Clinical Trial Requirements U.S. vs. EU Similarities and Differences

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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DISCUSSION/ QUESTIONS/COMMENTS

anita.fenty@covance.com ORregulatorypolicy@covance.com

609.452.855033