1. Standards-Setting in the Context of Regulatory Harmonization Carolyn Compton, M.D., Ph.D., CEO and President Critical Path Institute (C-Path) IOM Workshop International Regulatory Harmonization Washington, DC February 13, 2013

2. The Global Challenge  It takes 12 - 15 years to develop a new drug  Costs now exceed $1B USD*  The process is broken  Solutions require collaborative approaches that:  Include both the public (regulatory) and the private (industrial and academic) sectors  Are applicable on a global level * “The average drug developed by a major pharmaceutical company costs at least $4 billion, and it can be as much as $11 billion.” The Truly Staggering Cost of Inventing New Drugs. Forbes 2/20/12

3. Drug Development Process Throughout the domestic and global drug development enterprise, both between and within companies: o Data to demonstrate efficacy & safety are defined and collected differently o Measurements of efficacy and safety are based on differing criteria o Methodologies for design of clinical trials for new drugs differ widely

4. Standards As Solutions There is a fundamental need for global standards across the developmental and approvals procedures for regulated medical products.

5. Effective Standards Save Time, Money and Headaches 5 A good standard = A global solution A bad standard = A global problem

6. Standards Are at the Center of Process Improvement Effective standards require: Widespread consensus Widespread compliance Widespread availability (free not proprietary) Cost effective applicability Endorsement/enforcement by authoritative sources Global application 6

7. The Importance of International Standards Current technologies and modes of transportation erase international boundaries, allowing companies of any size to market products around the globe. Differing regulations and standards from country to country continue to cause delays and create barriers. The costs and logistics associated with this are high. A manufacturer may need to produce multiple versions of the same product in order to distribute that product to countries where standards and regulations differ. For medicines, differing standards and regulations are both medically and ethically unacceptable. 7

8. Moving Toward the Use of International Standards For international standardization to be successful, Standards Development Organizations, regulatory bodies, and industries around the world need to work together. 8

9. Moving Toward the Use of International Standards Other regulated industries such as information technology, telecommunications, finance have lead the way International Standards Development Organizations: International Organization for Standardization (ISO) American Society for Testing and Materials (ASTM) National Fire Protection Association (NFPA) Telecommunications Industry Association (TIA) International Electrotechnical Commission (IEC) International Telecommunications Union (ITU) 9

10. International Organization for Standardization What is a standard? Provides requirements, specifications, guidelines or characteristics that can be used consistently to ensure that materials, products, processes and services are fit for their purpose. What are the benefits of international standards? They ensure that products and services are safe, reliable and of good quality. They are strategic tools that reduce costs by minimizing waste and errors, and increasing productivity. 10

11. C-Path In A Nutshell Critical Path Institute functions as an orchestrator for development of new tools, approaches, and standards created through collaboration, reviewed and qualified by the FDA (EMA, PMDA), and subsequently made available to the community. 11

12. C-Path and Standards Development International Scientific Standards for Drug Development: “Drug Development Tools” Measurement standards o Molecular biomarkers for efficacy and patient classification o Molecular biomarkers for toxicity o Imaging biomarkers for efficacy and patient classification o Patient-, observer-, clinician- reported outcomes Methods standards o Disease models and clinical trial simulation tools o In vitro models Regulatory Qualification Recognition, approval for a given context of use

13. FDA and EMA Qualification: A Formal, Rigorous Process of Review and Acceptance 13 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM230597.pdf http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/WC500004201.pdf

14. C-Path: A Public-Private Partnership  Act as a trusted, neutral third party  Convene scientific consortia of industry, academia, and government for pre-competitive sharing of data/expertise  The best science  The broadest experience  Active consensus building  Shared risk and costs  Enable iterative FDA involvement in the development process  Regulatory participation and guidance  Official recognition through “qualification” of Drug Development Tools 14

15. Consortia: Cooperation, Collaboration, Consensus 15 7 global consortia collaborating with 1,000+ scientists and 41 companies

16. C-Path’s Global Landscape 16 Partners

17. Drug Development Tool Qualification and Implementation 17 Anticipated effects: Shorten the time, decrease the risks, and lower the costs of developing safe, effective medical products Create stronger scientific basis for decision-making (within both industry and regulatory agencies) Engender compliance through “ownership” and official regulatory recognition rather than “enforcement” Create public resources in a pre-competitive model for community benefit

