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Unresolved Issues in the Globalization of Clinical Trials


Robert M Califf MD Vice Chancellor for Clinical Research Globalization of Clinical Trials Current State Money Ethics Cultural environment Genetic variation ... – PowerPoint PPT presentation

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Title: Unresolved Issues in the Globalization of Clinical Trials

Unresolved Issues in the Globalization of
Clinical Trials
  • Robert M Califf MD
  • Vice Chancellor for Clinical Research

Globalization of Clinical Trials
  • Current State
  • Money
  • Ethics
  • Cultural environment
  • Genetic variation
  • Envisioning a positive future

  • 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
The Globalization of Clinical Investigators
Percent of Total 1572s Filed
Sources Tufts CSDD
Growth in Numbers of ActiveFDA-Regulated
Sources Tufts CSDD
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)
Creative Tension
  • Globalization of clinical research is a very good
    thing for the US and for all of us in a flat
  • 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

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
  • Duke University Medical Center

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

Globalization A Necessity
  • Proof of concept trialsthere are pharmacogenomic
  • Efficacy trialsthe context of clinical practice
  • Effectiveness trialsthe relative costs and
    balance of risk and benefits are context
  • 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

Economic Proposition to Industry From

1 10 billion
Potential local market opportunity
No requirement to match study populations to
target markets
maximize area
800 880 mil (2001)
Patent Expiration
Decrease costs or time
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

Image Source http//www.pandora.ca/pictures21/900
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!

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

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

Source Tufts CSDD
Protocol Designs More Complex and Burdensome
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
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
Cycle Time Metrics
69 - 75 Increase
12 20 Increase
Median Days Elapsed
Source Tufts CSDD
(No Transcript)
(No Transcript)
Clinical Trial Cost Estimates
In US 2007 Millions
Full Cost Industry
Streamlined Industry
More Streamlined
Source Roses AD. Nature 2000405857-865.
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)
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
-NEJM 360 2009
Cytochrome P-450 Polymorphisms and Clopidogrel
-NEJM 360 2009
Cytochrome P-450 Polymorphisms and Clopidogrel
-NEJM 360 2009
GENEVA, SWITZERLANDWorld 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
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

ACC/AHA Clinical Practice Guidelines
ACC/AHA Guidelines Level of Evidence of
ACC/AHA Guidelines More GuidelinesNo
Improvement in Proportion with High Quality!
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

Current Practices in ACS Care USA vs Rest of GRACE
Andrzej Budaj for the GRACE Investigators
Postgraduate Medical School, Grochowski Hospital,
Warsaw Poland
In-hospital ManagementAll ACS
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

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

Death and/or MI at 30 Days
  • Placebo Eptifibatide Total n
  • 16.88 13.89 6103
  • 13.68 14.88 3357

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
Timing of Angiography
North America
Western Europe
Eastern Europe
Latin America
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

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
(No Transcript)
A figure From the label
  • External Validity

Internal Validity
  • 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

Source Wathal. Outsourcing Clinical Trials
  • Extrinsic factors such as medical practice,
    disease definition and study population may
    influence applicability of foreign data to an EU
  • 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
  • Verification at time of evaluation of marketing
    authorization application that trials have been
    conducted in accordance with GCP and ethical
  • 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,
Source Reed SD, Drug Information Journal, 2007
Source Reed SD, Drug Information Journal, 2007
Source Reed SD, Drug Information Journal, 2007
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
  • 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?

The Ugly
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!

Source http//www.tampabay.com/news/business/art
Source http//www.tampabay.com/news/business/arti
Source http//www.tampabay.com/opinion/essays/art
Ethical Concerns in clinical trials in India an
  • 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
Ethical Concerns in clinical trials in India an
  • 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
Ethical Concerns in clinical trials in India an
  • 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

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
(No Transcript)
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.
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

Administrative Barriers
Source Dilts, DM et al. Journal of Clinical
Oncology Oct. 2006
IRB Approval Timeline for a Focus Group
discussing Health Insurance with Latinos
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
  • (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
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 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.
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.
Regulatory Oversight of International Clinical
  • Problem Regulatory agencies have little
    information on trials conducted outside their
  • 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.
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.
Genomic Information in Drug Development
  • Problem Lack of pharmacogenomic data for
    subjects limits confidence in generalizability of
  • Solutions
  • Expand FDA Voluntary Genomic Data Submissions
    program to international regulatory agencies
  • Develop global data warehousing and data analysis

Source Glickman, SW et al. NEJM 2009.
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
  • 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.
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.
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.
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.
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
  • The Clinical Trials Transformation Initiative
  • All stakeholders are involved in this initiative
    including government, industry, academia, patient
    advocates, clinical investigators, professional
    societies, and others

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

  • 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

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

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
  • 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.

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,
  • Steering Committee co-chairs, ex officio (James
    Ferguson, Briggs Morrison)

Member Organizations
Began recruiting members May 2008
  • 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

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