Darshan Hiranandani (Son of Niranjan Hiranandani).pdf
Globalization Of Clinical Trials 2010 Josep M. Badenas
1. Globalization of Clinical Trials
Josep M. Badenas
Mobile: +34 629 52 73 84
E-mail: 18182jbp@comb.cat
E-mail: josepmaria.badenas@gmail.com
2. Globalization
• Global trials bring drug to market more quickly.
• 96% of R&D dollars spent in developed countries (US: 49% & Western EU:
37%).
• Vast majority of trials still in US and EU* but US & EU lost 4.3% sites to
RoW (6,500 sites)*
• Need to identify strategies for enhancing the effectiveness and efficiency
of clinical trials.
2
* Value of Insight Consulting Report, 21 July 2009
3. Trial Density 2007
3
Density is in per country inhabitant (in millions; based on 2005 population censuses); darker orange/red denotes a
higher density. The trial density and average relative annual growth rate in percent is shown for selected
countries. The countries in grey had no actively recruiting biopharmaceutical clinical trial sites as of 12 April 2007.
Ref: Trends in the globalization of clinical trials, Fabio A. Thiers, Anthony J. Sinskey & Ernst R. Berndt
Nature Reviews Drug Discovery 7, 13-14 (January 2008)
5. Emerging Countries
– Play a vital role in global clinical development
– Governments develop clinical research infrastructure
– Improving the health systems and economies in emerging markets
– Trials in emerging countries conducted to global standards
– Regulations in emerging countries often more strict (all participants be equally
protected)
– FDA & EMEA resources for increased inspections
5
Global Development R&D Spend ($M) Source: PhRMA
6. India
• Very cost effective
• Huge population, good enrollment
• Longer regulatory lead times
• General use
Central Drugs Standard Control Organization
Directorate General of Health Services, Ministry of Health
and Family Welfare, Government of India
www.cdsco.nic.in
7. India - Proposed CTA Categories
Category A
• Clinical Trial already approved in the
following reference countries: USA, UK,
Switzerland, Australia, Canada, Germany,
South Africa, Japan, EMEA
• Assumption: Same Protocol
• Proposed Review Timeframe: 2 – 4 weeks
Category B
• All applications NOT categorized under
category A
• Note: ‘Switching’ to Category A is not
allowed once filed as Category B
• Proposed Review Timeframe: 8 – 12
weeks
CTA: Clinical Trial Application
8. China
• Huge patient population, but dissimilar to the U.S.
• Public and private hospitals
• Most public hospitals are linked to a university
• % of patients with health insurance is increasing, especially in big cities
• Patients select their own doctors
• No appointments are necessary
• Fee for a consultation at outpatient clinic around 10 yuan (1€)
• Medication is provided by hospital pharmacies
• Doctors make a provit from the medication they prescribe
• Special treatment for VIPs
• In general, diagnosis and treatment very similar to Western world
9. China – Clinical Trials
• Long regulatory lead times
• Mandatory for Chinese registration
• A program conducted in the U.S. will require new studies for China
• Clinical Trials must be approved by SFDA prior to ethics committee approval
• Trials must be conducted by designated hospitals
• Designated hospitals are pre-selected and accredited by SFDA and MOH, as Clinical Bases
• GCP works as guideline
• Large part trials for generics
• Only public hospitals are certified by the SFDA for clinical research
10. Cost per Patient
– In ECE (United Nations Economic
Commission for Europe), Latin America, and
parts of Asia, clinical trials can be cost
effective relative to the U.S.
– A center in India will charge $1500 to 2000
per patient, 1/10 the comparable rate in the
U.S.1
– NDAs will have thousands of patients (the
cost advantage can add up)
– An exception to this rule is Japan
11
1Garnier JP. Rebuilding the R&D engine in big pharma.
