Asian Ethnicity & Drug Development-Regulatory Risk

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

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?

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 Should Ethnicity be accounted for in treating Chinese patients with CBZ? NEJM 364: 1126-1133 , 2011

4. Should ethnicity be accounted for when prospectively developing new drugs? • Potential consequences of not accounting for ethnicity in new drug development: • 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

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

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

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

8. Are People Different?(mean weight (kg)) • 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 • CDC US mean body weight, height, bmi 1960-2002 http://www.cdc.gov/nchs/data/ad/ad347.pdf • A Survey on Nutrition and Health in Chinese Citizens. Wang Longde

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) 1997 • 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. 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 Bridging Review Dose-Response Phase 3 Confirm Reviews China SFDA U.S.-EU FDA Japan PMDA EMEA Approvals Approvals • China • PK study in China • Modified Phase 3 trial 100 patients each new drug + comparator 2. Parallel: Global development plan & Phase 3 trial(s), simultaneous approvals Reviews Dose-Response Phase 3 Confirm FDA U.S.-EU U.S.-EU • Japan • Dose-response • Efficacy-safety 1997 Global clinical trial EMEA Asia Asia SFDA (pk or dose-response) (multi-regional clinical trial) PMDA Which scenario meets local patient needs ?

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

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

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….. US-EU NDA ASIA NDA • Ethnicity • Local practices

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

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

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

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

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

21. 1. Simulate Chinese Pharmacokinetics from Prior Known Chinese Physiology (e.g., Simcyp, GastroPlus, Matlab) Drug Characteristics Physiologic PK Modeling • Physico-chemical (pKa, clogP, MW, solubility) • Tissue binding (plasma, blood, tissues) • Clearance • Fractional (renal, hepatic) • Hepatic microsomes (Vmax, Km) • 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) Decide which special populations are important to confirm in Chinese patients Decide if confirmation needed using PK only, PK-PD, or an efficacy-safety trial Simulate trial based on prior knowledge with this drug and others + earlier PBPK simulations Consider Bayesian trial design to be more efficient with patient numbers.

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