Unresolved Issues in theUnresolved Issues in the
Globalization of Clinical TrialsGlobalization of Clinical Trials
Robert M...
Globalization of Clinical TrialsGlobalization of Clinical Trials
 Current StateCurrent State
MoneyMoney
EthicsEthics
Cult...
• Since 2002, the number of FDA investigators outside
the US has grown by 15% annually, while the number
inside the US has...
The Globalization of Clinical Investigators
80% 77%
70%
62%
57%
9% 10%
11%
13%
14%
5%
12% 13%
19%
25% 29%
86%
9%
0%
25%
50...
Growth in Numbers of Active
FDA-Regulated Investigators
2001 2003 2006 5-yr Growth
Rate
Most Recent
3-yr Growth
Rate
Russi...
The test of a first-rate intelligence isThe test of a first-rate intelligence is
the ability to hold two opposed ideas int...
Creative TensionCreative Tension
 Globalization of clinical research is a very goodGlobalization of clinical research is ...
Dollars and Sense: Factors PushingDollars and Sense: Factors Pushing
Clinical Research Out of the U.S.Clinical Research Ou...
Globalization of Clinical Trials—The GoodGlobalization of Clinical Trials—The Good
 Larger sample sizes are neededLarger ...
Globalization: A NecessityGlobalization: A Necessity
 Proof of concept trials—there areProof of concept trials—there are
...
Economic Proposition to Industry FromEconomic Proposition to Industry From
GlobalizationGlobalization
Return
0
$
$800 – $8...
The Good– the US Needs to Wake Up!The Good– the US Needs to Wake Up!
 Rapid movement to moving clinical trials awayRapid ...
Image Source: http://www.pandora.ca/pictures21/900666.jpg
The Demise of EmpiresThe Demise of Empires
 Dominance at a point in timeDominance at a point in time
 Arrogance about su...
Data gathered by the Tufts Center for the
Study of Drug Development (Tufts CSDD)
 >90% of all clinical trials delayed due...
Patient Recruitment and RetentionPatient Recruitment and Retention
1999-2002 2003-2006
Percent Screened who
were Randomize...
8.7%
10.5%
12.1%
-7.9%
6.5%
Number of Unique
Procedures
Frequency of
Procedures
Execution Burden Number of
Eligibility Cri...
Performance ‘Impact’ of protocol complexityPerformance ‘Impact’ of protocol complexity
 Compared US-based pivotal trial p...
Cycle Time MetricsCycle Time Metrics
115 120
413
460
129 143
714
780
Protocol Ready to
FPFV
Protocol Ready to
Drug Availab...
Clinical Trial Cost EstimatesClinical Trial Cost Estimates
$0
$50
$100
$150
$200
$250
$300
$350
$400
$450
Total
Coordinati...
Source: Roses AD. Nature 2000;405:857-865.
Pharmacogenomics
Randomized Trial of Genotype-Guided
Dosing of Warfarin Therapy:
Influence of Genotype on Warfarin Dose?
Genotype
(N = 188)...
Randomized Trial of Genotype-Guided
Dosing of Warfarin Therapy
Boxplots of distribution of warfarin dose by
CYP2C9 and VKO...
-NEJM 360; 2009
Cytochrome P-450 Polymorphisms and
Clopidogrel Response
-NEJM 360; 2009
Cytochrome P-450 Polymorphisms and
Clopidogrel Response
-NEJM 360; 2009
                                                                                              
GENEVA, SWITZERLAND—World H...
The Good--More Research will be DoneThe Good--More Research will be Done
 Broader sources of fundingBroader sources of fu...
ACC/AHA Clinical Practice
Guidelines
19.0%
44.9%
36.3%
LoE A
LoE B
LoE C
ACC/AHA Guidelines: Level of
Evidence of Recommendations
0%
10%
20%
30%
40%
50%
60%
70%
A B C A B C A B C A B C A B C A B C
Atrial
Fibrillation
(2001-2006)
Heart
Failure
(2001-200...
The BadThe Bad
 Differences in practices can be found as aDifferences in practices can be found as a
function of geograph...
Andrzej Budaj
for the GRACE Investigators
Postgraduate Medical School, Grochowski Hospital, Warsaw Poland
Current Practice...
In-hospital Management
All ACS
USA Rest of GRACE
AA (%) 95 95
B-blockers (%) 88 82
ACE-I (%) 61 66
Statins (%) 65 66
B-blo...
Temporal trends
USA vs Rest of GRACE
4.2
4.8
4.0
4.7
4.4
4.9
6.3
5.7
2
3
4
5
6
7
8
2000 2002 2004 2006
USA
Rest of GRACE
%...
9808LB11,9808LB11, 3838
Death and/or MI at 30 Days
FemaleFemale
MaleMale
0.50.5 11 1.51.5
Placebo Eptifibatide
Total n
16....
9808LB11,9808LB11, 3939
Death and/or MI
FemaleFemale
MaleMale
FemaleFemale
MaleMale
FemaleFemale
MaleMale
FemaleFemale
Mal...
9808LB11,9808LB11, 4040
Timing of Angiography
0
25
50
75
100
72
Hours
7
Days
30
Days
72
Hours
7
Days
30
Days
72
Hours
7
Da...
