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Regulatory Issues International Perspective


Regulatory Issues International Perspective Claudio Dansky Ullmann, MD Head, Thoracic and Head & Neck Malignancies, Melanoma and Other Skin Cancer Therapeutics – PowerPoint PPT presentation

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Title: Regulatory Issues International Perspective

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

NCI Organization Chart
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
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
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
Phase 3
Non-CTEP Funded Resources
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

Group Collaborations Opportunities Types of
  • 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
  • Multimodality treatments
  • Translational studies. Incorporate correlative
    science and quality of life
  • Pooled resources
  • Tissue banking

Challenges in Clinical Trial Research
  • Enrollment often is not representative of the
    general population
  • Factors affecting enrollment are multiple and
  • Well designed controlled trials are necessary to
  • sometimes small benefits
  • Important time and human and infrastructure
    resources are
  • invested in the conception, launching, and
    execution of a
  • 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

Challenges for Coordinated Efforts
  • Standardizations of definitions for efficacy
  • Harmonized Data Elements
  • Identify and standardize translational research
    data elements to be commonly collected across
  • 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

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
  • Technical agreement on data collection and
  • Requirements for auditing of collaborating
    international institutions
  • Tissue banking Analysis
  • Drug distribution across borders and other
    regulatory issues

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

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//

  • 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
  • .

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

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
  • Standardization and Validation
  • Important ethical and regulatory implications

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

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

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

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

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
  • Covers all trials (even without new medications)
  • Barrier to international participation

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)

Critical Elements of Accelerated Approval
  • Serious or life threatening diseases
  • Provides a benefit over existing therapies
  • A surrogate reasonably likely to predict clinical
  • Subject to the requirement to verify benefit
  • Post-marketing trials would usually be underway
  • Applicant should carry out studies with due
  • 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

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

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

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.

NCI Common Toxicity Criteria Adverse Events
  • 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

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
  • 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

Dagher RN and Pazdur R, in Anticancer Drug
Development Guide, 2004 Chapter 20 p408
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,
  • Dear doctor letter
  • Dear patient letter
  • Communication to other stake holders/partners
  • Communication to FDA
  • Different regions/countries, may have different

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

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

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
  • New US CTCAE version 4.0 should be more
    consistent with European Union ICH rules

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

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).

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
  • If we work together, then we can study the impact
    of pharmacogenomics on cancer treatment.

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

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

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

Building a National Network
  • Depends on what you have
  • and what you want
  • Population available and accrual potential
  • Number of advanced care centers community
  • 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

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

Websites For Clinical Trials Resources
and Information
NCI websites
Cancer Trial Support Unit, links to cooperative groups
Cancer Therapy Evaluation Program
Physicians Desk Query (PDQ)

Registry of clinical trials in US and around the world
Muchas Gracias Por Su Atencion
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