Harvard Business Reviews 2008; 86:68-76
Relative Costs by Region
12. Challenges
– Cross-cultural differences
– Genetic polymorphism
– Different regulations
– IRB/EC roles and organizations
– Reputation: well publicized “ghosts”
from the past
– Patient access and availability of
patients
– Ethics
– Placebo
– Quality
– Cost
– Disease incidence
– Medical practice, treatment
differences
– Rating scales
– Statistical considerations
– Data generation and acceptability
– Other
13
13. Patient Access and Availability of Patients
• Regulatory requirements in Multiple Sclerosis include double-blind, placebo-controlled trials
of two years duration. Most patients in the US will not enroll in a trial of this design
• Most donepezil-naïve patients in Alzheimer-s disease are outside the US and Western Europe
• Lack of adequate medical care drives patients into clinical trials (Eastern Central Europe, Latin
America, Parts of Asia)
• Pain intensity and disease stage requested in diabetic neuropathic pain difficult to find in
Western EU
• Suicidal ideation in India
• Mild Cognitive Impairment (MCI) diagnosis
• Anxiety in Japan
14. Ethics – Vulnerable Populations
• Framework for conducting human subjects research: Core ethical concepts in the
Belmont Report.
• Interpreting and applying them in another cultural setting may be challenging.
• International guidelines for international research ethics outline and interpret changes,
advances and controversies in research ethics outside western countries.
• Researchers need a clear understanding of both the ethical guidelines and government
regulations pertaining to any proposed research, from both the U.S. and host country
governments.
Inuit family, The National Geographic
Magazine, Volume 31 (1917), page 564.
15. Drug Development Scorecard
16
Drug approvals and failures: implications for alliances. Czerepak EA, Ryser S.
Nature reviews/Drug Discovery. Vol. 7 March 2008
67 (65%)
16. Segmenting by Innovation Level
17
30%
30%
40%
Drug approvals and failures: implications for alliances. Czerepak EA, Ryser S.
Nature reviews/Drug Discovery. Vol. 7 March 2008
January 2006 – December 2007
17. Segmenting by Innovation Level (Jan 06 - Dec 07)
18
49
¾ from Biotech
½ from Biotech
½ from Biotech-pharma alliances
and Pharma Companies
18. Trends in Disease Focus of Drug Development
(Oct 05 - Sept 07)
19
2/3 of all protocols, 68%
2/3 of all sites, 74,1%
Rheumatology: 157.6%, highest relative growth
Cardiology: 74.3%, lowest relative growth
Trends in disease focus of drug development. Johan P. E. Karlberg. Nature Review/Drug
Discovery. Vol. 7. August 2008
19. Volume and Type of Clinical Trials Conducted
August 16, 2009
21. Exponential Growth in Inputs with No Numerical Increase in Outputs
Source: Rodney Zemmel, PhD., McKinsey & Company, Bernstein
Pharmaceuticals Longview Conference, May 5, 2010
22. Growth in Talk of "New Pharmaceutical Research Paradigms" Inversely Correlated
With NME Approvals
23. R&D Productivity Has Stagnated
Despite Technological Advances
Cost per NME Has Grown
Exponentially Over the Past 60 Years
24. R&D Productivity: (1) Merck, Eli Lilly, & Roche Have The Best 60yr Track Records; (2) Drug Output
Across The Industry Seems To Correlate With The Number Of Companies, Which Argues Against
M&A
27. New waves of innovation are beginning
ABPI, www.abpi.org.uk
28. Reminder
• Phase I: clinical trials test an experimental drug or treatment for the first time in a small group of people
(20−80) over the course of a few weeks or a month. Their goals are to assess the safety of the drug or
treatment, find a safe dosage range, and identify any side effects.
• Phase II: larger group of people (100−300) receives the experimental drug to determine whether it is
effective and further evaluate its safety. These trials involve subjects with the target disease and usually
last months.
• Phase III: once preliminary evidence from phase II reveals that a treatment is effective, phase III trials are
designed to fully examine the risk/benefit profile of an experimental drug or treatment and test it over a
longer period of time in a broader population (1,000−3,000). Because these trials are the last phase in the
preapproval process, they are often referred to as “pivotal” trials.
