Finding the Best Clinical Trial Investigators

Transcription

1 Finding the Best Clinical Trial Investigators Bill Gwinn, Vice-President Clinical Informatics Solutions February 7, 2012 SCOPE Summit for Clinical Operations Executives Global Site Selection, Feasibility Assessment, Operations and Site Management Session: Country Selection, Site Selection, and Study Planning Considerations

2 Agenda Introductions Insurance Claims Database Is There a Problem? Examine Industry Statistics Solutions Start with Understanding Investigator Population U.S. Statistics International Statistics Utilization of Medical Statistics Feasibility Site Ranking Case Studies on Site Selection Finding the the Best Investigators 2

3 UnitedHealth Group Companies UNH UnitedHealthcare Publicly Traded (NYSE) Over $100 Billion in Revenue Optum Health care coverage and benefits businesses, unified under a master brand Employer and Individual Community and State Medicare and Retirement Helping people live healthier lives Information and technology-enabled health services platform, encompassing: Technology solutions Intelligence and decision support tools Health management and interventions Administrative and financial services Pharmacy solutions Helping to make the health care system work better for everyone Employer and Individual; Medicare & Retirement; Community and State Health Information Population Health & Wellness Services Pharmacy Benefit Manager Finding the Best Investigators 3

4 Insurance Data Source UnitedHealth Group is the largest U.S. insurer. UnitedHealthcare brand name. 15% of commercial market Medicare + Medicaid (runs Medicaid in many states) 25% of Medicare Part D population (largest payer) Person-level data allows for accurate statistics with no double counting. Physician claims Patient goes to see their physician. Hospital claims Patient admitted to hospital. Pharmacy claims Patient receives Rx and goes to pharmacy to fill. Claims and Enrollment Adjudication Data Warehouse (Medical, Lab, Pharmacy, Hospital) Lab test results and Lab claims Patient goes for lab tests. Finding the the Best Investigators 4

5 Is There a Problem? The protocol drives the clinical development process. Protocol quality is a major determinate of site success. When the protocol is too difficult or compliance is onerous... Specified patients can t be found because they don t exist Clinical trial budgets increase Cycle times are delayed Patient retention fails Site inexperience compounds the problem. Is this happening? Is it getting worse? Finding the Best Clinical Trial Investigators 5 5

6 Inefficiency: U.S. R&D Spending is Up More Than New Active Substance Approvals, Sources: FDA, PhRMA, as cited in Risk Sharing and Innovative Contracting with CROs: Benefits and Challenges in Optimizing R&D Partnerships, Business Insights, Feb Finding the Best Clinical Trial Investigators 6

7 Growing Inclusion & Exclusion Criteria, By Trial Phase Linear regression analysis shows extremely strong positive correlation between months of delay and the number of criteria. 1,329 trials in 2009, p-value is 0.57%, under 5.0% is statistically significant. The growth in eligibility criteria reduce the available patients. It is hard to estimate how many are lost without an objective statistical source. Finding the the Best Investigators Source: Clinical Trial Recruitment Strategies, Delphi Pharma s Clinical 7 Trials Database, Business Insights Limited, 2010

8 Trends in Growing Protocol Complexity 31 (+58%) Total Eligibility Criteria Total Investigative Site Work Burden (Median Units) (+54%) Total Procedures Per Protocol (+49%) Unique Procedures Per Protocol (+38%) Units of Complexity Analysis of 10,038 Protocols, All Therapeutic Areas, All Phases Source: Tuffs Center for Study of Drug Development (Tufts CSDD) Published in July, 2010 issue of The CenterWatch Monthly Finding the the Best Investigators 8

9 Additional Manifestations of Delay Protocol Ready to Drug 120 Available (+19%) Protocol Ready to First Patient First Visit (+12%) Protocol Ready to Data Lock (+70%) Protocol Ready to Last Patient Last Visit (+73%) Median Days Elapsed Analysis of 10,038 Protocols, All Therapeutic Areas, All Phases Source: Tuffs Center for Study of Drug Development (Tufts CSDD) Published in July, 2010 issue of The CenterWatch Monthly Finding the the Best Investigators 9

