Applying ICH M7 and ICH S9 in Drug Safety

Transcription

1 Applying ICH M7 and ICH S9 in Drug Safety Chris Sheth Division of Hematology Oncology Toxicology Office of Hematology and Oncology Products FDA/CDER/OND

2 Overview 2

3 ICH S9 Nonclinical studies that will support an IND for an anticancer pharmaceutical under ICH S9 should: Pharmacology profile Toxicological profile Establish a safe start dose 1/10 th STD 10 or 1/6 th HNSTD 3

4 ICH S9 Starting dose for oncology indications 1/10 STD 10 in rodents or 1/6 HNSTD in nonrodents, in whichever is the most sensitive species 4

5 Start Dose Calculation Sprague Dawley rat: 0, 10, 30, 100 mg/kg 60, 180 or 600 mg/m 2 Beagle dogs: 0, 1, 3, 10 mg/kg 20, 60, or 200 mg/m 2 Scenario 1 The STD 10 was 100 mg/kg (600 mg/m 2 ) in the rat. The HNSTD was 10 mg/kg (200 mg/m 2 ) in the dog. Most sensitive species is rat, since 1/10 STD 10 (60 mg/m 2 ) is tolerated in dog. Use 1/10 STD 10 for the start dose = 1/ mg/m m 2 The rat study supports a start dose of 96 mg/day in patients with advanced cancer 5

6 Start Dose Calculation Wistar rats: 0, 50, 200, 600 mg/kg 300, 1200 or 3600 mg/m 2 Beagle dogs: 0, 3, 15, 60 mg/kg 60, 300, or 1200 mg/m 2 Scenario 2 The STD 10 was 600 mg/kg (3600 mg/m 2 ) in the rat. The HNSTD was 15 mg/kg (300 mg/m 2 ) in the dog. Most sensitive species is dog, since 1/10 STD 10 (360 mg/m 2 ) was not tolerated in the dog. Use 1/6 the HNSTD for the start dose = 1/6 300 mg/m m 2 The dog study supports a start dose of 80 mg/day in patients with advanced cancer 6

7 Start Dose Calculation Cynomolgus monkeys: 0, 20.6, 200, 810 μg/kg Scenario 3 Sponsor: FIH start dose (0.7 µg/kg) based on the repeat dose toxicity in monkeys with 10 fold safety factor Minimum Anticipated Biological Effect Level (MABEL) Approach is based on pharmacology studies examining most sensitive biological responses to the pharmaceutical Reviewer: Applied MABEL because ADAs limited exposure to mab by Day 8 An FDA oncology analysis of immune activating products and first in human dose selection H. Saber et al., Regul. Toxicol. Pharmacol., 81 (2016), pp

8 Start Dose Calculation The Sponsor s proposed start dose is 0.7 µg/kg: 0.7 µg/kg 60 kg = 42 µg (proposed start dose, assuming a 60 kg patient) 42 µg / 2800 ml = 15 µg/l 15 ng/ml (120 pm) (expected plasma concentration at start dose, assuming 2.8 L plasma volume) Study title Engineering and Binding Characterization Redirected T cell cytotoxicity with anti CD20 mab Redirected T cell cytotoxicity (T cells from donors and CD20 expressing cell lines) Scenario 3 Results Binding affinity for CD3: K D = 5.5 nm (688 ng/ml) EC 50 = 24 ng/ml (192 pm) Most sensitive cytotoxicity assay: EC 50 = 8.1 ng/ml (64.8 pm) Most sensitive CD69 induction assay: EC 50 = 9.6 ng/ml (76.8 pm) 8

9 Start Dose Calculation The Reviewer applied MABEL was used to confirm the acceptability of the Sponsor s proposed starting dose. Hill Equation (sigmoidal O 2 binding curve) can quantify the fraction of the target bound by drug as a function of the drug concentration Scenario 3 MABEL approach using RO (for CD3): RO = [mab] / ([mab] + K D ) RO = [120 pm] / ([120 pm] nm) RO = 2.1% (on the low safe end) Most sensitive optimized activity assay: PA = [mab] / ([mab] + EC 50 ) PA = [120 pm] / ([120 pm] pm) PA = 64.9% (modest activity) Least sensitive optimized activity assay: PA = [mab] / ([mab] + EC 50 ) PA = [120 pm] / ([120 pm] pm) PA = 38.5% (minimal activity) 9

