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Cosponsored by
FDA’s Office of Critical Path Programs (OCPP)
and
The Clinical Trials Transformation Initiative (CTTI)
FDA’s Clinical Investigator Course
Pharmacology/Toxicology in the
Investigator Brochure
Brenda J. Gehrke, Ph.D.
Office of New Drugs/CDER/FDA
November 2013
Abbreviations
• ADME: absorption, distribution, metabolism,
excretion
• HU: hydroxyurea
• IB: Investigator Brochure
• ICH: International Conference on Harmonisation
• IGFR: insulin-like growth factor receptor
• IND: Investigational New Drug application
• MOA: mechanism of action
• mTOR: mammalian target of rapamycin
• PNH: paroxysmal nocturnal hemoglobinuria
Objectives
• An overview of Pharmacology/Toxicology
(nonclinical) information
– Pharmacology
– Safety Pharmacology
– Toxicology
• General toxicology
• Genetic toxicology
• Other toxicology studies: reproductive toxicity
• Examples of toxicity data
Nonclinical information included
in the Investigator Brochure (IB)
– Pharmacology
– Safety Pharmacology
– Toxicology
• General toxicology
• Genetic toxicology
• Other toxicology studies
– Pharmacokinetics
Pharmacology
Pharmacology
• Used to define intended and
unintended targets/ effects
• Amount of information varies
– Type of molecule (e.g. small
molecule vs biologic)
– Stage of drug development
– Indication
How much attention to pay to the
pharmacology?
• Drug not the first in class? Better
idea of toxicities
• For biologics (e.g. an antibody):
which species best predicts toxicities
in humans
• Can explain some toxicities seen in
animals: exaggerated pharmacologic
effects
Safety Pharmacology
Safety Pharmacology
• Cardiovascular
– In vitro
– In animals (dogs or monkeys)
• CNS (usually rodents)
• Pulmonary (usually rodents)
General Toxicology
General toxicology
• Toxicology studies with the same
route and schedule of administration
as proposed in subjects:
– Duration of nonclinical studies relative
to clinical development described in
ICH guidance M3R2
– Anticancer pharmaceuticals follow ICH
S9
Purpose of these studies
• Determine whether it is safe to put drug
candidate into humans
• Determine an initial safe dose for human
clinical trials
• Help determine a safe stopping dose (if
necessary)
• Identify dose limiting toxicities (what
should be monitored in clinical trials)
• Assess potential toxicities that cannot be
identified in clinical trials
Which Species to Test
• Regulatory guidelines accept data
from a variety of species
• In practice, only a small number of
rodent and nonrodent species are
consistently chosen
• Species are chosen because they
have been used before, and studied
extensively
Species Commonly Used
• Rodents
– Rats
– Mice
• Non Rodents
– Beagle dogs
– Cynomolgus and
Rhesus monkeys
– Rabbits
Species in toxicology studies
• For biotech derived products, e.g. an
antibody, the species should be
pharmacologically relevant. Toxicology
studies in a second species may be waived if
no other relevant species has been identified.
Toxicity information in the IB: Real
examples
• Indication: Treatment of systemic
amyloidosis
• Target: amyloid fibrils
• Drug: Humanized IgG1 monoclonal
antibody
• Target not present in healthy animals
(pivotal tox studies are conducted in healthy animals)
• How is toxicity assessed in the absence of
a relevant species? What to monitor in
patients?
Toxicity information in the IB: Real
examples
• Drug/Indication: Microtubule inhibitor
being developed for treatment of
advanced solid tumors
• Produced irreversible optic nerve
degeneration at mid and high doses in rat
repeat-dose toxicology study
• Based on concerns monitoring was
increased (optic exams and imaging), and
information was added to the protocol and
informed consent
Toxicity information in the IB: Real
examples
• Ab-drug conjugate (indication: cancer)
• Cynomolgus monkey was the relevant
species
• Findings in monkeys: mainly
myelosuppresion
• Findings in rats: myelosuppression, also
severe hepatotoxicity (necrosis, increased
liver enzymes)
• How much to worry about hepatotoxicity?
