Regulatory Issues International Perspective

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Regulatory Issues International Perspective

• Claudio Dansky Ullmann, MD
• Head, Thoracic and Head Neck Malignancies,
• Melanoma and Other Skin Cancer Therapeutics
• Cancer Therapy Evaluation Program
• National Cancer Institute

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NCI Organization Chart
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CANCER THERAPY EVALUATION PROGRAM Jeff Abrams
Operations Informatics Branch Steve Friedman
Clinical Grants and Contracts Branch Roy Wu
Clinical Investigations Branch Meg Mooney
Regulatory Affairs Branch Jan Casadei
Investigational Drug Branch James Zwiebel
Pharmaceutical Management Branch Charles Hall
Clinical Trials Monitoring Branch Gary Smith
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Cancer Therapy Evaluation Program - CTEP
Therapeutics Development Program
Specialty Resources /Other
Basic Resources
Adult U01 Phase 1 Program (14 phase 1 sites)
Clinical Center, Phase 0/ Expl IND Cancer
Centers
Phase 1
Pediatric Phase 1 Consortium
CNS Consortia Pediatric, NABTT, NABTC
N01 Phase 2 Program (9 phase 2 sites)
Phase 2
SPORES, R21, R01, P01
Cooperative Groups
CCOPs
Phase 3
Non-CTEP Funded Resources
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Essential Elements for a National CancerClinical
Trials Network Basis for Collaboration

• Qualified investigators from qualified
  institutional sites with important
  scientific/therapeutic hypotheses and experienced
  in clinical trial conduct
• Infrastructure for protocol development and
  conduct of clinical trial in multi-institutional
  setting (Operations Office)
• Infrastructure for collecting and
  quality-checking data (Data/Statistical Center)
• Biological tissue specimens/correlative studies
• Financial support
• Patients

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Group Collaborations Opportunities Types of
Trials

• Studies whereby an efficient process is required
• Large RCTs
• Strategic Phase II trials
• Uncommon diseases or less common presentations of
  common diseases
• Integrate new agents into standard regimens
• Compare two or more approaches to an accepted
  standard
• Multimodality treatments
• Translational studies. Incorporate correlative
  science and quality of life
• Pooled resources
• Tissue banking

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Challenges in Clinical Trial Research

• Enrollment often is not representative of the
  general population
• Factors affecting enrollment are multiple and
  complex
• Well designed controlled trials are necessary to
  identify
• sometimes small benefits
• Important time and human and infrastructure
  resources are
• invested in the conception, launching, and
  execution of a
• clinical trial. AVOID DUPLICATION IS CRITICAL
• Timely completion of trials is key
• Well developed regional, national, and
  international networks
• and collaborations are important to obtain
  definitive results to
• advance cancer research and patient management

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Challenges for Coordinated Efforts

• Standardizations of definitions for efficacy
  endpoints
• Harmonized Data Elements
• Identify and standardize translational research
  data elements to be commonly collected across
  trials
• Specimen collection SOPs
• Data Sharing System
• Share electronic data files to allow for the
  study of specific questions across trials
• Create a system that provides a data mining
  capability that should allow more contemporaneous
  and frequent analysis of pooled resources from
  contributing groups
• Publication guidelines

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Hurdles to International Collaboration

• Scientific agreement on clinical study design
• Close communication and interaction essential
• U.S. requirement for international institutions
  to obtain Federal Wide Assurance (FWA)
• If receiving U.S. funds or exchanging patient
  data
• Technical agreement on data collection and
  submission
• Requirements for auditing of collaborating
  international institutions
• Tissue banking Analysis
• Drug distribution across borders and other
  regulatory issues

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International Regulatory Issues

• Harmonization of clinical practice across all
  sites
• Registration of investigators
• National and local regulatory approval
• Harmonization of data collection
• Reporting of adverse events
• Insurance requirements
• Global variation in regulations

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International Committee of Harmonization (ICH)

• It is ICHs mission to achieve greater
  harmonization in the interpretation and
  application of technical guidelines and
  requirements for product registration, thereby
  reducing duplication of testing and reporting
  carried out during the research and development
  of new medicines.
• http//www.ich.org/home.html

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ICH

• Drug regulatory authorities and pharmaceutical
  trade associations of Europe, Japan, and the
  United States discuss scientific and technical
  aspects of product registration.
• QSEM
• Quality
• Safety
• Efficacy
• Multidisciplinary
• .

