitorable toxicity? • Species specific?
Guide clinical study plans – Safe first dose in humans: Clinical starting dose and dosing duration
• Acute/Subchronic toxicity • Safety Pharmacology (CNS, cardiovascular, respiratory systems) • Identify appropriate safety margin • A larger therapeutic index/safety margin over the clinical target dose enables
greater flexibility in the clinical development plan
– Possible biomarkers of toxicity
– Support later stages of clinical development to licensure • Identify concerns with special populations (e.g. reproductive toxicity) • Chronic toxicity, carcinogenicity if applicable
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Comparative Nonclinical Study Requirements (LT versus Non-LT)
ICH S9 (SM & LM) ICH M3 SM ICH M3 LM IND-enabling Repeat Dose Studies
~1 month supports P1 & P2
~1 month supports P1 ~1-3 mos supports P1
Chronic Repeat Dose Studies
3 mos. Supports P3 and NDA
6 mos (rodent) 9 mos (nonR) supports P3 and NDA
6 mos (1 species) supports P3 and NDA
Safety Pharmacology Studies
CV Studies; Endpts in RD studies
CV studies; endpts in RD studies; Respiratory; Neuro
No dedicated studies unless warranted
Genotoxicity Studies Needed for NDA Needed for P1 Not warranted
Carcinogenicity Studies
Not warranted 2 species for NDA May be warranted
Reproductive Toxicology Studies
Embryo-Fetal for NDA Embryo-Fetal (WOCBP, P2); Fertility; Peri-Post Natal for NDA
Embryo-Fetal (P3) Peri-Post Natal for NDA
Special Studies Impurities (limits) Phototox for P3 Local Tolerance (LM)
Impurities: (Limits and GTI) Phototox (P1)
Impurities Local Tolerance
Important differences
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How Are Tox Species Chosen?
• Default is 1 Rodent (Rat/Mouse) and 1 Non-rodent (Dog/Monkey)
• Major considerations for species selection:
§ Pharmacological target activity and tissue distribution similar to human (at least 1 species)
§ Metabolic Profile Similar to Humans (small molecules only)
§ Acceptable exposure to enable testing a wide safety range (e.g. exposure multiples)
• Regulatory authorities may also require toxicity evaluation in a model of disease/activity
§ Toxicity profile can differ substantially between animal models (target expression level, pattern, strain differences)
§ In these cases, efficacy/PK studies can be utilized to help identify tox liabilities and select appropriate models for future studies
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The dose makes the poison
• Typically, substances become more toxic with increasing dose
• Most toxicology studies
examine effects over a range of doses: – Is there an effect threshold,
and if so what is it? – What does the dose-
response curve look like? – Are different systems
impacted at different dose levels?
DE Johnson, Expert Rev. Clin. Pharmacol. 3: 231-242, 2010
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Slide 19 5/5/14 Large versus Small Molecules
Points to Consider Large Molecules Small Molecules
Species Selection 1 or 2 species 2 species
Toxicity
On- target Typically exaggerated pharmacology
On- and off-target Typically more toxicity expected; due to lack of specificity and metabolism Receptor profiling, in vitro genotoxicity screening, in vitro cardiotoxicity screening, lead optimization tox screening
Drug Product Simple Non-toxic Formulations Complex Formulations –
Excipient toxicity is of concern
Species Identification Relevant pharmacologic response, binds clinical candidate or surrogate
Metabolite Identification
Maximum Tolerated Dose Often Limited By Max Feasible Dose - formulation/volume limit
Defined by animal studies
PK/ADME
Specific antigen binding, can be target dependent, long t½
Assays for whole antibody
Less specific binding, short t½, may have one or more metabolites with or without pharmacologic activity
Assays for drug product + metabolites (if applicable)
Immunogenicity assays Yes No
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3Rs – Reduce, Replace, Refine Slide 20 5/5/14
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Repeat Dose Small Molecule Toxicity Studies: Enable Full Evaluation of Systemic Toxicity Potential
First Definitive (GLP) Toxicology Studies for IND • Designed to support Phase 1 • Generally 4 weeks in duration for small molecules (determined by CDP) • Biologics 8 to 12 weeks
“Subchronic” Study - Approximately 13 weeks duration • Continue to characterize toxicity • Supports longer-term clinical trials up to 3 months duration and Life
Threatening disease indications • For Small Molecules, conducted to bridge to chronic study
