Transcript Regulatory Requirements

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
Office of the
Director
Division of Cancer
Prevention
Division of
Extramural
Activities
Center for Cancer
Research
Division of Cancer
Treatment and
Diagnosis
Division of Cancer
Epidemiology and
Genetics
Radiation
Research Program
Developmental
Therapeutics
Program
Cancer Diagnosis
Program
Cancer Imaging
Program
Translational
Research Program
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Cancer Therapy
Evaluation Program
Division of Cancer
Biology
Division of Cancer
Control and
Population
Sciences
CANCER THERAPY EVALUATION PROGRAM
Jeff Abrams
Operations & Informatics Branch
Steve Friedman
Clinical
Clinical
Regulatory
Investigational
Pharmaceutical
Grants and
Investigations
Affairs Branch
Drug Branch
Management
Contracts
Branch
Branch
Roy Wu
Branch
Jan
Casadei
Meg
Mooney
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James Zwiebel
Charles Hall
Clinical
Trials
Monitoring
Branch
Gary
Smith
Cancer Therapy Evaluation Program - CTEP Therapeutics
Development Program
Basic Resources
Adult U01
Phase 1 Program
(14 phase 1 sites)
Phase 1
Phase 2
Pediatric Phase 1
Consortium
N01
Phase 2 Program
Specialty Resources /Other
*Clinical Center,
Phase 0/ Expl IND
*Cancer Centers
CNS Consortia
Pediatric, NABTT,
NABTC
(9 phase 2 sites)
*SPORES,
R21, R01, P01
Phase 3
Cooperative
Groups
*Non-CTEP Funded Resources
*CCOPs
Essential Elements for a National Cancer
Clinical Trials Network – Basis for Collaboration
1. Qualified investigators from qualified institutional
sites with important scientific/therapeutic hypotheses
and experienced in clinical trial conduct
2. Infrastructure for protocol development and conduct
of clinical trial in multi-institutional setting
(Operations Office)
3. Infrastructure for collecting and quality-checking data
(Data/Statistical Center)
4. Biological tissue specimens/correlative studies
5. Financial support
6. Patients
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Group Collaborations – Opportunities – Types of Trials
• Studies whereby an efficient process is
required
• Large RCT’s
• 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
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Scientific agreement on clinical study design
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Close communication and interaction essential
U.S. requirement for international institutions to obtain Federal
Wide Assurance (FWA)
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If receiving U.S. funds or exchanging patient data
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Technical agreement on data collection and submission
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Requirements for auditing of collaborating international
institutions
5.
Tissue banking – Analysis
6. Drug distribution across borders and other regulatory issues
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International Regulatory Issues
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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 ICH’s 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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Punta del Este, Uruguay
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 country’s 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
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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 benefit:risk 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
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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)
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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 sintomas> 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
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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, pharma
•Dear doctor letter
•Dear patient letter
•Communication to other stake holders/partners
•Communication to FDA
•Different regions/countries, may have different sop.
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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
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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
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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
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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…
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Participate in international clinical trials by experienced
cancer trial organization (e.g., EORTC)
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Experience, GCP standards, data submission, submission of
biological specimens, oversight
Commercial trials
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Experience and revenue for infrastructure
Explore governmental and charitable funding
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Websites For Clinical Trials
Resources and Information
NCI websites
Cancer Trial Support Unit,
links to cooperative groups
Cancer Therapy Evaluation
Program
Physician’s Desk Query
(PDQ)
Registry of clinical trials
in US and around the world
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www.cancer.gov
www.ctsu.org
ctep.info.nih.gov
www.cancer.gov/cancerinfo/pdq
www.clinicaltrials.gov
Muchas Gracias
Por Su Atencion
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