The New ICH Guideline on Genotoxicity (S2)

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5 years ago
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1 ICH S2 の概要および遺伝毒性研究における発がん性の意味本間正充国立医薬品食品衛生研究所変異遺伝部

2 TOPICS ICH S2(R1) ガイドライン ( 案 ) のポイント他のガイドラインや研究分野への影響遺伝毒性発がん物質のリスク評価と管理

3 The International Conference on Harmonisation of Technical Requirements for the Registration of Pharmaceuticals for Human Use (ICH) The ICH is an initiative undertaken by three regions, the European Union, Japan and the United States, with six co-sponsors European Union (EU) US Food and Drug Administration (FDA) Japanese Ministry of Health, Labour and Welfare (MHLW) European Federation of Pharmaceutical Industries and Associations (EFPIA) Japan Pharmaceutical Manufacturers Association (JPMA) Pharmaceutical Research and Manufacturers of America (PhRMA)

4 ICH Guidelines Q "Quality" Topics, i.e., those relating to chemical and pharmaceutical Quality Assurance. Examples: Q1 Stability Testing, Q3 Impurity Testing S "Safety" Topics, i.e., those relating to in vitro and in vivo pre-clinical studies. Examples: S1 Carcinogenicity Testing, S2 Genotoxicity Testing E "Efficacy" Topics, i.e., those relating to clinical studies in human subject. Examples: E4 Dose Response Studies, Carcinogenicity Testing, E6 Good Clinical Practices. (Note Clinical Safety Data Management is also classified as an "Efficacy" topic - E2) M "Multidisciplinary" Topics, i.e., cross-cutting Topics which do not fit uniquely into one of the above categories.

5 ICH Guideline of S2A and S2B (

6 Standard Battery of Genotoxicity Tests in ICH (1997) In Vitro; 2 Tests Bacterial Reverse Mutation Assay Chromosome Aberration Test or Mouse Lymphoma Assay (MLA) In Vivo; 1 test Micronuclei Test Choice one of two tests

7 Performance of Individual Genotoxicity Tests in Detecting Rodent Carcinogens Reports Ames MLA Chrom. Ab. MN (Vitro) MN (Vivo) Krikland et al., Mutat. Res. 584, 1, 2005 Sens. Spec Zeiger Reg. Tox. Pharm. 28, 85, 1998 Sens. Spec Sens. (Sensitivity): % of positive results among rodent carcinogens. Spec. (Specificity): % of negative results among rodent non-carcinogens.

8 High Frequency of Positive Results of in Vitro Mammalian Cell Genotoxicity Test The positive results are generally week and not relevant under in vivo condition. The positive results are due to un-physiological experimental conditions (high cytotoxicity, insolubility), but not to true genotoxicity. The positive results lead to a great deal of follow-up testing (in vivo) to assess whether there is any genotoxic risk. We should take actions to reduce the high frequency of in vitro test and avoid the wasteful follow-up tests.

9 Process of Revision of the S2 Guideline in ICH June 2006 in Yokohama, Japan October 2006 in Chicago, USA May 2007 In Brussels, Belgium October 2007 In Yokohama, Japan February 2008 June 2008 In Portland, USA May 2009 In Yokohama, Japan The ICH Steering Committee (SC) agreed to initiate a revision of the genotoxicity guideline (Step 1). The ICH Expert Working Group (EWG) discuss revision and plan the approach to a revised guideline. The EWG reached a consensus of the revised issues and agree to make a draft guideline according to the consensus. The EWG finalized the new guideline for Step2. Postal sign-off for Step2. The EWG worked for answering public comments and further discussed for Step 4. The step 4 process?

10 Yokohama Wednesday June 10, 2009 The EWG will not sign off on the Step 4 in Yokohama.

11 2.5 years later-----

12 Sevilla, Spain- Wednesday November 9, 2011

13 Major Revisions in S2 (R1) Mammalian cell assays: Decreased top dose from 10 mm to 1 mm Reinforce cytotoxicity limits Two options considered equally acceptable: Option 1: Battery with in vitro mammalian cell assay Ames In vitro mammalian cell assay In vivo micronucleus test (integrated into repeat-dose toxicology study if possible) Option 2: Battery without in vitro mammalian cell assay Ames Genotoxicity measured in vivo in two different tissues, (integration or combination if possible)

14 Proposed New Recommended Test Battery Ames Option 1 Option 2 In vitro mammalian cell test a b No in vitro mammalian cell test Negative Positive MNT (integrated if possible) (No 2nd in vivo) MNT (integrated if possible) + 2nd end-point/tissue MNT (integrated if possible) + 2nd end-point/tissue (integrated or combined if possible)

15 Choice of In Vivo Assays: 2nd Endpoint / Tissue Liver typically preferred tissue, but choice should be based on factors such as type of effect seen in vitro any knowledge of the potential mechanism of the exposed tissues thought to be relevant Options considered as acceptable DNA strand break assays (Comet, alkaline elution) Transgenic animal mutation assays UDS assay Comet assay in liver is highly recommended as the 2 nd in vivo test