Study Undertaken by FDAStudy Undertaken by FDA
statisticians to evaluatestatisticians to evaluate
possibility of systemati...
difference of log-hazard ratios
Study % US
-1.5 -1.0 -0.5 0.0 0.5 1.0 1.5
311
452
273
94
45
196
437
388
49
7410
7411
912
3...
A figure
From the
label
External ValidityExternal Validity
Internal ValidityInternal Validity
GoalGoal
X
Article cites numerous examples of trials, which produceArticle cites numerous examples of trials, which produce
parameter...
Extrinsic factors such as medical practice, disease definition andExtrinsic factors such as medical practice, disease defi...
Verification at time of evaluation of marketingVerification at time of evaluation of marketing
authorization application t...
Source: Reed SD, Drug Information Journal, 2007
Source: Reed SD, Drug Information Journal, 2007
Source: Reed SD, Drug Information Journal, 2007
The UglyThe Ugly
 Differences in reported adverse events can beDifferences in reported adverse events can be
found in dif...
The UglyThe Ugly
Non-Non-
AdherencAdherenc
ee
WithdrawaWithdrawa
l:AE’sl:AE’s
WithdrawaWithdrawa
l: Subjectl: Subject
pref...
The ObsceneThe Obscene
 When the per patient reimbursement exceedsWhen the per patient reimbursement exceeds
reasonable l...
Source: http://www.tampabay.com/news/business/article934677.ece
Source: http://www.tampabay.com/news/business/article934633.ece
Source: http://www.tampabay.com/opinion/essays/article934654.ece
Ethical Concerns in clinical trials in India:
an investigation
• Lapatinib, GlaxoSmithKline
– The majority of breast cance...
• Risperidone, Johnson & Johnson
– Patients in trial were suffering from an acute
attack of a psychiatric condition that w...
• Quetiapine fumurate extended release,
AstraZeneca
– These two placebo-controlled trials of
quetiapine were conducted on ...
Factors Pulling Research Offshore
• Cost: cost per patient may be 1/10 the cost in
the US (Garnier, JP).
• Availability: u...
Factors Pushing Research Offshore
• Costs (Clinical Care)
• Costs (Administrative)
• Systems that developed to govern sing...
Administrative Barriers
Source: Dilts, DM et al. Journal of Clinical Oncology Oct. 2006
CommentsEvent Time
IRB Approval Timeline for a Focus Group
discussing Health Insurance with Latinos
Oct 2007
Feb 2008
Apr ...
Contracting for Clinical Research
“…the system would be better served if
there were universally accepted
contractual langu...
(1) I am familiar with, and will
comply with, applicable federal
regulations and guidance for the
protection of human subj...
Source: Glickman, SW et al. NEJM 2009.
Selection of Patients in Multinational Trials
• Problem: Research in communities that are not
intended to be major markets...
Transparency of Clinical Trial Results in
Developing Countries
• Problem: Protection of publication rights and access
to t...
Regulatory Oversight of International
Clinical Research
• Problem: Regulatory agencies have little
information on trials c...
Training and Experience of Clinical
Investigators
• Problem: Investigators in developing countries are
typically less expe...
Genomic Information in Drug
Development
• Problem: Lack of pharmacogenomic data for
subjects limits confidence in generali...
IRB Quality and Inefficiency
• Problem: Redundancy in review process may harm
patient safety by requiring diversion of eff...
Payment Compliance
• Problem: Increased costs and delays in payment
for research subjects divert financial support
from re...
Commercial Contracts
• Problem: Variety of contracting practices
brings complexity and delays to research
• Solutions
– Ad...
Confidentiality Agreements in
Commercial Contracts
• Problem: Confidentiality agreements reduce the
transparency and effic...
A collaborative effort to find solutions
 In light of these issues the U.S. FDA’s Office of
Critical Path Programs and Du...
Mission
 To identify practices that through broad
adoption will increase the quality and
efficiency of clinical trials
Scope
 CTTI will conduct projects in support of
its mission to identify practices that will
increase the quality and effi...
Scope (continued)
 CTTI will generate evidence about how
to improve the design and execution of
clinical trials
Projects...
Scope (continued)
 While CTTI focuses on clinical trials, it
may study other types of clinical
research (e.g., registries...
Executive Committee
 FDA: (Rachel Behrman, OC, Co-chair; Bob Temple,
CDER, Bram Zuckerman, CDRH)
 Duke: (Rob Califf, Co-...
Member Organizations
Category # organizations
Pharmaceutical companies 7
Clinical research organizations 7
Academic instit...
Projects
 Priority areas defined by Executive Committee:
Design principles
Data quality and quantity (including monitor...
Life Expectancy at Birth: Developed
and Developing Countries, 1955-2002
Source: World Health Report 2003
Unresolved Issues in the Globalization of Clinical Trials
Unresolved Issues in the Globalization of Clinical Trials
Unresolved Issues in the Globalization of Clinical Trials
Unresolved Issues in the Globalization of Clinical Trials
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  • Life expectancy is increasing, but there is still a wide gap between richer and poorer countries. The term “developed countries” includes Australia, Canada, European countries, former Soviet countries, Japan, New Zealand and the USA. High-mortality developing countries include those in sub-Saharan Africa, and countries with high child and adult mortality in Asia, Central and South America and the Eastern Mediterranean. Other developing countries are referred to as “developing – low mortality.”
