Tag: Clinical Research

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Hello, clinical researchers and clinical research educators!

I feel highly informed of FDA regulations and guidance documents with respect to clinical investigation. If you’re dying to know how this training ended, I URGE you to read this post. I encourage you to also read my other two posts regarding the first two days of the FDA CITC session:

• FDA Clinical Investigator Training Course: Day 1 Insights
• FDA Clinical Investigator Training Course: Day 2 Insights

Before you begin…

Please remember to be kind to yourself.

This is a complicated subject matter. Don’t expect to become an expert right away. Take your time and focus on one topic area at a time. Reach out and ask questions to subject-matter experts who can make this information easier to understand.

In this post, I will cover what was discussed for Day 3 of the course:

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Clinical Trial Quality as Fitness for Purpose

We started off with a previously mentioned FDA regulation, 21 CFR Part 314. 126 (Adequate and well-controlled studies).

Reports of adequate and well-controlled investigations provide the primary basis for determining whether there is “substantial evidence” to support the claims of effectiveness for new drugs.

eCFR :: 21 CFR 314.126 — Adequate and well-controlled studies.

Under this regulation, there are seven characteristics of adequate and well-controlled studies. The presentation carried on that there are several stakeholders involved to optimize clinical trial quality:

• Sponsors
• Contract Research Organizations (CROs)
• Institutional Review Boards (IRBs)
• Clinical Investigators

It was also noted that the quality of a clinical trial starts right at the design phase. The following resource related to design was shared: CTTI Quality by Design. Clinical investigators should focus on critical-to-quality (CTQ) factors. CTQ factors are factors whose integrity impacts:

• Protecting participants
• Reliability and interpretation of study results
• Decision making based on study results

The rest of the presentation primarily focused on the International Council for Harmonization (ICH) Good Clinical Practice (GCP) E6(R3). With respect to quality, the primary principles that solidify this concept are listed below:

• Principle #6: Quality should be built into the scientific and operational design and conduct of clinical trials.
• Principle #7: Clinical trial processes, measures and approaches should be implemented in a way that is proportionate to the risks to participants and to the importance of the data collected.
• Principle #8: Clinical trials should be described in a clear, concise and operationally feasible protocol.

Investigator Responsibilities – Regulation and FDA Expectations for the Conduct of Clinical Trials

I want to warn you that there are MANY references in this section. PLEASE take your time as you process this information. I was overwhelmed gathering all the links that were mentioned!

We started off by defining the difference between an “investigator” and a “sponsor” per 21 CFR Part 312.3 (Definitions and interpretations). Then, we were introduced to the following regulations that ensure the
integrity of clinical data on which product approvals are based and to help protect the rights, safety, and welfare of human subjects:

• 21 CFR Part 312: Investigation New Drug Application
• 21 CFR Part 50: Protection of Human Subjects
• 21 CFR Part 54: Financial Disclosure by Clinical Investigators
• 21 CFR Part 56: Institutional Review Boards
• 21 CFR Part 11: Electronic Records; Electronic Signatures
• 21 CFR Part 314: Applications for FDA Approval to Market a New Drug
• 21 CFR Part 320: Bioavailability and Bioequivalence Requirements
• 21 CFR Part 601: Licensing
• 21 CFR Part 812: Investigational Device Exemptions
• 21 CFR Part 814: Premarket Approval of Medical Devices
• 42 CFR Part 11: Clinical Trials Registration and Results Information Submission

Next, we reviewed FDA regulations related to a clinical investigator’s responsibilities. It was noted that this is NOT an all-inclusive list:

• 21 CFR Part 312.60: General Responsibilities for Investigators
• 21 CFR Part 213.66: Assurance of IRB Review
• 21 CFR Part 312.64: Investigator Reports
• 21 CFR Part 312.62: Investigator Recordkeeping and Record Retention
• 21 CFR Part 11: Electronic Records; Electronic Signatures
• 21 CFR Part 312.61: Control of the Investigational Drug
• 21 CFR Part 312.69: Handling of Controlled Substances

It was noted per 21 CFR 312.53(c) that investigators must submit a completed and signed Form FDA-1572 to the sponsor prior to conducting their clinical investigation. Several investigator oversight responsibilities were discussed and the following guidance was shared: Investigator Responsibilities – Protecting the Rights, Safety, and Welfare of Study Subjects. With respect to informed consent, the following regulation and resources were mentioned:

• 21 CFR Part 50 Subpart B: Informed Consent of Human Subjects
• Informed Consent: Guidance for IRBs, Clinical Investigators, and Sponsors
• Use of Electronic Informed Consent Questions and Answers Guidance for Institutional Review Boards, Investigators, and Sponsors

The presentation concluded by discussing Clinicaltrials.gov reporting requirements. It was noted that registration is required within 21 days of first human subject enrolled.

