Unresolved Issues in the Globalization of Clinical Trials

1
Unresolved Issues in the Globalization of
Clinical Trials

• Robert M Califf MD
• Vice Chancellor for Clinical Research

2
Globalization of Clinical Trials

• Current State
• Money
• Ethics
• Cultural environment
• Genetic variation
• Envisioning a positive future

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
The Globalization of Clinical Investigators
Percent of Total 1572s Filed
Sources Tufts CSDD
5
Growth in Numbers of ActiveFDA-Regulated
Investigators
Sources Tufts CSDD
6
The test of a first-rate intelligence is the
ability to hold two opposed ideas in the mind at
the same time, and still retain the ability to
function.F. Scott Fitzgerald, "The Crack-Up"
(1936)US novelist (1896 - 1940)
7
Creative Tension

• Globalization of clinical research is a very good
  thing for the US and for all of us in a flat
  world
• We need more evidence to guide effective practice
  in the US
• So does every other country in the world
• Driving globalization because of poor efficiency
  in the conduct of research in the US is a bad
  thing for the US
• By the way, the same thinking could be applied to
  any economically advantaged country that begins
  to think it is above it all

8
Dollars and Sense Factors Pushing Clinical
Research Out of the U.S.
American Federation for Medical Research
(AFMR) April 14, 2009

• Kevin Schulman, MD
• Director, Health Sector Management Program
• The Fuqua School of Business
• Director, Center for Clinical and Genetic
  Economics
• Duke University Medical Center

9
Globalization of Clinical TrialsThe Good

• Larger sample sizes are needed
• Modest treatment effects predominate
• Subgroups must be validated
• Will become even more important in
  personalized or stratified medicine
• Competition spurs improvement
• More research will be done
• Collaboration leads to shared learning
• Practice patterns
• Ethics
• Will ensure transparency on results reporting
• Adequate sample sizes/study designs to understand
  genetic heterogeneity

10
Globalization A Necessity

• Proof of concept trialsthere are pharmacogenomic
  differences
• Efficacy trialsthe context of clinical practice
  matters
• Effectiveness trialsthe relative costs and
  balance of risk and benefits are context
  dependent
• The question is not whether we globalize, it is
  why we do it, how we handle cultural differences
  and how we lump or split findings

11
Economic Proposition to Industry From
Globalization

duration
1 10 billion
Pre-Launch
Potential local market opportunity
No requirement to match study populations to
target markets
Return
fall-off
speed
ROI
maximize area
800 880 mil (2001)
0
Patent Expiration
Patent
Launch
Decrease costs or time
12
The Good the US Needs to Wake Up!

• Rapid movement to moving clinical trials away
  from US
• US is inferior in
• Study cost index
• Population indicators (tx naïve patients)
• Business environment
• US is better, but losing ground quickly in
• Clinical research personnel qualification
• Study site organization
• Thought leader quantity

13
Image Source http//www.pandora.ca/pictures21/900
666.jpg
14
The Demise of Empires

• Dominance at a point in time
• Arrogance about superiority
• Failure to pay attention to quality of work
• Leaders content to ride the wave
• Entrenched interests can buy stability through
  controlling laws and regulations
• Inability to create or respond to innovation
• Cost of transactions exceeds cost of actually
  doing the work!

15
Data gathered by the Tufts Center for the Study
of Drug Development (Tufts CSDD)

• gt90 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
Patient Recruitment and Retention

• Performance data on 57 phase II and III (across
  TAs) protocols provided by five pharmaceutical
  companies

Source Tufts CSDD
17
Protocol Designs More Complex and Burdensome
(2000-2006)
Annual Growth Rate
Compensation per Procedure
Represents 10,038 industry protocols provided by
Fast Track Systems Work effort values based on
Medicares RVU methodology
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
18
Performance 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
Cycle Time Metrics
69 - 75 Increase
12 20 Increase
Median Days Elapsed
Source Tufts CSDD
20
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21
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22
Clinical Trial Cost Estimates
In US 2007 Millions
Full Cost Industry
Streamlined Industry
More Streamlined
23
Pharmacogenomics
Source Roses AD. Nature 2000405857-865.
24
Randomized Trial of Genotype-Guided Dosing of
Warfarin Therapy Influence of Genotype on
Warfarin Dose?
Herman et al, The Pharmacogenomics J 41-10. 2005
(From L. Lesko)
McClain et al, ACMG Presentation, October 30,
2006 (In Press)
25
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 1062329
26
-NEJM 360 2009
27
Cytochrome P-450 Polymorphisms and Clopidogrel
Response
-NEJM 360 2009
28
Cytochrome P-450 Polymorphisms and Clopidogrel
Response
-NEJM 360 2009
29
                                             
                                                 
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officials expressed disappointment Monday at the
group's finding that, despite the enormous
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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."
30
The Good--More Research will be Done

• Broader sources of funding
• Many governments now giving tax breaks for
  industry funded research
• Do the research where costs are less
• Do the research where barriers to trial
  initiation are less

31
ACC/AHA Clinical Practice Guidelines
32
ACC/AHA Guidelines Level of Evidence of
Recommendations
LoE A
LoE B
LoE C
33
ACC/AHA Guidelines More GuidelinesNo
Improvement in Proportion with High Quality!
34
The Bad

• Differences in practices can be found as a
  function of geography
• Differences in outcomes can be found as a
  function of geography
• Differences in treatment effect can be found as a
  function of geography

35
Current Practices in ACS Care USA vs Rest of GRACE
Andrzej Budaj for the GRACE Investigators
Postgraduate Medical School, Grochowski Hospital,
Warsaw Poland
36
In-hospital ManagementAll ACS
USA
Rest of GRACE
AA () 95 95
?
B-blockers () 88 82
?
B-blockers iv () 27 9
?
ACE-I () 61 66
?
ARB () 7 5
Statins () 65 66
?
Other lipid lowering () 8 3

