Linking CMC and Toxicology: The Use of Cumulative Carcinogenic Risk for Multiple Genotoxic Impurities Criteria

1. Linking CMC and Toxicology: The Use of Cumulative Carcinogenic Risk for Multiple Genotoxic Impurities Criteria Wherly Hoffman, Daniel Ness, Elan Pharmaceuticals, Inc. Cindy Lee, Joel Bercu, Eli Lilly and Company Midwest Biopharmaceutical Statistics Workshop, Muncie Indiana, May 18-20, 2009

2. REFERENCE Quantitative Assessment of Cumulative Carcinogenic Risk for Multiple Genotoxic Impurities in a New Drug Substance Regulatory Toxicology and Pharmacology 2008. 51(3):270-277. by Joel Bercu, Wherly Hoffman, Cindy Lee, Daniel Ness

3. Overview • Background • Genotoxic impurity (GTI) - formation, qualification • Regulatory guidance on risks - one GTI, multiple GTIs • Motivation • Evaluation of cancer risk of multiple GTIs • Derivation of cancer risks • Data source • Key factors • Simulation design • Results • Summary MBSW May 18-20, 2009

4. BackgroundGTI Formation in a Drug Substance Prestarting Material Reagent Starting Material Intermediate By-Product Solvent Drug Substance Penultimate MBSW May 18-20, 2009

5. BackgroundQualification of Genotoxic Impurities Drug Substance Impurities Qualified with toxicology studies for API (ICH Q3A) Level Relative to Drug Substance Risk-based approach to qualify Not qualified with toxicology studies for API Genotoxic Impurities MBSW May 18-20, 2009

6. Background-Regulatory guidance Risk Assessment for One GTI • Available guidances • PhRMA - Muller et al. Regul Toxicol Pharmacol. 2006 Apr;44(3):198-211. • EMEA CHMP – Guideline on the limits of genotoxic impurities. 2006 • FDA draft – Genotoxic and carcinogenic impurities in drug substances and products: Recommended approaches. 2008 • Acceptable exposure of GTI • Threshold of toxicological concern (TTC) • Adapted from food industry (Kroes et al. 2004) • TTC = 1.5 mg/day = 1 in 100,000 excess cancer risk MBSW May 18-20, 2009

7. Background-Regulatory guidance Threshold of Toxicological ConcernTTC TTC World of Carcinogens Percentage of compounds not exceeding 10-5 lifetime risk 1.5 mg/day Dose MBSW May 18-20, 2009

8. Background-Regulatory guidance Regulatory Guidance on Multiple GTIs EMEA CHMP Structurally dissimilar – Individual limits of 1.5 mg/day for each impurity Structurally similar – Total exposure to all impurities can not exceed 1.5 mg/day FDA (guidance similar to EMEA CHMP) “Threshold approach to individual impurities is not intended to limit the overall excess cancer risk to 10-5 from all impurities in a single drug product or from multiple drug products concomitantly administered.” Structurally similar compounds with similar mechanisms – “…the total daily exposure to the related compounds should be evaluated relative to the recommended threshold exposure.” MBSW May 18-20, 2009

9. Background- Motivation FACTS Multiple GTIs exist in a new drug substance Risk assessment of multiple GTIs is limited currently Acceptable level for multiple GTIs is needed ACTION Assess the acceptable number of genotoxic impurities MBSW May 18-20, 2009

10. Evaluation of Cancer Risk of Multiple GTIs - DerivationTD50s from 2-year Carcinogenicity Studies Compound : developing a selected tumor at a target site Never DEPENDS Always • TD50 : average daily dose at which 50% of the population will stay tumor free for a lifetime (Peto et al., 1984). >1 study : TD50 (Species, Site) = harmonic mean of TD50s >1 site and/or species : Most potent TD50 reported MBSW May 18-20, 2009

11. Evaluation of Cancer Risk of Multiple GTIs - DerivationFrom TD 50 to Cancer Risk = = for a 70 kg person receiving 1.5 mg/day MBSW May 18-20, 2009

12. Evaluation of Cancer Risk of Multiple GTIs - Derivation Cumulative Cancer Risk of 2 Compounds Impurity B, dose dB, prob of developing cancer: pB Impurity A, dose dA, prob of developing cancer: pA Prob of developing cancer from joint CDF of A & B :pAB Approximate the low rising surface of the joint CDF with a plane + + = 0, where a, b and c are nonzero constants ab > 0, ac < 0 MBSW May 18-20, 2009

13. Evaluation of Cancer Risk of Multiple GTIs - Derivation Cumulative Cancer Risk of 2 Compounds Impurity B, dose dB, prob of developing cancer: pB Impurity A, dose dA, prob of developing cancer: pA Prob of developing cancer from joint CDF of A & B : pAB pAB = pA + pB = + 0 = + + 0 + + = 0 + MBSW May 18-20, 2009

14. Evaluation of Cancer Risk of Multiple GTIs – Data sourceCPD: Cancer Potency Database Genotoxic Compounds • What’s the impact of x on cumulative cancer risk? -> Prepare CPDs x = 10, CPD = {756 nonzoro risks and 6804 zero risks} x = 50, CPD = {756 nonzero risks and 756 zero risks} x = 80, CPD = {756 nonzero risks and 189 zero risks} Carcinogenic x % NonCarcinogenic (100-x) % • Gold carcinogenicity database (http://potency.berkeley.edu). -> 756 TD50’s of carcinogenic compounds MBSW May 18-20, 2009

