Adaptive Risk Systems. Risk Assessment & Management Made Simple SM

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2 Adaptive Risk Systems Risk Assessment & Management Made Simple SM

3 TOTAL REGISTERED CLINICAL TRIALS PER YEAR Introduction into the Industry The Cost to Develop and Win Marketing Approval for a New Drug is $2.6 Billion 5 and as seen in the ClinicalTrials.gov table below, the numbers of clinical trials continue to rise. Registered Clinical Studies per Year as of Feb 2017 (Ref: ClinicalTrials.gov) Total Reference YEAR Adaptive Risk Systems, Inc 3

4 Industry Background: Clinical Research Over the past twenty (20) years, the pharmaceutic industry has seen drastic changes in patient populations, protocol designs, organizational structures and processes making the management of clinical trials very complex. Clinical Research Drivers for Industry Change Complex Studies Mixed Organizational Structure & Processes Increase in Study Cleanups Increase in noncompliance Costs The complexity contributing to a cascade of negative impacts to the pharmaceutical industry at Sponsor, CRA and Clinical Investigative Site levels. Increase in FDA Monitoring & Site Findings 2013: New FDA Guidance w/risk-based Monitoring (RBM) approach 2016: New ICH-GCP E6R2 Regulations w/rbm approach These negative impacts ultimately driving industry regulators in 2013 and 2016 to revise current industry regulations with a focus on quality, risk-based monitoring and management of clinical trials. The Clinical Research industry turns to electronic solutions to meet new regulatory requirements for quality and risk-based monitoring Reference Adaptive Risk Systems, Inc 4

5 Industry Background: Clinical Trial Complexities The chart below provides detail on the increasing complexities and protocols related to clinical trials that are contributing to rising R&D costs related specifically to the clinical trial process. Complexity Indicator Change Median Clinical Trial Treatment Period 140 days 175 days 25% Median Clinical Trial Site Work Burden 28.9 units 47.5 units 64% Number of Eligibility Criteria 31 criteria 46 criteria 58% Number of Case Report Form Pages per Protocol 55 pages 171 pages 227% Number of Procedures per Trial Protocol % Increases in the number of eligibility criteria, case report for pages and the number of procedures directly impact the amount of clinical monitoring required and compound the current issues. Reference Adaptive Risk Systems, Inc 5

6 Industry Background: Most Common Sponsor & Study Monitor (SM) Deficiencies Per the Bioresearch Monitoring Metrics (BIMO) 2015 results, the most common sponsor and monitoring deficiency noted out of 117 inspections was inadequate monitoring 15. Reference Adaptive Risk Systems, Inc 6

7 Industry Background: Most Common Clinical Investigator (CI) Deficiencies Deficiencies are another way of stating non-compliance s. The table below shows the frequency of non-compliances identified during FDA inspections at U.S. and Foreign clinical investigator sites. Non-compliances also are indicative of inadequate study monitoring. Protocol non-compliances are the #1 finding in the U.S. and Non-U.S. countries. ALL non-compliances impact the study either directly or indirectly requiring additional CRA monitoring to bring the site back into compliance and clean up study data discrepancies. Reference Adaptive Risk Systems, Inc 7

8 Industry Background: Impacts to CRA The drastic changes in the industry have directly impacted the role of the CRA making an already difficult and complex job challenging to perform successfully leading to inadequate Monitoring clean-up time impacts to study budget & timelines protocol and regulatory noncompliances nonmarket approvals According to the FDA, the top 2 most common compliance deficiencies during inspections of: Sponsors/Monitors (S/M) in 2015 included: Inadequate monitoring 20 Failure to bring investigators into compliance 20 Clinical Investigator (CI) in 2015 included: Failure to follow the investigational plan and/or regulations 20 Protocol deviations 20 The bottom line CRAs play a significant role in the site performance 29. References Adaptive Risk Systems, Inc 8

9 Industry Background: The role of the Monitor So what exactly is a Monitor and how important is their role??? A Monitor, also called a clinical research associate (CRA) or trial monitor, is a healthcare professional that reviews and verifies study & site data to ensure: protocol & regulatory compliance accuracy of study data subject safety Adaptive Risk Systems, Inc 9

