Clinical Trials in Emerging Markets C5’s Forum on Ensuring Compliance & Managing Legal Risks in Structuring & Conducting Clinical Trials, December 2006, London: Clinical Trials in Emerging Markets C5’s Forum on Ensuring Compliance & Managing Legal Risks in Structuring & Conducting Clinical Trials, December 2006, London Nermeen Varawalla, MD, DPhil (Oxon), MBA Vice President, Corporate Development PRA International


Agenda: Clinical Trials in Emerging Markets: Agenda: Clinical Trials in Emerging Markets Value Proposition Trial Execution Addressing Concerns Looking Ahead


Emerging Markets of Clinical Development: Mexico Brazil Argentina Chile Poland Russia Hungary Other CEEC South Africa Australia & New Zealand China South East Asia India Emerging Markets of Clinical Development Although at different stages of maturity, member countries are remarkably similar.


Emerging World Clinical Development: the Balancing Act: Emerging World Clinical Development: the Balancing Act Nascent clinical development environments Prolonged regulatory processes Relatively poor commercialisation potential Ethical dilemmas Concerns regarding Intellectual Property protection Large patient populations with diseases of both developed and developing world Fewer competitor trials Motivated investigators Potential for cost savings High growth markets of tomorrow Attractions Challenges


Cancer Patients in India: Cancer Patients in India About 3 million diagnosed cases 850,000 new cases every year (1 million in USA) 50%+ of cancer cases: oral cavity, lung and cervix Other common cancers: breast, head & neck, and pancreas Potentially much higher true cancer caseload The speed of patient recruitment for oncology clinical trials in India is up to seven times faster than in the United States.


Speedy Recruitment for Oncology Studies in Central and Eastern Europe: Speedy Recruitment for Oncology Studies in Central and Eastern Europe PRA Experience – 2003 in Poland, Hungary, Czech Republic & Slovakia


Patient Recruitment can be up to 10 times Faster than in the US.: Patient Recruitment can be up to 10 times Faster than in the US. Breast Cancer, Phase III, PRA Study Cumulative Enrolment by Country (N=723 Patients) 20 patients / site 10 Sites 15 Sites 15 Sites 200 Sites 0 50 100 150 200 250 300 Poland Russia Mexico USA


Enhanced Site Effectiveness (pts/site) in Emerging Countries: Enhanced Site Effectiveness (pts/site) in Emerging Countries Asia-Pacific South-Central America CE Europe Western Europe United States Pts / site Source: Sponsor Experience 2001 - 2005


Fewer Ineffective Sites in Emerging Countries: Fewer Ineffective Sites in Emerging Countries Asia-Pacific South-Central America CE Europe Western Europe United States Source: Sponsor Experience 2001 - 2005 % of sites with 0-1 pts


Slide10: 0 5 10 15 20 25 30 Estonia Hungary Lithuania Poland Russia Austria Belgium France Germany Italy Spain Sweden Holland UK No of Sites Patient/Site Comparison of Site Performance across Europe Queries/Pt Source: PRA Experience 2002 - 2005


Slide11: Source: Freedom of Information FDA, 2005 Findings of FDA Inspections %


Slide12: Source: Freedom of Information FDA, 2005 Outcomes of FDA Inspections %


Clinical Study Cost Comparisons by Country: Clinical Study Cost Comparisons by Country 0.72 1.09 0.71 1.56 0.93 1 0.42 0.4 0.52 0.56 Poland UK France Germany Spain US Australia Russia China India Source: FastTrack Systems Global Cost Databases, 2006


Cost Savings from utilising Emerging Countries can be Substantial: Cost Savings from utilising Emerging Countries can be Substantial Treatment costs 30% of those in the US Lower costs for medication, investigations and hospitalisation Reduced and cheaper domestic travel Urban concentration of sites Cheaper fares & tariffs Support Services Printing, translation, local courier Data Management