100% homology to
human sequences
100% homology to
human sequences
Toxicity information in the IB: Real
examples
• Fusion protein to inhibit the
complement pathway (immune system)
• Indication: PNH
• 60% homology to protein sequences in rat
• 90% homology to protein sequences in
Cyno
• Deaths in rats and monkeys, due to
– Immunogenicity
• Is immunogenicity relevant to humans?
Cont’d
General toxicology used to define
the starting dose in humans
Should I worry about the starting dose?
• The review team reviewed the IND
package and agreed on the starting
dose.
• Be aware of toxicities
• Understand what the nonclinical data
mean and how relevant they are
… and how relevant are they?
• ADME differences between test
animals and humans (e.g., N-acetylation)
• Species differences in anatomy (gall
bladder) and physiology (folate
levels)
• Species differences in
pharmacodynamic responses
(binding affinities)
Other limitations
• Adverse reactions that can only be
communicated verbally by the patient
are not normally recognized in
animals (e.g. pain)
• Concomitant drugs in humans may
exacerbate toxicity
In general, animals are good
predictors of toxicities in humans
• Signal transduction pathways, e.g.
IGFR/mTOR inhibition and
hyperglycemia
• Infusion reaction in monkeys to
antisense oligonucleotide
– Cmax-related: slower infusion reduces
infusion reaction
• Hematologic toxicities of cytotoxic
drugs predicted by animal studies
Genetic Toxicology
Genotoxicity
• Data from genotoxicity studies are used
as a surrogate for carcinogenicity during
clinical trials.
• Results from carcinogenicity studies are
generally not available until the time of
product approval. Many people, including
healthy volunteers, will have been
exposed to pharmacologically active
doses before carcinogenicity data are
available.
Types of genotoxicity assays
• in vitro
– An assay in bacteria to detect mutations in a
target gene
• Ames Test - Salmonella and E.Coli
– An assay in mammalian cells to detect
chromosomal damage
• Chinese Hamster Ovary (CHO) cells
• Mouse lymphoma cells
• in vivo
– An assay in a rodent species to detect
chromosomal damage to hematopoietic cells
• Other genotoxicity assays are available and may
be conducted
Timing
• Timing of genetic toxicology studies relative
to clinical development
– Gene mutation assay for single dose clinical
studies
– Add chromosomal damage study for multiple
dose clinical studies
– Complete battery conducted prior to phase 2
– Submit with marketing application for anticancer
drugs
Worried about results of genetic
toxicity studies?
• Review team made a decision that the trial is
reasonably safe to proceed
– Negative results in genotoxic assays
– Positive or likely/possibly to be positive (based on
MOA, other drugs in the same class, equivocal
results)
• Life-threatening indication/ cancer? Genotox studies not
needed until marketing application; short life-expectancy
• Serious condition and no other therapy? HU in sickle cell
• A single, small/sub-therapeutic dose in humans?
A few typical daily exposures to carcinogens
Source of carcinogen Carcinogen Average daily human
exposure
Indoor air Formaldehyde
Benzene
598 µg
155 µg
Tap water Bromodichloro-
methane
chloroform
13 µg
17 µg
Celery 8-methoxy psoralen 4.9 µg
Coffee Catechol
Hydroquinone
Caffeic acid
1.3 mg
333 µg
23.9 mg
Lettuce Caffeic acid 7.9 mg
Brown mustard Allyl isothiocyanate 62.9 µg
Other toxicity studies:
Reproductive toxicology
Teratogenicity
• Thalidomide is a well-known example
• Prescribed to pregnant women for nausea and
insomnia.
• Resulted in over 10,000 births with severe limb
malformations.
• Link between exposure and adverse effects was
possible because of the potency of the drug and
relatively short time period between exposure
and manifestation of effects.
