1. Asian Ethnicity & Drug Development-Regulatory Risk Bob Powell Clinical Pharmacology Roche Beijing bob.powell@roche.com Ethnic Differences and Global Drug Development Drug Information Association Beijing, China May 18,2011 1

2. If there are true ethnic differences we should: Decide if ethnic differences (e.g., disease biology) are likely to be clinically significant – When unclear, possibly do further research to clarify significance Account for clinically significant differences in big decisions (e.g., development strategy, trial design, approval, labeling) Do we do either in a systematic manner? 2

3. Preventing Lethal Drug Effect in Chinese Patients A Case Study Carbamazepine (CBZ): most common cause of Steven-Johnson Syndrome (SJS) & Toxic Epidermal Necrolysis (TEN) in SE Asia Mortality SJS (5%) & TEN (25-35%). Fever, malaise, skin lesions like a bad burn…skin detaches. Genetic test (HLA-B*1505 allele) predictive in Han Chinese (98.3% sensitivity, 95.8% specificity) Prospective study: 4877 Taiwanese patients prospectively tested for HLA-B*1505 allele, 7.7% positive-advised to avoid CBZ SJS-TEN did not develop in any negative patient taking CBZ NEJM 364: 1126-1133, 2011 Should Ethnicity be accounted for in treating Chinese patients with CBZ? 3

4. Should ethnicity be accounted for when prospectively developing new drugs? Drug companies – Efficacy & Safety: uncontrolled. Trial design. Trial failure – Dosing. Same for all. – Clinical trials:  failure rate  delayed approval   revenue – Labeling. Local directions may not provide accurate information guiding use –  market if product not well tolerated Regulators (CDE) – Ambiguous trial results making approval decision more difficult – Inaccurate estimates of true efficacy &/or toxicity – Potential post-market problems if significant toxicity issues occur….if they can be detected Patients-Physicians – Drug does not perform as advertised. Market may decrease Potential consequences of not accounting for ethnicity in new drug development: 4

5. Can Diseases in China-Asia be Different? Chinese-Asian known disease differences – Prevalence GI cancers ↑ (stomach, liver, bowel) Hepatitis Self inflicted injuries – Disease biology NSCLC-EGFR+ 3-4x Hepatitis B &C genotypes – Phenotype Type 2 diabetes-Children – obese ↑+ Adults normal weight → ↑Risk Breast cancer- menopausal Pre > Post – Criteria for diagnosis & assessment Depression & other diseases described by symptoms-behaviors 5

6. Can Therapeutics in China-Asia be Different? Therapeutic response – Better Asian response Non small cell lung cancer- 3-4X ↑ EGFR+ Hepatitis C-size – Worse Asian response Hepatitis B-viral genotype Breast cancer response to tamoxifen-(↓active metabolite) Drug toxicity – Chemotherapy – Interferon (HBC) – Carbamazepine 6

7. Are Chinese-Asians Different Regarding: Dosing – Increased effect due to either ↑ exposure (↓clearance) or ↑ dynamic effect: ethanol, prasugrel, heparin, propranolol, …. Physiology: Differences in size, gastric acidity, metabolism, transporters Variability (weight as biomarker) Chinese > Japanese Disease stage at diagnosis Baseline treatment 7

8. 8 Are People Different? (mean weight (kg)) USA 1 2002 (50-59 years) China 2002 2 (45-59 years) Big City (>500k) Town (200-500k) Rural 1 (richer) Rural 2Rural 3Rural 4 (poorest) Males 88.868.966.663.060.563.657.9 Females 76.961.159.457.554.858.152.3 Clcr (ml/min) estimated for 59 yo, 88.8 kg American ♂versus 52.3 kg Chinese ♀ is 99.9 ml/min versus 50.0 ml/min. Might weight difference (amount, composition) lead to pharmacologic differences? Size differences not accounted for in clinical trial planning-rather post hoc analysis 1.CDC US mean body weight, height, bmi 1960-2002 http://www.cdc.gov/nchs/data/ad/ad347.pdf http://www.cdc.gov/nchs/data/ad/ad347.pdf 2.A Survey on Nutrition and Health in Chinese Citizens. Wang Longde

9. 9 Historically Assumed ethnic differences limited to drug metabolism as reflected in pharmacokinetics ICH5 ‘ ETHNIC FACTORS IN THE ACCEPTABILITY OF FOREIGN CLINICAL DATA’ (http://www.ich.org/LOB/media/MEDIA481.pdf) 1997http://www.ich.org/LOB/media/MEDIA481.pdf – Premise. Development efficiency- sharing development data for regulatory decisions between regions ‘Acceptability of the foreign clinical data component of the complete data package depends then upon whether it can be extrapolated to the population of the new region.’ – Focus. Pharmacokinetics, pharmacodynamics, dose-response, efficacy, safety, clinical trial standards. – Disease topics….limited discussion Endpoints for assessing treatment effectiveness Medical and diagnostic definitions acceptable to the new region

10. 10 Japanese Approved (2001-7, N=137) Drug Dose Ratios (US/Japan) Clin Pharm Ther 87:714, 2010

11. Current Development-Regulatory Scenarios 1. Sequential: approve elsewhere, local bridge  2-5 year market lag 2. Parallel: Global development plan & Phase 3 trial(s), simultaneous approvals U.S.-EU Asia U.S.-EU Asia Phase 3 Confirm Dose-Response Approvals Bridging China Japan SFDA Review Reviews FDA EMEA SFDA Dose-ResponsePhase 3 ConfirmReviews FDA EMEA U.S.-EU PMDA (multi-regional clinical trial)(pk or dose-response) China PK study in China Modified Phase 3 trial 100 patients each new drug + comparator China PK study in China Modified Phase 3 trial 100 patients each new drug + comparator Japan Dose-response Efficacy-safety 1997 Global clinical trial Japan Dose-response Efficacy-safety 1997 Global clinical trial Which scenario meets local patient needs ? 11

12. 12 Global Development Paradigm 1 (sequential) Bridging (lag time 2-5 years in bridged countries)

13. 13 Global Development Paradigm 2 (parallel) (Global Clinical Trials-Japanese Recommendation) What if major ethnic differences exist in disease or pharmacology?