Variability of Clinical Grants (USD) : Variability of Clinical Grants (USD) 0 2000 4000 6000 8000 10000 12000 14000 Netherlands USA Germany Australia Canada Mexico Argentina Peru Poland Brazil Russia Source: FastTrack Systems Global Cost Databases, 2006


Correlation of Data Quality with Clinical Grants. : Correlation of Data Quality with Clinical Grants. Clinical Grant USD/pt No of queries / 100 CRF pages 8.6 11.1 12.5 8.4 22.7 13.6 15.0 18.5 12.0 9.0 8.9 0 5000 10000 15000 Netherlands USA Germany Australia Canada Mexico Argentina Peru Poland Brazil Russia 0 4 8 12 16 20 24 Source: FastTrack Systems Global Cost Databases, 2006


Key Advantages of Emerging Markets : Key Advantages of Emerging Markets   


Emerging Countries have Future Commercial Value: China Example: Emerging Countries have Future Commercial Value: China Example 0 5 10 15 20 25 2004 2005 2010 Pharmaceutical Market Size in USD Billion 7th largest pharmaceutical market in the world in revenue Rapid growth fuelled by: Population = 1.33 bn in 2005 60 yr olds = 160 M in 2005, 280 M in 2025 Relatively low baseline: per capita drug expenditure at 12 USD is 2% of that in the US Urbanisation & affluence Conversion from the exclusive use of Traditional Chinese Medicine Most large pharmaceutical companies have a major presence in China


Regulatory Approval Times: Regulatory Approval Times 0 30 90 270 China Brazil India Czech Republic Poland Australia / NZ South Africa Russia Taiwan Korea Hong Kong Singapore US Days Trend is for regulatory approval timelines to further decrease Uncertainty around approval times is reducing Countries have processes with clear instructions for documentation Local knowledge and liaison with regulator is essential


Slow Regulatory Process in China: Slow Regulatory Process in China State Food and Drug Administration (SFDA) Application acceptance Notification for drug specifications validation & verification Centre for Drug Evaluation (CDE) Technical review National Institute for the Control of Pharmaceutical & Biological Product (NICPBP) Drug specifications validation & verification Additional information / revisions requested Single collated submissions within 4 months CDE reviews supplemental submission Application SFDA final review Clinical trial approval Protocol, ICF, EC approval Study sites & investigators submitted & filed with SFDA before study start Approval refused - 85 days - - 20 days - - 120 days - - 40 days - - 20 days -


Slide21: Countries like Korea have Streamlined their Regulatory Approvals.


Slide22: Healthcare Systems in Emerging Countries Conducive for Clinical Research Private Private Pharmacies Private Hospitals Private Outpatient Centers Dentistry Ophthalmologists Gynecologists Dermatologists Pharmacies Pediatricians GPs Psychiatry Suited for global clinical trials in hospital based populations


Asia offers a Wide Choice of Investigative Sites. : Asia offers a Wide Choice of Investigative Sites. INDIA CHINA East ASIA Queen Mary University Hospital, Hongkong with 1400 beds serves a population of 1.5 million people Singapore’s National University Hospital - a 930 bedded acute and specialist hospital Veteran’s General Hospital, Taipei, Taiwan has 440 specialists, 300 beds, 2.5 M patients attend out patients clinics and 1 M receive in patient care per year The National Taiwan University Hospital has 4,000 staff serves approximately 0.6 M inpatients and 2.4M outpatients per year Renji Hospital, Pudong Shanghai has 1,000 beds & 2,300 staff Ruijin Hospital, Shanghai has 1,385 beds & 3,242 staff Peking Union Medical College Hospital is upgrading to better serve international sponsors Asian Clinical Trial Networkcovers Korea, Malaysia, Thailand, Vietnam and Taiwan.