Thalidomide-induced birth defects
Reproduction Toxicity Testing
• For small molecules
– Protocols are standard
– Covers fertility, embryo-fetal, and pre- and post-
natal periods
– Follow ICH S5R2
• For biotechnology derived pharmaceuticals
– More case-by-case
– Study designs evolving based on revisions to ICH
S6
In general, animals are good
predictors of toxicities in humans
• Thalidomide-like limb abnormalities
in monkeys are induced by
thalidomide analogs.
• Hormonal agents (e.g. estrogen
receptor agonists) and loss of
pregnancy
Reproduction Toxicity Testing
• Women of child bearing potential
– Generally, where appropriate preliminary reproduction toxicity
data are available from two species, and where precautions
to prevent pregnancy in clinical trials are used, inclusion of
WOCBP (up to 150) receiving investigational treatment for a
relatively short duration (up to 3 months) can occur before
conduct of definitive reproduction toxicity testing.
• Pregnant women
– Before the inclusion of pregnant women in clinical trials, all
female reproduction toxicity studies and the standard battery
of genotoxicity tests should be conducted. In addition, safety
data from previous human exposure should be evaluated.
Reproduction Toxicity Testing
• Follow ICH M3R2
• Males
– can be included in Phase I and II trials before the conduct of
the male fertility study since an evaluation of the male
reproductive organs is performed in the repeated-dose toxicity
studies.
– A male fertility study should be completed before the initiation
of large scale or long duration clinical trials (e.g., Phase III
trials).
• Women not of childbearing potential
– Women not of childbearing potential (i.e., permanently
sterilised, postmenopausal) can be included in clinical trials
without reproduction toxicity studies if the relevant repeated-
dose toxicity studies (which include an evaluation of the
female reproductive organs) have been conducted.
– Postmenopausal is defined as 12 months with no menses
without an alternative medical cause.
References
ICH Guidances and Guidelines
• fda.gov/cder/guidance or ich.org
– S1 Carcinogenicity
– S2 Genetic toxicity
– S3 Toxicokinetics
– S4 Duration of Chronic Toxicity Testing
– S5 Reproductive toxicity
– S6 Biotechnology
– S7 Safety Pharmacology
– S8 Immunotoxicology
– S9 Nonclinical studies for development anticancer drugs
and biologics (under development)
– M3 Nonclinical Safety Studies for the conduct of Human
Clinical Trials
– Other guidances available from fda.gov
Thank You

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FDA 2013 Clinical Investigator Training Course: Pharmacology/Toxicology in the Investigator Brochure

  • 1. Cosponsored by FDA’s Office of Critical Path Programs (OCPP) and The Clinical Trials Transformation Initiative (CTTI) FDA’s Clinical Investigator Course
  • 2. Pharmacology/Toxicology in the Investigator Brochure Brenda J. Gehrke, Ph.D. Office of New Drugs/CDER/FDA November 2013
  • 3. Abbreviations • ADME: absorption, distribution, metabolism, excretion • HU: hydroxyurea • IB: Investigator Brochure • ICH: International Conference on Harmonisation • IGFR: insulin-like growth factor receptor • IND: Investigational New Drug application • MOA: mechanism of action • mTOR: mammalian target of rapamycin • PNH: paroxysmal nocturnal hemoglobinuria
  • 4. Objectives • An overview of Pharmacology/Toxicology (nonclinical) information – Pharmacology – Safety Pharmacology – Toxicology • General toxicology • Genetic toxicology • Other toxicology studies: reproductive toxicity • Examples of toxicity data
  • 5. Nonclinical information included in the Investigator Brochure (IB) – Pharmacology – Safety Pharmacology – Toxicology • General toxicology • Genetic toxicology • Other toxicology studies – Pharmacokinetics
  • 7. Pharmacology • Used to define intended and unintended targets/ effects • Amount of information varies – Type of molecule (e.g. small molecule vs biologic) – Stage of drug development – Indication
  • 8. How much attention to pay to the pharmacology? • Drug not the first in class? Better idea of toxicities • For biologics (e.g. an antibody): which species best predicts toxicities in humans • Can explain some toxicities seen in animals: exaggerated pharmacologic effects
  • 10. Safety Pharmacology • Cardiovascular – In vitro – In animals (dogs or monkeys) • CNS (usually rodents) • Pulmonary (usually rodents)
  • 12. General toxicology • Toxicology studies with the same route and schedule of administration as proposed in subjects: – Duration of nonclinical studies relative to clinical development described in ICH guidance M3R2 – Anticancer pharmaceuticals follow ICH S9
  • 13. Purpose of these studies • Determine whether it is safe to put drug candidate into humans • Determine an initial safe dose for human clinical trials • Help determine a safe stopping dose (if necessary) • Identify dose limiting toxicities (what should be monitored in clinical trials) • Assess potential toxicities that cannot be identified in clinical trials
  • 14. Which Species to Test • Regulatory guidelines accept data from a variety of species • In practice, only a small number of rodent and nonrodent species are consistently chosen • Species are chosen because they have been used before, and studied extensively
  • 15. Species Commonly Used • Rodents – Rats – Mice • Non Rodents – Beagle dogs – Cynomolgus and Rhesus monkeys – Rabbits
  • 16. Species in toxicology studies • For biotech derived products, e.g. an antibody, the species should be pharmacologically relevant. Toxicology studies in a second species may be waived if no other relevant species has been identified.
