Page 1
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`FDA Perspective on
`International Clinical Trials
`
`Kassa Ayalew, M.D., M.P.H.
`Branch Chief
`Division of Good Clinical Practice Compliance
`Office of Scientific Investigations
`Office of Compliance
`Center for Drug Evaluation and Research
`Food and Drug Administration
`
`Exhibit 1126
`IPR2017-00807
`ARGENTUM
`
`000001
`
`
`
`FDA Perspective on
`International Clinical Trials
`
`Kassa Ayalew, M.D., M.P.H.
`Branch Chief
`Division of Good Clinical Practice Compliance
`Office of Scientific Investigations
`Office of Compliance
`Center for Drug Evaluation and Research
`Food and Drug Administration
`
`Exhibit 1126
`IPR2017-00807
`ARGENTUM
`
`000001
`
`
`
`Page 2
`
`Disclaimer
`The Views expressed in this presentation are
`those of the speaker and not necessarily those of
`the Food and Drug Administration
`
`2
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`Page 3
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`Outline
`
`1. Background
`2. International Clinical Investigators &
`Clinical Trials
`3. Drivers to Conduct Clinical Trials Outside
`the USA
`4. Law Governing International Clinical Trials
`5. Challenges
`6. Addressing the Challenges
`
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`Page 4
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`Foreign Clinical Trials (FCTs)
`BACKGROUND
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`Page 5
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`Foreign Clinical Trials (FCTs)
`• Prior to the 1962 Kefauver-Harrison
`Amendments, it was uncommon for a
`Sponsor to submit FCTs data
`• In 1975 provisions that permit submission of
`FCTs data not conducted under an IND
`were codified in 21CFR312.120
`• Since then medical product discovery &
`development have become increasingly
`globalized
`
`000005
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`
`
`Past 3 Decades & FCTs
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`Page 6
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`• In the past three decades, drug
`development, production & distribution
`
`moved from a national and regionally‐
`
`centered activity to a global one
`
`
`• This increase in shift has significant
`implications on FDA’s perspective on
`international clinical trials
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`Page 7
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`International Clinical Investigators &
`Clinical Trials
`METRICS
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`Rate of Increase for FDA Regulated
`Investigators: 1996-2006
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`Page 8
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`• During the 10 year period, the % of total for U.S. based investigators
`declined by 20% (annual growth rate 1.8%)
`• The number of active FDA–regulated investigators who are based
`
`outside the United States has grown
`http:// appliedclinicaltrialsonline.findpharma.com/appliedclinicaltrials/Regulatory/Global-Clinical-Trials-Activity-in-the-Details/ArticleStandard/Article/detail/453243?ref=25
`8
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`Rate of Increase for FDA Regulated
`Investigators: 2000-2014
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`Page 9
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`Dramatic shift in the location of clinical trials
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`9
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`% of Total 1572s Filed
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`Page 10
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`OIG Report:
` • Over half of all
`clinical trial sites are
`
`outside the U.S.
`• % of non-U.S.
`clinical investigators
`conducting trials
`under INDs has
`doubled over the
`last decade
`
`
`
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`Page 11
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`OIG Report:
` • 80 % of applications for
`drugs & biologics contain
`
`data from ex-U.S.
`studies
`• 78 % of all subjects were
`enrolled outside the U.S.
`• 87 % of all subjects in
`recent biologics trials
`were enrolled outside
`the U.S.
`
`
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`Distribution of Studies
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`Page 12
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`All studies registered on ClinicalTrials.gov: Data as of September 04, 2014
`
`# of studies
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`Studies Distribution Map
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`Page 13
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`Data as of September 04, 2014
`
`ClinicalTrials.gov currently lists 174,156 studies with locations in 187 countries
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`Page 14
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`What Drives Companies to Conduct
`Clinical Trials Outside the USA?
`DRIVERS
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`Page 15
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`Pushing & Pulling Forces
`Non U.S.
`U.S.