• Phase IV: or postmarketing trials take place after a drug has been approved. They provide additional
evidence on the risks and benefits of the drug or treatment and how it can be used optimally.
32. Improving the Return on Small-molecule R&D
33
Pharmaceutical R&D: the road to positive returns. David E. Tramontin T. Zemmel R.
Nature Reviews/Drug Discovery. Vol. 8. August 2009.
Change what they are doing
Reduce cost of drug failure
6-month delay to launch = $ 100 million in NPV or a reduction of 0.5% in IRR
Can cost hundreds of millions of dolars if made too late
Current high attrition rate in Phase III: 106 failures 90-07 (45% efficacy vs.
placebo, 24% insufficient differentiation vs. standard of care)
33. 34
Trust
• Harvard University-affiliated hospitals move toward transparency on industry
gifts
• Bloomberg News (4/10, Lauerman) reports, "A group of Harvard Medical School-
affiliated hospitals will adopt new conflict-of-interest guidelines that forbid industry gifts
to eliminate potential bias in patient care research and recommendations.“ etc,…By John
Lauerman, April 10 (Bloomberg)
• Pharma executives seen as lacking scientific expertise
• The Financial Times (4/6, Jack) reports, "Only one large western pharmaceutical
company [Eli Lilly] will be run by a scientist following completion of the current round of
acquisitions, in spite of the growing need for strengthened innovation to develop new
medicines." etc, ….By Andrew Jack in London. Published: April 5 2009 16:58 | Last
updated: April 5 2009 16:58
34. 35
Trust
• Publication of fragments
• Fraud and misconduct
• Anesthesiologist admits to fabricating data in
pain studies. The New York Times (3/11, A22,
Harris) reports, "In what may be among the
longest-running and widest-ranging cases of
academic fraud, one of the most prolific
researchers in anesthesiology has admitted
that he fabricated much of the data
underlying his research, said a spokeswoman
for the hospital where he works.“ (March 10,
2009)
• Underpowered studies
• “Ghost” writers
• Image manipulation (fine line between
acceptable enhancements and scientific
misconduct)
http://www.nature.com/news/2009/091009/full/news.2009.991.html
35. 36
Restoring Trust - Clinical Trials Registries
• FDAMA* 1997 – www.clinicaltrials.gov
• ICMJE** announces policy to require registration as pre-requisite for publication
(Sept 2004)
• PhRMA*** announces voluntary listing of all hypothesis-testing trials by member
(Jan 2005)
• Major benefit – enhances transparency
* Food and Drug Administration Modernization Act
** International Committee of Medical Journal Editors
*** The Pharmaceutical Research and Manufacturers of America
36. 37
FDAMA (Food and Drug Administration Modernization Act) 1997 – www.clinicaltrials.gov
37. Initiatives - Trends
– Improve execution
– Improve decision-making process: Translational medicine (from preclinical
to Proof-of-Concept).
– Biomarkers
– Study designs
– Pharmacogenomics
– Personalized medicine
38. Trial Execution
Top Causes of Study Conduct Delays
Source: CenterWatch, N = 612, 2005
Ken Getz.. Senior Research Fellow. Tufts Center for the Study of Drug Development. (CSDD), Kenneth.getz@tufts.edu Phone: +1
617-636-3487
39. Trial Execution
Investigators
– Only 1/3 of the investigators in a study meet or exceed enrolment targets
– 30% of investigator sites enrol no subjects
– US and Western Europe are seeing a decline in experienced clinical investigators
– There are over 700,000 practicing physicians in the US, yet there is a shortage of
qualified investigators (1)
• The total number of investigators declined by 6% between 2001 and 2004 (2)
• There is a core population of at most 2,200 principle investigators, and an annual
turnover of about 40% of the rest (2)
• Only 6% of investigators have conducted 4 or more trials,
• 52% only have conducted only one trial
(1) American Medical Association, June 2005
(2) Journal of Clinical Research Best Practices, July 2005
40. Trial Execution
Distribution of Complaints Received (2006)
Source: FDA Division of Scientific Investigations, CDER
Ken Getz. Senior Research Fellow. Tufts Center for the Study of Drug Development. (CSDD), Kenneth.getz@tufts.edu
Phone: +1 617-636-3487
41. The Quick Win, Fast Fail Drug Development Paradigm
Translational Medicine
42. Translational Medicine
– Transition between basic research and applied pharmaceutical research.