  • Unresolved Issues in the Globalization of Clinical Trials

    1. 1. Unresolved Issues in theUnresolved Issues in the Globalization of Clinical TrialsGlobalization of Clinical Trials Robert M Califf MDRobert M Califf MD Vice Chancellor for Clinical ResearchVice Chancellor for Clinical Research
    2. 2. Globalization of Clinical TrialsGlobalization of Clinical Trials  Current StateCurrent State MoneyMoney EthicsEthics Cultural environmentCultural environment Genetic variationGenetic variation  Envisioning a positive futureEnvisioning a positive future
    3. 3. • Since 2002, the number of FDA investigators outside the US has grown by 15% annually, while the number inside the US has declined by 5.5%. • One-third of phase 3 trials of the 20 largest US pharmaceutical companies are being conducted solely outside the US. • For those same firms and studies, a majority of study sites (13,521 of 24,206) are outside the US. Source: Glickman, SW et al. NEJM 2009
    4. 4. The Globalization of Clinical Investigators 80% 77% 70% 62% 57% 9% 10% 11% 13% 14% 5% 12% 13% 19% 25% 29% 86% 9% 0% 25% 50% 75% 100% 1997 1999 2001 2003 2005 2007P US-Based Western Europe Rest of WorldPercent of Total 1572s Filed Sources: Tufts CSDD
    5. 5. Growth in Numbers of Active FDA-Regulated Investigators 2001 2003 2006 5-yr Growth Rate Most Recent 3-yr Growth Rate Russia 176 317 623 28.8% 25.3% Poland 215 314 322 8.4% .8% Brazil 139 296 292 16% -.5% Costa Rica 12 20 22 12.9% 3.2% Argentina 174 305 462 21.6% 14.8% China 80 120 307 30.9% 36.8% India 64 145 464 48.6% 47.4% Sources: Tufts CSDD
    6. 6. The test of a first-rate intelligence isThe test of a first-rate intelligence is the ability to hold two opposed ideas inthe ability to hold two opposed ideas in the mind at the same time, and stillthe mind at the same time, and still retain the ability to function.retain the ability to function. F. Scott FitzgeraldF. Scott Fitzgerald,, "The Crack-Up" (1936)"The Crack-Up" (1936) US novelist (1896 - 1940)US novelist (1896 - 1940)
    7. 7. Creative TensionCreative Tension  Globalization of clinical research is a very goodGlobalization of clinical research is a very good thing for the US and for all of us in a flat worldthing for the US and for all of us in a flat world We need more evidence to guide effective practiceWe need more evidence to guide effective practice in the USin the US So does every other country in the worldSo does every other country in the world  Driving globalization because of poor efficiencyDriving globalization because of poor efficiency in the conduct of research in the US is a badin the conduct of research in the US is a bad thing for the USthing for the US By the way, the same thinking could be applied toBy the way, the same thinking could be applied to any economically advantaged country that begins toany economically advantaged country that begins to think it is “above it all”think it is “above it all”
    8. 8. Dollars and Sense: Factors PushingDollars and Sense: Factors Pushing Clinical Research Out of the U.S.Clinical Research Out of the U.S. Kevin Schulman, MD Director, Health Sector Management Program The Fuqua School of Business Director, Center for Clinical and Genetic Economics Duke University Medical Center American Federation for Medical Research (AFMR) April 14, 2009
    9. 9. Globalization of Clinical Trials—The GoodGlobalization of Clinical Trials—The Good  Larger sample sizes are neededLarger sample sizes are needed Modest treatment effects predominateModest treatment effects predominate Subgroups must be validatedSubgroups must be validated Will become even more important in “personalized” orWill become even more important in “personalized” or “stratified” medicine“stratified” medicine  Competition spurs improvementCompetition spurs improvement  More research will be doneMore research will be done  Collaboration leads to shared learningCollaboration leads to shared learning Practice patternsPractice patterns EthicsEthics Will ensure transparency on results reportingWill ensure transparency on results reporting  Adequate sample sizes/study designs to understand geneticAdequate sample sizes/study designs to understand genetic heterogeneityheterogeneity
    10. 10. Globalization: A NecessityGlobalization: A Necessity  Proof of concept trials—there areProof of concept trials—there are pharmacogenomic differencespharmacogenomic differences  Efficacy trials—the context of clinical practiceEfficacy trials—the context of clinical practice mattersmatters  Effectiveness trials—the relative costs andEffectiveness trials—the relative costs and balance of risk and benefits are contextbalance of risk and benefits are context dependentdependent The question is not whether we globalize, it isThe question is not whether we globalize, it is why we do it, how we handle culturalwhy we do it, how we handle cultural differences and how we lump or split findingsdifferences and how we lump or split findings
    11. 11. Economic Proposition to Industry FromEconomic Proposition to Industry From GlobalizationGlobalization Return 0 $ $800 – $880 mil (2001) $1 – $10 billion* PatentPatent LaunchLaunch PatentPatent ExpirationExpiration Pre-LaunchPre-Launch fall-off*fall-off*speed*speed* duration*duration* maximize area*maximize area* Decrease costs or time Potential local market opportunity No requirement to match study populations to target markets ROI
    12. 12. The Good– the US Needs to Wake Up!The Good– the US Needs to Wake Up!  Rapid movement to moving clinical trials awayRapid movement to moving clinical trials away from USfrom US  US is inferior in:US is inferior in: Study cost indexStudy cost index Population indicators (tx naïve patients)Population indicators (tx naïve patients) Business environmentBusiness environment  US is better, but losing ground quickly in:US is better, but losing ground quickly in: Clinical research personnel qualificationClinical research personnel qualification Study site organizationStudy site organization Thought leader quantityThought leader quantity
    13. 13. Image Source: http://www.pandora.ca/pictures21/900666.jpg
    14. 14. The Demise of EmpiresThe Demise of Empires  Dominance at a point in timeDominance at a point in time  Arrogance about superiorityArrogance about superiority  Failure to pay attention to quality of workFailure to pay attention to quality of work  Leaders content to “ride the wave”Leaders content to “ride the wave”  Entrenched interests can buy stability throughEntrenched interests can buy stability through controlling laws and regulationscontrolling laws and regulations  Inability to create or respond to innovationInability to create or respond to innovation  Cost of transactions exceeds cost ofCost of transactions exceeds cost of actually doing the work!actually doing the work!