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Harmonization of clinical practice

• Patient eligibility pathologic diagnosis,
  imaging studies, laboratory tests
• Surgical treatment
• Chemotherapy and biologic treatment
• Radiation therapy
• Supportive care
• Surveillance and follow-up

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Patient Selection Lab Assays

• Nowadays in the era of personalized medicine it
  is critical that patient selection based on a
  specific biomarker is done using properly
  standardized assays
• Are we really testing what we want to test?
• Are we really categorizing adequately?
• EGFR mut, BRAF mut, EML4/ALK, ERCC1, Risk
  classifiers
• Standardization and Validation
• Important ethical and regulatory implications

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Registration of investigators sites

• Harmonization of registration
• US FDA 1572 form or equivalent
• Copies of curriculum vitae and medical licenses
  for physicians
• Financial disclosure forms for physicians
• Certification of laboratories for clinical tests
• Inspection of study site before trial opens

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Regulatory approval

• Approval of trial by national trial regulatory
  agency (equivalent of US Food and Drug
  Administration)
• Approval by independent ethics committee
• National, regional, or local
• In some cases, approval by scientific review
  committee
• Documentation of approvals required

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Harmonization of data collection

• Case report forms
• Collection by mail, fax, or internet
• Collection of images (CXR, CT, etc)
• Collection of pathologic specimens
• Tumor, plasma, blood, normal tissue
• Central review of images and pathology?
• Core laboratories

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Harmonization of data collection

• Important for all trials
• For registration trials, some specific data to be
  collected may originate from discussions and
  agreement between the lead institution, the
  sponsor, and the countrys regulatory agency
  based on a particular trial, drug or claim
• Case Report Forms, Central review of images

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Global variation in regulatory requirements

• European Union Clinical Trials Directive
• Directive 2001/20/EC
• Required each member country in EU to pass
  national legislation concerning clinical trials
  which evaluate new medications
• Problems
• Little harmonization 27 different laws for 27
  countries
• Covers all trials (even without new medications)
• Barrier to international participation

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FDA Approvals

• Regulatory approval substantial evidence of
  clinical benefit demonstrated prior to approval
  based on prolongation of life, a better life or
  an established surrogate of either of the above
• Accelerated approval (AA) designed to hasten the
  delivery of products appearing to provide a
  benefit for serious or life threatening illnesses
  lacking satisfactory treatments
• AA regulations 1992
• 21 CFR Part 314, Subpart H (for drugs)
• 21 CFR Part 601, Subpart E (for biologics)

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Critical Elements of Accelerated Approval

• Serious or life threatening diseases
• Provides a benefit over existing therapies
• A surrogate reasonably likely to predict clinical
  benefit
• Subject to the requirement to verify benefit
• Post-marketing trials would usually be underway
• Applicant should carry out studies with due
  diligence
• If post-marketing studies fail to demonstrate
  clinical benefit or applicants fail to perform
  required post-marketing studies with due
  diligence, FDA may withdraw approval, following
  an open public hearing

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EMA Approvals

• Approval types
• Normal, Exceptional, Conditional
• Conditional Marketing Authorization(CMA)
• Demonstrates positive benefitrisk based on
  preliminary evidence
• Specific Obligations to provide further data
  necessary to become Normal approval
• Authorization valid for one year (renewable)
• Clear information to patients and providers on
  the conditional nature of the approval
• Financial penalties if fail to observe
  obligations

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Data Reporting Regulatory Requirements

• Method of data reporting
• Multi-center guidelines
• Reporting requirements
• Collaborative agreement language

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Reporting of adverse events

• All clinical trials must collect data on adverse
  events associated with the trial.
• Some adverse events must be reported immediately,
  within 48-72 hours.
• Adverse events must be reported to the study
  sponsor, the independent ethics committee, and
  the national regulatory authority.
• The toxicities which patients experience may
  require modification to the trial.

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NCI Common Toxicity Criteria Adverse Events
(CTCAE)

• Recently underwent 3rd revision (CTCAE v4)
• Grade I mild
• Grade II moderate
• Grade III severe
• Grade IV life-threatening
• Grade V death
• 30 de la toxicidad es basada en sintomasgt el
  resto en parametros de laboratorio o hallazgos
  clinicos

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Trial Data Monitoring

• Data Monitoring Committee (DMC) of Data
  Monitoring Safety Board (DMSB)
• To review safety and efficacy data from phase
  III trials on a
• continuing basis
• Recommendations to the trial steering committee
• Closing the trial in case of large therapeutic
  benefit
• Closing a trial for futility or safety
• Changing the trial design / eligibility criteria
• Early publication
• Closing a poorly accruing trial
• Decisions with ethical, regulatory, commercial
  implications

Dagher RN and Pazdur R, in Anticancer Drug
Development Guide, 2004 Chapter 20 p408
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Trial Data Monitoring Early Closure Process

• If DMC/DMSB recommends early closure for safety,
  futility, efficacy, there is a regulatory process
  to be followed
• Communications between government, leading group,
  pharma
• Dear doctor letter
• Dear patient letter
• Communication to other stake holders/partners
• Communication to FDA
• Different regions/countries, may have different
  sop.