10 ICH S9 Pharmacology ICH S9 ICH M3R2 Relevant species, proof of concept, safety pharmacology (CNS, cardiovascular, respiratory) C Pharmacokinetics max, AUC 0, T 1/2 C max, AUC 0, T 1/2 Plus ADME Genetic toxicology At marketing To support clinical trial Acute toxicity Repeat dose toxicology Preliminary PK/PD and possible target organs of toxicity 3 months in two species, often in one species 6 months/9 months in two species Developmental and Reproductive Toxicology Carcinogenicity EFD with NDA or postapproval Fertility and PPND postapproval Often none or postapproval Early in clinical development Premarket 10

11 DART within ICH S9 Q. The guidance allows for testing in only one species if there is a positive signal for embryofetal lethality or teratogenicity. If clear evidence of embryofetal lethality or teratogenicity is observed in a dose range finding study in one species, is a definitive study in that species recommended? A. If a study shows clear signs of embryolethality or teratogenicity in one species, then that study may be sufficient to support marketing even if it is a pilot/dose range finding study. 11

12 DART within ICH S9 Q. In cases where the mechanism of action is expected to yield a reproductive toxicity risk and/or knock out animals or use of surrogate biologics in rodents have demonstrated a reproductive risk, should these approaches be considered sufficient for hazard identification, or should a study in pregnant Non Human Primates (NHPs) be conducted? A. A weight of evidence assessment of reproductive risk should be provided. An NHP study to assess EFD hazard should not be considered a default approach. Development toxicity studies in NHP can only provide hazard identification according to ICH S6 (R1). The expected reproductive hazard should be appropriately indicated in the label. 12

13 DART within ICH S9 Does weight of evidence (WoE) support a waiver of the regulatory requirement to assess classical in vivo DART effects of the biologic when only relevant species are NHPs? Programmed Cell Death (PD) 1 or PD L1 Cytotoxic T lymphocyte antigen (CTLA) 4 Novel immune checkpoint inhibitors 13

14 DART within ICH S9 Alternative approaches might be considered appropriate if scientifically justified. 1. Transgenic rodents Ipilimumab in CTLA 4 / (also ran eppnd in NHPs) 2. Rodent homologous proteins Blinatumomab murine surrogate crossed the placenta and had PD effects in dams (not in fetus) 3. Tool molecules Maybe a small molecule can interact with the target of the biologic 14

15 ICH S9 Q&A

16 Recovery groups ICH S9 Q&A The inclusion of recovery groups may be more important in the shorter term studies used to support initiation of clinical trials than in the 3 month studies needed to support marketing. 16

17 ICH S9 Q&A ADC 17

18 ICH S9 Q&A Pediatrics 18

19 Combination toxicology ICH S9 Q&A Drugs to be used exclusively in patients with cancer may be able to use abbreviated development programs for regulatory agencies. 19

20 ICH S9 Q&A Impurities Mutagenic impurities in genotoxic anticancer pharmaceuticals (ICH Q3A/Q3B) Mutagenic impurities in nongenotoxic anticancer pharmaceuticals (ICH Q3A/Q3B) Mutagenic impurities in non oncology drugs (ICH M7) 20

21 Metabolites ICH S9 Q&A If an impurity is also a metabolite, it may be acceptable to not have an impurity qualification toxicology study for it. If a disproportionate amount of the API is converted to a human specific metabolite then a toxicology study may be needed. 21

22 ICH M7

23 ICH M7 Find your actual and potential synthetic impurities and degradation products Hazard assessment to classify as: Class 1 known carcinogen Class 2 known mutagen Class 3 QSAR+ unrelated to DS and no Ames data Class 4 QSAR+ related to DS and those are Ames Class 5 QSAR expert rule / statistical Risk Characterization Control 23

24 ICH M7 Class 1 known mutagenic carcinogen Chemical specific risk assessment is possible Based on a TD 50 value, which is the mg/kg dose that induces tumors in half of the test animals, from most sensitive rodent species, sex, and tumor site 24

25 ICH M7 Class 1 known mutagenic carcinogen TD 50 50,000 corrected for body weight Example impurity TD 50 = 10 mg/kg/day = (10 mg/kg/day 1000 μg/mg) 50,000 = 0.2 μg/kg/day 50 kg body weight = 10 μg/day is an Acceptable Intake (AI) 25

26 ICH M7 26

27 ICH M7 Class 1 PDE (non mutagenic) Aniline (non linear accumulation in spleen and splenic tumors occur) PDE = (7.2 mkd 50 kg) ( )= PDE = 720 μg/day US EPA IRIS (linearized multistage procedure): dose associated with 1 in 100,000 lifetime cancer risk is 120 μg/day 27

28 ICH M7(R1) 28

29 ICH M7 Class 2 or 3 known mutagen (Ames+) or (QSAR+ unrelated to DS) In absence of compound specific carcinogenicity data, a default lifetime TTCbased acceptable intake of 1.5 μg/day is considered associated with negligible risk 29