14. 14 Global Development Paradigm 3 (Bi-Regional Multicenter Clinical Trials) Might this be more informative and lower risk than Global trials? Or…. designing trials based on patient comparability

15. The Troll Under the Bridge is Named….. Ethnicity Local practices US-EUASIA NDA 15

16. 16 Country-Region Knowledge Needed to Support Drug R&D (links to genetics & ethnicity) Population Demographics Pharmacology (ADME PK-PD) Epidemiology Disease Biology Value Body effect on drug & drug effect on body Disease in whom, outcomes & relationships? Disease mechanism(s) Who lives there? Valuable prior knowledge   development risk

17. 17 Governments Need to Support Information Development & Sharing (supporting drug & device development) Information Gap Needs to be Filled Information Gap Needs to be Filled Local Government Primary Responsibility

18. Demographics Disease pathophysiology & epidemiology Pharmacology Pharmacokinetics Pharmacodynamics Medical practice New Chemical Entity (NCE) Global Development Planning NCE + Target Product Profile Ethnic-Regional Analysis Quantitative-Qualitative ? Ethnic-Regional Patients the Same Yes No Development- Regulatory Strategy DosingTrial Design SameGlobal DifferentRegional 18

19. Demographics Disease pathophysiology & epidemiology Pharmacology Pharmacokinetics Pharmacodynamics Medical practice New Chemical Entity (NCE) Global Development Planning NCE + Target Product Profile Ethnic-Regional Analysis Quantitative-Qualitative ? Ethnic-Regional Patients the Same Yes No Development- Regulatory Strategy DosingTrial Design SameGlobal DifferentRegional Phase 3 Global Clinical Trial Planning Uniform inclusion-exclusion criteria Same dose for all Does not include ethnicity curiosity (disease, drug, patient size, local practice) on trial outcome 19

20. Demographics Disease pathophysiology & epidemiology Pharmacology Pharmacokinetics Pharmacodynamics Medical practice New Chemical Entity (NCE) Global Development Planning NCE + Target Product Profile Ethnic-Regional Analysis Quantitative-Qualitative ? Ethnic-Regional Patients the Same Yes No Development- Regulatory Strategy DosingTrial Design SameGlobal DifferentRegional Prior Knowledge Disease-drug modeling Simulate scenarios Decide 20

21. Physico-chemical (pKa, clogP, MW, solubility) Tissue binding (plasma, blood, tissues) Clearance Fractional (renal, hepatic) Hepatic microsomes (Vmax, Km) Physiologic PK ModelingDrug Characteristics 1. Simulate Chinese Pharmacokinetics from Prior Known Chinese Physiology (e.g., Simcyp, GastroPlus, Matlab) Chinese Adults Children Elderly Renal failure Hepatic failure

22. 2. Decide Dose-Response Information Needed in Chinese Patients Options (simulated design) PK only Single dose PK-PD Multiple dose PK-PD Dose-ranging in patients (PK-PD) Phase III Confirmation (simulated design, population PK-PD) Global multi-center clinical trial Regional MRCT Local (China) MRCT Submit NDA

23. 3. Postmarket confimation in special populations (pediatrics, elderly, organ failure) a)Decide which special populations are important to confirm in Chinese patients b)Decide if confirmation needed using PK only, PK-PD, or an efficacy-safety trial c)Simulate trial based on prior knowledge with this drug and others + earlier PBPK simulations d)Consider Bayesian trial design to be more efficient with patient numbers.

24. 24 Summary Size, disease & pharmacology can lead to significant differences in efficacy, safety & dose requirements between global regions Should ICH E5 be revised or ammended? ‘Bridging’ is becoming bi-directional (west to east, east to west) Recognizing patient potential differences requires greater curiosity & flexibility in drug development Asian governments need to better define patient ethnicity similarities-differences making information publically available Companies and regulators need to invest in ethnicity prediction…. initial basis for ethnicity importance Greater regulatory ethnicity emphasis & clarity is needed. Is there a need for a yearly science conference?

25. Ethnicity Significance in Drug Research & Development) (Disease, Dosing, Efficacy & Safety) a proposed yearly conference Objectives – To review ethnicity science for disease (biology, demographics, morbidity, mortality) and pharmacology-therapeutics (dose-response, efficacy, safety) – To describe local differences in medical practice likely to influence clinical trial outcome – To consider the impact of global development scenarios when drugs are developed in one region and seek registration in others. – To evaluation ethnicity prediction based on laboratory tests and in silico models – To identify significant information gaps requiring research Format – 2 day yearly international conference held in China Participants – Physicians, biostatisticians, clinical pharmacologists, epidemiologists – Academia, pharmaceutical industry, regulatory agencies 25