Dagher RN and Pazdur R, in Anticancer Drug
Development Guide, 2004 Chapter 20 p408
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Insurance Requirements

• Institutional insurance
• Protects local institution from claims that
  institution made mistakes in giving therapy on
  trial or that the therapy on the trial was
  incorrectly designed
• Patient insurance
• Provides insurance to cover treatment of
  complications associated with trial
• Requirements vary from country to country

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Model Agreements

• Confidential Disclosure Agreement (CDA)
• Cooperative Research and Development Agreement
  (CRADA)
• Materials Cooperative Research and Development
  Agreement
• Clinical Supply Agreement (CSA)
• Material Transfer Agreement (MTA)
• Pediatric Preclinical Testing Program MTA

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Global variation in regulatory requirements I

• National and local regulatory approval
• Length of time required for review varies from
  country to country
• Some countries have established principle for
  only one fast review
• Adverse event reporting
• US and European Union have slightly different
  requirements
• New US CTCAE version 4.0 should be more
  consistent with European Union ICH rules

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Global variation in regulatory requirements II

• Drug importation (import)
• paperwork required to import experimental drugs
  varies from country to country
• Legal rights to experimental drug can vary from
  region to region Often one company has the
  rights to a drug in the US, while a second
  company has the rights to the drug outside the US
• Transportation of specimens
• Some countries do not permit specimens to be
  shipped to another country

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Room for improvement Accrual

• How can we strengthen international collaboration
  and complete trials faster?
• If a trial accrues too slowly, then the trial
  result may no longer be important when the trial
  is finished.
• If a trial accrues too slowly, then doctors and
  patients lose interest in the study (in
  particular if a study of high complexity).

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Room for improvement Overcoming barriers with a
collaborative effort

• If we work together, then we can complete larger
  trials faster.
• If we work together, then we can complete trials
  for patients with a specific molecular biology or
  with a rare tumor or with a less common stage of
  cancer.
• If we work together, then we can study the impact
  of pharmacogenomics on cancer treatment.

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Room for improvement Better planning,
harmonization, and coordination

• We must plan our clinical research together
• Complementary trials
• Joint trials
• We must harmonize regulation
• Fast review, approval and activation of trials
• Adverse event reporting
• Insurance requirements

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Regulatory Structure Conclusions

• Regulatory structure needs both to protect
  patient safety and facilitate clinical research
• Clinical trials help define optimal cancer care
  and guide public policy
• Government, academia, patients, public, and
  industry must collaborate to strengthen clinical
  trials

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Building a National Network

• Investments to Conduct National Trials
• National dialogue among cancer scientists,
  clinical investigators and practitioners
• National awareness campaign regarding cancer and
  clinical trials
• Develop national infrastructure
• Establish common registration, data submission
  and document approach
• Establish data submission network
• Establish quality assurance program

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Building a National Network

• Depends on what you have
• and what you want
• Population available and accrual potential
• Number of advanced care centers community
  hospitals
• Number of investigators and research nurses
• Private practice component in cancer care
• Cancers to be investigated
• Phase II or phase III trials
• Studies involving specific treatment modalities
• Single network or multiple networks (competing
  studies requires adequate patient base)
• Stable infrastructure

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Building a National Network

• Steps forward
• Participate in international clinical trials by
  experienced cancer trial organization (e.g.,
  EORTC)
• Experience, GCP standards, data submission,
  submission of biological specimens, oversight
• Commercial trials
• Experience and revenue for infrastructure
• Explore governmental and charitable funding

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Websites For Clinical Trials Resources
and Information
NCI websites www.cancer.gov
Cancer Trial Support Unit, links to cooperative groups www.ctsu.org
Cancer Therapy Evaluation Program ctep.info.nih.gov
Physicians Desk Query (PDQ) www.cancer.gov/cancerinfo/pdq

Registry of clinical trials in US and around the world www.clinicaltrials.gov
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