15. Evaluation of Cancer Risk of Multiple GTIs –Key factorsStructural Alerts and Cancer Risks Any Relationship? underlying mechanism conjecture structurally similar genotoxic impurities implication similar cancer risks Risk range: over 100-million fold in general allow 100-fold for similarly structured compounds Structural Alerts Categories: 18 (Ashby and Tennant, 1991; Cheeseman et al., 1999; Kroes et al., 2004). MBSW May 18-20, 2009

16. Evaluation of Cancer Risk of Multiple GTIs –Key factorsWhat does Similar Mean? How do we define “similarity”? Based on structural alert (SA)? Based on fingerprinting? Different techniques (Tanimoto, Manhattan, Euclidean) How similar is similar – 30%, 60%, 80% 2D structure or 3D conformation? Do compounds similar in structure act biologically similar? MBSW May 18-20, 2009

17. Evaluation of Cancer Risk of Multiple GTIs Three key factors • Co-administration of up to three genotoxic impurities • Proportion of carcinogenic genotoxic impurities among all genotoxic impurities: 10%, 50%, 80% • Structural similarity among multiple genotoxic impurities:100-fold total risk range or 10-fold from one impurity MBSW May 18-20, 2009

18. Evaluation of Cancer Risk of Multiple GTIsSimulation Design - General • Given a CPD with x% of carcinogenic genotoxic impurities (x=10, 50, 80) • Estimate cumulative risk of K genotoxic impurities each at TTC of 1.5 mg/day 1. Randomly select one cancer risk from the CPD. 2. Repeat the previous step K times. 3. Obtain cumulative cancer risk for the combination of K impurities by summing K risks. 4. Repeat all steps 20,000 times. Estimate 90th, 93rd and 95th percentiles from these 20,000 simulated cumulative cancer risks. MBSW May 18-20, 2009

19. Evaluation of Cancer Risk of Multiple GTIsSimulation Design – Structurally Similar • Given CPD with x% of carcinogenic genotoxic impurities (x=10, 50, 80) • Estimate cumulative risk of K genotoxic impurities each at TTC of 1.5 mg/day Randomly select one risk, r, set risk range [r/10,r*10] If r = 0, then cumulative risk = 0, else 1. Randomly select one nonzero cancer risk from [r/10,r*10] 2. Repeat Step 1 K-1 times 3. Obtain cumulative cancer risk for the combination of K impurities by summing K risks 4. Repeat steps 1-3 20,000 times Estimate 90th, 93rd and 95th percentiles from these 20,000 simulated cumulative cancer risks and the 0’s. MBSW May 18-20, 2009

20. Evaluation of Cancer Risk of Multiple GTIsResults – Multiple Genotoxic Impurities The percentiles of cumulative cancer risks No. of Impurities Percentile of Cancer Risk 90% 93% 95% 1 3.27E-06 6.57E-06 1.03E-05 2 9.85E-06 1.50E-05 2.32E-05 3 1.73E-05 2.73E-05 3.79E-05 Note 1. Each impurity is controlled to a TTC of 1.5 mg/day Note 2. Assume 50% of the impurities are carcinogens MBSW May 18-20, 2009

21. Evaluation of Cancer Risk of Multiple GTIsResults - Multiple Genotoxic Impurities TTC of 1.5 mg/day per impurity. 50% impurities are carcinogens MBSW May 18-20, 2009

22. Evaluation of Cancer Risk of Multiple GTIsResults – Proportion of GTIs being Carcinogenic The 90th percentiles of cumulative cancer risks No. of Impurities Percent of Carcinogens 10% 50% 80% 1 1.79E-10 3.27E-06 7.71E-06 2 2.67E-07 9.85E-06 1.79E-05 3 1.09E-06 1.73E-05 3.08E-05 Note. Each impurity is controlled to a TTC of 1.5 mg/day MBSW May 18-20, 2009

23. Evaluation of Cancer Risk of Multiple GTIsResults – Structural Similarity of GTIs The %tiles of cumulative cancer risk of GTIs in 10-fold range No. of Impurities Percentile of Cancer Risk 90% 93% 95% 1 3.27E-06 6.57E-06 1.03E-05 2 7.70E-06 1.25E-05 1.92E-05 3 1.20E-05 1.83E-05 2.87E-05 Note 1. 50% genotoxic impurities are carcinogens Note 2. Each impurity is controlled to a TTC of 1.5 mg/day MBSW May 18-20, 2009

24. Evaluation of Cancer Risk of Multiple TGIsResults-Structural similarity with 10-fold risk range TTC of 1.5 mg/day per impurity. 50% impurities are carcinogens MBSW May 18-20, 2009

25. Evaluation of Cancer Risk of Multiple GTIsResults – Proportion of GTIs being Carcinogenic, with 10-fold risk range The 90th percentiles of cumulative cancer risks No. of Impurities Percent of Carcinogens 10% 50% 80% 1 1.79E-10 3.27E-06 7.71E-06 2 9.83E-10 7.70E-06 1.46E-05 3 1.84E-09 1.20E-05 2.16E-05 Note. Each impurity is controlled to a TTC of 1.5 mg/day MBSW May 18-20, 2009

26. Evaluation of Cancer Risk of Multiple GTIsResults – 93rd %tiles of cancer risks of GTIs with and without 10-fold risk range TTC of 1.5 mg/day per impurity. 50% impurities are carcinogens MBSW May 18-20, 2009

27. Summary • Single GTI results are consistent with literature • Favorable/lower cancer risks result from GTIs that are structurally similar than not. • Slight increases in cancer risks result from more GTIs and higher proportions of carcinogenic GTIs. NOT A CONCERN! • Up to 3 GTIs, structurally related or not, are acceptable in pharmaceutical development. • Four or more GTIs, a less likely scenario, discuss case-by-case. MBSW May 18-20, 2009