10 Industry Background: The Act of Monitoring Methods used to oversee the conduct of, and reporting of study data from, clinical investigations 11 Monitoring activities include: FDA Definition of Monitoring Communication with the Clinical Investigator (CI) and study site staff Review of the investigative site s processes, procedures, and records Verification of the accuracy of study data submitted to the sponsor. References 11, Adaptive Risk Systems, Inc 10

11 Industry Background: Risk-Based Monitoring (RBM) Risk-based monitoring is the process of ensuring the quality or safety of clinical trial by: Identifying Risks Assessing Risks Monitoring Risks Mitigating Risks References Adaptive Risk Systems, Inc 11

12 FDA s Risk-Based Monitoring Recommendations FDA s Risk-Based Monitoring Recommendations Focus on critical study parameters Oversight activities that mitigate important and likely risks Identification of deficiencies Utilization of a quality risk management approach Tailor Monitoring Plans to the needs of the Study Use of a combination of monitoring activities: Onsite and Central monitoring (remote and inhouse) Monitor data quality through routine review of submitted data Conduct routine data and statistical analysis Analyze site characteristics, performance metrics Risk-based approach that facilitates continual improvement in Study conduct and oversight Identification and Verification of critical source data remotely as described in the monitoring plan Target on-site monitoring by identifying higher risk clinical sites Use of various routes of communication with Site (teleconferences, phone, ) Conduct routine data and statistical analysis Reference 11: Guidance for industry: Oversight of Clinical Investigations A Risk-Based Approach to Monitoring, August Adaptive Risk Systems, Inc 12

13 Industry Background: Risk-Based Monitoring The New Industry Standard Risk-Based Monitoring is now encouraged by the FDA and European Medicines Agency (EMA) Risk-based monitoring (RBM) is garnering enormous attention as a change agent in the conduct of clinical trials. This reimagined approach to monitoring promises to reduce the time-consuming and costly practice of ON-SITE 100% source data verification (SDV) while refocusing efforts on improving data quality. References Adaptive Risk Systems, Inc 13

14 The Problem: Current Monitoring Practices References Adaptive Risk Systems, Inc 14

15 The Problem: Current Monitoring Practices Analyzes study data and uses discrepancies to drive risk management and monitoring. Does not allow for SDV or on-site visits to be conducted based on a clinical sites risk score Centralized monitoring of clinical data by clinical, statistical and data management personnel at locations other than at the site 100% Source Document Verification (SDV) of all data, FDA s preferred method Targeted on-site visits to higher risk Clinical Investigators Frequent, comprehensive onsite visits to all CI sites by sponsor personnel or representatives Limits on-site visits to sites with higher enrollment, does not allow for monitoring of specific risk areas and has potential to miss out on correction for other sites that may have critical areas of risk References 11, Adaptive Risk Systems, Inc 15

16 The Problem: The Act of Clinical Monitoring Currently, assessment of study and site non-compliance (deficiencies) is captured in reports where the issues are buried in several long reports or in very complex reports that are difficult to interpret. Making it difficult to quickly and easily detect study and site level non-compliance risks, to perform trend analyses on a continual basis, and to notice improvement or worsening of study and site noncompliance risks. Per the FDA s BIMO Inspection Finding s for 2015, the most common Sponsor & Monitor finding was: Inadequate Monitoring & Failure to bring Investigators into compliance (2016 finding s for S/M were not available) 20. Per the FDA s BIMO Inspection Finding s for 2016, the most common Clinical Investigator finding was: Protocol noncompliance 19. References 19, Adaptive Risk Systems, Inc 16

17 The Problem: The Act of Clinical Monitoring The data management/statistical approach has been used for the past decade and study data clean-up better known as study rescue continues to rise There is now a proliferation of CROs offering services for rescue studies 9. Inadequate monitoring and site non-compliances continue without change As evidenced by the comparison of FDA BIMO 2007 and 2015 inspection findings 20,21 Centralized monitoring or Centralized Data Analysis (CDA) is taking hold With monitoring activities driven by data management and statistical metrics The Study Monitor is the primary contact for the site and directly oversees and monitors site compliance to the protocol and regulations But monitoring activities are based on data management metrics instead of the monitor report The monitor report is not used to identify site risks, assess risk trends and manage site risks due to the structure of the report The Monitor report is one of the first indicators and verification of a sites performance References 9, 20, Adaptive Risk Systems, Inc 17

