Critical Success Factors for Clinical Trials in Emerging Markets

Critical Success Factors for Clinical Trials in Emerging Markets Dr Victoria Elegant, LRCP, MRCS, MBBS, DRCOG, FFPM Vice-President Medical, Regulatory & Clinical Affairs Asia-Pacific Area Baxter Healthcare

Asia-Pacific Challenges Overview of regional requirements Critical success factors Conclusions

Focus on Asia Pacific Aging Population Increasing Life Expectancy Increasing Incidence of major Disease Increasing Health Consciousness Higher Disposable Income Over 30% of new expenditures on healthcare worldwide are attributable to Asia Pacific. Page 4

Money Time Resources Seasonality Why Asia Pacific for Clinical trials? Cost of clinical trials in Asia can be lower than in US/EU (30-50%), but not always Start-up timelines have become more favorable (other than China) and are 4-6 months covering all applications, site selection, contract negotiations, etc. Population exceeds 4 billion and is genetically diverse High incidence of some indications: Diabetes Mellitus (> 11%), Hepatitis B, etc. Ability to recruit patient naïve and advanced case patients Southeast Asia: Advantage for seasonal indications (e.g. influenza), Australia/NZ Potential benefit for patients in access to medicines Page 5

Challenges of performing clinical trials in Asia Pacific Complex evolving regulations, minimal harmonization Languages Large geography Differing standards Expertise of investigators performing trials Expertise of regulators Data Protection Ethical considerations Talent attraction, training and retention Time zones Communication and engagement with global colleagues

Unique and different culture, climate and economies Asia Pacific has 35 countries of which 20 currently have regulatory requirements There is some synergy between the ASEAN countries and ANZ. Overall most countries operate individually with negligible mutual recognition within the region Classification in terms of Regulatory requirements Major Countries: Japan, Australia, New Zealand, China, India, Singapore, Taiwan, Korea, Malaysia, Thailand, Indonesia, Philippines, Vietnam Minor countries: Brunei, Myanmar, Cambodia, Sri Lanka, Bhutan, Nepal, Bangladesh, Laos

AP-Regulatory needs for Drugs & Biologics GMP documentation+ site inspections: Korea, Malaysia (non PIC/s), Singapore (Non PIC/s), Taiwan (for products prioritized by TFDA) GMP documentation requirements- Taiwan, Australia Dossier ICH: Japan, China, Korea, ANZ, Taiwan Testing needs: Korea, China, India, Taiwan, Japan Variation Filing requirements: All major countries Local clinical study needs: Japan, China, Korea, India, Vietnam & Taiwan Local PMS needs: Japan, China, Korea, India, Taiwan, Philippines, Australia Dossier ASEAN: Singapore, Malaysia, Philippines, Indonesia, India, Thailand & Vietnam

Regulatory requirements devices ASEAN countries Thailand, Philippines, Singapore, Malaysia, Cambodia, Laos, Brunei, Vietnam, Indonesia, Myanmar Moving from voluntary device registration to mandatory device registration, eg Singapore, Malaysia, Thailand Japan, China device registration required, may require clinical data, sometimes local Australia follows European EC marking Taiwan, Korea, India device registration required, clinical data required in some cases Classifications vary from country to country, as do registration requirements

Global clinical trials by location Clinicaltrials.gov May 15 th 2013

South East Asia Clinicaltrials.gov May 15 th 2013

Greater China and Korea Clinicaltrials.gov May 15 th 2013

Asia Regulatory and Start-up Timelines Key Items Regulatory Regulatory and Ethics Regulatory Ethics Regulatory followed by Ethics Ethics in parallel Ethics Regulatory Ethics followed by Regulatory Submission preparation time Import license application and customs clearance Site Contract negotiation and signature First SIV Weeks Prep. w1 w2 w3 w4 w5 w6 w7 w8 w9 w10 w11 w12 w13 w14 w15 w16 w17 w18 w19 w20 w21 w22 w23 w24 w25+ New Zealand 4w 7 weeks 8-12 weeks Contract sign off within 1-2 weeks after EC approval 2-3 weeks 1-2 weeks Australia 4w 12-16 weeks 2 weeks Contract sign off within 1-2 weeks after EC approval 2 weeks 1-2 weeks China 8w 20-22 months "+" 4-8 weeks 2 weeks Malaysia 4w 4-8 weeks 6-8 weeks Contract sign off within 1-2 weeks after EC approval 4-8 weeks for issue of import license 2 weeks 1-2 weeks Philippines 4w 8-12 weeks 8-12 weeks Contract sign off within 1-2 weeks after EC approval South Korea 4w 8-12 weeks 6-8 weeks 1-2 weeks 2-8 weeks (Some Ecs require CA approval letter) Contract sign off within 1-2 weeks after EC approval 8-12 weeks for issue of import license 1 week 1-2 weeks Taiwan 4w 8-12 weeks 8-12 weeks Contract sign off within 1-2 weeks after EC approval 8-12 weeks for issue of import license 2 weeks 1-2 weeks *Note: China not to scale Page 14

