Carcinogenicity endpoint:
waiving of 2‐years rat study based
on integrated data assessment
Sandra De Jonghe & Steven Spanhaak
Sept 22, 2014
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Outline
• Current carcinogenicity testing
• Retrospective analysis on predictivity of carcinogenicity
endpoints
– PhRMA: NEGCARC proposal
– PDR (physicians’ desk ref) review by Alden et al.
• Prospective analysis: Regulatory Notice document
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Current practice carcinogenicity assessment
• Regulatory requirements: ICH Guidelines M3, S1A, S1B, S1C,
S2, and S6
• In general:2-yr rat study + a 2-yr mouse or an alternative 6month transgenic mouse carcinogenicity study
• ICH S1A:
– pharmaceuticals (small molecules) dosed for ≥ 6 months
(continuously or in a frequent and intermittent manner)
– carcinogenic concern (~product class, SAR, preneoplastic lesions
in RD tox studies; long-term tissue retention)
– other factors considered: genotoxicity, indication & patient
population, route of exposure, extent of systemic exposure
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Transgenic mouse models
• accepted in 1997 for carcinogenicity assessment
• TgrasH2 for non-genotoxic and p53+/- for genotoxic
compounds; Tg.AC for topical
• 6m; n=25/group
• TgrasH2 and p53+/- provide comparable predictivity to the rat
and mouse 2 yr bioassays for known IARC Group 1 and
probable IARC Group 2A human carcinogens
• ↓ false-positive rate
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Disadvantages and limitations 2 yr study
• High numbers of animal required, cost and impact on
timelines
• Suboptimal for predicting human cancer risks
• High % False Positives; animal Mode Of Action often no or
limited relevance to human, e.g.
– Thyroid tumors ~ ↑ metabolism thyroid hormones
– Kidney tumors ~ α2u-globulin nephropathy in male rats
– Testicular Leydig cell tumors ~ feedback stimulation LH
=> experts have attempted to set the scene to revise the current
carcinogenicity testing paradigm (publications, PhRMA LD-KIT)
Mechanisms human neoplasia
The following 4 mechanisms account for the large majority of
human carcinogens:
• genotoxicity
• hormonal modulation
• immunosuppression
• chronic toxicity
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Retrospective analyses - PhRMA
PhRMA NEG CARC Database driven proposal
(Negative for Endocrine, Genotoxicity, and Chronic study Associated
histopathologic Risk factors for Carcinogenicity in the Rat)
Compounds negative for microscopic
proliferative changes in chronic rat studies
(6m), negative for genotoxicity and
negative for (possible) hormonal
perturbations =>
NO 2 yr rat carcinogenicity testing
PhRMA NEG CARC
• 2-yr rat carcinogenicity data from 13 pharmaceutical companies and
182 compounds with matching rat chronic studies were compiled into
a PhRMA Searchable Database
=> for 30-40% of the 182 compounds a negative outcome of the
carcinogenicity study could be predicted (Sistare et al, 2011), based
on
–“negative” histopathology in a chronic rat study
– together with a negative result in genotoxicity
– and negative evidence of a hormonal mechanism
• Regulatory Authorities raised questions regarding the impact of the
pharmacological properties of the compounds, first for the false
negative compounds, but with consequences for all compounds.
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Retrospective analyses – Regulatory Authorities
• EU conducted an analysis and concluded:
Often link tumors – pharmacodynamic action compound
Liver - thyroid - testes
some compounds associated with hepatocellular hypertrophy or liver enzyme
induction were prone to induce tumours not only in liver, but also in thyroid
and testes
• JPMA and FDA performed independent analyses of an additional 64
and 50 unique pharmaceuticals with similar conclusions:
negative predictivity // PhRMA
relation with pharmacology // EU
• PhRMA+ reg. authorities: total of ± 290 compounds
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Retrospective analyses - Proposal by
Alden et al.
• Reviewed Thompson Micromedex electronic version of the
PDR
• Improve human cancer risk assessment by demonstration of
(1) immunosuppression, (2) hormonal modulation, (3)
genotoxicity,(4) chronic toxicity responses, and(5) rasH2 and
p53+/- bioassay responses without conducting 2 yr rodent
bioassay
=> substantial↓ false-positive and false-negative rate
Vet Path, 48: 772-784, 2011
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Final Conclusion
• Based on pharmacology, genotoxicity, and chronic toxicity
data the negative or positive outcome of the 2-yr rat
carcinogenicity study can be predicted when carcinogenic
signals are absent/present
• In between a category of compounds remains for which the
outcome cannot be predicted with sufficient certainty
• Supports revision of the S1 guidance and reduction of the
number of required carcinogenicity studies
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Prospective analysis: Regulatory
Notice Purpose
• Description of prospective evaluation period and procedure
• Confirm prospectively, whether or not identified data sets
can properly predict
– outcome of the 2-yr rat carcinogenicity study
– human carcinogenic risk
– need to perform 2-yr rat study
• Goals:
– evaluate predictivity of Weight Of Evidence (WOE) factors
– evaluate accordance Regulatory agencies – sponsor – final
outcome
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Regulatory Notice Document
•Predict that compound will fall into 1of 3 main categories
(based on integrated pharmacologic and toxicologic data):
Category 1: likely tumorigenic in humans (in label)
=> 2-yr rat study would not add value
Category 2: tumorigenic potential for humans is uncertain
=> 2-yr rat study adds value to human risk assessment
Category 3a: probably tumorigenic in rats, not in humans;
well-known rat-specific mechanisms
=> 2-yr rat study would not add value
Category 3b: likely not tumorigenic in both rats or humans
=> no 2-yr rat study is needed
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Regulatory Notice Document: CAD
•Sponsors to submit a Carcinogenicity Assessment
Document (CAD) that would (in the future) justify a waiver
request to omit the conduct of 2-yr rat study
– Pre-defined Weight Of Evidence (WOE) factors
– submit CAD to 1 Regulatory Authority prior to knowing the
outcome of carcinogenicity testing
–anonymous electronic CAD, cover letter
•Within scope:
–all investigational small molecule pharmaceuticals subject to a 2yr rat carcinogenicity study (ICH S1A)
–pharmaceuticals with ongoing rat carcinogenicity studies ≤18 mts
± 50 CADs will be reviewed (± 2 years)
•
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Prospective analysis
Success depends on the active participation by pharmaceutical
companies in submitting CADs!
14 CAD’s have been submitted
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Thank You
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