    15. 15. Data gathered by the Tufts Center for the Study of Drug Development (Tufts CSDD)  >90% of all clinical trials delayed due to over-ambitious timelines and difficulty with patient enrollment  Top reasons for delays in trials: Protracted budget negotiations Slow IRB review and approval Poor patient recruitment and retention  Estimated 20% of PIs fail to enroll a single patient and 30% under-enroll in a given trial  Between 2000 and 2005 38% of PIs who participated in clinical trials in a given year did not return in a subsequent year through 2008 Up from 26% in previous 5 years
    16. 16. Patient Recruitment and RetentionPatient Recruitment and Retention 1999-2002 2003-2006 Percent Screened who were Randomized 75% 59% Percent Randomized who Completed the Study 69% 48% Screen : Complete 50% 25% Source: Tufts CSDD •Performance data on 57 phase II and III (across TAs) protocols provided by five pharmaceutical companies
    17. 17. 8.7% 10.5% 12.1% -7.9% 6.5% Number of Unique Procedures Frequency of Procedures Execution Burden Number of Eligibility Criteria AnnualGrowthRate Compensation per Procedure Protocol Designs More Complex and BurdensomeProtocol Designs More Complex and Burdensome ((2000-2006)2000-2006) Sources: Tufts CSDD; Getz et al. Assessing the Impact of Protocol Design Change on Clinical Trial Performance. American Journal of Therapeutics. 2008 15(5); 450 - 457 Represents 10,038 industry protocols; provided by Fast Track Systems Work effort values based on Medicare’s RVU methodology
    18. 18. Performance ‘Impact’ of protocol complexityPerformance ‘Impact’ of protocol complexity  Compared US-based pivotal trial protocols executed 1999-2002 (lower complexity) and 2003-2006 (higher complexity):  Number of CRF pages rose to an average of 180 pages vs. 55  Controlling for treatment duration, cycle times increased substantially across all measures  Enrollment rates worsened Source: Tufts CSDD
    19. 19. Cycle Time MetricsCycle Time Metrics 115 120 413 460 129 143 714 780 Protocol Ready to FPFV Protocol Ready to Drug Available Protocol Ready to LPLV Protocol Ready to Data Lock 1999-2002 2003-2006 12% – 20% Increase 69% - 75% Increase MedianDaysElapsed Source: Tufts CSDD
    20. 20. Clinical Trial Cost EstimatesClinical Trial Cost Estimates $0 $50 $100 $150 $200 $250 $300 $350 $400 $450 Total Coordinating Center Site Payments Other Full Cost Industry Streamlined Industry More Streamlined $ In US 2007 Millions
    21. 21. Source: Roses AD. Nature 2000;405:857-865. Pharmacogenomics
    22. 22. Randomized Trial of Genotype-Guided Dosing of Warfarin Therapy: Influence of Genotype on Warfarin Dose? Genotype (N = 188) Prevalence % Enzyme Activity S/R Warfarin (mg/L) Daily Doses (mg) Clearance/LB W (ml/min/kg) 2C9 *1/*1 64% 100% 0.45 (0.11) 5 (2.5) 0.065 (0.025) 2C9 *1/*2 *2/*2 21% 50-70% 0.69 (0.28) 3 (1.5) 0.041 (0.021) 2C9 *1/*3 *2/*3 *3/*3 15% 10% 1.43 (0.63) 2 (1.0) 0.020 (0.011) Herman et al, The Pharmacogenomics J 4:1-10. 2005 McClain et al, ACMG Presentation, October 30, 2006 (In Press)(From L. Lesko)
    23. 23. Randomized Trial of Genotype-Guided Dosing of Warfarin Therapy Boxplots of distribution of warfarin dose by CYP2C9 and VKORC1 genotype Sconce et al. Blood 2005; 106:2329
    24. 24. -NEJM 360; 2009
    25. 25. Cytochrome P-450 Polymorphisms and Clopidogrel Response -NEJM 360; 2009
    26. 26. Cytochrome P-450 Polymorphisms and Clopidogrel Response -NEJM 360; 2009
    27. 27.                                                                                                GENEVA, SWITZERLAND—World Health Organization officials expressed disappointment Monday at the group's finding that, despite the enormous efforts of doctors, rescue workers and other medical professionals worldwide, the global death rate remains constant at 100 percent. Death, a metabolic affliction causing total shutdown of all life functions, has long been considered humanity's number one health concern. Responsible for 100 percent of all recorded fatalities worldwide, the condition has no cure. "I was really hoping, what with all those new radiology treatments, rescue helicopters, aerobics TV shows and what have you, that we might at least make a dent in it this year," WHO Director General Dr. Gernst Bladt said. "Unfortunately, it would appear that the death rate remains constant and total, as it has inviolably since the dawn of time."