“Chronic” Study - 6 to 9 months duration (6 months for LMs) • Dose selection focused on long term tolerability • Required for non-Life Threatening indications projected to be taken chronically
Carcinogenicity - up to 2 years (actually 3 with data analysis!) • Alternative models are considered (i.e. 6 mos transgenic mouse models) • Driven by indication and intended clinical use - ie lifetime • Required for non-LT disease indications of long dosing durations
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Integration of Many Data Points Slide 22 5/5/14
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Slide 23 5/5/14 Safety Pharmacology
q Objective: Assess for Cardiovascular, CNS or Respiratory Changes q Study design and focused evaluations specified by ICH guidance S7A
q Cardiovascular q In vitro - hERG
q QT prolongation - Prolonging the cardiac action potential due to block of hERG channels increases the QT interval and can lead to arrhythmias
q In vivo - telemetry q QT prolongation q Blood pressure q ECG changes
q CNS q Any evidence of ataxia, decreased motor activity, behavioral changes
q Respiratory q Any effects on respiration rate, lung capacity
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Slide 24 5/5/14 Repeat Dose Toxicity Study
q Conducted for Large and Small Molecules
q Objective q Characterize toxicity of molecule
q Apoptosis/proliferation - bone marrow, gut, lymphoid q Metabolic effects - pancreas, liver, thyroid, body wt, food con. q Degeneration/atrophy - bone, gonads, CNS q Necrosis - target organ vs. general q Vascular system effects q Inflammation q And more!!!!!
q Identify potential safety liabilities of long-term dosing q Special evaluations of repeat dose toxicity
q Reproductive Toxicity q Carcinogenicity
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Slide 25 5/5/14 Repeat Dose Toxicity Studies - later stages
q First Definitive (GLP) Toxicology Studies for IND q Designed to support Phase 1 q Generally 4 weeks for small molecules, 4-12 weeks for biologics
q Subchronic to Chronic Studies – q Subchronic ~ 13 weeks duration
q Supports longer-term clinical trials up to 3 months duration q Chronic ~ 6-9 months duration
q To support lifetime administration
q Carcinogenicity - up to 2 years q Significant questions surrounding utility/appropriateness for biologics q Driven by indication and intended clinical use – i.e. lifetime therapy for non-life threatening
diseases
q Reproductive and Developmental Toxicity q Characterize effects does the compound have on any phase of reproduction and on the
offspring q Different stages of evaluation: from fertility through post-natal developement
Repro Label example: Pregnancy Category D IRESSA may cause fetal harm when administered to a pregnant woman. … When pregnant rats treated with 5 mg/kg from the beginning of organogenesis to the end of weaning gave birth, there was a reduction in the number of offspring born alive.
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Slide 26 5/5/14 IND-Enabling Program - Small Molecule
General Toxicity Acute toxicity study in rodent (may be possible to use pilot tolerability data) Pilot repeat dose studies in 2 species
Daily dosing - 1 month dosing/1 month recovery rodent Daily dosing - 1 month dosing/1 month recovery non-rodent
Genetic Toxicology Battery
Ames Chromosomal Aberrations (human peripheral lymphocytes) In vivo rat micronucleus study
Safety Pharmacology hERG (in vitro) Non-rodent cardiovascular safety pharmacology study (telemetry) Respiratory safety pharmacology study Mouse Irwin (neurobehavioral study)
Note: Program will vary according to molecule and clinical program (Target expression, species specificity, patient population, clinical development plans…)
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Slide 27 5/5/14 IND-Enabling Program- Large Molecule
Tissue cross-reactivity To evaluate potential for nonspecific/unexpected binding in off-target tissues Limitations of assay sometimes make this challenging to conduct and interpret General Toxicity Intermittent dosing (qw or q2w, based on clinical plan and PK) Dosing over 1 to 3 month with recovery (generally in non-human primate due to
limited species cross-reactivity)
Safety Pharmacology Non-rodent cardiovascular safety pharmacology - often included as part of
general toxicology study No hERG
q Large molecules unable to access the inner pore and bind amino acid residues to inhibit channel function; generally cannot bind external regions of channel
q Formulation components may interfere with assay
Note: Program will vary according to molecule and clinical plan
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So How is Non-Clinical Data Utilized Clinically?