37
Temporal trends USA vs Rest of GRACE
Death in hospital All ACS

38
Death and/or MI at 30 Days

• Placebo Eptifibatide Total n
• 16.88 13.89 6103
• 13.68 14.88 3357

PlaceboBetter
EptifibatideBetter
PT-E2-7
39
Death and/or MI
Placebo Eptifibatide Total n 16.16 12.35 2499 1
2.89 10.57 1328 16.03 13.03 2542 12.10 15.52 115
4 20.35 20.43 814 19.05 21.78 727 21.43 16.39 2
48 5.63 15.58 148
NA WE EE LA
PlaceboBetter
EptifibatideBetter
PT-E2-8
40
Timing of Angiography
Overall
North America
Western Europe
Eastern Europe
Latin America
PT-C-17
41
Study Undertaken by FDA statisticians to evaluate
possibility of systematic regional differences

• Major cardiovascular outcome studies evaluated
  over the last 10 years
• Overall study result statistically positive, ie.
  demonstrated overall effect
• Region never pre-specified as a factor to be
  evaluated statistically
• 16 independent studies

42
Estimates and confidence intervals for
difference between US and Non-US treatment
effects for each study
In 13 of 16 , US log hazard above 0
J. Lawrence
43
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44
A figure From the label
45
Goal

• External Validity

X
Internal Validity
46

• Article cites numerous examples of trials, which
  produce parameter estimates of questionable value
  to Western European decision makers and
  highlights differences between emerging regions
  and Western Europeans, which suggest the two are
  mutually incomparable.
• Proposed that these differences may confound
  study outcomes, decision-making parameter
  estimates and data pertaining to the incidence of
  adverse drug interactions
• Further research should be undertaken in order to
  explore the relationship between geographical
  variance and external validity, particularly
  where safety data derived from relatively drug
  naïve regions are assumed to pertain to a
  maximally treated populations elsewhere in the
  world

Source Wathal. Outsourcing Clinical Trials
www.samedanltd.com
47

• Extrinsic factors such as medical practice,
  disease definition and study population may
  influence applicability of foreign data to an EU
  setting
• Global drug development doesnt necessarily
  support approval of unrestricted indications in
  an EU population
• Consider and discuss possible influence of
  extrinsic factors on interpretation of results
  and wording of indications
• In depth, prospective analysis of potential
  ethnic factors when conducting a clinical trial
  in a certain region.
• Depending on the outcome of analyses can be
  decided whether certain clinical trials conducted
  in a specific area of the world would be relevant
  to EU setting or if there are reasons to perform
  additional clinical trials within the EU

Source European Medicines Agency,
Pre-Authorization Evaluation of Medicines for
Human Use. Feb. 19, 2009
48

• Verification at time of evaluation of marketing
  authorization application that trials have been
  conducted in accordance with GCP and ethical
  standards
• Greater transparency of this process and its
  outcome should be described in the European
  Public Assessment Report (EPAR)
• Increased GCP inspection including further
  extension of GCP policy on increasing numbers of
  routine inspections as part of the need for
  greater supervision of the conduct and ethical
  standards of clinical trials performed outside
  the 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
49
Source Reed SD, Drug Information Journal, 2007
50
Source Reed SD, Drug Information Journal, 2007
51
Source Reed SD, Drug Information Journal, 2007
52
The Ugly

• Differences in reported adverse events can be
  found in different countries
• Is there a relationship between relative
  financial incentive and lower rates of side
  effects?
• Differences in adherence can be found in
  different countries
• Is there a relationship between lack of access to
  health care outside of the trial and adherence?

53
The Ugly
54
The Obscene

• When the per patient reimbursement exceeds
  reasonable levels, the human experimentation
  entrepreneurs will be tempted
• When the FDA cannot inspect, the cheaters will
  figure out how to get the data looking real good!

55
Source http//www.tampabay.com/news/business/art
icle934677.ece
56
Source http//www.tampabay.com/news/business/arti
cle934633.ece
57
Source http//www.tampabay.com/opinion/essays/art
icle934654.ece
58
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
59
Ethical Concerns in clinical trials in India an
investigation

• 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

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
60
Ethical Concerns in clinical trials in India an
investigation

• 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.

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
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62
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 RD engine in
big pharmacy. Harv Bus Rev 20088668-76.
63
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)

64
Administrative Barriers
Source Dilts, DM et al. Journal of Clinical
Oncology Oct. 2006
65
IRB Approval Timeline for a Focus Group
discussing Health Insurance with Latinos
66
Contracting for Clinical Research

• the system would be better served if there were
  universally accepted contractual language Such
  language would help safeguard theintegrity of
  the research process.
• -JEFFREY M. DRAZENEditor-in-Chief, New England
  Journal of Medicine

Source Drazen, JM. NEJM Oct. 24, 2002
67

• (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
68
Source Glickman, SW et al. NEJM 2009.
69
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.
70
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.
71
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.
72
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.
73
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.
74
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.
75
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.
76
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.
77
Confidentiality Agreements inCommercial 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.
78
A collaborative effort to find solutions

• In light of these issues the U.S. FDAs 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

79
Mission

• To identify practices that through broad adoption
  will increase the quality and efficiency of
  clinical trials

80
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

81
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.

82
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.
  

83
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)

84
Member Organizations
Began recruiting members May 2008
85
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

86
Life Expectancy at Birth Developed and
Developing Countries, 1955-2002
Source World Health Report 2003