10 Growing Complexity = Growing Burden Protocol Burdens Change Comment Number of Case Report Form Pages Per Protocol (CRF Median) % CRF Pages Have More Than Doubled Study Volunteer Enrollment Rates 75% 59% -16 Study Volunteer Retention Rates 69% 48% -21 Enrollment Rates Down 16 Points Retention Rates Down 21 Points Analysis of 10,038 Protocols, All Therapeutic Areas, All Phases Source: Tuffs Center for Study of Drug Development (Tufts CSDD) Published in July, 2010 issue of The CenterWatch Monthly Finding the the Best Investigators 10

11 Average Delays in Clinical Trials % of Trials 10% More Than 100% Late 35% Up To 100% Late (Twice the Time of Goal) 25% On Time 1,300 trials tabulated through third quarter, % Early Source: Clinical Trial Recruitment Strategies, Delphi Pharma s Clinical Trials Database Business Insights Limited, 2010 Trial Delay %, Versus Planned Completion Finding the the Best Investigators 11

12 Delay and Variable Site Performance Are Ongoing Industry Pains 15-20% of sites DON T perform Enroll 0 Evaluable Patients 30% of sites UNDER-perform Enroll 5% of Evaluable Patients 20% of sites are AVERAGE Enroll 25% of Evaluable Patients 30% of sites are TOP performers Enroll 70% of Evaluable Patients Source: Mckinsey and Company, 2004 Center for Information & Study on Clinical Research (CISCRP): 90% of sites failed to meet enrollment targets 20% of sites enroll 55% of the target number 20% of sites fail to enroll a single patient Tufts Center for Drug Development: 59% of trials failed to meet their enrollment targets between 2004 and 2007 Drop of 21% against the 2000 to 2003 period Business Insights, Optimizing Clinical Trails with IT, May, 2011 Finding the the Best Investigators 12

13 Trials are Expensive and Getting Much More Expensive Per Patient Costs Phase (Graph) Change 1 $15,023 $21, % 2 $20,009 $36, % 3a $25,280 $47, % 3b $25,707 $47, % 4 $13,011 $17, % Source: Clinical Operations: Benchmarking Per-Patient Trial Costs, Staffing, and Adaptive Design, Cutting Edge Information, July, 2011 Finding the Best Clinical Trial Investigators 13

14 Now that we have some issues Let s look at solutions. Start with Who the Investigators Are, U.S. and International 14

15 How Many Investigators Are There, and How Did We Find Them? Comprehensive project identified 116,191 current U.S. investigators (at least one trial in past 5 years) Three Major Sources: 1. Food & Drug Administration Bioresearch Monitoring Information System (BMIS) file contains information submitted to FDA identifying clinical investigators. An investigator must file a 1572 Form for every trial. FDA releases Principal Investigator names only. 2. Web Scraping Finds Secondary Investigators (increases list size by about one third). Cooperative project with Infinata. 3. Master File of All Practicing Physicians From insurance operations, OptumInsight Provider360. If the physician is not on file, the physician does not get paid. Has 918,000 individual physicians at 660,000 unique locations. Proportion: 116,191 of 918,000 physicians, or 12.6%, are investigators. Finding the Best Investigators 15

16 Distribution of U.S. Investigators by State 116,191 (4 th Quarter, 2011) Top 5 States Count California 13,069 New York 10,081 Texas 7,811 Florida 7,745 Pennsylvania 6,695 Finding the the Best Investigators 16

17 Most Investigators Have Light Experience Trial Experience By Trial Count, Last 10 Years % of Investigators 50% 45% 47% 40% 35% 30% 33% 25% 20% 15% 10% 13% 5% 6% 0% Only 1 2 to 4 5 to 10 Over 10 Number of Trials, Past 10 Years, Safest to Hire in Green Finding the the Best Investigators