  • 17. Toxicity information in the IB: Real examples • Indication: Treatment of systemic amyloidosis • Target: amyloid fibrils • Drug: Humanized IgG1 monoclonal antibody • Target not present in healthy animals (pivotal tox studies are conducted in healthy animals) • How is toxicity assessed in the absence of a relevant species? What to monitor in patients?
  • 18. Toxicity information in the IB: Real examples • Drug/Indication: Microtubule inhibitor being developed for treatment of advanced solid tumors • Produced irreversible optic nerve degeneration at mid and high doses in rat repeat-dose toxicology study • Based on concerns monitoring was increased (optic exams and imaging), and information was added to the protocol and informed consent
  • 19. Toxicity information in the IB: Real examples • Ab-drug conjugate (indication: cancer) • Cynomolgus monkey was the relevant species • Findings in monkeys: mainly myelosuppresion • Findings in rats: myelosuppression, also severe hepatotoxicity (necrosis, increased liver enzymes) • How much to worry about hepatotoxicity?
  • 20. 100% homology to human sequences 100% homology to human sequences Toxicity information in the IB: Real examples • Fusion protein to inhibit the complement pathway (immune system) • Indication: PNH
  • 21. • 60% homology to protein sequences in rat • 90% homology to protein sequences in Cyno • Deaths in rats and monkeys, due to – Immunogenicity • Is immunogenicity relevant to humans? Cont’d
  • 22. General toxicology used to define the starting dose in humans Should I worry about the starting dose? • The review team reviewed the IND package and agreed on the starting dose. • Be aware of toxicities • Understand what the nonclinical data mean and how relevant they are
  • 23. … and how relevant are they? • ADME differences between test animals and humans (e.g., N-acetylation) • Species differences in anatomy (gall bladder) and physiology (folate levels) • Species differences in pharmacodynamic responses (binding affinities)
  • 24. Other limitations • Adverse reactions that can only be communicated verbally by the patient are not normally recognized in animals (e.g. pain) • Concomitant drugs in humans may exacerbate toxicity
  • 25. In general, animals are good predictors of toxicities in humans • Signal transduction pathways, e.g. IGFR/mTOR inhibition and hyperglycemia • Infusion reaction in monkeys to antisense oligonucleotide – Cmax-related: slower infusion reduces infusion reaction • Hematologic toxicities of cytotoxic drugs predicted by animal studies
  • 27. Genotoxicity • Data from genotoxicity studies are used as a surrogate for carcinogenicity during clinical trials. • Results from carcinogenicity studies are generally not available until the time of product approval. Many people, including healthy volunteers, will have been exposed to pharmacologically active doses before carcinogenicity data are available.