    28. 28. The Good--More Research will be DoneThe Good--More Research will be Done  Broader sources of fundingBroader sources of funding Many governments now giving tax breaks forMany governments now giving tax breaks for industry funded researchindustry funded research  Do the research where costs are lessDo the research where costs are less  Do the research where barriers to trial initiationDo the research where barriers to trial initiation are lessare less
    29. 29. ACC/AHA Clinical Practice Guidelines
    30. 30. 19.0% 44.9% 36.3% LoE A LoE B LoE C ACC/AHA Guidelines: Level of Evidence of Recommendations
    31. 31. 0% 10% 20% 30% 40% 50% 60% 70% A B C A B C A B C A B C A B C A B C Atrial Fibrillation (2001-2006) Heart Failure (2001-2006) Stable Angina (1999-2002) Unstable Angina (2000-2007) PCI (2001- 2005) Pacemaker (1998-2002) ACC/AHA Guidelines: More Guidelines No Improvement in Proportion with High Quality!
    32. 32. The BadThe Bad  Differences in practices can be found as aDifferences in practices can be found as a function of geographyfunction of geography  Differences in outcomes can be found as aDifferences in outcomes can be found as a function of geographyfunction of geography  Differences in treatment effect can be found asDifferences in treatment effect can be found as a function of geographya function of geography
    33. 33. Andrzej Budaj for the GRACE Investigators Postgraduate Medical School, Grochowski Hospital, Warsaw Poland Current Practices in ACS Care USA vs Rest of GRACE
    34. 34. In-hospital Management All ACS USA Rest of GRACE AA (%) 95 95 B-blockers (%) 88 82 ACE-I (%) 61 66 Statins (%) 65 66 B-blockers iv (%) 27 9 ARB (%) 7 5 Other lipid lowering (%) 8 3     
    35. 35. Temporal trends USA vs Rest of GRACE 4.2 4.8 4.0 4.7 4.4 4.9 6.3 5.7 2 3 4 5 6 7 8 2000 2002 2004 2006 USA Rest of GRACE % Death in hospital All ACS
    36. 36. 9808LB11,9808LB11, 3838 Death and/or MI at 30 Days FemaleFemale MaleMale 0.50.5 11 1.51.5 Placebo Eptifibatide Total n 16.88 13.89 6103 13.68 14.88 3357 Placebo Better Eptifibatide Better PT-E2-7PT-E2-7
    37. 37. 9808LB11,9808LB11, 3939 Death and/or MI FemaleFemale MaleMale FemaleFemale MaleMale FemaleFemale MaleMale FemaleFemale MaleMale 0.20.2 11 55 Placebo Eptifibatide Total n 16.16 12.35 2499 12.89 10.57 1328 16.03 13.03 2542 12.10 15.52 1154 20.35 20.43 814 19.05 21.78 727 21.43 16.39 248 5.63 15.58 148 Placebo Better Eptifibatide Better NA WE EE LA PT-E2-8PT-E2-8
    38. 38. 9808LB11,9808LB11, 4040 Timing of Angiography 0 25 50 75 100 72 Hours 7 Days 30 Days 72 Hours 7 Days 30 Days 72 Hours 7 Days 30 Days 72 Hours 7 Days 30 Days 72 Hours 7 Days 30 Days % Male Female Overall North America Western Europe Eastern Europe Latin America PT-C-17PT-C-17
    39. 39. Study Undertaken by FDAStudy Undertaken by FDA statisticians to evaluatestatisticians to evaluate possibility of systematicpossibility of systematic regional differencesregional differences Major cardiovascular outcome studiesMajor cardiovascular outcome studies evaluated over the last 10 yearsevaluated over the last 10 years Overall study result statisticallyOverall study result statistically positive, ie. demonstrated overallpositive, ie. demonstrated overall effecteffect Region never pre-specified as a factorRegion never pre-specified as a factor to be evaluated statisticallyto be evaluated statistically 16 independent studies16 independent studies
    40. 40. difference of log-hazard ratios Study % US -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 311 452 273 94 45 196 437 388 49 7410 7411 912 313 2914 1715 9016 Estimates and confidence intervals for difference between US and Non-US treatment effects for each study J. Lawrence In 13 of 16 , US log hazard above 0
    41. 41. A figure From the label
    42. 42. External ValidityExternal Validity Internal ValidityInternal Validity GoalGoal X
    43. 43. Article cites numerous examples of trials, which produceArticle cites numerous examples of trials, which produce parameter estimates of questionable value to Westernparameter estimates of questionable value to Western European decision makers and highlights differencesEuropean decision makers and highlights differences between emerging regions and Western Europeans, whichbetween emerging regions and Western Europeans, which suggest the two are mutually incomparable.suggest the two are mutually incomparable. Proposed that these differences may confound studyProposed that these differences may confound study outcomes, decision-making parameter estimates and dataoutcomes, decision-making parameter estimates and data pertaining to the incidence of adverse drug interactionspertaining to the incidence of adverse drug interactions Further research should be undertaken in order to exploreFurther research should be undertaken in order to explore the relationship between geographical variance andthe relationship between geographical variance and external validity, particularly where safety data derivedexternal validity, particularly where safety data derived from relatively drug naïve regions are assumed to pertain tofrom relatively drug naïve regions are assumed to pertain to a maximally treated populations elsewhere in the worlda maximally treated populations elsewhere in the world Source: Wathal. Outsourcing Clinical Trials www.samedanltd.com