18 Low-Volume Investigators Are Growing 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 4.5% 3.8% 3.6% 1.7% 0.7% 24.6% 23.9% 25.1% 21.0% 16.0% 70.9% 72.3% 71.3% 77.3% 83.3% One Two to Four Five or More Annual Number of 1572 s Filed Site Landscape Shrinking, Losing Most Active PIs, The CenterWatch Monthly, January, 2012 Finding the the Best Investigators 18

19 Novice Investigators Are Growing 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 63% 67% 56% 44% 37% 33% New Experienced Site Landscape Shrinking, Losing Most Active PIs, The CenterWatch Monthly, January, 2012 Finding the the Best Investigators 19

20 Investigator Turnover (Drop-Outs) Are High Worldwide Investigators Not Filing Second 1572 Form After 2006 U.S.A. Turnover Rate 35.0% Canada 41.2% Europe 55.1% South America 52.8% Asia Pacific 52.9% Africa 47.0% 0.0% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0% Site Landscape Shrinking, Losing Most Active PIs, The CenterWatch Monthly, January, 2012 Finding the the Best Investigators 20

21 Distribution of U.S. Investigators by Specialty Top 10 Specialties Percentage 1. Internal Medicine 32.4% 2. Family Practice 5.4% 3. Pediatrics 4.8% 4. Psychiatry 2.7% 5. Ophthalmology 2.6% 6. Surgery - General 2.6% 7. Obstetrics and Gynecology 2.4% 8. Neurology 2.4% 9. Oncology - Radiation 2.1% 10. Nephrology 1.9% Source: OptumInsight Investigator Database, 4 th Quarter, 2011 Finding the the Best Investigators 21

22 Investigators by Gender & by Foreign Language Spoken Female 21.5% Male 78.5% Foreign Language Count % Speak 1 Foreign Language Speak 2 Foreign Languages Speak 3 Foreign Languages Total Multilingual Physicians 49, % 22, % 11, % 82, % Total Physicians 116, % Number of Spanish Speaking Physicians 32, % Source: OptumInsight Investigator Database, 4 th Quarter, 2011 Finding the the Best Investigators 22

23 Process for Investigator Profiling in USA Step 1 Step 2 Step 3 Quarterly Cross Match FDA and Ingenix Physician Database Merge Sponsor & Optum physicians, protocol compliant patients Analysis Master Investigator File: 117,000 Sites Investigator List For Trial Investigators with many patients Investigator Distribution by Specialty FDA BMIS 1572; & FDA Adverse Actions Claims Database: 40+ Million Web Scraping: More Investigators Claims Database: Over 78 Million Lives Sponsor s Investigators Geographic Profiling Finding the Best Investigators 23

24 International Perspective: Locations of Studies Registered in U.S. 119,594 Current Studies, ClinicalTrials.gov, January, 2012 Finding the Best Investigators 24

25 Investigator Profiling, Rest of World Quarterly Cross Match FDA and Ingenix Physician Database Merge Sponsor, QM and UHG physicians Raw Treating protocol compliant Information patients Updated Quarterly Analysis Focused web crawlers scrape investigator data from known web sites, worldwide. Standardized Data Investigators Classified By Therapeutic Area Ranked on Relevancy Score: Studies and Publications Search on Therapeutic Indication of Past Trials 150,000+ Investigators 170+ Countries Finding the Best Investigators 25

26 International Investigators: Top 10 Countries (After U.S.) Rank Country Count % 1 Germany 18, % 2 France 16, % 3 United Kingdom 13, % 4 Canada 12, % 5 Japan 11, % 6 Italy 10, % 7 Spain 9, % 8 Netherlands 7, % 9 China 7, % 10 Australia 6, % Total 195 Countries 198, % Source: OptumInsight/Infinata Master Investigator File, January, 2012 Finding the Best Investigators 26

