Regulatory Challenges of Global Clinical Trials

1
Regulatory Challenges of Global Clinical Trials

• Melanie A. Bruno, PhD, MBAVice President, Global
  Regulatory Quality, KendleSeptember 25, 2007

2
Agenda

• Drivers of Global Clinical Trials
• In relation to Global Clinical Trials
• Challenges of Global Clinical Trials
• Challenges of Global Investigators
• Challenges of Regulatory Authorities IRB/Ethics
  Committee
• Summary

2
3
Drivers of Global Clinical Trials
4
Drug Development Process
5
Driver of Global Clinical TrialsTherapeutic
Expertise
Source Goldman Sachs Research estimates, Company
data.
6
Driver of Global Clinical TrialsPatient Access
Allocation of development spending by global
region current
Expected development spending allocation by 2010
significant increase in A/P, ROW
6
Source Jefferies, CRO Survey, March 2007
7
Driver of Global Clinical TrialsAdverse Event
Detection
JJ Gou 2006
8
Foreign Data for US Applications

• May or may not be conducted under US IND
• Good Clinical Practice ICH E6
• Disease being studied needs to be representative
  of the disease state in the United States
• Conditions of diagnosis and study conduct need to
  be in accordance with medical practice in the US
• Concommitant medicines used in foreign countries
• Consider racial balance
• Consideration of ethnicity

9
Regulatory ChallengesGlobal Clinical Trials
10
Global Clinical Trials - Challenges

• Regional differences in medical practice
• Trial design
• Translation of documents
• Validation of measurement tools
• Import and analysis of clinical product
• Laboratory specimens

11
Regional Differences in Medical Practice

• Treatment algorithms
• Can impact inclusion/exclusion criteria
• Can impact available population due to exposure
• Rheumatoid arthritis, first line treatments vary
  globally
• Methotrexate vus hydroxychloroquine or
  sulfasalazine
• Available medications
• Controls
• Comparator
• Blinding of controls or comparator medications

12
Regional Differences in Medical Practice

• Use of medical technologies
• Relationships between Physician and Patients
• Interpretation of soft endpoints and cultural
  impact
• Cultural issues
• Consent influencers
• Payments to Investigators

13
Global Trial Design Considerations

• Primary Endpoint
• Number of patients required
• Enrollment
• Number of sites globally
• Inclusion/Exclusion criteria
• Birth control
• Length of trial
• Start-up timing due to Regulatory Authority and
  IRB/EC approvals
• Necessary technologies to capture endpoint
• ECG, Bone Density, Venograms

14
Translations for Global Clinical Trials

• Certified translations often required for
  documents
• Translate into another language
• Back translate to original language
• Review to make sure nothing has been lost
• Obtain documentation to prove certified
  translation

15
Translation of documents

• Before Trial Initiation
• Protocol synopsis
• Protocol
• Investigators Brochure
• Informed Consent (in India this can be as many as
  14 languages)
• Patient diary or questionaires
• Clinical supply labels
• Approval letters from Regulatory Authorities and
  IRB/EC
• Investigator 1572s and CVs
• Instructions for automatic randomization

16
Translation of Documents

• After trial initiation
• Serious Adverse Events
• Annual Reports
• Notice of Study Discontinuation or close-out
• MOH/EC communications
• Protocol amendments
• Investigators Brochures

17
Validation of Measurement Scales

• Why do measurement scales need to be validated?
• Many of these scales have soft endpoints
• To guarantee that information is understood as
  intended for comparability of data
• Patient questionnaires
• Validation required for each language
• Some countries have multiple languages
• Some words just dont translate or are socially
  offensive

18
Import Analysis of Clinical Product

• Why do imported clinical study products have to
  have undergo analytical analysis before use?
• Different pharmacopoeia standards (not yet
  harmonized)
• EU does not recognize US GMP data
• Drug product originating in US must be
  re-analyzed in EU and vouched for by Qualified
  Person
• Reciprocity within EU, Canada, Australia, New
  Zealand, Japan, Switzerland

19
Laboratory Specimens

• Standardize testing
• How to get in and out of country
• Biologic samples-some countries require
  specialize approval, some countries do not allow
  biological samples to leave the country
• Refrigerated or special transportation
• Timing requirements
• For inclusion/exclusion
• For integrity of specimens

20
Clinical Supply Labeling Requirements

• Identify country-specific requirements
• Inner packaging (bottle)
• Outside packaging
• Certified translations
• Types of information for labeling
• Chemical name, for Investigational Use statement,
  Name/Address of Sponsor (in-country),
  Manufacturing lot number, batch number, storage
  conditions, expiration date, protocol name,
  dosage form, number of units, route of
  administration, subject number, directions for
  use, Keep out of reach of children, For
  Investigational Use

