US Clinical Research

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1 US Clinical Research IOM Drug Forum Clinical Trials Workshop Ronald Krall, MD October 7, 2009 October 7, 2009 IOM Drug Forum Clinical Trials Workshop - R Krall 1

2 Conflict of Interest Disclaimer Consultant to Frazier Healthcare Ventures; Bogart, Delafield & Ferrier, LLC Designing a workshop on drug safety for GSK Consultant and investor, Naurex, Inc. Member, Executive Board, Observational Medical Outcomes Partnership, FNIH Member, External Advisory Board, Center for Bioethics, University of Pennsylvania Previous positions with Lorex, Abbott, Zeneca, AstraZeneca, GlaxoSmithKline; now retired October 7, 2009 IOM Drug Forum Clinical Trials Workshop - R Krall 2

3 Acknowledgements Institute of Medicine Grant Emily R. Krall, Research Associate Deborah Zarin, Nicholas Ide, ClinicalTrials.gov, National Library of Medicine Zorba Lieberman and Christine Blazynski, Citeline Scott Martin, KMR Alex Lancksweert, GSK October 7, 2009 IOM Drug Forum Clinical Trials Workshop - R Krall 3

4 Outline Rationale Study Methods Findings Observations Comments October 7, 2009 IOM Drug Forum Clinical Trials Workshop - R Krall 4

5 Rationale/Premise Learning Healthcare System requires mechanism for acquiring information to inform policy and practice Many kinds of evidence can inform, but the gold standard will remain controlled clinical trials What s the US capability to conduct controlled clinical trials? Does the current capability meet the needs? October 7, 2009 IOM Drug Forum Clinical Trials Workshop - R Krall 5

6 Study Questions How much clinical research is being conducted in the US? How many trials? How many subjects? What kind of research? Interventions Diseases Innovation Who is carrying out the research? Where is the research being conducted? How effective is it? October 7, 2009 IOM Drug Forum Clinical Trials Workshop - R Krall 6

7 Study Methods Sources of Data Clinicaltrials.gov Citeline KMR Specific pharmaceutical company data Tufts Center for Study of Drug Development Impact Report on Investigators Survey of investigators who completed trials in 2008 October 7, 2009 IOM Drug Forum Clinical Trials Workshop - R Krall 7

8 Clinicaltrials.gov Efficacy trials for serious and life-threatening conditions; and interventions regulated by FDA FDA Modernization Act 1997 Registration required for publication October 7, 2009 IOM Drug Forum Clinical Trials Workshop - R Krall 8 ICMJE Legal requirement for registration of trials of drugs, biologics, devices FDA Amendments Act 2007

9 Clinicaltrials.gov Data Elements Title FDA Information Human Subject Review Sponsors Study Description Status Study Design Arms, Groups and Interventions Conditions and Keywords Eligibility Protocol Location, Contact and Investigator Information Related Information October 7, 2009 IOM Drug Forum Clinical Trials Workshop - R Krall 9

10 Clinicaltrials.gov Clinical Trials Datasets Ongoing Open Interventional At least one US Center As of August 16, 2009 Completed in 2008 Interventional Trials with at least one US Center Completed in the year 2008 As of July 31, 2009 October 7, 2009 IOM Drug Forum Clinical Trials Workshop - R Krall 10

11 Tufts Center for Study of Drug Development Data FDA Bioresearch Monitoring Information System 1572 Forms investigators Annual analysis since 1990 Source: Ken Getz, Stephanie Rochon, Rachel Zuckerman Impact Report, Volume 11, Number 1, January/February, 2009 October 7, 2009 IOM Drug Forum Clinical Trials Workshop - R Krall 11

12 How much clinical research is being conducted in the US? What kind of research? October 7, 2009 IOM Drug Forum Clinical Trials Workshop - R Krall 12

13 Ongoing US Clinical Research As of August 16, ,974 trials October 7, 2009 IOM Drug Forum Clinical Trials Workshop - R Krall 13

14 Ongoing US Clinical Research As of August 16, ,974 trials 2,836,948 subjects October 7, 2009 IOM Drug Forum Clinical Trials Workshop - R Krall 14

15 Ongoing US Clinical Research Interventions being tested 10,974 Trials 2.8M Subjects October 7, 2009 IOM Drug Forum Clinical Trials Workshop - R Krall 15

16 Ongoing US Clinical Research Trials by Phase 10,974 Trials October 7, 2009 IOM Drug Forum Clinical Trials Workshop - R Krall 16

17 Ongoing US Clinical Research Subjects by Phase 2.8M Subjects October 7, 2009 IOM Drug Forum Clinical Trials Workshop - R Krall 17

18 Trials by phase for the regulated interventions: drugs, biologics, devices, dietary supplements October 7, 2009 IOM Drug Forum Clinical Trials Workshop - R Krall 18

19 Ongoing US Clinical Research Regulated Interventions being tested 8,386 Trials 1.9M Subjects October 7, 2009 IOM Drug Forum Clinical Trials Workshop - R Krall 19