30 ICH M7 Class 4 or 5 non mutagen (QSAR+ related to DS)/(Ames ) or (QSAR / ) Treat as non mutagenic impurity 30

31 ICH M7 Less than lifetime (LTL) exposure approach to AI or PDE Assumes similar risk for cumulative lifetime dose distributed over shorter durations Additional safety factors applied for durations up to 1 year yield more conservative values compared to 1 in 100,000 excess risk 31

32 32

33 ICH M7 LTL exposure approach for AI or PDE AI or PDE can be adjusted for shorter duration of use in same proportion as Table 2or not more than 0.5%, whichever is lower. 33

34 ICH M7 LTL exposure approach for AI or PDE If AI = 15 μg/day for lifetime exposure (10 fold from default lifetime TTC of 1.5 μg/day) LTL limits can be increased 10 fold to a daily intake of 100 μg (> 1 10 years treatment duration), 200 μg (> 1 12 months) or 1200 μg (< 1 month). However, for a drug with a maximum daily dose of, for instance, 100 mg the acceptable daily intake for the < 1 month duration would be limited to 0.5% (500 μg) rather than 1200 μg. 34

35 ICH M7 LTL exposure approach for AI or PDE When there are three or more Class 2 or Class 3 impurities specified on the drug substance specification, total mutagenic impurities should be limited as described in Table 3 for clinical development and marketed products. Duration of treatment 1 month > 1 12 months > 1 10 years > 10 years to lifetime Daily Intake [μg/day]

36 ICH M7 Exceptions and Flexibility in Approaches Higher acceptable intakes: food or endogenous metabolism Severe disease, reduced life expectancy, late onset but chronic disease, or with limited therapeutic alternatives. Cohort of Concern: aflatoxin like, N nitroso, and alkyl azoxy structures (very potent) 36

37 ICH M7 Control Material attributes Facility and equipment operating conditions Design of the manufacturing process In process controls Release testing on drug substance and drug product 37

38 ICH M7 Control What if Sponsor cannot control to TTC? It is often acceptable to exceed the TTC By how much? (handled on a case by case basis) Requires inclusion of additional information Drug s indication, intended duration of use, availability of other drugs, patient populations, CMC input (efforts to reduce/achievable levels) 38

39 Scenario 1 When a new manufacturing process leads to a previously unseen process related impurity Can we proceed by having the first dose in humans at a level that allows low exposure to the impurity, and then the next dose could be the desired/recommended dose? What is the API; i.e. how toxic? What is the dose of the API and the absolute amount of impurity patients receive from the impurity. Is the impurity API related? 39

40 Scenario 1 continued In the end, when a qualification toxicology study is required for new impurities: Ideally it will be a multi dose GLP tox study in a relevant species for two weeks or greater in duration 40

41 Scenario 2 Hypothetical start dose = 10 mg/m 2 An impurity in the DS with a proposed limit of NMT 4% (i.e., above ICH qualification threshold) is claimed be qualified by a toxicology study. Generally acceptable early in development. However, the clinical dose may be escalated such that the dose of the impurity may exceed the amount qualified by the original study (PMR?). 41

42 Scenario 3 S9 or M7? GTI or PGI = 80 ppm 0.008% The total dose of GTI or PGI is 2.4 µg/ 30 mg dose of an API (2 doses are to be administered over two weeks to healthy volunteers) % is below the reporting threshold for ICH Q3A so acceptable if ICH S9 applies. The TTC for genotoxic impurities administered for a month or less is 120 µg/day, so the proposed limits of 80 ppm would be acceptable based on ICH M7 as well. 42

43 Scenario 4 Use of a treatment duration factor to account for use in populations expected to be treated for between 1 to 10 years (10 μg/day) in addition to those to be treated for greater than 10 years to lifetime (1.5 μg/day). Proposed factor was TTC x (10/1.5). 1.5 μg/day would be recommended if the majority of indications were those to be treated for greater than 10 years to lifetime. 43

44 Scenario 5 TD 50 is a cancer risk estimate, whereas LD 50 is an acute toxicity dose metric LD 50 has been used in lieu of TD 50 for calculating TTC, probably because the values are easier to find in the literature. LD 50 would not be an acceptable basis for calculating limits for mutagenic impurities. 44

45 Summary S9 nonclinical development of anticancer pharmaceuticals M7 controling mutagenic impurities in pharmaceutical drug products FDA is open to reviewing a variety of development approaches Scenarios 45

46 Acknowledgements AAPS Meeting Organizers John Leighton Michael Manning Shawna Weis Mark Powley OHOP PMAS 46

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