18. Facilitates Global Drug Developer Interaction and Dialog with Global Regulators Close FDA/EMA/ PMDA/SFDA Interaction Collaboration Open Dialogue Diverse Expertise Efficiency Resource Sharing Data Sharing Diverse Expertise

19. Qualification Processes for Regulatory Agencies Not Fully Harmonized FDA EMA PMDA Process Start 2006 2007 2009 Scope← Regulatory Review/Acceptance → Fees 0 $100,000 $30,000 Minimum # Steps 24 12 11 Months to Decision 24 6 6 Qualification Decisions 3 6 1 Modified from Frederico Goodsaid 2012

20. 20 What About Data Standards ? A Data Standard ≠ A Common Data Element Date of Birth= CDE Jan. 15, 2011 January 15, 2011 1/15/11 1/15/2011 15/1/11 15 January 2011 15-1-11 2011-1-11 Gender = CDE Male:Female M:F 0:1 1:2 Mal:Fem ML:FM

21. Data Standards and Regulatory Process Efficiency In 2012, CDER at FDA received about 1280 study datasets per week, up to 10GB in size (if electronic) Extreme variability and unpredictability of data format and content present a major obstacle to timely, consistent, and efficient review and the use of sophisticated analysis systems

22. FDA Communicates the Adverse Impact of the Lack of Data Standards 22 Charles Cooper, Computational Science Center, CDER Presented at CDISC European Interchange, April 18, 2012

23. 23 Standards Change the Focus of Effort in Regulatory Review Demographics, Adverse events, Disposition, Toxicity Standards Shift Emphasis to Interpretation and Decision-making – “Thinking”

24. Data Standards As Drug Development Tools For clinical trials, there is value in using standards from the start 60% 70-90% BenchmarkWith CDISC time in months 0 5 10 15 24 http://www.cdisc.org/business-case Time savings: 8 months

25. How Will Clinical Content Data Standards Help? Improve efficiency of drug review Facilitate use of sophisticated analytic tools Enable data sharing and data pooling Enhance the ability to perform complex analyses Build a foundation for broader benefits in clinical research, premarket analysis and safety signal detection Establish “common language” for disease and therapeutic areas through information models, concepts and controlled terminologies - Dr. Janet Woodcock, Director CDER, FDA 25

26. C-Path and International Standards Development DATA STANDARDS FOR DRUG DEVELOPMENT Therapeutic (Disease) Area Data Standards o Coalition For the Acceleration of Standards and Therapies (CFAST) o Partnership between C-Path and the Clinical Data Interchange Standards Consortium (CDISC) o CDISC : Standards development organization for data standards for medical research Global, open, multi-disciplinary, vendor-neutral, non-profit (SDO), founded 1997, incorporated 2000 FDA Needs for Data Standards 58 disease areas in 5 years to achieve the 2017 goal 26

27. Section XII – Improving the Efficiency of Human Drug Review Through Electronic Submissions and Standardization of Drug Application Data Clinical Terminology Standards: Using a public process that allows for stakeholder input, FDA shall develop standardized clinical data terminology through open standards development organizations with the goal of completing clinical data terminology and detailed implementation guides by FY 2017. FDASIA Section 1136: Allows FDA to require standardized fully electronic submissions related to marketing applications by 2017 FDA Safety and Innovation Act (FDASIA):

28. Moving Toward Global Regulatory Harmonization For international standardization to be successful, Standards Development Organizations, regulatory bodies, and industries around the world need to work together. It is only with collaboration among all these entities that international standardization will become a reality. Regulatory bodies have the added challenge of working within the laws of their countries, which may restrict their ability to act in concert with one another Is FDASIA an example? 28

29. Moving Toward Global Regulatory Harmonization Through Standards STANDARDS EMA Europe PMDA Japan Diverse Expertise TPD Canada FDA USA TGA Australia SFDA China

30. Standards-Setting in the Context of Regulatory Harmonization Carolyn Compton, M.D., Ph.D., CEO and President Critical Path Institute (C-Path) IOM Workshop International Regulatory Harmonization Washington, DC February 13, 2013