    44. 44. Extrinsic factors such as medical practice, disease definition andExtrinsic factors such as medical practice, disease definition and study population may influence applicability of foreign data to anstudy population may influence applicability of foreign data to an EU settingEU setting Global drug development doesn’t necessarily support approval ofGlobal drug development doesn’t necessarily support approval of unrestricted indications in an EU populationunrestricted indications in an EU population Consider and discuss possible influence of extrinsicConsider and discuss possible influence of extrinsic factors on interpretation of results and wording offactors on interpretation of results and wording of indicationsindications In depth, prospective analysis of potential ethnic factors whenIn depth, prospective analysis of potential ethnic factors when conducting a clinical trial in a certain region.conducting a clinical trial in a certain region. Depending on the outcome of analyses can beDepending on the outcome of analyses can be decided whether certain clinical trials conducted in adecided whether certain clinical trials conducted in a specific area of the world would be relevant to EUspecific area of the world would be relevant to EU setting or if there are reasons to perform additionalsetting or if there are reasons to perform additional clinical trials within the EUclinical trials within the EU Source: European Medicines Agency, Pre-Authorization Evaluation of Medicines for Human Use. Feb. 19, 2009
    45. 45. Verification at time of evaluation of marketingVerification at time of evaluation of marketing authorization application that trials have been conducted inauthorization application that trials have been conducted in accordance with GCP and ethical standardsaccordance with GCP and ethical standards Greater transparency of this process and itsGreater transparency of this process and its outcome should be described in the Europeanoutcome should be described in the European Public Assessment Report (EPAR)Public Assessment Report (EPAR) Increased GCP inspection including further extension ofIncreased GCP inspection including further extension of GCP policy on increasing numbers of routine inspectionsGCP policy on increasing numbers of routine inspections as part of the need for greater supervision of the conductas part of the need for greater supervision of the conduct and ethical standards of clinical trials performed outsideand ethical standards of clinical trials performed outside the EEAthe EEA Source: European Medicines Agency, EMEA strategy paper: acceptance of clinical trials conducted in the third countries, for evaluation in Marketing Authorization Applications. Feb. 5, 2008
    46. 46. Source: Reed SD, Drug Information Journal, 2007
    47. 47. Source: Reed SD, Drug Information Journal, 2007
    48. 48. Source: Reed SD, Drug Information Journal, 2007
    49. 49. The UglyThe Ugly  Differences in reported adverse events can beDifferences in reported adverse events can be found in different countriesfound in different countries Is there a relationship between relative financialIs there a relationship between relative financial incentive and lower rates of side effects?incentive and lower rates of side effects?  Differences in adherence can be found inDifferences in adherence can be found in different countriesdifferent countries Is there a relationship between lack of access toIs there a relationship between lack of access to health care outside of the trial and adherence?health care outside of the trial and adherence?
    50. 50. The UglyThe Ugly Non-Non- AdherencAdherenc ee WithdrawaWithdrawa l:AE’sl:AE’s WithdrawaWithdrawa l: Subjectl: Subject preferencepreference WithdrewWithdrew ConsentConsent UKUK 39.7%39.7% 12%12% 17%17% 5555 USUS 35.5%35.5% 7%7% 16%16% 166166 PolandPoland 14.8%14.8% 2%2% 9%9% 22 ChinaChina 6.1%6.1% 5%5% 5%5% 11 ArgentinaArgentina 13.6%13.6% 2%2% 8%8% 11
    51. 51. The ObsceneThe Obscene  When the per patient reimbursement exceedsWhen the per patient reimbursement exceeds reasonable levels, the human experimentationreasonable levels, the human experimentation entrepreneurs will be temptedentrepreneurs will be tempted  When the FDA cannot inspect, the cheaters willWhen the FDA cannot inspect, the cheaters will figure out how to get the data looking realfigure out how to get the data looking real good!good!