– Takes basic research into the first phases of product development and initial
human trials, producing new findings that answer questions about safety and
efficacy.
– May increase scientists’ knowledge about disease.
– Leading to critical Proof-of-Concept (PoC) phase.
43. Genomic Biomarkers are the Foundation of
Personalized Medicine
– We look for variability in drug response for every molecule and the source of
that variability
– Biomarkers are typically in the causal pathway of disease pathology or drug
pharmacology
– Qualification of biomarkers refers to the extent of information needed to
understand its clinical utility
– Qualification is for a specific intended use that informs a regulatory and/or
medical decision
44
44. Biomarkers
– Diagnostic
– Prognostic: outcome related to disease, but not necessarily to drug therapy
– Predictive: outcome necessarily related to therapeutic intervention
– Validation
– Clinical Trial vs. Clinical utility
– Should an enrichment or a stratification strategy be used?
• Upfront stratification
• Biomarker-based strategy
45
45. Biomarkers - FDA
– Development and implementation of new or improved biomarkers, models
and methods to predict safety and efficacy of regulated products including
drugs, biologics, devices and foods
– Among the high priority Critical Path projects:
• Biomarker Qualification: The ability to define useful biomarkers will improve efficacy of
medical products, enhance safety and use in the era of personalized medicine. In June 2008,
the Critical Path Institute, co-founded by FDA, announced the qualification of seven urinary
biomarkers of kidney injury for use in certain regulatory decisions. This was a collaborative
effort with preclinical data provided by Novartis, Merck, Harvard Medical School and FDA.
46
46. Study Design
Biomarkers – Example Upfront stratification
47
Test
M+, randomize
M-, randomize
Treatment A
Treatment B
Treatment A
Treatment B
47. Study Design
Sheiner’s Principles – Adaptive Designs
Assignment
Learn: Many regimens, doses
Confirm: Few regimens, doses
Observation
Learn: Many variables, outcomes
Confirm: Few variables, outcomes
Analysis & approach
Learn: Bayesian, iterative, decision-
trees
Confirm: Null hypothesis - yes/no
48
Learning Versus Confirming in Clinical Drug Development. Sheiner, LB, Clin. Pharm Ther 1997; 61:275-291
Adaptive Design
48. 49
Study Design
From “phased” to “seamless”
… to Learn and Confirm
Phase RPhase R
Transition Zone
IND NDA SubmissionPOC
ConfirmLearn
… to Learn and Confirm
Phase RPhase R
Transition Zone
IND NDA SubmissionPOC
ConfirmLearn
Phase 2
From today ’ s phased approach …
IND POC NDA Submission
Phase 1 Phase 2 Phase R
Transition time
Phase 3Phase 2
From today’s phased approach……..
IND POC NDA Submission
Phase 0/1 Phase 2 Phase R
Transition time
Phase 3
Learning Versus Confirming in Clinical Drug Development. Sheiner, LB, Clin. Pharm Ther 1997; 61:275-291
49. 50
Study Design
Adaptive Design: Regulatory Perspective
• FDA has had little experience with adaptive design to date
• No NDAs had been approved based on them yet, but almost every
review division has had between 1 to 3 to review under INDs
• Reality is very likely somewhere in the middle
50. Clinical Trial Design and Analysis - FDA
• Implementation of clinical trial design and analysis methodologies to more rapidly
and efficiently evaluate safety and efficacy of FDA regulated products.
