globalization is the need of trials – conducting clinical...

Michael A. Grosso, MD, FACS Executive Director, CV Clinical Development Daiichi Sankyo, Inc.

Globalization is the need of trials – Conducting Clinical Trials around the globe for successful and long lasting effects

2 | CONFIDENTIAL 2 | CONFIDENTIAL

Global Drug Development 2016

Global Pharma Market value $300 Billion /year ~7,000 drugs currently in clinical development globally Only 1 in 10,000 compounds will actually be brought to market Only 2 of 10 marketed return revenues equal or exceed R&D costs 2015 Pharma invested $58.8 billion in R&D; 10% increase from 2014 10 year Patent to recoup R&D cost before generic competition 600% increase in drug development cost from 1970 to 2010 50% increase in Global Clinical trial market from 2011 to 2015

Sources: Aiello, Healthcare BusinessToday; Office of Health Economics CMRI Data Report; Krall, IOM Transforming Clinical Research



~7,000 drugs currently in clinical development globally ~11,000 ongoing clinical trials with at least one US site Seeking to enroll nearly 3 million subjects

Sources: Aiello, Healthcare BusinessToday; Office of Health Economics CMRI Data Report; Krall, IOM Transforming Clinical Research



Leading Trends/Challenges:

Source: BioPharmaDive/Catalent; *1/3 revenue $10+ Billion USD ** 1/5 market $163 billion 2014

* **



Leading Trends/Challenges: Aging Population- longer, not healthier Rising #Age related and Chronic Diseases- $$

Cancer, CV, Neurolgic/Dementia Spiraling Development Costs Demands for Biologics-Complex analytical/manufacturing Increasing role of CRO/CDMOs Increasing Political/Legislative focus- access/cost of medication Interaction with Regulatory/Health Agencies Payers demanding “value proposition” Increasing Role of Generics/Biosimilars Enhanced Focus on novel Drug Delivery Mechanisms Enhanced Growth (and risk) Opportunities in Manufacturing Process Threat from Counterfeit Drugs- $75 Billion/year

Source: BioPharmaDive/Catalent



Clinical Trial Trends/Challenges: RECRUITMENT

Incremental improvements: complex, long, large studies: mega-trials CV

Orphan drug development RETENTION

15-40% dropout REGULATORY SETBACKS / Poor

Communication w/ Health Agencies

FAILURES 50% of NDA/BLA failures due to

efficacy 30% of NDA/BLA failures due to safety

Source: BioPharmaDive/Catalent



Clinical Trial Trends/Challenges: DEVELOPMENTAL COSTS :

Bench to Bedside: 12 + years, $2.6 billion USD (2013) $300+ million USD post-approval costs

PAYORS: “Real world” data beyond clinical trials; “p “value no longer sufficient Comparative effectiveness beyond SOC (often evolving rapidly) “Value” propositions

REGULATORS Greater post-marketing surveillance

INCREASING NEED/RELIANCE on CRO/CDMO Specialized technologies/technical support Biologics / Analytics Controlled Release/Combination formulations; enhance LCM/patent life

Source: BioPharmaDive/Catalent; Tufts Center Study Drug Development 2014



Clinical Trial Trends/Challenges: OUTSOURCING MANUFACTURING steadily rising

Lower cost labor / land ? Offset by increased regulatory risk

STRATEGIC PARTNERSHIPS Risk and Profit sharing models for Drug development and Manufacturing

PDUFA / GDUFA Impact 21st Century Cures Act remains stalled

Source: BioPharmaDive/Catalent; Tufts Center Study Drug Development 2014


WHY are Global Clinical Trials Necessary in 2016

REGULATORY Regulators often require minimum numbers of patients from a specific

region or with specific ethnic factors to support a regulatory approval Inclusion of multiple ethnic populations in accordance with guidelines (ICE E5

Guidance on Ethnic Factors in the Acceptability of Foreign Clinical Data)

SCIENTIFIC Ethnic and population differences may lead to differential efficacy and safety

outcomes Growing understanding of human genome diversity enhanced by global

clinical trials



Forces Driving Clinical Trials outside US Availability of large numbers of patients Drug naïve subjects Trial naïve subjects Patients willing, eager to participate (access) CROs available and focused on global trials Faster recruitment rates

High urban density Shorter start up times: Reduced logistical barriers (contracts, regulatory) Shorter overall trial timelines Widespread adoption of harmonized guidelines ICH-GCP Intellectual Property protection Cost