27 Leading Therapeutic Areas of International Investigators Top Three Countries Therapeutic Indication of Past Trials First Second Third 1. Germany Cardiovascular Cancer Trauma 2. France Cancer Cardiovascular Trauma 3. UK Cancer Cardiovascular Pain Source: OptumInsight/Infinata Master Investigator File, January, 2012 Finding the Best Investigators 27

28 Utilization of Medical Statistics Patient recruitment is the single largest cause of delay in clinical trials. With medical statistics from insurance claims and related sources, you can: Correctly plan trials by understanding available patients Identify the best geographic concentration of patients Locate the best sites (with specific data about individual medical practices) Finding the Best Clinical Trial Investigators 28

29 BEFORE Selecting Sites, Ensure Trial is Feasible Key Questions Will the specifications in the protocol create enough matching patients to conduct the trial quickly? Are there criteria that eliminate too many patients? What is the demographic profile of patients? Benefits of Answers Identify unrealistic protocol criteria. Plan more sites when patient counts are low. Identify top back-up sites if enrollment falls behind How to Get Answers Fax-blasted questionnaires to physicians (not accurate) True large-scale chart reviews (automated network, etc.) Small samples from insurance processing Large national databases using insurance claims Finding the the Best Investigators 29

30 Site Ranking Which investigators have the access to specified patients? Count the patients at each site with insurance claims Get better accuracy than a questionnaire Finding the Best Investigators 30

31 Does Site Assessment Work? 31

32 Assess Investigators with Metrics Retrospective Study Background: After rescuing a client whose trial was behind schedule, OptumInsight assessed how well its information predicted investigator success. The study was for a leading chronic condition in 2008, at 232 investigator sites. The study looked for highly successful clinical trial investigators, who randomized and retained at least four patients. The median in the study was two patients. Overall, 37% of the investigators were highly successful. Finding the Best Investigators 32

33 Assess Investigators with Metrics Retrospective Study Results: There were more highly successful investigators when the OptumInsight metrics were high. These metrics forecast success: Access to Patients Percentage of the investigator s patients who qualified under the inclusion/exclusion criteria. Clinical Trial Experience Number of clinical trials conducted by the investigator in the past five years. Finding the Best Investigators 33

34 Highly Successful Investigators Access to Patients Predicts Success 60% 50% 40% Access to Patients The green bar shows that 52% of investigators were highly successful if their number of matching patients was high. High matching was defined as 6% or more of their insured patient population. The percentage of successful investigators was lower if the percentage of matching patients was low or medium. 30% Low Medium High Percentage of Matching Patients Finding the Best Investigators 34

35 Highly Successful Investigators Experience Predicts Success 60% 40% 20% 0% Clincial Trial Experience Low Medium High Number of Trials The red bar = 48% of investigators were highly successful if they conducted a high number of trials: 4 or more in past 5 years. The percentage of successful investigators was sharply lower if the trial count was low or medium. Finding the Best Investigators 35

36 Case Study Could OptumInsight s Research Meet Client s Gold Standard? Rare patient type (oncology) Client had already recruited very good, very high-performing sites. This set a standard, but there were not enough sites to meet the objectives. Using the metrics shown earlier, could OptumInsight meet the standard? Would new sites be as good, or even better? Sponsor had 24 sites and OptumInsight added another 14 sites. Finding the Best Clinical Trial Investigators 36

37 Patients/Site Case Study Summary lower screen-failure rate higher patient-enrollment rate Average Screened and Enrolled Patients Per Month Active Sites Only Met Gold Standard Screen Failure Rate Enrollment Rate Sponsor OptumInsight Based Finding the Best Clinical Trial Investigators 37

38 What Should You Do? Do not rely on epidemiology studies and investigator questionnaires as the only sources for protocol feasibility. Published studies do not capture nuances. Questionnaire answers are inaccurate without chart reviews. Incorporate objective metrics for planning into the business process. Be willing to change if this is not business as usual. Get the data early. Avoid the infamous rescue mode by knowing the needed resources and best investigators in advance. Seek objective external data to find new investigators and to rank them, especially for new or difficult trials. Finding the Best Clinical Trial Investigators 38