CDER/FDA Regulations Regarding Foreign Clinical Trial Data

In the last 5 years, use and submission by pharmaceutical companies of non-US (foreign) data to FDA is on the rise. FDA sets conditions in the CFR Register under which such data can be used in support of clinical research, clinical submission and marketing application approval in the US. Non-US data must be reviewed for regulatory rigor, quality, statistical confidence, therapeutic value and clinical significance. I strongly recommend that a due diligence review and quality audit be performed on all non-US data and documentation prior to integration and submission to FDA.

CDER/FDA Requirements:

• Foreign studies are conducted under a filed IND with FDA
• If the studies are not conducted under a filed IND with FDA but meet criteria specified in FDA CFR regulations, exceptions to include non-US may be granted
• Foreign data and study documentation, final study reports must meet US IND 21 CFR 312 requirements.

CDER/FDA may accept foreign studies not conducted under a filed IND if the studies are:

• Well designed
• Well conducted
• Performed by qualified clinical investigators
• Performed at qualified clinical sites
• Conducted in accordance with ethical principles acceptable to the WHO
• Conducted in accordance with the Declaration of Helsinki
• Conducted in accordance with laws and regulations of the country where the clinical research is conducted
• Country-specific regulations meet standards set forth by with CDER/FDA - 21 CFR 312.120(a).

CDER/FDA - Clinical Investigator Responsibilities - Informed Consent Form 1572

Accurate execution of FDA Form 1572 is critical to FDA regulatory requirements and GCP compliance, as well, will ensure the subject is fully informed of their rights, benefits and risks of the investiagtional drug. It is the responsibility of the sponsor and the clinical investigator to ensure the informed consent accurately explains clinical trial conduct and protocol procedures.

Form 1572 includes names of investigators and sub-investigators who will be participating and/or assisting in the conduct of the clinical investigation. Proper execution of Form 1572 - the investigators make a commitment to:

• Follow current clinical protocol
• Personally conduct and/or supervise the clinical investigation
• Ensure all persons assisting in the clinical trials are informed of obligations
• Inform subjects of investigational drugs
• Ensure informed consent (21 CFR Part 50) and IRB review, approval and reporting (21 CFR Part 56) are conducted under GCP compliance and FDA regulatory requirements
• Report to pharma sponsor all adverse events (21 CFR 312.64)
• Inform all clinical site associates of changes to protocol
• Maintain adequate and accurate records and make available all records and source documents for FDA/DSI inspection, for cause or otherwise (21 CRF 312.68)
• Ensure initial and continuing review by IRB
• Report all changes to protocol and clinical research
• Report all anticipated or unanticipated problems involving risks and benefits to subjects
• Ensure no changes to the clinical protocol in general
• Ensure good clinical conduct
• Ensure that no changes are made to the clinical protocol without IRB approval except where necessary to eliminate immediate hazards and life-threatening events to subjects
• Comply with all FDA regulatory requirements in 21 CFR 312.

CDER Assessment of FDA Regulatory Requirements - Sponsor and Clinical Investigator Compliance with GCP

How does CDER assess FDA regulatory requirements pertaining to sponsor and clinical investigator compliance with GCP?

Sponsor Responsibilities (21 CFR 312.50-312.58) - General and Specific Responsibilities of Sponsors include:

• Select qualified investigators
• Provide investigators with the information they need to conduct an investigation properly
• Ensure that the investigation is conducted in accordance with the protocol
• Maintain an effective IND for the investigators
• Maintain an effective IB for the investigators
• Maintain an effective communication with the investigators
• Ensure that FDA and participating investigators are promptly informed of significant new adverse events or risks with the clinical trial drug
• Ensure that FDA and participating investigators are promptly informed of significant changes to the protocol
• Ensure that FDA and participating investigators are promptly informed of significant new data, preclinical, clinical, same chemical class or otherwise
• Ensure that sponsor and investigators protect subject rights on study.
• More to come...

CDER's Role in FDA's BIMO, DSI and GCP Goals

CDER's role in FDA's Bioresearch Monitoring (BIMO) Programs and Human Subject Protection primarily focus on 4 areas which are Compliance, DSI Manufacturing/Product Quality, Compliance Risk Management/Surveillance and the Division of New Drugs/Labeling Compliance.
In an earlier post, goals of CDER's BIMO were clarified and presented.

What are the goals of CDER's FDA's DSI and GCP divisions?

DSI - For the Review Divisions -

• DSI will arrange for routine data audit GCP inspections to determine data quality, data integrity and safety of subjects in pivotal clinical trials and provide the inspection reports to the review division prior to the Division Action Goal Date.