    52. 52. Source: http://www.tampabay.com/news/business/article934677.ece
    53. 53. Source: http://www.tampabay.com/news/business/article934633.ece
    54. 54. Source: http://www.tampabay.com/opinion/essays/article934654.ece
    55. 55. Ethical Concerns in clinical trials in India: an investigation • Lapatinib, GlaxoSmithKline – The majority of breast cancer patients in India cannot afford proper treatment. This trial required seriously ill patients who had not received treatment for their condition. – Their economic vulnerability forces patients in India to take part in trials in order to get access to treatment and to disregard the potential risks that participating in clinical trials entails. By carrying out this clinical trial in India GlaxoSmithKline (GSK) took advantage of the vulnerable position of breast cancer patients. Source: Srinivasan S, et al. Ethical concerns in clinical trials in India: an investigation. Center for Studies in Ethics and Rights, Mumbai, India. Feb. 2009
    56. 56. • Risperidone, Johnson & Johnson – Patients in trial were suffering from an acute attack of a psychiatric condition that would have caused them much distress. – They were harmed because they were taken off all treatment before they were put on either the active drug or a placebo. – Those on the placebo were also harmed because they were deprived of an effective treatment Ethical Concerns in clinical trials in India: an investigation Source: Srinivasan S, et al. Ethical concerns in clinical trials in India: an investigation. Center for Studies in Ethics and Rights, Mumbai, India. Feb. 2009
    57. 57. • Quetiapine fumurate extended release, AstraZeneca – These two placebo-controlled trials of quetiapine were conducted on patients with schizophrenia. An immediate release formulation of the drug had already been approved and these trials were of an extended release version of the drug. – A patient in one of the quetiapine trials committed suicide after 173 days of being on placebo. Ethical Concerns in clinical trials in India: an investigation Source: Srinivasan S, et al. Ethical concerns in clinical trials in India: an investigation. Center for Studies in Ethics and Rights, Mumbai, India. Feb. 2009
    58. 58. Factors Pulling Research Offshore • Cost: cost per patient may be 1/10 the cost in the US (Garnier, JP). • Availability: untreated or under-treated patients may speed recruitment of patients to clinical trials reducing the time costs of research. • Regulations: local processes may be more variable (and potentially less restrictive) than in the US. Source: Garnier JP. Rebuilding the R&D engine in big pharmacy. Harv Bus Rev 2008;86:68-76.
    59. 59. Factors Pushing Research Offshore • Costs (Clinical Care) • Costs (Administrative) • Systems that developed to govern single site studies are inefficient in oversight of multicenter, multinational studies • IRB (redundant site level process) • Contracting (redundant site level process) • Compliance (research as a potential criminal issue)
    60. 60. Administrative Barriers Source: Dilts, DM et al. Journal of Clinical Oncology Oct. 2006
    61. 61. CommentsEvent Time IRB Approval Timeline for a Focus Group discussing Health Insurance with Latinos Oct 2007 Feb 2008 Apr 2008 Oct 2008 Jan 2009 Aug 2007 Aug-Sep 2007 May-Sep 2008 Rewritten study submitted to IRB Continued negotiations between local cultural center and IRB Local cultural center requests major changes to study Initial study approved by IRB Study rewritten and submitted as expedited Discussions with IRB about rejection of exempt status Study Submitted to IRB as Exempt IRB requested additional changes Incorporate relevant cultural concerns in initial study design IRB requested extensive changes Focus groups may not qualify for IRB exempt status IRB rejected exempt status Final Study Approved
    62. 62. Contracting for Clinical Research “…the system would be better served if there were universally accepted contractual language … Such language would help safeguard the integrity of the research process.” -JEFFREY M. DRAZEN Editor-in-Chief, New England Journal of Medicine Source: Drazen, JM. NEJM Oct. 24, 2002
    63. 63. (1) I am familiar with, and will comply with, applicable federal regulations and guidance for the protection of human subjects: HHS regulations at 45 FR 46 and associated guidance; FDA regulations at 21 CFR Parts 50, 54, 56, 312, 314, 601, 812, and 814 and associated guidance; the HIPAA privacy regulations at 45 CFR Parts 160 and 164 and associated guidance; the DUHS Federal-Wide Assurance; and relevant institutional policies and procedures for the protection of human research subjects. Source: DUHS Principal Investigator Agreement form. Version 6/25/08
    64. 64. Source: Glickman, SW et al. NEJM 2009.
    65. 65. Selection of Patients in Multinational Trials • Problem: Research in communities that are not intended to be major markets for the products under testing can be ethically problematic • Solutions – Sponsors should describe how trial populations match intended markets – Create target enrollment according to region on the basis of intended use of product, similar to target enrollment of women and minorities Source: Glickman, SW et al. NEJM 2009.
    66. 66. Transparency of Clinical Trial Results in Developing Countries • Problem: Protection of publication rights and access to trial data for investigators is necessary to preserve the integrity of research • Solutions – Publish all data regardless of research location, and reinforce requirements according to FDA Amendments Act of 2007 – Preserve publication rights globally through legal agreements at onset of trial – Create trial leadership that incorporates representatives of countries involved in study Source: Glickman, SW et al. NEJM 2009.