• Among the high priority Critical Path projects:
– Clinical Trials Transformation Initiative: Effective, well designed clinical trials are the basis
for most FDA regulatory decisions. In November 2007, as part of FDA’s Critical Path
Initiatives, FDA in collaboration with Duke University Medical Center announced the
creation of a Public-Private Partnership to improve the quality and efficiency of clinical
trials. In May 2008, a 12 member Executive Board including representatives from
academia, industry, government and patient advocacy was named.
51
51. – Identify individual’s profile of drug response
and predict the best possible treatment
option for this individual.
• e.g. Test detects patients who don't respond to
Plavix
• e.g. Genetic variant may be linked to tamoxifen
response in breast cancer patients
– Shorter timelines (time to achieve endpoint);
smaller number of subjects needed; lower
failure rate; enhanced safety; enhanced
patient loyalty (fewer non-responders)
52
Gene Protein
Target
Chemical
Diversity Screen and
Identify Hits
(compound
library)
Chemical propety and
potency evaluation
Lead
identification
Lead
optimization
Pre-clinical development
(safety and efficacy)
Phase I
Safety and dosage
Phase IIA Phase IIB
Phase III
Comparative safety and efficacy: randomized and controlled
Pharmacogernetic screen
Phase I Phase IIA Phase IIB Phase III Phase III
Product licensing
Product licensing
Placebo
Placebo
Larger safety,
efficacy and dose-
rangingstudies
Small efficacy and
safety studies
a
b
c
Roses AD. Nat Rev Gen 2004;5:645-56
Pharmacogenomics in the R&D Process
52. 53
Application of Pharmacogenomics to Patient’s Care
• Find new uses for existing drugs
• Enhance efficacy or safety with a diagnostic test
• To predict dosage requirement
• To help select a drug regimen
• To optimize a patient’s response to their medication
• To prevent ADE’s
53. 54
Pharmacogenomics - Drugs and Tests
• Development of drugs with tests that help to make better decisions about how to use the
drug in question. There are two types of such tests:
– Tests that are being developed in conjunction with the drug and are “required” for drug use (e.g.
Her2/neu measurement for trastuzumab (Herceptin®) therapy.
– Tests that have been developed after a drug has come to market, e.g. CYP2C9 and VKORC1 for better
determining the starting dose for warfarin; azathioprine and MTPT.
An advertisment from a Farm Magazine 1958 European Atrial Fibrillation Trial Study Group. N Engl J Med 1995; 333:5-10
54. 55
Gene Therapy in Parkinson’s Disease
– Safety and tolerability of intraputaminal delivery of CERE-120 (adeno-associated virus
serotype 2–neurturin) to patients with idiopathic Parkinson’s disease: an open-label, phase I
trial
– Most experts acknowledge that if these goals could be achieved…it would revolutionize the
treatment of PD
Lancet Neurol 2008; 7: 400–08
Stereotactic neurosurgery for Parkinson’s disease gene therapy
55. 56
AAV-NTN: opportunity for innovative therapy for Parkinson’s disease
– Target dopamine nigrostriatal neurons: degeneration implicated as key
pathogenic event in disease
• Provide constant supply of neurotrophic factor
• Enhancing condition and function of neurons
• Strengthening their ability to withstand degeneration
Lancet Neurol 2008; 7: 400–08
56. 57
Key Registration Authority Committee review points
– Questions regarding efficacy of CERE-120
– Kinetics and accumulation of NTN in brain
– ‘Multiple brain regions’ targeted and spread of protein to non-targeted brain
regions
– The use of non-regulatable vector
– Question of ‘rescue strategy’
– Cerebellar toxicity reported in select, GDNF protein-treated monkeys
– Rationale for dosing schedule in humans
57. 58
Gene Therapy in Parkinson’s Disease
– Extensive safety monitoring in all patients revealed no clinically significant
adverse events at 1 year.