Tata Memorial Hospital, Mumbai—ideal for Oncology Studies: Tata Memorial Hospital, Mumbai— ideal for Oncology Studies 25,000 cancer patients visit each yr from India & neighboring countries 1,000 patients attend out-patient clinics each day 441 in-patient beds 10,000 major operations each yr 5,000 radiotherapy & chemotherapy treatments delivered each yr Equipped with spiral CT scanner, gamma cameras, linear accelerator, bone marrow transplant facilities etc. Clinical Research Secretariat to coordinate clinical trials Satellite hospital with beds assigned for clinical trial participants


Smart Design of Global Clinical Trials: Smart Design of Global Clinical Trials Divide patient enrolment between North America, Western Europe & Emerging Countries Include 3-4 Emerging Countries Plan for enough sites & patients / region to make it worthwhile Utilise study start up time to identify investigators & subjects Confirm protocol feasibility Ensure access to capabilities Obtain a US IND & initiate US sites first Perform the vast majority of global data management in India Obtain quality data to meet FDA / MHRA requirements Reduce patient recruitment times Address commercial imperatives Mitigate risk Capture efficiencies Goals Actions


India—Compelling for Data Management: India—Compelling for Data Management Large and growing resource pool Highly developed process innovation skills Credible data quality Operational flexibility to manage “crunch” periods Cost-effectiveness Software options Established data management software e.g. Oracle Clinical, Clintrial, PRA Flex DMS™ Range of services available Data entry & verification Statistical analysis, medical writing, software programming The case for off-shoring global data management to India


Addressing Sponsors’ Concerns: Addressing Sponsors’ Concerns Regulatory approval process more streamlined & predictable Study start-up up to 12 weeks from regulatory submission Regulatory approval timelines need to further decrease Government / industry initiatives to strengthen ethics committee approval processes Recognition of critical importance of informed consent Overall benefit to healthcare delivery in Emerging Countries Data for pivotal studies accepted by the FDA / EMEA Successful FDA audits Investment in education & training: state & private Quality Regulatory Approvals Ethics Apparent commitment to uphold and enforce Intellectual Property protection as per international standards IP Protection


Benefits for Healthcare Delivery in Emerging Countries. : Benefits for Healthcare Delivery in Emerging Countries. Treatment arm study participants access biomedical innovation All participants enjoy improved care Injection of resources into local healthcare system Standards of medical practice improve: communication, record keeping, evidence based medicine Not exploitation! – provided ICH GCP standards are followed: informed consent, expanded access


Concerns about functioning of Ethics Committees are being addressed: Concerns about functioning of Ethics Committees are being addressed Local Ethics Committee exist in > 200 clinical centres ICMR (Indian Council for Medical Research) to review & audit the functioning of ECs introduce a national accreditation system for ECs develop the Independent Forum for Ethics Review Committees, a training body Revised Schedule Y of Drugs and Cosmetics Act governing clinical trial conduct has prescribed roles and responsibilities of ECs composition as per ICH GCP guidelines formats for the EC approval letter provisions for inspection The India Example


Changing Mix of FDA-Regulated Clinical Investigators: Changing Mix of FDA-Regulated Clinical Investigators % of total 1572s filed Source: Tufts CSDD


Building & Nurturing Investigator Networks : Building & Nurturing Investigator Networks Recognizing critical importance Patient Access Data Quality Ethical Integrity Growing the Investigator Pool Proactive acquisition Training Nurturing Investigator Networks Ongoing training / education “Respectful” feasibility Site level support Investigator & Site Relationship Management


Slide32: Mexico Brazil Argentina Chile Poland Russia Hungary Other CEEC South Africa Australia & New Zealand China India Requirements to Unlock the Clinical Trial opportunities in Emerging Countries. Thorough knowledge of local regulatory processes & operations Deep relationships with local physicians and medical centres Expertise in clinical development for FDA / MHRA Local application of global processes & systems


Questions…..: Dr Nermeen Varawalla, MD, DPhil (Oxon), MBA Vice President Corporate Development, PRA International Pacific House Imperial Way, Worton Grange Reading, Berkshire RG2 OTD, UK Tel: +44 7900 227783 E-mail: varawallanermeen@praintl.com Website: www.prainternational.com 6th floor Sterling Center Dr Annie Besant Road, Mumbai 400 018, INDIA Questions…..