Regulatory Challenges Regarding Clinical Trials in Emerging Markets, with Focus on Asia Pacific Alistair Davidson, Senior Director, Global Regulatory Affairs DIA RI SIAC Monthly Call, 12 June 2012

Why Run Trials in Asia Pacific? …therefore expectations are high for region success Patient Availability: Large, highly-motivated patient population Improved patient compliance Large target patient population per investigator –Large regional referral centers –Fewer doctors/specialists per head of population (compared to NA & EU) Treatment-naïve patients Less competition for patients compared to NA & W.EU Investigators: Many physicians trained in Western countries English is often used in source documentation Good exposure to clinical trials Investigator participation driven by interest in disease, research & publication Investigator fees go to research, not investigator salaries (less incentive for fraud) Many investigators are also considered global opinion leaders Cost Effective: Lower inv. fees & salaries Low or absent institutional fees Higher patient recruitment per site translates into lower study management costs Shorter recruitment time means reduced costs Generally lower cost environment, lower charge-out rates Increasing sophistication & commercial awareness IP protective legislation WHO TRIPs signatories Streamlining regulatory process & reducing times –Local ethics committees / GCP / English document review Therapeutic Indications: 75% global Phase III studies in oncology, infectious diseases & CNS Highest global incidence of diabetes is in APAC –6 of the top 10 countries with highest incidence 40% of tuberculosis global burden 330,000 HIV/AIDs new cases in South/Southeast Asia (the region may surpass Africa in incidence in 2010) World leader in infectious diseases ( cases per 100,000 people reported per annum, populous countries makes containment difficult – SARs)

Key Aspects of Regulatory Environment North Asia – China, Japan, Korea, Taiwan Highly advanced, sophisticated and actively evolving Locked into multi-country clinical trial concept in Phase III – broad fit with China strategy China-Japan-Korea tripartite discussions driving closer understanding of respective systems and requirements Close to ICH and moving closer New guidances and continued improved early access to regulators can be expected. SEAsia No harmonisation yet of CTA/IND processes and requirements Mix of predictable countries (e.g. Malaysia, Singapore) and ones with regular change/challenges (e.g. Indonesia, Vietnam) Generally manageable requirements and timelines with no firm need for local studies for registration (ex. Vietnam) India Strongly independent; accelerating evolution of regulations Political/DCGI changes and flux complicate predictability Introduction of New Drug Advisory Committees in India IND regulatory timelines, after a period of change, are moving back towards global benchmarks

China/Japan/Korea/Taiwan: require a level of local (or Asian) supporting data CHINA: Most common registration route is Class III registration – chemical drugs Phase I PK data in Chinese patients Phase III data in at least 100 Chinese patients per arm for global clinical trials JAPAN: Full Japanese ‘bridging’ clinical development (Phase I-III) required, per ICH E5 PMDA will accept Asian data provided “significant number” of Japanese patients KOREA: Require local bridging data to global clinical data package, per ICH E5 Phase III Safety/efficacy data in Korean patients and no official patient numbers stated TAIWAN: Require ‘bridging data’ to global clinical data package, per ICH E5 No minimum patient numbers stated, but flexible in accepting Asian, non-local Phase III data Incentives in terms of speed, help with study and reimbursement outcome 4 Regulatory Requirements: N. Asia

China - Regulatory Environment, no longer just a “Great Wall” Has always been considered complex −Long lead times compared to others −Difficult to predict review outcomes −Requires IND and NDA reviews and sample testing −Overload in period with drug application up to 20,000 cases annually , approx 6,000 applications annually. But… −Becoming much more professional; re-organisation SFDA and CDE −Access to more resources; formal/informal links to other agencies −Development of new specific regulations and guidances, eg. Special review −Publishing targets and results −Globalising: e.g. participating in APEC; Tripartite forum (China, Japan, Korea), ICH GCG PIC/S: Pharmaceutical Inspectorate Cooperation Scheme (e) CTD: electronic Common Technical Document GRP: Good Regulatory/Review Practice DMF: Drug Master File

USA FDA cf China SFDA USA - FDA Around total employees 400 pharma companies, 300 biotech companies Excellent infrastructure, Progressive, innovative, transparent, accountable PDUFA - set standards for review timelines IND review fast China - SFDA Staff strength: 180 at SFDA (19 for registration and administration); 120 in CDE for drug review), 400 at the different centres working for SFDA and 1500 in 30 provinces Approx 5000 pharma manufacturers, including biotech companies 6294 applications received in 2010; 61.7% are generics Need to improve technical knowledge and better understand international review practices (FDA/EMEA)

Application Submission Dossier content and format checking by SFDA (35 days) Technical evaluation by CDE (90/80 days) Final approval by SFDA (30 days) CTA issued by SFDA Supplementary data from applicant within 4 months Supplementary data from applicant within 4 months Supplementary data from evaluation by CDE (40/25 days ) by CDE (40/25 days ) Supplementary data from evaluation by CDE (40/25 days ) by CDE (40/25 days ) Based on the regulations, official timeline for IND is around 7 months. However, because of some delays in SFDA/CDE, the actual duration is up to months. If queries received from CDE then an additional 4+ months is needed. After IND, there will be 1-2 months for EC/IRB approval. Panel meeting (40 days) China: Procedure and Timeline of Global Trial IND- Chemical Drug Approval for EC/IRB (1-2 months) Approval for EC/IRB (1-2 months) Dossier preparation (2~3 months) (2~3 months) Dossier preparation (2~3 months) (2~3 months) *All days are working days