Relative Cost of Clinical Trials outside US

Source: Kaitin, Tufts Center for Study of Drug Development 2008


Breakdown of Costs for a Large, Global Clinical Trial

Global Clinical Trials in 2016

Expense Cost ( %)*

Site Payments 50%

Site Monitoring 30%

Data Management and Statistics 8%

Project and Clinical Leadership 8%

Interactive Voice Response (IVRS); Drug distribution 3.5%

Publications 0.5%

Source: *Califf 2009;



Relative Cost of Clinical Trials outside US

Source: Tufts

India 0.36

Poland 0.39

Russia 0.41

China 0.50

Brazil 0.50

Germany 0.50

Argentina 0.65

Australia 0.67

USA 1.0



BRIC Brazil Russia India China Brazil: ~4000 active clinical sites 30% Oncology; 10% CV ANVISA overhaul/ ?economy

Russia ~7,000 sites, #10 globally 800 active trials, 60% Phase III

India 67% population rural based Healthcare GDP low # of active sites declining, <2,000 Cautious approach

China On track to be #2 global pharma market ~6,000 sites, ~48% oncology, 13th globally Strong focus on domestic driven development

Source: Goatman Applied Clinical Trials



Emerging countries will account for 29% of global pharma revenue by 2018 In 2012, Brazilian and Chinese pharma markets grew

by 16% and 21%, compared average market growth of - 2% for the five major EU and - 1 % for the U.S.

Number of US Investigators has declined 3.5% annually since 2001

Number of Investigators outside of US has increased 13.5% annually since 2001

Rare and chronic diseases require new patient pools

Delays and timeline extensions result in loss of millions of dollars AND Delay regulatory clearance, product

launch/sales

Source: Lionbridge LIFE SCIENCES; Bairu 2014



RECRUITMENT/RETENTION Increased competition Incremental improvements: complex, 2x long, large studies: mega-trials- CV Patient recruitment delay accounts for average 4.6 months lost per trial Lost revenue ~ $8 million UDS each day drug is delayed from market 80% of all trials delayed at least one month due to R/R issues Not an issue solely for industry- also affects NIH, academic organizations,

research foundations

Source: Lionbridge LIFE SCIENCES; Bairu et al 2014; Metadata Solutions 2013


Global Clinical Trials in 2016 Challenges Increased logistics Varied rules/regulations: contracts, insurance, legal documentation Cultural barriers / Translation (CRFs, IBs, ICs, Protocols) Religion/Contraception

Investigational drug provision at trial end Concomitant med provisions Acceptability of placebo controls



Global Clinical Trials in 2016 Recruitment/Retention barriers Subject-related

Inconvenient scheduling clinic visits / long clinic waiting times Uncertainty of treatment Unrealistic expectations/“mis”-Informed Consent Increasingly mobile work force

Investigator-related Lack of time/under-estimation of time needed for R/R Improper feasibility design/response

Protocol-related Study impact on local clinical practice Overly complex design

Others Lack of engagement of KOLS Negative media Unrealistic timelines Source: Sullivan, Applied Clinical Trials



Source: 2015 CISCRP Perceptions & Insights Study – All Respondents (n=12,009)



Source: Glickman NEJM 2009


Global Clinical Trials in 2016 Challenges Increased logistics Varied rules/regulations: contracts, insurance, legal documentation Cultural barriers / Translation (CRFs, IBs, ICs, Protocols) Religion/Contraception

Investigational drug provision at trial end Concomitant med provisions Acceptability of placebo controls

Robust, critical FEASIBILTY Assessment Public education on value of Clinical Trial Participation Reliance on Local Expertise Full Service CRO / Risk-Cost sharing / Strategic Partnerships




Future Trends Impact of Brexit? EMA/CHMP

Electronic Medical Record EMR Potential for large scale registry/observational data

FDA Mini-Sentinel pilot project post-marketing surveillance Currently over 250 different providers Top five garner 50% market but lack consistent ability to share data effectively

across platforms Data Privacy HIPAA 1997 ?Update/Improvement

Mobile and Wearable Technology Insulin/glucose levels, Cardiac activity, Respiratory rate, CHF Rx Compliance/ RF chip


Pharma Innovation and Global Longevity Growth

Source: Lichtenburg 2012


globalization is the need of trials – conducting clinical...

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