IRB and Regulatory Approval Timelines Country Total (Months) Regulatory (Months) IRB (Months) Comments Singapore 1-2 1-2 1-2 Parallel submissions; duster IRB Malaysia 2-3 1.5-2 1-3 Parallel submissions; network IRB Philippines 2-4 1-2 2-4 Parallel submissions Thailand 3-4 1-3 2-4 Sequential submissions; central government IRB Indonesia 2-3 1-1.5 1-2 Sequential submissions Vietnam 3-4 3 1 Sequential submissions Hong Kong 2-4 2-4 1-2 Parallel submissions; duster IRB Taiwan 2-3 2-2.5 2-3 Parallel submissions; joint IRB possible Wong E,Drug Information Journal, Vol. 43, pp. 57 61, 2009 0092-8615/2009

Phase III industry-sponsored clinical trials conducted in Asia Pacific Source: Clinical Trial Magnifier Vol. 4:2 Apr 2011

China

Overall Regulatory Environment Evolving Challenges and Opportunities Ever-changing and unpredictable policy & rules Conservative CFDA(previous SFDA) climate Lengthy IND/CTP process (22 ± 2 M vs 1 M in US) Local sample testing & clinical trial required Biologics stringent guidelines and longer review

China Regulatory Roadmap - Drug IND 22 ± 3 months Clinical Trial Duration ( Months (BE) Years (trial) NDA 18 months * If locally manufactured drug, another 6 months to add for on-site inspection Standard process: 4-5 years Source: RDPAC survey in 2009, 2010, 2011, (38 member companies)

Recommendation of RDPAC benchmark Type of Submission Items Chemical Biotherapeutics 2011 IDL MRCT CTA 17±2 months 20±2 months NDA 18±2 months 20±2 months Category 1 10 ±2 months 20±2 months Category 3/7 9±2 months 18±2 months Type of Submission Items Chemical Biotherapeutics 2012 IDL MRCT NDA CTA 22±2 months 20±2 months (not including ANDA) 22±2 months 20±2 months Category 1 10 ±2 months 20±2 months Category 3/7 13±2 months 18±2 months

Regulatory Routes for Commercialization Regulatory Filing Options Description China launch relative to US launch Confirmatory Trial MNT (multinational trial) IND (innovative drug) Local development (Generic) China only China participates in global MNT Full development in China (local man f sample for Phase I/II/III in parallel to global plan) CMC + BE/CT + local man f 4 5 years 1.5 years 6 months China controls the timing

Possible pathways 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 Global Timeline Global Phase III NDA Submission US approval Option1 China join global trial CTP Global Trial wait IDL Option2 China registration trial IDL approval China Launch CTP Local Trial IDL IDL China approval Launch Note: the timeline is just for illustration

Where is China now in terms of clinical research quality? ICH GCP Adoption International medical practice Patient Consent Protocol Compliance Infrastructure in place(units number is still small) Experienced, Motivated Investigators (although limited) Documentation Short of Well trained monitors, investigators and coordinators Lack of trained experienced staff and high turnover is a problem

FDA Inspection on China Studies VAI - Voluntary Action Indicated. Objectionable conditions were found but the problems do not justify further regulatory action. Any corrective action is left to the investigator to take voluntarily. NAI - No Action Indicated. No objectionable conditions or practices were found during the inspection. 04 Drug accountability 05 Investigational plan 06 Records 16 Adverse reaction 26