Technical evaluation by CDE (90/80 days) Final approval by SFDA (30 days) CTA issued by SFDA Supplementary data from applicant within 4 months Supplementary data from applicant within 4 months Supplementary data from evaluation by CDE (40/25 days ) by CDE (40/25 days ) Supplementary data from evaluation by CDE (40/25 days ) by CDE (40/25 days ) Based on the regulations, official timeline for IND is around 7 months. However, because of some delays in SFDA/CDE, and the difficulty of QV testing on biological product in NIFDC, the actual duration is up to months. If queries received from CDE then an additional 4+ months is needed. After IND, there will be 2 months for EC/IRB approval. Panel meeting (40 days) China: Official Procedure and Timeline of Global Trial IND: Biotech Drug Approval for EC/IRB (1-2 months) Approval for EC/IRB (1-2 months) Application Submission Dossier content and format checking by SFDA (35 days) Dossier preparation (2~3 months) (2~3 months) Dossier preparation (2~3 months) (2~3 months) *All days are working days 80 days: special review treatment, can only apply to 1 st submission of a product 90 days: all other cases Normally only applicable for the 1 st submission of an NCE/IMD NIFDC QV testing (60/90 days)

China Regulatory Challenges – Regulation and Guidance High-level guidance hurdles Still evolving – but currently not developed enough to provide specific guidance Requirements are not very transparent Intention is to steadily improve over next few years – this has started Ensuring a strategy to manage: Need senior RA people with deep knowledge and long-term working experiences Keep close eye on SFDA/CDE movement Good relationship with SFDA/CDE officials Strong analysis on flexibility: regulation vs. reality Capability to forecast 9

Multi-centre Regional Trials: other considerations Epidemiology/disease prevalence/perceived seriousness of disease in East Asia/China Comparator drug East Asia/China vs USA/EU Commercial priority Ethnosensitivity: clinical relevance of observed differences East Asia/China cf other populations Effective planning −Necessary in order to meet varied East Asia/China regulatory/IND/IRB/EC/import licence lead-times −Sufficient patients allocated to meet regulatory requirements and expectations −Appropriate recruitment window for East Asia/China Speed to licensure −A multi-regional/country/global clinical trial will normal be faster than separate local studies Protocol design −Dose selection (vs USA/EU), relevance of comparators, endpoints Regulatory planning −High variation in of regulatory requirements and timelines across region −Variable opportunities/quality for pre-study consultation on strategy/design Acceptance of data for USA/EU regulatory submissions

Key Timeline Factors: Process Process −EC process −MoH process o Interdependencies of above −Import licence −Site identifciation and preparedness −Validity period of Clincial trial certificate Rate limiting steps −Agreement on strategy and plan: o Countries/numbers of patients o Protocol o Sites −Agreements/contracts with sites, inc budget −Availability of documentation −Understanding of need for and timing of various documentations −Translations o Multi-language o Authority/Ethics documents vs documents for patients

Key timeline factors: critical for success Critical success factors −Understand the process −Teamwork across all elements of process −Early provision of required documents −Early provision of sponsor budget; PI approval on the budget −Excellent translation agency or local translation −Good relationship with site for LEC follow up −Status of trial in other countries −Need for export of biosamples

Future Clinical Development Map? Current Future Use data gathered in US/EU to justify registration in Asia Use data gathered in Asia to justify registration in US/EU

4 pillars for operational regulatory success ALIGNMENT −Ensure plans match up: HQ-Region-Country-Regulatory Agencies −Ensure plans are flexible enough to change quickly PEOPLE −Hiring, training, coaching, retention. −Differentiating roles: leader, strategist, writer, compiler, publisher, expert INTELLIGENCE −Capture, harness, interpret and exploit. −Map the future and relate to present. −Use external sources carefully PROCESSES −Drive compliance, consistency, efficiency and measures −Change when you work for them, rather than vice-versa

Key Regulatory Success Factors Local RA team/manager owns authority relationship and requirements Good relationships critical −Internal RA: central  local  external Supplier  Authorities −Key functional partners: commercial, clinical, legal, BD Regular communication Build and store goodwill, someday you will need it Business plans WILL change at short notice Proactively add value to business −Not “you can’t” −“You can” Own and solve regulatory resource issues −Internal re-allocations −Outsourcing/off shoring Integrity, openness, transparency 15

Conclusions:….the next 10 years… 16 Known: Continued evolution of the North/East Asia clinical development model Improvements in time and quality of IND review in China Increase in quality/ capacity of resources at authorities in Asia: probably increases in fees to cover some of this Significantly increased Asia-ation and globalisation of local companies, through organic expansion, partnerships, alliances R&D + Manufacture + authority competence = time for an Asian authority to core group of “referenced” countries. Possibilities for different regulatory/ development models, especially for products for regional-specific diseases.