The Global Regulatory Submissions Primer,
Meredith Brown-Tuttle, RAC, RA Focus, March 2007,
Vol. 12, No. 3, pg 17
21
Regulatory ChallengesGlobal Clinical
Investigators
22
Challenges for Global Investigators

• Good Clinical Practice (GCP)
• Site Selection
• Training of Investigator and Staff
• Safety Reporting
• Audit readiness

23
GCP for Global Investigators

• ICH E6 Good Clinical Practice Guidance
• Expectation conduct clinical trials in
  accordance with the ethical and scientific
  standards outlined in E6
• Reasons
• Patient protection
• Data integrity for approval
• Training, testing
• Monitoring of Investigators for compliance to GCPs

24
Site Selection

• Site selection is driven by
• Protocol design
• Number of patients
• Types of tests
• Qualifications of the Investigator
• Contract negotiations (site overhead),
  country-specific requirements-insurance
• Enrollment ability
• Regulatory Authority approval timings
• IRB/Ethics Committee approval timings

25
Site Selection
Database search for relevant experience
Confidentiality Agreement

• Patient population
• Recruitment approaches
• Potential challenges
• Motivation interest
• Projected metrics
• Competing studies
• Investigator fees
• Central vs. Local IRB capabilities

Assessment of Potential Investigator
Questionnaire
Pre-Study Site Visit
Final site selection
26
Staff Training in Global Clinical Trials

• How is site staff training affected in global
  clinical trials?
• Naïve staff need more training
• Eager to learn
• Eager to please
• Less educated in GCP
• Training materials must be in appropriate
  languages (more translations)
• Training affected
• Length of Investigator Meeting
• More, geographic-specific
• Length of Initiation Visit and number of
  monitoring visits

27
Safety Reporting in Global Trials

• General Requirement
• Must report unexpected and serious adverse events
  to Regulatory Authorities in each participating
  country, regardless of country of origin
• Electronic
• Paper
• Safety Alert Letters to update Investigator
  Brochures
• Time Sensitive
• Have a good plan

28
Audit Readiness

• Local Regulatory Authority
• Foreign Regulatory Authority
• Audits most often occur because of
• Large patient enrollment number
• Perceived irregularity or problem
• Soft endpoints
• Areas of interest to Auditors
• Qualifications/training files of personnel/SOPS
• Familiarity with GCP including local
  interpretation
• Knowledge of trial protocol
• Trial Master File - status
• All safety update information

29
Regulatory ChallengesRegulatory Authorities and
IRB/Ethics Committee
30
Global Regulatory Project Team

• Need a global team for global clinical studies
• Need a Global Regulatory Project leader
• Team members
• Think globally
• Have local regulatory knowledge of a
  region/countries requirements
• Have local cultural knowledge of local Regulatory
  Authorities, medical culture country culture
• Global Regulatory Team
• Need representation on Global Project Team

31
Global Regulatory Project Plan

• Team needs to develop a clear Regulatory Project
  Plan
• Plans for meeting with appropriate Regulatory
  Authorities
• Required documents
• Identify documents needing translation
• Translation timings
• Timings of submissions- complexity, parallel or
  sequential submissions
• Estimated timings of approval-affects choice of
  countries/tradeoff-enrollment
• Considerations of re-loops and questions from
  Regulatory Authorities or IRB/EC Committees
• How to handle ongoing amendments, safety
  reporting, annual reports for each participating
  country

32
Regulatory Requirements

• Documents for Initiation of a Clinical Trial
• Protocol
• Informed Consent
• Any materials or advertising shared with subjects
• Drug manufactured under GMP
• Regulatory Filing
• Investigational New Drug Application (IND)
• Clinical Trials Application (CTA)
• Investigative Medicinal Product Application
  (IMPD)
• Ongoing documentation
• Amendments
• Safety reporting and updates
• Annual Reports
• Sponsor presence or a local agent in the country

33
Regulatory Authority IRB/EC Approvals

• Two different requirements to gain approval for
  initiation of a clinical trial
• Competent Regulatory Authority
• IRB/EC
• Local
• Central
• Major concerns
• Patient safety
• Data to date
• Design of trial with safety monitoring
• Informed patients
• Appropriate consents
• No coercion- especially important in countries
  with disadvantaged economies
• Data integrity

34
Regulatory IRB/Ethics Approvals
35
SummaryChallenges of Global Clinical Trials

• Finding the patients
• Trial designs that can be used globally
• Regulatory, Medical and Cultural considerations
• Clinical Investigator that meet GCPs
• Multiple interfaces with many Regulatory Agencies
  and IRB/ECs
• Timing of approval can influence country choice
• Need Global Regulatory Strategy
• Global Thinking
• Local Regulatory Knowledge

36
Real people. Real results.