– Several secondary measures of motor function showed improvement at 1
year
Lancet Neurol 2008; 7: 400–08
58. Gene Therapy Submissions – Western Europe
– Many health authorities have a specific division for Gene Therapy
– All follow the recommendations of the EU Directive
– Mean time for approval in the countries is 6 months
– Some of the ECs in these countries are specific to gene therapy e.g. GTAC in the UK
– Roll of the investigator is critical
59. Personalized Medicine - Rational
– Variability in drug response, adverse events and absence of benefit
• “If it were not for the great variability among individuals, medicine might have well been
a science and not an art”. Sir William Osler (1849 – 1919) The Father of Modern
Medicine
• “One important characteristic of biology is its diversity, its variation. It’s why
personalized medicine is so important” Dr. Andy Kessler (1958 -) Author and Hedge Fund
Manager
60. Categories of Personalized Medicine
– Diagnostic test used to select (potential for benefit) or avoid (potential for harm) a
drug
– Diagnostic test used to select an optimal initial and/or maintenance dose of drug
– Biomarker discovered during drug development to inform subsequent clinical trial
design
– Rigorous qualification and regulatory oversight is mandatory in the first two
categories, and highly desirable in the third category; implications of false + and
false
62. Personalized Medicine and Nutrition - FDA
• Development of individualized approaches to therapeutics and nutrition, such as
toxicogenomics, pharmacoselection, and complex prognostic and predictive devices, and the
use of these techniques to accelerate product development and provide enhanced product
and food safety.
• Among the high priority Critical Path projects:
• Genomics coordination:
– In June 2008, FDA held a symposium to assess “omics” (including genomics, proteomics and
metabolomics) needs across the Agency and to develop recommendations for use of and
development of “omics” data at FDA. One of the recommendations of this symposium reiterated the
need for formal coordination of “omics” across the Agency as identified in the Science Board Report.
An Agency-wide Genomics Coordinator has been recruited as of February 1, 2009, to integrate
“omics” across the Agency. This person will facilitate “omics’ efforts and will establish a core group
including at least 3 bioinformatics experts to provide cross-center expertise in large data set
analyses.
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63. FDA Cannot do it Alone
• Centers of Excellence with Academia:
– Within academic medical centers there is expertise in scientific areas that form the foundation of
FDA regulatory science. Partnering with these centers is an important approach to developing the
datasets that form the foundation of FDA regulatory decisions. FDA will identify through a
competitive process academic centers that have depth and breadth of scientific expertise in areas
critical to FDA’s public health mission. Centers would be recipients of specific funding from the FDA
to tackle FDA mission-critical scientific issues.
• Resource Networks with Biotechnology Firms:
– Small biotechnology firms represent a flexible resource. They are operationally and scientifically
nimble and often have the capability to devote a large proportion of human capital to a single
project. Biotech firms that have an interest in partnering to resolve mission-critical FDA questions
will be identified and engaged through contracts and other funding mechanisms.
• Partnerships with industries in the “pre-competitive” space:
– We will explore how FDA can harness the extensive expertise of regulated industries in areas that are
of mutual benefit, such as drug-induced liver toxicity [see II (f)]. Such partnerships with industry
already exist in the area of safety assessment of kidney toxicity and the Sentinel initiative [see II (e)].
64
64. 65
Conclusions
• The pharmaceutical industry continues to face substantial challenges at multiple levels.
• Confluence of major patent expiries and low pipeline productivity will force significant change over a
multi-year period for the average company.
• What lies ahead is a period of inevitable contraction (tied to patent expiries) that could one day lead to a
new and smaller base off of which growth might ultimately be achieved.
• Ongoing efforts to revamp R&D are at least partially successful.
• When will this potential rebound occur? Not for several years to come. For certain names, the "patent
cliff" appears to extend even beyond 2015, yet for a lucky few the impact will likely be much more modest.
• Clinical trial experts from academic research centers, pharmaceutical companies, contract research
organizations, government, nonprofit research networks, and patient advocacy groups should come
together to discuss their clinical trial successes and failures, the challenges they face in conducting clinical
research, and strategies for improving the efficiency of clinical trials while maintaining the highest
standards for the data generated.