`• Difficulty recruiting patients
`• Reduced cost or economic drivers
`(clinical care/Operational/training)
`– Fewer feel need to participate
`• Motivated subjects & investigators
`• Higher standard of care
`• Rx naïve subjects willing & eager
`• Mistrust (historical infamy
`to participate
`Tuskegee trial)
`• Faster recruitment rates/ short
`• Requirement for larger # of Pts
`timeline
`•
`Insurance precluding
`• Availability of large # of patients
`participation/HIPAA
`• Countries and institutions trying to
`attract research and clinical trials
`• Higher costs: clinical
`care/Operational/
`• Availability of CROs focused on
`global trialsr
`documentation & training)
`Less regulatory red tape
`
`
`
`
`
`
`
`•
`
`15
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`Overall Clinical Trial Costs
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`Page 16
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`The cost of conducting CR in Russia, Argentina, China & India is about half the cost to the US ( manpower, rental, IT & operational costs)
`16
`Dr. Ken Kaitin, Tufts Center for the Study of Drug Development (2008)
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`Annual Growth in Clinical Investigations
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`Page 17
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`Increasing Annual Growth of Clinical Trials Outside the US
`17
`Dr. Ken Kaitin, Tufts Center for the Study of Drug Development (2008)
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`Page 18
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`Current Law Governing Foreign
`Clinical Studies
`21CFR312
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`Page 19
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`Foreign Study Conducted Under IND
`
`• When a study is conducted under an IND
`but is located outside of the United States,
`the study still must comport with all
`relevant FDA regulations as if it were
`being conducted within the United States
`• A Sponsor is not required to conduct an
`FCT under an IND in order to use it as
`support for an NDA or IND
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`Page 20
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`Foreign Clinical Trials
`Not Conducted Under An IND
`21CFR312.120
`
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`Page 21
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`Acceptance of Foreign Clinical Data
`• FDA Accepts Foreign Clinical data from studies
`not conducted under an IND if the following
`conditions are met:
`I. Study was conducted in accordance with
`Good Clinical Practice (GCP)
`II. FDA is able to validate the data from the
`study through an onsite inspection
`
`
`
`
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`Page 22
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`GCP
`• Sponsor shall submit to FDA a description
`of actions taken to ensure research
`conformed to GCP:
`– Defined as a standard for the design, conduct,
`performance, monitoring, auditing, recording,
`analysis, and reporting of clinical trials in a
`way that provides assurance that the data
`&reported results are credible and accurate
`and that the rights, safety, and well-being of
`trial subjects are protected
`
`
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`Page 23
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`Supporting information
`7. Name & address of the
`1. CI's qualifications
`IEC, a summary of the
`2. Description of the
`IEC's decision
`research facilities
`8.A description:
`3. Summary of the protocol
`– how IC was obtained
`& results of the study &,
`should FDA request,
`– what incentives, if any,
`case records
`were provided to
`subjects in the study
`4. Description & details of
`the product/drug used
`– how the sponsor(s)
`monitored the study
`Information showing that
`the study is adequate &
`– how CIs were trained
`well controlled
`to comply with GCP
`
`
`5.
`
`
`
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`Page 24
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`Validation of Data: Onsite
`Inspections
`• Help to ensure the protection of rights,
`safety and welfare of research participants
`• Help to ensure data that are submitted in
`marketing applications are fit for purpose
`– For regulatory decision making (Approval)
`– As evidence base for clinical use of drug (Label)
`• Allow evaluation of compliance with FDA
`regulations
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`Page 25
`
`Assigning International Inspections
`
`• Clinical sites likely to be audited when:
`– only foreign data are submitted to support an
`application
`– insufficient domestic data
`– domestic and foreign data show conflicting
`results pertinent to decision-making
`– there is a serious issue to resolve (e.g.,
`suspicion of fraud, scientific misconduct,
`significant human subject protection
`violations)
`
`
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`Page 26
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`
`Useful Guidance
` • FDA Acceptance of Foreign Clinical Studies Not
`Conducted Under an IND Frequently Asked
`Questions
`– Issued March 2012
`– Provides clarifications for sponsors and applicants on
`how to demonstrate compliance with the
`requirements of 21 CFR 312.120
`
`
`http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM294729.pdf
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`Page 27
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`THE CHALLENGES
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`Page 28
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`Increase in Breadth of Inspections
`• Increasing volume to data from other
`regions submitted in support of
`marketing submissions submitted to
`FDA
`• Increase in breadth of international
`inspections
`
`000028
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`Global Coverage of GCP Inspections
`
`
`Page 29
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`29 Conducted for FDA/CDER from 1984 through Sept 3, 2013; Based on
`Inspections with a start date in CDER/OC/OSI database
`
`000029
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`Distribution of Subject Enrollment
`
`Page 30
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`* 118 Applications with Clinical Investigator Site Selection Tool Dataset
`
`30
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`000030
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`Page 31
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`Finite inspection resources
`• Breadth of international inspections
`coupled with finite inspection resources
`result in inspection of a limited number of
`sites
`• Despite the large portion of clinical studies
`being conducted abroad, the OIG 2010
`Report found that the FDA only inspected
`0.7% of all foreign clinical sites in 2008,
`compared to 1.9% of all domestic clinical
`sites.