    67. 67. Regulatory Oversight of International Clinical Research • Problem: Regulatory agencies have little information on trials conducted outside their countries • Solutions – Mechanism for sharing regulatory oversight among government agencies worldwide – Public registry of IRBs and inventory of country-specific provisions for ethical oversight – Comprehensive study of the globalization of clinical research by IOM or WHO – Central statistical monitoring system to find unusual data patterns suspicious for fraud Source: Glickman, SW et al. NEJM 2009.
    68. 68. Training and Experience of Clinical Investigators • Problem: Investigators in developing countries are typically less experienced than investigators in developed countries • Solutions – Formal training programs for clinical research for investigators in developing countries to expand global clinical research leadership capacity and improve collaboration worldwide – Mechanism for tracking investigators who are trained to conduct clinical trials and those who have been prohibited from conducting trials Source: Glickman, SW et al. NEJM 2009.
    69. 69. Genomic Information in Drug Development • Problem: Lack of pharmacogenomic data for subjects limits confidence in generalizability of results • Solutions – Expand FDA Voluntary Genomic Data Submissions program to international regulatory agencies – Develop global data warehousing and data analysis capabilities Source: Glickman, SW et al. NEJM 2009.
    70. 70. IRB Quality and Inefficiency • Problem: Redundancy in review process may harm patient safety by requiring diversion of effort to unnecessary procedures and practices • Solutions – Greater use of centralized IRBs (eg, Central IRB Initiative, European Union Clinical Trials Directive) – Mutual acceptance of proposal review in consortia (eg, Biomedical Research Alliance of New York) – Streamlined best practices to reduce unnecessary work for investigators (eg, Clinical Trials Transformation Initiative) Source: Glickman, SW et al. NEJM 2009.
    71. 71. Payment Compliance • Problem: Increased costs and delays in payment for research subjects divert financial support from research to administration and make research less attractive to investigators because of risk of criminal penalties • Solutions – Establish nonpunitive mechanism for reconciliation of payment – Expand mechanisms to pay for usual care services (eg, within Medicare and Medicaid) Source: Glickman, SW et al. NEJM 2009.
    72. 72. Commercial Contracts • Problem: Variety of contracting practices brings complexity and delays to research • Solutions – Adopt standard contract language for clinical research agreements Source: Glickman, SW et al. NEJM 2009.
    73. 73. Confidentiality Agreements in Commercial Contracts • Problem: Confidentiality agreements reduce the transparency and efficiency of clinical research • Solutions – Adopt standard confidentiality language for clinical research agreements Source: Glickman, SW et al. NEJM 2009.
    74. 74. A collaborative effort to find solutions  In light of these issues the U.S. FDA’s Office of Critical Path Programs and Duke University joined together as founding members of a public-private partnership: The Clinical Trials Transformation Initiative (CTTI)  All stakeholders are involved in this initiative including government, industry, academia, patient advocates, clinical investigators, professional societies, and others
    75. 75. Mission  To identify practices that through broad adoption will increase the quality and efficiency of clinical trials
    76. 76. Scope  CTTI will conduct projects in support of its mission to identify practices that will increase the quality and efficiency of clinical trials “Quality” - the ability to effectively answer the intended question about the benefits and risks of a medical product (therapeutic or diagnostic) or procedure, while assuring protection of human subjects
    77. 77. Scope (continued)  CTTI will generate evidence about how to improve the design and execution of clinical trials Projects about design will address principles generally applicable to clinical trials to assure that they are fit to accomplish their intended purpose.
    78. 78. Scope (continued)  While CTTI focuses on clinical trials, it may study other types of clinical research (e.g., registries) that can provide data to regulatory agencies.  Although CTTI will concentrate initially on the design and conduct of clinical trials in the United States, it seeks to identify practice improvements that can be applied internationally.
    79. 79. Executive Committee  FDA: (Rachel Behrman, OC, Co-chair; Bob Temple, CDER, Bram Zuckerman, CDRH)  Duke: (Rob Califf, Co-chair)  NIH liaison: (Amy Patterson)  Industry: (Glenn Gormley, Jay Siegel, Susan Alpert, Alberto Grignolo)  Academia: (David DeMets)  Patient representative: (Nancy Roach)  At-large representative: (Ken Getz)  Non-US regulatory liaison: (Hans-Georg Eichler, EMEA)  Steering Committee co-chairs, ex officio (James Ferguson, Briggs Morrison)
    80. 80. Member Organizations Category # organizations Pharmaceutical companies 7 Clinical research organizations 7 Academic institutions 7 Professional societies 7 Device companies 6 Biotechnology companies 5 Government 4 (FDA, CMS, NIH, OHRP) Clinical investigator groups 3 Trade organizations 3 Patient representatives 2 (TBD) Private equity firm 1 Regulatory law firm 1 *Began recruiting members May 2008
    81. 81. Projects  Priority areas defined by Executive Committee: Design principles Data quality and quantity (including monitoring) Study start-up Adverse event reporting  Information about the process for submission, review, and approval of projects available at CTTI Web site: www.trialstransformation.org/projects
    82. 82. Life Expectancy at Birth: Developed and Developing Countries, 1955-2002 Source: World Health Report 2003

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