20 Ongoing US Clinical Research Regulated Product Trials, by Phase 8,386 Trials October 7, 2009 IOM Drug Forum Clinical Trials Workshop - R Krall 20

21 Ongoing US Clinical Research Regulated Product Trials, by Subjects 1.9M Subjects October 7, 2009 IOM Drug Forum Clinical Trials Workshop - R Krall 21

22 Regulated Products, Phase II Trials: Subjects 2606 Trials October 7, 2009 IOM Drug Forum Clinical Trials Workshop - R Krall 22

23 Regulated Products, Phase III Trials: Subjects 1105 Trials October 7, 2009 IOM Drug Forum Clinical Trials Workshop - R Krall 23

24 Regulated Products, Phase IV Trials: Subjects 2283Trials October 7, 2009 IOM Drug Forum Clinical Trials Workshop - R Krall 24

25 Phase II Note: 50 epoch value is 1235 Phase III Phase IV October 7, 2009 IOM Drug Forum Clinical Trials Workshop - R Krall 25

26 What diseases are being studied? October 7, 2009 IOM Drug Forum Clinical Trials Workshop - R Krall 26

27 US Ongoing Clinical Research October 7, 2009 IOM Drug Forum Clinical Trials Workshop - R Krall 27

28 Diabetes Research October 7, 2009 IOM Drug Forum Clinical Trials Workshop - R Krall 28

29 Depression Research October 7, 2009 IOM Drug Forum Clinical Trials Workshop - R Krall 29

30 Cardiovascular Research October 7, 2009 IOM Drug Forum Clinical Trials Workshop - R Krall 30

31 Cancer Research October 7, 2009 IOM Drug Forum Clinical Trials Workshop - R Krall 31

32 Who s carrying out the research? Where s the research being done? How effective is it? October 7, 2009 IOM Drug Forum Clinical Trials Workshop - R Krall 32

33 Tufts Center for Study of Drug Development Impact Study 26,000 FDA registered Investigators % of investigators are participating in only 1 trial 50% filing in one calendar year do not participate in subsequent years October 7, 2009 IOM Drug Forum Clinical Trials Workshop - R Krall 33

34 Tufts Center for Study of Drug Development Impact Study 14,000 US Investigators 3.5% annual decline since % of total investigators ROW investigators: 8.5% Central and Eastern Europe 5.5% Asia 5.5% Latin America October 7, 2009 IOM Drug Forum Clinical Trials Workshop - R Krall 34

35 Industry sponsored trials -investigators KMR 2006 Data (15 large pharma companies) 46% of subject visits occurred in US Per $1M clinical operations expense 902 patient visits ex-us 860 patient visits US Pharmaceutical company data 27% of US investigators fail to enroll any subjects 19% ROW 75% of US investigators fail to enroll target number of subjects ROW not very different US investigators enroll 4.6 subjects ROW % of all trials extend their enrollment period October 7, 2009 IOM Drug Forum Clinical Trials Workshop - R Krall 35

36 Summary 10,974 Active Interventional Trials in the US; 2.8M subjects Drug and Biologics trials: 68% of trials and 57% of subjects Behavioral trials: 10% of trials and 16% of subjects For regulated products Phase IV research accounts for 27% of trials and 25% of subjects Phase IV research is characterized by many small trials and veryfew large trials Almost half of all active interventional trials are cancer trials More than 10% of all sought subjects are for CV trials Cancer trials are characterized by small number of subjects per trial, where CV trials seek large numbers of subjects per trial Most investigators are participating in only a single trial Only 57% of investigators are from the US, and only 46% of industry sponsored trial patient visits are in the US Industry trials: 27% of US investigators fail to enroll any subjects; 75% miss their target 90% of trials miss their target for completion of subject enrollment October 7, 2009 IOM Drug Forum Clinical Trials Workshop - R Krall 36

37 Observations Clinicaltrials.gov as a data source Loopholes Accuracy and timeliness of data recording Lack of clarity in certain data elements Drugs vs Biologicals Phases Funding source Investigator-sites The current active research calls for the enrollment of perhaps 1/200 Americans as subjects There is a lot of waste in the conduct of clinical trials October 7, 2009 IOM Drug Forum Clinical Trials Workshop - R Krall 37

38 Controlled Clinical Trial enterprise What questions are asked? Finding subjects Health information technology Identify patient-subjects Collect data Practice settings Research roles Organization October 7, 2009 IOM Drug Forum Clinical Trials Workshop - R Krall 38

39 US Clinical Research IOM Drug Forum Clinical Trials Workshop Ronald Krall, MD October 7, 2009 October 7, 2009 IOM Drug Forum Clinical Trials Workshop - R Krall 39

40 Backups October 7, 2009 IOM Drug Forum Clinical Trials Workshop - R Krall 40

41 Phase I Trials: Subjects October 7, 2009 IOM Drug Forum Clinical Trials Workshop - R Krall 41

42 Phase I Trials: Subjects October 7, 2009 IOM Drug Forum Clinical Trials Workshop - R Krall 42

43 $32.2B October 7, 2009 IOM Drug Forum Clinical Trials Workshop - R Krall 43