Presentation title Slide no 28 05-Apr-2011

Regulatory System is Multi-layered and Extensive Ministry of Health and Family Welfare Main Policy Maker DRUGS CONTROLLER GENERAL OF INDIA (DCGI) Central License approving authority for manufacture, sale or distribution of Drugs, Biologics and Medical Devices Approval process has 3 stages 1.Application under Rule 122A - Form 44 (fee Rs. 50,000/-) - Approval granted in Form 45, 2.Marketing authorization Form 41 ( Fee USD 1000 + 1500) 3.Import License in Form 10 (Fee INR 1000) Recent developments in India Regulatory Regime REGISTRATION OF NEW PRODUCTS New drug approval becoming increasingly stringent Clinical trials pre-requisite for NDA CT costs would need to be build in product registration costs post 2012/13 REGULATIONS FOR BLOOD PRODUCTS Incomplete, variable and loosely enforced Currently different levels of regulatory requirements for local and global manufacturers - Level field in budding stages Baxter key partner in formulating Testing Policy for Blood products, Clinical development plan and Pharmacopeia recommendations EXPERT COMMITTEES (NDACs) 1. Evolving stages resembles USFDA structurally 2. Relationship based regime 3. Frequent visits needed to the NDAC members for knowledge sharing and expediting the approval process INTERFACING OFFICES 1. Port offices 2. Testing labs (CDTLs and NIB) REGULATIONS FOR MEDICAL DEVICES AND LABELING COMPLIANCE Partial Regulation ; ambit being increased gradually Compliance to India specific labeling requirements (SWAMA guidelines) National Pharmacovigilance Program Separate section in CDSCO office Post market Surveillance for AE reporting and Patient safety

Registration Process - Drugs & Devices Application for New Drug/Device ( 122A) Product can be legally imported with India specific requirements Waiver granted Clinical Trial YES Submit CTA in Form 44 (fee Rs. 50,000/-) Review by DCGI Office + NDAC* Apply for Import Permit in Form 8 & 9 CT permission 5-6 months 9 months Apply for Marketing Permission in Form 40 ( Fee USD 1000 + 1500) CT conduct and submission of CSR NDAC New Drug Approval Committee Clinical Trials needed only for specific Medical Devices.

India challenges India: compensation clause gazette 30 Jan 2013 has caused global sponsors to put on hold clinical trials in India over concerns with a) Drug related injury b) Therapeutic inefficiency clause c) Placebo clause for compensation due to therapeutic non performance d) 24 hr timeline for reporting deaths to DCGI from the time PI is informed. Following intense lobbying and discussions, amendments were presented to Drug Technical Advisory Board meeting on 16 th May for legal approval and the outcome is awaited.

Significant Rebounce Expected From Jan-Apr 13 grant of Clinical Trial approvals was stalled. However, most applications have been fully processed and 33 trials have been approved by APEX committee on 29-Apr-13. In response to serious representation by all stake holders including industry, compensation clause amendments have been drafted with following modifications. a) Drug related injury b) Removal of therapeutic inefficiency clause c) Removal of placebo clause for compensation due to therapeutic non performance d) 24 hr timeline for reporting deaths to DCGI from the time PI is informed. These amendments were presented to Drug Technical Advisory Board meeting on 16 th May for legal approval and the outcome is awaited.

ASEAN

Regulatory Agencies in S.E. Asia

Outcome of FDA inspections Country No. of Inspections Wong E,Drug Information Journal, Vol. 43, pp. 57 61, 2009 0092-8615/2009

Critical Success Factors - 1 Strategic project plan consider: Complexity of protocol Experience of Investigators, resource to conduct study, SMO use In source vs. outsource model (oversight and escalation pathway) Saturation of therapeutic areas detailed feasibility is critical Realistic budget Experienced local staff, esp Taiwan, Korea, China, India even if out-sourced need face of the company Investigator meetings in the region, with interpreters, on the weekend, global attendance Robust Risk Management Plan (monthly review and update), Quality Assurance plan and Quality Control plan per country Realistic timelines best/worst case scenarios, with back up sites and countries Korea, Taiwan, Hong Kong lengthy contract process previous relationship eg CRO can help Ongoing training and mitigation plan to counteract high turnover and relative lack of experience of staff

Critical Success factors - 2 China long approval timelines, huge patient pool, consider China early in strategy Consider parallel regional study for countries that require registration studies (Korea, India, Taiwan, China, (Japan) ) Needs to be identified/considered very early in the development program China, India and Korea consultation with MOH critical for successful registration Indonesia - not so favorable for studies as restrictions on export of blood samples Sri Lanka and Vietnam, new to clinical trials - start with simple protocols minimal risk to projects/programs Regulatory intelligence critical, can lead to delays - India

Conclusions Regulations are complex and evolving in a large non homogeneous region Deep local knowledge and continuous intelligence is critical to keep abreast of constant change Conducting trials in the region, including regional strategies: Allows gains in efficiencies and cost savings Access to large populations Supports global programmes Conducting clinical trials in China: Access to China May help registration in Japan, HK, Taiwan, Korea, Japan

Key: Developing and maintaining expertise in the region is critical to ensure success of programmes Flexibility, constant review and revision of strategy critical for success

It is not the strongest of the species that survive, nor the most intelligent, but the one most responsive to change. Charles Darwin