`
`000031
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`
`
`Clinical Inspections*: CDER 2004-2013
`U.S. & Non-U.S. Investigators Non-U.S. Investigators
`Sponsor/CRO
`
`Page 32
`
`475
`
`408
`
`416
`
`404
`
`353
`
`366
`
`368
`
`393
`
`361
`
`139
`
`62
`
`105
`
`68
`
`318
`
`100
`
`49
`
`75
`
`72
`
`93
`
`104
`
`87
`
`21
`2004
`
`32
`2005
`
`33
`2006
`
`25
`2007
`
`47
`2008
`
`127
`
`118
`
`75
`
`62
`
`2009
`
`2010
`
`2011
`
`2012
`
`2013
`
`500
`450
`400
`350
`300
`250
`200
`150
`100
`50
`0
`
`000032
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`
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`Clinical Investigator Inspections by Location*
` (CDER, FY 2013)
`
`Page 33
`
`*Based on inspection start date – [OSI database as of January 31, 2014]
`
`33
`
`000033
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`
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`Inspections Overseen by CDER,
`OSI* (CDER, FY 2004 - FY 2013)
`
`Page 34
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`*Based on inspection start date – [OSI database as of January 31, 2014]
` IRB includes only CDER numbers – previously reported metrics may have used combined data across CDER, CBER and CDRH
` Sponsor (GCP) includes Sponsor/CRO/Sponsor-Investigator
` Postmarketing Adverse Drug Event and Risk Evaluation and Mitigation Strategy inspection programs incorporated into OSI June 2011
`34
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`000034
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`Page 35
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`Strategies
`ADDRESSING THE CHALLENGES
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`000035
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`Page 36
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`Leveraging Knowledge/ Resources
`• Utilize finite resources strategically and
`efficiently and leverage inspection
`– EMA-FDA Collaboration GCP Inspection Initiative:
`• Initiated in Sept. 2009 as pilot to:
`• Develop a joint GCP program
`– Plan, coordinate, schedule, and conduct collaborative
`GCP inspections
`• Establish joint procedures
`– Share information related to drug applications
`– FDA International Offices:
`• Provide a platform for inspection of foreign facilities
`• Offices collect & leverage local & regional knowledge
`36
`
`
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`000036
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`Page 37
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`Building Quality
`
`• Build quality in during the planning stages:
`– incorporate quality management approach
`into clinical studies & their oversight to
`prevent the critical/errors, and monitor for
`those errors (perhaps centrally (remotely/real
`time)) and focus less on the less important
`matters
`
`
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`000037
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`Page 38
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`Utilize Data Standards
`
`• Encouraging sponsors to utilize data
`standards to improve analysis and site
`selection for inspection
`• Risk-Based Monitoring and Inspection
`– Using innovative strategies & tools to identify
`sites for clinical inspection(ex. GCP risk-
`based site selection tool for clinical
`inspection)
`
`
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`000038
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`
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`Page 39
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`Science-Based Standards
` • Working to converge regulatory standards (to
`share a common foundation of science-based
`goals for product safety, quality, and efficacy).
`– Continue to work to converge regulatory standards,
`processes, and procedures for the pharmaceutical
`industry( ex. ICH, ICH Global Cooperation Group
`Members)
`• Strengthening regulatory capacity of
`governments to manage, assess, and regulate
`drug development ( such as providing
`information, tools, training & exchange
`programs)
`
`
`39
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`000039
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`Page 40
`
`Final Thought
`“Wherever you stand, the
`majority of clinical trials
`are being conducted
`elsewhere, and yet we all
`as regulators use these
`data to allow or disallow
`marketing of a product,
`and physicians and
`patients use these data to
`decide to use or not use a
`medicine.”
`
`Fergus Sweeney, EMA
`40
`
`
`“Today we recognize that to
`successfully protect U.S.
`public health, we must think,
`act, and engage globally.
`Our interests must be
`broader than simply those
`within our own borders.”
`Margaret Hamburg, FDA
`Commissioner
`
`000040
`
`
`
`Page 41
`
`Helpful Link
`
`• Guidance for Industry and FDA Staff: FDA
`Acceptance of Foreign Clinical Studies Not
`Conducted Under an IND Frequently Asked
`Questions
`– Issued March 2012
`– Provides clarifications for sponsors and applicants on
`how to demonstrate compliance with the
`requirements of 21 CFR 312.120
`– http://www.fda.gov/downloads/RegulatoryInformation/
`Guidances/UCM294729.pdf
`
`
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`000041
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`Page 42
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`kassa.ayalew@fda.hhs.gov
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`000042
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