NOAEL or STD10/HNSTD*
Safety Margin
Nonclinical In Vivo Data
ü Starting Dose ü Dose Escalation Range (how high to dose) ü Dosing Duration
Phase I Clinical Development Plan
* No Adverse Effect Level (non-onc) & Highest Non-Severely Toxic Dose (onc)
Identified Target Organ Toxicity Severity
Type Reversibility Monitorability Mechanism?
ü Starting Dose/Escalation ü Clinical Monitoring ü Exclusion Criteria ü Stopping Rules ü Labeling
Phase I & Beyond
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Impact of toxicology data on clinical plan
Clinical development plan considerations: – Nature of nonclinical toxicities, including potential translatability and
monitorability in humans
– Safety margin for starting dose
– Dose escalation to maximum anticipated (target) dose level
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30 Repro and developmental tox – definitions
• The goal of reproductive tox testing is to identify any effect on mammalian reproduction
Fertility (Segment I) – If exposed to drug, does it impact your normal reproductive
function and your ability to conceive? Embryonic development (Segment II)
– If exposed to drug while pregnant, what happens to the fetus? Postnatal function of offspring (Segment III)
– If exposed to drug later in pregnancy and/or during lactation, is the offspring physiologically normal?
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31 When are these studies (generally) done?
JAPAN: SEG I & II EU: SEG II US: w/ appropriate tests & monitoring
ALL: SEG I Men
1CP Women (on birth control)
EU: SEG I US: SEG I & II ALL: SEG III
Phase I Phase II Phase III Preclinical
NonCP Women
1childbearing potential
ALL: No additional studies needed
Pregnant Women (includes women not using highly effective birth control &/or of unknown status)
ALL: All reproductive toxicity studies & previous human safety data (if available) are needed prior to inclusion in clinical trials
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The Impact of Dose-Response on Safety Margins
Additional factors that influence the magnitude of the Safety Margin required:
• Severity of the Toxicity
• Monitorability
Eff
icac
y
Tox
icit
y
Max
EE
Efficacious Exposure (EE)
Toxicity Exposure (TE)
[Drug]plasma
TE1 TE2
TE3
Dose-Response Relationships: Slope of Change is important!
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The Concept of Monitorability of Toxicity (Safety Biomarkers)
Scenario A: No Warning that Road is Out
(no monitorability)
Scenario B: Warning Just before Road is Out
(monitorable, but steep response curve)
< Scenario C: Ample Warning before Road is Out
(monitorable & shallow response curve)
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Why do drugs fail… for safety?
• Unacceptable risk to patients, outweighing the potential benefit § This is especially challenging in certain indications where a clear “benefit” is difficult
to establish, especially in animal models § High bar for safety is also due to long treatment durations required for efficacy in
some indications (e.g. CNS)
• Poor therapeutic window or safety margin § Safety margin required depends on nature of toxicity and patient population § Based off of the anticipated efficacious dose prior to FIH trials
• Steep dose-response curve for toxicity
• Lack of predictability, reversibility and/or monitorability for concerning safety findings
• Human variability is not reflected in animals, and power in numbers § Currently difficult to detect rare events in early stages of development
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How Attrition Informs Safety Lead Optimization
§ Leading Causes of Toxicology-related Attrition (1960-2007)
Laverty. 2011. British J Pharmacology. 163:675.
Stevens & Baker (2009) Drug Disc. Today 14:162-167
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A Few Key Take-Aways…
§ Studies in animals are required by regulatory authorities to protect patients, prior to first human exposure and throughout clinical development
§ Differences in structure/activity between large and small molecule drugs mandate slightly different approaches, with small molecules more prone to “off-target” side effects
§ Ultimate interpretation of toxicity findings and potential tolerability in patients requires a thorough risk/benefit analysis including understanding disease, co-morbidities/co-medications, etc.
§ Safety evaluations can also provide insight into the biology of a target or pathway; assessment strategies that begin in the discovery phase can significantly improve chances for a drug’s success!