  • 28. Types of genotoxicity assays • in vitro – An assay in bacteria to detect mutations in a target gene • Ames Test - Salmonella and E.Coli – An assay in mammalian cells to detect chromosomal damage • Chinese Hamster Ovary (CHO) cells • Mouse lymphoma cells • in vivo – An assay in a rodent species to detect chromosomal damage to hematopoietic cells • Other genotoxicity assays are available and may be conducted
  • 29. Timing • Timing of genetic toxicology studies relative to clinical development – Gene mutation assay for single dose clinical studies – Add chromosomal damage study for multiple dose clinical studies – Complete battery conducted prior to phase 2 – Submit with marketing application for anticancer drugs
  • 30. Worried about results of genetic toxicity studies? • Review team made a decision that the trial is reasonably safe to proceed – Negative results in genotoxic assays – Positive or likely/possibly to be positive (based on MOA, other drugs in the same class, equivocal results) • Life-threatening indication/ cancer? Genotox studies not needed until marketing application; short life-expectancy • Serious condition and no other therapy? HU in sickle cell • A single, small/sub-therapeutic dose in humans?
  • 31. A few typical daily exposures to carcinogens Source of carcinogen Carcinogen Average daily human exposure Indoor air Formaldehyde Benzene 598 µg 155 µg Tap water Bromodichloro- methane chloroform 13 µg 17 µg Celery 8-methoxy psoralen 4.9 µg Coffee Catechol Hydroquinone Caffeic acid 1.3 mg 333 µg 23.9 mg Lettuce Caffeic acid 7.9 mg Brown mustard Allyl isothiocyanate 62.9 µg
  • 33. Teratogenicity • Thalidomide is a well-known example • Prescribed to pregnant women for nausea and insomnia. • Resulted in over 10,000 births with severe limb malformations. • Link between exposure and adverse effects was possible because of the potency of the drug and relatively short time period between exposure and manifestation of effects.
  • 35. Reproduction Toxicity Testing • For small molecules – Protocols are standard – Covers fertility, embryo-fetal, and pre- and post- natal periods – Follow ICH S5R2 • For biotechnology derived pharmaceuticals – More case-by-case – Study designs evolving based on revisions to ICH S6
  • 36. In general, animals are good predictors of toxicities in humans • Thalidomide-like limb abnormalities in monkeys are induced by thalidomide analogs. • Hormonal agents (e.g. estrogen receptor agonists) and loss of pregnancy
  • 37. Reproduction Toxicity Testing • Women of child bearing potential – Generally, where appropriate preliminary reproduction toxicity data are available from two species, and where precautions to prevent pregnancy in clinical trials are used, inclusion of WOCBP (up to 150) receiving investigational treatment for a relatively short duration (up to 3 months) can occur before conduct of definitive reproduction toxicity testing. • Pregnant women – Before the inclusion of pregnant women in clinical trials, all female reproduction toxicity studies and the standard battery of genotoxicity tests should be conducted. In addition, safety data from previous human exposure should be evaluated.
  • 38. Reproduction Toxicity Testing • Follow ICH M3R2 • Males – can be included in Phase I and II trials before the conduct of the male fertility study since an evaluation of the male reproductive organs is performed in the repeated-dose toxicity studies. – A male fertility study should be completed before the initiation of large scale or long duration clinical trials (e.g., Phase III trials). • Women not of childbearing potential – Women not of childbearing potential (i.e., permanently sterilised, postmenopausal) can be included in clinical trials without reproduction toxicity studies if the relevant repeated- dose toxicity studies (which include an evaluation of the female reproductive organs) have been conducted. – Postmenopausal is defined as 12 months with no menses without an alternative medical cause.
  • 40. ICH Guidances and Guidelines • fda.gov/cder/guidance or ich.org – S1 Carcinogenicity – S2 Genetic toxicity – S3 Toxicokinetics – S4 Duration of Chronic Toxicity Testing – S5 Reproductive toxicity – S6 Biotechnology – S7 Safety Pharmacology – S8 Immunotoxicology – S9 Nonclinical studies for development anticancer drugs and biologics (under development) – M3 Nonclinical Safety Studies for the conduct of Human Clinical Trials – Other guidances available from fda.gov