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Clinical Trial Requirements
Similarities and Differences
US vs. EU
Anita FentyCovance, Inc
OBJECTIVES
To provide a concise overview of the clinical trial requirements for the United States and the European Union emphasizing similarities and differences
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LEGAL FRAMEWORK
• United StatesFederal statues and
regulations applicable to all 50 states
Individual state laws apply
Authorized representative required
• European UnionEU Directives
applicable to all members
National laws applyLegal representative
required
CLINICAL TRIAL APPLICATIONUS
IND written approval not required to proceed commence CT
May proceed 30-days after FDA receives IND unless notified otherwise
IND annual report requiredFormat paper or electronic, US format or CTDNo feesRequired to register applicable trials in
www.clinicaltrials.gov
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CLINICAL TRIAL APPLICATIONEU
CTA written approval requiredApproval timeframe variesAnnual safety report only requiredFormat CTD paper or electronicNational CTA fees may applyCompetent Authorities will register clinical
trial in EudraCT database – details will be made public from late 2009
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INSTITUTIONAL REVIEW BOARD/ETHICS COMMITTEE
• United States IRB approval
required IRB registration
required
• European UnionEC approval requiredECs appointed or
authorized by States
CONDUCT OF CLINICAL TRIALUS
Form FDA 1572 is required to be signed by the PI, if study is conducted in US and submitted to IND
Form FDA 3674 certification that all requirements of section 402(j) of PHS Act are met
Protocol amendments maybe implemented once received by FDA, with exceptions (e.g. safety issues or protocol study design issues)
Protocol Waivers are acceptable under certain circumstances
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CONDUCT OF CLINICAL TRIALEU
Statement of Investigator not required by member states
Protocol Amendment implementation varies upon classification (e.g., substantial vs. non-substantial)
Protocol Waivers are considered a breach of GCP
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ESSENTIAL DOCUMENT RECORD RETENTION
USRecord retention 2 years after
marketing application is approvedRecord retention 2 years after last
shipment and delivery of IMP if marketing application is not approved
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ESSENTIAL DOCUMENT RECORD RETENTION
US Foreign study record retention is 2 years after
the Agency makes a decision on an application whose data was submitted in support of a MA
Foreign study record retention is 2 years after the submission of the IND if the study is submitted in support of an IND but not an application for marketing approval
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ESSENTIAL DOCUMENT RECORD RETENTION
EUEssential Document Record includes
CRF, excluding medical records:≥ 5 years (Directive 2005/28/EC and
Annex 17)≥ 15 years or CT discontinuation if data
used to support a marketing application (Directive 2001/83/EC and Annex 1)
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ESSENTIAL DOCUMENT RECORD RETENTION
EU ≥ 2 years after the last marketing authorization
granted in the European Community and there are no pending or contemplated MA in the European Community (Annex 1); Or
≥ 2 years after formal discontinuation of clinical development of the IMP (Annex 1)
Ethics Committee Retain all relevant records for ≥ 3 years
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INVESTIGATIONAL MEDICINAL PRODUCT (IMP) REQUIREMENTS
US
Label must be in English, except for Puerto Rico
The following statement is required: “Caution: New Drug Limited by Federal (or United States) law to investigational use”
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INVESTIGATIONAL MEDICINAL PRODUCT (IMP) REQUIREMENTS
EU
Label must comply with Annex 13 of EU Directive 2001/83/EC
Language requirements varies between member states
Sponsor is responsible for destruction of unused and/or returned IMP
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INVESTIGATIONAL MEDICINAL PRODUCT (IMP) REQUIREMENTS
EU
IMP batch records retention is ≥ 5 years after completion of CT or formal discontinuation of the last study in which the batch was used
Retain sufficient samples of IMP and key packaging components used for each finished product IMP for ≥ 2 years after completion of CT or formal discontinuation of the last study in which the batch was used
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ADVERSE EVENT REPORTINGUS
Investigator Responsibilities:Required to report to the Sponsor any adverse
events caused by or probably caused by IMP, promptly
Immediately report any to the Sponsor any adverse event that is fatal or life threatening
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ADVERSE EVENT REPORTINGUS
Sponsor Responsibilities: Review all relevant information received on the IMP
from any source Notify FDA and all participating investigators in a
written IND safety report of:• Any adverse experience associated with the use
of the drug that is both serious and unexpected; or
• Any finding from tests in laboratory animals that suggests a significant risk for human subjects including reports of mutagenicity, teratogenicity, or carcinogenicity
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ADVERSE EVENT REPORTINGUS
Sponsor Responsibilities• Required to report unexpected fatal or
life threatening experiences ASAP, but not later than 7 days; Follow-up reports ASAP but no later than 15 days of receipt of new information;
• Form FDA 3500A for US and CIOMS I for foreign reports
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ADVERSE EVENT REPORTINGUS
Sponsor Responsibilities: IND Annual Report
• Summary of most frequent and most serious SAEs by body system
• Summary of all IND safety reports submitted during the past year
• List of subjects who died during while participating in the clinical trial in the study, with the cause
• List of subjects who dropped out during the course of the clinical trial associated with any adverse experience, regardless of cause
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ADVERSE EVENT REPORTINGEU
Competent Authority Responsibilities:Review and monitors the safety information
of IMPs used in clinical trials conducted in their respective territories through the use of the EudraVigilance Clinical Trial module (EVCTM)
Conducting inspections of clinical trial sites to verify GCP
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ADVERSE EVENT REPORTINGEU
Investigator Responsibilities:Report to the sponsor all serious adverse events
immediately, except for those identified in the protocol or IB; followed by detailed, written reports
Report to the sponsor adverse events and/or laboratory abnormalities identified in the protocol as being critical to the safety evaluation (reported as per time frames in protocol).