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Slide 37 5/5/14 The ICH Guidelines: Repeated Dose Toxicity Studies to Support the Conduct of Clinical Trials in all Regions
Maximum Duration of Clinical Trial
Minimum Duration of Repeat Dose Toxicity Studies to support Clinical Trials
Rodents Non-rodents Up to 2 weeks 2 weeks 2 weeks Between 2 weeks and 6 months
Same as clinical trial Same as clinical trial
> 6 months 6 months 9 months*
*6 months may be justified in certain circumstances e.g., intermittent treatment or life threatening diseases such as cancer or when immunogenicity or tolerance problems confound conduct of longer term studies. In EU, studies of 6 mo duration in non-rodents is acceptable. However, a global package would require 9 mo study. Clinical trials of longer duration than 6 mo can be initiated providing the data are available from a 3 mo rodent and a 3 mo non-rodent study, and complete data from the chronic rodent and non-rodent study are available before 3 mo of dosing is exceeded in the clinical trial (ICH M3) Biopharmaceuticals which produce immunosuppression may require longer duration studies to determine potential for emergence of virally related tumors Ref: ICH M3, July 2008
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Slide 38 5/5/14 ICH Guidelines: Marketing Authorization
Duration of Indicated Treatment
Rodent Non-rodent
Up to 2 weeks 1 month 1 month
>2 weeks to 1 month 3 months 3 months
>1 month to 3 months 6 months 6 months
>3 months 6 months 9 months*
*6 months may be justified in certain circumstances e.g., intermittent treatment or life threatening diseases such as cancer or when immunogenicity or tolerance problems confound conduct of longer term studies. Clinical trials of longer duration than 6 mo can be initiated providing the data are available from a 3 mo rodent and a 3 mo non-rodent study, and complete data from the chronic rodent and non-rodent study are available before 3 mo of dosing is exceeded in the clinical trial. Ref: ICH M3, July 2008
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Slide 39 5/5/14 The ICH Guidelines: Reproduction Toxicity*
• Evaluation of reproductive organs performed in Repeat Dose toxicity studies prior to exposure. • Men can be included in Phase I and II trials if the above is conducted and data is supportive. • Women not of childbearing potential can be included in trials if evaluation of reproductive organs have been conducted. • All female reproduction toxicity and genotoxicity studies should be conducted prior to inclusion of pregnant women or women
not using birth control or if pregnancy status is not known.
For Women Of Child Bearing Potential
US EU Japan
Segment I Fertility and early embryonic development to implantation
Ph III Ph III in exceptional cases may be conducted concurrent with Ph III
Ph III
Segment II Embryo-fetal development; teratogenicity Implantation to birth
Ph III (With the use of effective contraceptive methods) May not be required if a drug is teratogenic because of MOA e.g oncology products
Ph I Exceptions: with adequate birth control, in clinical trial of short duration or predominance of disease in women. If MOA known, type of agent, half-life etc. May not be required if a drug is teratogenic because of MOA until Ph III
Ph I Exceptions: with adequate birth control in short duration clinical trials or predominance of disease in women. If MOA known, type of agent, half-life etc
Segment III pre- & postnatal development and maternal function
MA MA MA
* Please note that the above timeline is based on draft guidance ICH M3 (July 2008) which could change. Current guideline for Japan require both Seg I & II prior to Phase I.
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Slide 40 5/5/14
q Information on acute toxicity of pharmaceutical agents to predict the consequences of human overdose situations should be available prior to Phase III.
q Historically, acute toxicity information has been obtained from single dose tox studies in 2 mammalian species using both the clinical and parenteral route of administration
q Information can also be obtained from dose escalation studies, short duration dose ranging studies that define a maximum tolerated dose, studies that achieve saturation of exposure, or use the maximum feasible dose.
The ICH Guidelines: Acute Toxicity for small molecules
Ref: ICH M3, July 2008
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Slide 41 5/5/14 ICH Guidelines: Carcinogenicity Studies
Study US EU Japan Carcinogenicity/Tumor Promotion e.g. required for biopharmaceutic with >6 months of continual or intermittent dosing If pt to live more than 2-3 yrs or if treatment prolongs life, or exposure is prolonged or cause for concern (e.g. growth factors, immune suppressors). Generally not required for oncology products
Marketing application or post approval in certain cases e.g. serious diseases.
Marketing application or post approval in certain cases e.g. serious diseases
Marketing application or post approval in certain cases e.g. serious diseases
Ref: ICH M3, July 2008