18 The Problem: The Act of Monitoring Monitoring activities comprise 25-50% of Clinical Trial costs % of clinical trials run behind schedule 9. Sponsors stand to lose between $600K to $8M for each day that a clinical trial is delayed 9. At least 1/3 of clinical trials end up needing repair or being rescued 7 Protocol Noncompliances, specifically study data discrepancies are one of the leading causes attributed to repair/rescue work, CRA re-work costs, delays in study timelines and increased budgets. With monitoring activities comprising 25-50% of Clinical Trial costs 17, the impacts to study timelines and study budgets for the re-monitoring of discrepant data can be exponentially high and unnecessary if identified and addressed by the CRA early on in the study. References 7, 9, Adaptive Risk Systems, Inc 18

19 The Problem: The Monitoring Report Structure Report completion Report questions Monitor responses Site performance assessment Risk assessment & management Risk trend analysis input is freetext timeconsuming are too broad and difficult to interpret vary depending on the monitors: Experience & Training is assessed by reading report content is not readily available Is dependent on the monitors experience is performed by reading the report and followup action items is performed by manually re-reading reports manual comparison to previous report content Adaptive Risk Systems, Inc 19

20 The Solution: IRMA A Risk-Based Monitoring Report Tool Because the CRA is the 1. first to assess site performance & 2. first line of defense against data discrepancies & protocol non-compliance from clinical trial start-up to close-out Centralized monitoring Defined based on IRMA report risk score & findings Targeted on-site visits based on IRMA assigned site risk criteria and risk score achieved It makes sense to utilize IRMA to promote early identification and continuous assessment of clinical site areas of risk and improvement. With IRMA, Monitoring activities are driven by the risk criteria and risk score achieved within the monitoring report. With IRMA Results can be used to support data management metrics IRMA Encourages interdepartmental risk communication 100% Source Document Verification Depending on study and site risks 17 Algorithm-based site risk assessment following customized parameters per study Comprehensive on-site visits Source data review and verification is based on assigned site risk criteria and risk score achieved Critical risk areas can be targeted allowing for reduced monitoring and potential for 15-20% cost savings Adaptive Risk Systems, Inc 20

21 IRMA Risk-Based Monitoring Components Risk-Based Tool Components Ability to Perform Study Level Risk Assessments Ability to Perform Site Level Performance and Risk Assessments Ability to Focus on Critical Study Parameters Ability to Review Risk Trends at the Site and/or Study Levels Provides Mitigation & Corrective Action Plans References Global Regulations: ICH/GCP, FDA CFR, EU Directives Assists in Identifying Protocol & Regulatory Non-compliance s Risk-based Monitoring Report Tailored to Study Identifies Remote and On-site Monitoring Requirements Ability to identify and focus monitor site visits based on actual risk scores achieved for Particular area(s) of the monitor report. Incorporates IRMAs Risk-Based Monitoring Plan IRMA Model Adaptive Risk Systems, Inc 21

22 References Adaptive Risk Systems, Inc 22

23 References (1) Reference 1: Battelle Technology Partnership Practice; Biopharmaceutical Industry Sponsored Clinical Trials: Impact on State Economies; [On-line: March Reference 2: Mordor Intelligence: Global Clinical Trials Growth, Trends and Forecasts ( ); August 2016; [On-line: Reference 3: ClinicalTrials.gov: Reference 4: CSDD Tufts Center for the Study of Drug Development [On-line]. Available: Reference 5: CSDD Tufts Center for the Study of Drug Development: Outlook Reference 6: CSDD Tufts: Clinical Study Failures Vary Widely by Phase of Study and Therapeutic Class. 10 September [On-line: Reference 7: emedonline: Pharmaceuticals; [On-line: Reference 8: Califf RM. ACS and Acute Heart Failure Models. Speaker presentation at the Institute of Medicine Workshop on Transforming Clinical Research in the United States; October 7 8, 2009; Washington, DC [ On-line: Califf, ] Reference 9: Morgan, Craig, Rescue studies: The importance of getting clinical trials off to a good start. 14Dec2015. [On-line: Reference 10: PRNewswire: New Trends in the 2015 Global Clinical Development Outsourcing Market. 30 June [On-line:

24 References (2) Reference 11: USDHHS, FDA, CDER, CBER, CDRH, OGCP, ORA: Guidance for Industry: Oversight of Clinical Investigations- A Risk-Based Approach to Monitoring,. August Reference 12: Global Markets for Contract Pharmaceutical Manufacturing, Research and Packaging. BCC Research, June Reference 13: Sullivan, Linda; Applied Clinical Trials: The Current Status of Risk-Based Monitoring. 27March2015. [On-line: Reference 14: Morrison et al. Monitoring the Quality of Conduct of Clinical Trials: A Survey of Current Practices. Clin Trials. 8: (2011). Reference 15: Business Wire: Research and Markets: The New 2015 Trends of Global Clinical Development Outsourcing Market. 30 January [On-line: Development#.VXHHFFxVikp]. Reference 16: Applied Clinical Trials. Winchell, Terry: The 3 Essential Factors Affecting FDA Inspection Outcome. 30 March [On-line: Reference 17: Franco R, Hronec M, Karacsony A, et al. Risk-based monitoring: Reduce clinical trial costs while protecting safety and quality. PwC Reference 18: BCC Research Report: Global Markets for Contract Manufacturing, Research and Packaging. 09 Sep [On-line: Reference 19: FDA BIMO for Clinical Investigator (CI) Deficiencies. FY [On-line: pdf] Reference 20: (Ref: Food and Drug Administration (FDA). FY Bioresearch Monitoring (BIMO) Metrics FY BIMO Inspection Metrics [On-line]. Available:

25 References (3) Reference 21: Food and Drug Administration (FDA). FY Bioresearch Monitoring (BIMO) Metrics FY BIMO Inspection Metrics [On-line: Reference 22: Bio Industry Analysis: David W. Thomas, Justin Burns, John Audette, Adam Carroll, Corey Dow-Hygelund, Michael Hay; Clinical Development Success Rates Reference 23: Grainger, David: Why Too Many Clinical Trials Fail -- And A Simple Solution That Could Increase Returns On Pharma R&D. 29Jan2015. [On-line: Reference 24: Harrison, Richard K.: Recent Trends in clinical trial failures: Phase II and phase III failures Nature Reviews Drug Discovery 15, 817/818 (2016). [On-line: Reference 25: U.S. FDA, Oversight of Clinical Investigations A Risk-Based Approach to Monitoring Guidance, (August 2013). Reference 26: Morgan, Craig, Better Study Startup Means Less Study Rescue. 19Feb2016. [On-line: Reference 27: Partnerships in Clinical Trials: 52 Perspectives: Paradigm Shifts in Sponsor/CRO Interactions. 03Mar2011. [On-line: Reference 28: Branch, Emillie: Ways to Lower Costs of Clinical Trials and How CROs Help. 30Apr2016. [Online: Clinical-Trials-and-How-CROs-Help/]. Reference 29: Bhatt, Arun: Quality of Clinical Trials: A Moving Target. Oct-Dec2011. Perspectives in Clinical Research Oct-Dec; 2(4):

26 References (4) Reference 30: Market and Market: eclinical solution Market worth 5.98 B USD by [On-line: Reference 31: Global Business Intelligence (GBI): eclinical Trial Solutions Market. July2012. [On-line: Reference 32: Global Industry Analysts, Inc.: Press Release: e-clinical Trial Technologies a Global Strategic Business Report. 04 February [Online: Reference 34: Clinical Trial Management System Market by End-user (Pharmaceutical & Biotechnology, Medical Device Companies, CROs), Delivery Mode (Web Hosted, On-premise, Cloud-based), Type (Enterprise, Site), Component (Software, Service) - Global Forecast to [Online: Reports/clinical-trial-management-systems-market-470.html]. Reference 35: Clinical Trial Management System (CTMS) Market Analysis By Type (Enterprise, Site), By Delivery Mode (Web-based, Cloud-based, On-premise), By Component (Software, Service) By End-user (Pharmaceutical And Biotechnology Firm, CROs, Medical Device Firm) And Segment Forecasts To [Online: Reference 36: Grand View Research: CTMS Market Size Projected To Reach $2.2 Billion By October [online: Reference 37: Sytnik, Maria. Healthcare Solutions Specialist. Latest trends in Healthcare IT solutions. 17Apr2013. Reference 38 PRNewswire-CTMS Market Analysis by type, by delivery mode, by component, by end-user and segment forecasts to Dec Reference 39: Scalar Market Research: Clinical Trial Management System (CTMS) Market Projected to Reach 2.95M by Dec [Online: html]