Download American Society of Clinical Oncology

Regulatory Issues - US
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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Development of New Therapies
 Drug development is an orderly process designed to minimize
risk and determine benefit
 Clinical studies are required by the FDA to produce the
evidence to determine risks and benefits to humans
 Clinical development is most effective with understanding and
communication between all involved
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A Collaborative Effort Against Cancer
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Government Involvement-Regulatory Perspective
• Registration of trial in national database
• Evaluation of trial before it opens
– for patient safety
– For adequacy of trial design to prove efficacy for new
agent or device
• Ethical review
– National, regional, and/or local
• Ongoing review of toxicity/adverse events
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NCI Pathways - Development of New Agents
NCI
Agent
Industry
Review Data
NExT
DTP
Development Plan
IDSC review
CTA/CDA
Preclinical
Development
Developmental
Therapeutics Program
Development
Academia
Activity
Formulation
Toxicology
CTEP
Clinical
Development
Cancer Therapy
Evaluation Program
Clinical Trials
under CTEP IND
Regulatory Affairs Branch (RAB)
Drug Regulatory Group
 Preparation and submission of Investigational New Drug Applications (INDs)
 Review of protocols/protocol amendments
 Liaison with FDA
 Liaison with intramural and extramural investigators
Agreement Coordination Group
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Liaison with pharmaceutical companies
Preparation of agreements (CTAs and CRADAs) for clinical development of agents
Coordination of company interactions with NCI and investigators
Preparation of MTAs for basic research with investigational agents in clinical trials
Investigator’s Handbook
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Collaborative R&D Agreements with CTEP
 Clinical Collaborative Agreements provide the framework for clinical trials
and non-clinical studies sponsored by the NCI with agents provided
primarily by industry collaborators and some academic investigators.
 The purpose of the R&D Agreements is to set the stage for the exchange of
funds, materials and information between NCI, industry, and academia, while
addressing issues such as human safety, cGCP, data sharing, intellectual
property, etc.
 The key clinical agreements are CRADA, CTA and CSA.
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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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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
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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
(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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Central Institutional Review Board
The NCI CIRB Initiative
Target questions:
– Could a CIRB reduce the significant local
administrative burdens for multi-site trials
while maintaining a high level of human
subjects protection
– Would a CIRB enhance the protection of
research participants by providing consistent
expert IRB review at the national level before
the study is distributed to local investigators
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OHRP Model Options
• Model A– Central IRB review only
– Appropriate where no local IRB exists
– Understanding of local context obtained via
site visits, audits, teleconferences
• Model B– Central IRB review with some local
IRB review
– More appropriate where local IRB exists
– Value of this model: LIRB provides
understanding of local context and avoid
expense of site visits, etc.
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CIRB - Selecting a Model - Division of Responsibilities
• NCI chose Model B for practical reasons
– Local IRBs already exist and NCI chose to interface with them
– Who better to understand local research context than local IRB
Chair/members?
– This model permitted NCI to offer its CIRB free of cost to local sites
• CIRB and LIRB share regulatory responsibilities
• The CIRB’s primary function is initial and continuing review of
studies
• The local institution’s primary function is consideration of local
context, oversight of local performance, review of locally occurring
adverse events
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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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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
•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
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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SPONSOR
• Primary organization that oversees
implementation of the study and is responsible
for data analysis
– Industry
– Government
– Cooperative Group
– Academia
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Sponsors Responsibilities - Regulatory
• Ensuring proper monitoring of the investigation(s)
• Ensuring that the investigation(s) is conducted in accordance with
the general investigational plan and protocols contained in the IND
• Ensuring that FDA and all participating investigators are promptly
informed of significant new adverse effects or risks with respect to
the drug
• Ethical review
• Maintaining an effective IND with respect to the investigations
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Code of Federal Regulations 21CFR312
Sponsor Responsibilities:
Informed Consent
• Ensuring that an informed consent document accurately
informs the potential subjects of the true risks and
potential benefits of participating in the study, while at the
same time presenting the material as briefly as possible
and in ordinary language.
FDA regulations and the ICH require that “the information that is given
to the subject or the representative shall be in language
understandable to the subject or the representative.
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Sponsor Responsibility
• Same responsibilities across industry, government,
academia
• Priority and focus may differ, but all play a unique
role cancer research
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Clinical Trials Provisions for All CTEP
Collaborative Agreements
IND
Sponsorship
Intellectual
Property
Drug Supply
Protocols
NCI
Collaborative
Agreements
Adverse
Event
Reporting
Data Rights
Monitoring
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Publications
NCI- Cooperative Group- Industry Relationship: Summary
of Obligations and Guidelines
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Proprietary Agents
Confidentiality
Indemnification/Liability
Intellectual Property and Extramural Inventions
Exclusive access to Proprietary Data
Procedures under which Collaborator may contact Coop Groups, Member
Institutions or Individual Clinical Investigators
Contact of Cooperative Groups by NCI
Nature and form of information supplied to the Collaborator
Cooperative Groups – Collaborator Agreements (w/out direct NCI involvement)
Publications
Financial Disclosure
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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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Approvals - FDA
• FDA remains committed to the accelerated approval
pathway
– 49 new oncology indications since 1995
– 3.3 oncology indications per year since 2005
• AA has provided early access to clinically beneficial
cancer therapies (i.e. pemetrexed, sunitinib, bortezomib)
– 27 oncology indications have confirmed benefit in post-marketing
trials
– Made available a median of 3.6 years prior to the verification of
their clinical benefit
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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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Muchas Gracias
Por Su Atencion
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