DSI - For the Public -

• DSI will investigate complaints related to the conduct of clinical trials, including arranging for directed or "for cause" inspections and take appropriate regulatory action.
• DSI will arrange for routine surveillance inspections of IRBs to determine if rights, safety and welfare of human subjects are protected.

DSI - GCP -

• Issue assignments to the Office of Regulatory Affairs (ORA) field investigators and participate on inspection when expertise is required.
• Evaluate the results of inspections from a scientific and regulatory perspective.
• Recommend and implement regulatory actions.
• Provide expert advice on program design, policy issues and guidance.
• Educate and inform program constituents - communication within CDER, FDA, otherwise.

CDER's Role in FDA's Monitoring and Subject Safety

Several companies recently requested clarity pertaining to CDER's role in FDA's Bioresearch Monitoring Program and Human Subject Protection. The Center for Drug Evaluation and Research (CDER) consists of the following offices and divisions:

• Office of the Center Director
• Office of Compliance
• Division of Scientific Investigations (DSI)
• Division of Manufacturing and Product Quality
• Division of Compliance Risk Management and Surveillance
• Division of New Drugs and Labeling Compliance.

The Division of Scientific Investigations (DSI) consists of a Director, Deputy Director, Field Investigator, Good Clinical Practice (GCP) Branch 1, GCP Branch 2 and Good Laboratory Practice (GLP)/Bioequivalence and Quality (BEQ).

CDER's Bioresearch Monitoring (BIMO) Inspection Programs consist of :

• Clinical Investigators
• Sponsor/Monitor/CRO Investigators
• IRB/RDRC Investigators
• Bioequivalence/Good Laboratory Practice Investigators.

The goals of BIMO:

• validity of data from studies in support of pending marketing applications
• adherence to FDA GCP/GLP/BEQ regulations
• whether the rights and safety of subjects have been protected.

More to come on CDER's role and organization...

Annual Safety Report - Table of Ongoing Clinical Trials

Annual safety reports all include a table of past, present, ongoing, completed and proposed clinical trials as per FDA requirement and rigor. In some instances, a 6 month safety report is requested and required by FDA. For the 6 month safety report, a table of ongoing clinical trials will suffice. The table will include information for all ongoing clinical trials at the time of the safety report submission and will include information pertaining to each ongoing clinical study:

• study number
• study subjects treated
• study design
• study status
• study dosing
• study type
• number of clinical study investigative sites
• date of first subject screened
• date of first subject randomized
• date of first subject enrolled
• date of last subject enrolled
• date of last subject completed.

A safety "cut-off" date is agreed to between pharma and FDA for the reporting period for the 6 month safety report. Remember to review previously submitted safety materials, submissions, narratives, reports and otherwise to ensure accuracy and consistency of data and documentation and reporting - current, ongoing vs. all previously submitted. Remember, safety of the patient or subject on clinical trial is the primary objective of FDA and supersedes the evaluation of effectiveness and efficacy objectives at all times during, pre-, post-submission...all approvals.

Annual Safety Report Composition and Quality Control

Annual Safety Reports (ASRs) are required by pharma each year for a drug, device and/or biologic, under clinical development and is triggered by an anniversary date linked to safety timelines, IND, CDP, subject exposure, safety of subjects on clinical trial and serious adverse reports (SARs). The Table of Contents (TOC) is much the same, generic in fact, for clinical development programs with agreed upon expansion, between pharma and FDA. An Annual Safety Report TOC for a inhalation device delivery system for example is presented below.

List of Appendices

List of Abbreviations and Definitions of Terms

1. Introduction
2. Review of Subjects Safety on Clinical Trial
3. Overall Safety Evaluation
4. Conclusion

Appendix A

Appendix B

Appendix C

Appendix D

Section 2, Review of Subjects Safety on Clinical Trial...

• Relation of Safety Information with Dose, Duration and Time of Onset of Adverse Reaction
• Reversibility of Serious Adverse Reports (SARs)
• Previously Unidentified or Other Increased Frequency of Adverse Reactions
• Overdose
• Drug Interactions or Other Associated Risk Factors
• Special Subject Groups
• Pregnancy and/or Lactation
• Product Abuse
• Risks Related to the Investigational or Diagnostic Procedures of the Clinical Trial
• Risks Which Might Be Associated with Insufficient Quality of the Investigational Medicinal Product.

ASR submission supporting text, data and documentation must be referenced, appended and quality controlled and quality assured. The ASR is submitted electronically to FDA and is expected to be received on the anniversary date for the ASR. There must be an appendix which includes a line listing of all suspected SARs (Appendix A) and another appendix (Appendix B) with a summary tabulation of all suspected SARs. It is strongly recommended that the line listing and the tabulation of all suspected SARs are quality controlled for consistency, data, documentation and accuracy vs. ASR intext tables and text.