Provide the sponsor and the EC committee with any additional requested information requested, especially in relation to deaths
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ADVERSE EVENT REPORTINGEU
Sponsor Responsibilities: Responsible for all pharmacovigilance activities
including having systems in place to record and analyze reported adverse events/ reactions
Required to keep records of all adverse events received for the PI and provide to the CA is requested
Promptly notifies to all PIs, EC and CA ethics of results that could adversely affect the health of the clinical trial patient or have an impact on the conduct of the trial or alter the CA authorization to continue the trial
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ADVERSE EVENT REPORTINGEU
Sponsor Responsibilities Expedited Reporting of suspected unexpected serious
adverse reactions (SUSARs) is applicable to Phase I to IV clinical trials with ≥ 1 ongoing clinical trial in an EU member state, and the IMP is not a marketed product
• Fatal or life-threatening adverse reactions: Report to CA of the concerned Member State(s) within 7 days and also be sent to the EC within 7 days. A follow-up report must be submitted within an additional eight days
• Other SUSARs: Report to CA of the concerned Member State(s) and also send to the EC within 15 days
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ADVERSE EVENT REPORTINGEU
• Sponsor ResponsibilitiesSUSARs occurring in third countries that use
an IMP that is also used in an EU member state clinical trial is required to be reported in same manner as an EU expedited report
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ADVERSE EVENT REPORTINGEU
Sponsor Responsibilities Other Expedited Reports : report to CA and EC within 15
days• An expected serious adverse reaction that has an
increase in the rate of occurrence which is judged to be clinically important
• Significant hazard to the subject population (e.g., lack of efficacy with a medicinal product used in treating a life-threatening disease)
• When a clinical trial conducted in another country is discontinued or temporarily stopped due to safety reasons by the same sponsor
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ADVERSE EVENT REPORTINGEU
Sponsor ResponsibilitiesRequired to provide annual report to CA
and EC of member state where the clinical trial is conducted and EC
• Analysis of patient safety• Listing of all adverse reactions• Summary tabulations of all adverse events
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REGULATORY COMPLIANCEUS
All clinical trials must comply with 21 CFR Parts 50, 54, 56, 58 and 312
Phase 1 IMPs are exempt from certain parts of 21 CFR Part 211, unless the clinical trial involves a marketed drug product or one that was manufactured in a Phase 2 and/or 3 study
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REGULATORY COMPLIANCEUS
21 CFR Part 210.2(c) Applies to Phase 1 drugs manufactured in small or
large scale environments designed to assess tolerability, or feasibility for further development
Allow industry to Implement manufacturing controls appropriate for Phase 1
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REGULATORY COMPLIANCEUS
21 CFR Part 210.2(c) Allows industry to achieve product quality between
investigational and commercial batches for all Phases of drug development
Phase 2 and 3 drugs and nonexempt Phase 1 drugs (e.g. IMPs manufactured for Phase 2 and 3 clinical trials, and marketed products used in a Phase 1 clinical trial ) must comply with 21 CFR Parts 210 and 211
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REGULATORY COMPLIANCEUS
Phase 1 IMPs are exempt from the following sections of 21 CFR Part 211:
Fully validated manufactured process (21 CFR 211.110(a)
Rotation of stock for drug product containers (21 CFR 211.150)
Repackaging and relabeling of drug product (21 CFR 211.130(b)
Separate packaging and production areas (21 CFR 211.130(a);
Warehousing (21 CFR 211.142)
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REGULATORY COMPLIANCEEU
Verification of compliance (GCP and GMP) is covered under Article 15 of Directive 2001/20/EC
CA responsible for implementing provisions for the suspension of a CT, conducting inspections and verifying compliance
Inspection reports may also be made available to Sponsor, EC, EMEA and other member states
Must comply with Good Distribution Practices (GDPs) and Good Laboratory Practices (GLPs)
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REGULATORY COMPLIANCEEU
There is no comparable EU regulation specific to Phase 1 CGMPs (Annex 13 guideline provides flexibility dependent upon the stage of development of the product)
IMP manufacturing and importation facilities in the EU must have authorization
Each IMP batch must be certified by a Qualified Person (QP) within the EU before released
Comparators and placebo must comply with cGMPs and have a QP
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