16 Impacts on Other International Guidelines OECD: Development of new in vivo genotoxicity test guidelines Transgenic Rodent Somatic and Germ Cell Gene Mutation Assays (TG488, July 2011) In vivo Comet assay (under validation) Revision of in vitro mammalian cell assays Reduction of top dose (from 10mM to?) Deletion, refinement, and development of TGs (MLA) ICH-M7:Development of DNA reactive (mutagenicity) impurity guideline Risk based qualification

RISK Hazard Identification (Weight of Evidence)

17 Paradigm Shift in Genetic Toxicology; From Hazard Identification to Risk Assessment HAZARD VERSUS RISK Hazard Identification (Weight of Evidence) Hazard Characterization (Mode of Action) Exposure Assessment

18 遺伝毒性 VS 発がん物質遺伝毒性発がん物質遺伝毒性非発がん物質遺伝毒性陽性結果は無視される遺伝毒性偽陽性? 非遺伝毒性発がん物質非遺伝毒性非発がん物質遺伝毒性陰性結果は無視されるエピジェネティック?

19 遺伝毒性からみた発がん物質の特徴直接遺伝毒性発がん物質間接遺伝毒性発がん物質非遺伝毒性発がん物質 DNA へ直接作用 DNA 損傷あり突然変異の誘発あり閾値なし不可逆的変化放射線紫外線アルキル化剤多環芳香族炭化水素芳香族アミンアフラトキシン等 DNA へ間接作用 DNA 損傷なし突然変異の誘発あり閾値あり不可逆的変化 DNA 合成阻害剤トポイソメラーゼ阻害剤細胞分裂阻害剤等 DNA へ間接作用 DNA 損傷なし突然変異の誘発なし閾値あり可逆的変化塩素化合物ペルオキシゾーム増殖剤ホルボールエステルホルモン類催眠薬 ( フェノバルビタール ) 等

20 遺伝毒性閾値と TTC 反応閾値あり化合物 ( 非遺伝毒性物質間接遺伝毒性物質 ) 閾値反応 TTC 閾値を問わない反応閾値なし化合物 ( 直接遺伝毒性物質 ) 閾値なし用量用量安全性量安全性量? 実質安全性量 (VSD) 用量

21 TTC レベル 0.15μg/person/day 未知の化学物質の 10% が発がん物質と仮定してその 99% が 10-6 の発がんリスクで担保される設定閾値食事中に低レベルで存在する遺伝毒性 ( 変異原性 ) 発がん物質 1.5μg/person/day 未知の化学物質の 10% が発がん物質と仮定してその 99% が 10-5 の発がんリスクで担保される設定閾値食事中に低レベルで存在する非遺伝毒性発がん物質医薬品中に不純として含まれる遺伝毒性 ( 変異原性 ) 発がん物質

22 医薬品の不純物に関する ICH ガイドライン ICH Q3B: 製剤の不純物に関するガイドライン最大一日投与量安全性確認が必要な閾値 <10 mg 1.0% 又は 5 0 μg/ 日の低い方 10 mg ~ 100mg 0.5% 又は200 μg / 日の低い方 100 mg ~ 2 g 0.2% 又は3 mg/ 日の低い方 >2 g 0.15% 3mg/ 日まで許容 ICH M7( 案 ):DNA 反応性不純物に関するガイドライン Marketed Product Duration of Treatment 1 month Daily Intake (µg/day) months 1-10 years > 10 years

23 遺伝毒性発がん性物質適切なリスク評価適切なリスク管理発がん性を考慮した定量的評価個別評価化学構造によるクラス別評価

24 発がん性 vs 遺伝毒性 ( エームス試験 ) Cohort of concern メカニズム解析化学構造クラス分類他の試験によるフォローアップ新しい試験法の開発鈴木孝昌 Environ. Mutagen Res., 24: (2002) Risk mitigation

25 発がん性 vs 遺伝毒性 (TG 試験 ) 遺伝毒性試験結果の定量化発がん性との量的相関性鈴木孝昌 Environ. Mutagen Res., 24: (2002)

26 まとめ遺伝毒性発がん性物質のリスク評価と管理ーハザードからリスクへー適切な条件下での in vitro 試験の実施メカニズムに基づく in vivo/in vitro 試験法の開発包括的リスク管理 (TTC) と個別のリスク管理適切なリスク評価のための手法の開発遺伝毒性試験結果の定量化と発がん性リスク評価への適用

ICH M7 Genotoxic Impurities Expert Working Group Meeting

ICH M7 Genotoxic Impurities Expert Working Group Meeting M7: 潜在的発がんリスクを低減するための医薬品中 DNA 反応性 ( 変異原性 ) 不純物の評価および管理 Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk 2012 年 12 月 14 日国立医薬品食品研究所変異遺伝部