International Clinical Trials

Clinical trials conducted internationally has the ability to:

• Provide access to diverse populations
• Promote enhanced generalizability of results
• Accelerate patient recruitment
• Address health issues that affect various regions around the world
• Enables sponsors to enter multiple markets simultaneously

It was noted that inclusion of U.S. participants is crucial for FDA evaluation. This is especially important if the trial results are intended to support regulatory approval in the United States. Clinical investigators conducting an FDA-regulated study outside the US can
request a waiver from FDA 1572 Signature. This is because IND applications are NOT required for clinical trials conducted outside of the United States. Next, FDA inspections for international clinical trials was discussed. The common pitfalls found during an FDA inspection are listed below:

• Failure to follow investigational plan/protocol
• Inadequate/inaccurate records
• Inadequate drug accountability
• Failure to obtain and/or adequately document informed
  consent
• Failure to report adverse drug reactions and issues
  related to IRB communication

The presentation concluded by discussing the key updates in ICH E6 (R3) and shared the following resources:

• 21 CFR Part 314.106: Foreign Data
• FDA Acceptance of Foreign Clinical Studies Not Conducted Under an IND: Frequently Asked Questions
• FDA Inspections of Clinical Investigators
• FDA Clinical Trials Guidance Documents
• ICH Efficacy Guidelines

FDA’s Good Clinical Practice (GCP) Compliance Review for NDAs and BLAs

First, the FDA Bioresearch Monitoring Program was discussed. This is a comprehensive program of on-site inspections and data audits designed to monitor all aspects of the conduct and reporting of FDA-regulated research. These inspections are in accordance with:

• Good Laboratory Practice (GLP)
• Clinical investigators in accordance with Good Clinical Practice (GCP)
• Sponsors/Contract Research Organizations (CROs)
• Clinical trial monitors
• In vivo bioequivalence facilities
• Institutional review boards (IRBs)
• Radioactive drug research committees
• Postmarketing adverse drug experience reporting (PADE), and
• Risk evaluation and mitigation strategies reporting (REMS)

The presentation shifted its focus to specifically Good Clinical Practice (GCP) inspections. The goal of GCP inspections is to provide assurance that the data are reliable and that the rights of participants are protected. We also learned about the various stakeholders involved in GCP inspections such as:

• Clinical Investigators
• Sponsors
• Sponsor-Investigators
• Contract Research Organizations (CROs)

I was surprised to learn that GCP inspections are not required as
part of the marketing application review process. Lastly, we learned more about FDA’s organizational structure. Specifically:

• The Office of Inspections and Investigations
• The Office of Scientific Investigations

Clinical Investigator Inspection Readiness

The purpose of conducting clinical investigator inspections is to ensure that:

• The clinical investigator conducts their investigation according to the investigational plan

• The clinical investigator obtains institutional review board (IRB) review and approval
• The clinical investigator obtains informed consent
• The clinical investigator controls the investigational product(s) under investigation

There are routine/surveillance and for-cause inspections. Inspections typically follow this format:

• Pre-announcement (typically five days before the start of the inspection and provides the scope of the investigation)
• Form FDA 482 (Notice of Inspection) and Opening Meeting
• Inspection
• Closeout Meeting and Form FDA 483 (Inspectional Observations, if issued)
• Post-inspection Activities

Finally, the following resources were shared throughout the presentation (and a bonus one I found):

• Warning Letters and Notice of Violation Letters to Pharmaceutical Companies
• Clinical Investigators – Disqualification Proceedings Database
• Investigations Operations Manual
• Regulatory Procedures Manual
• Bonus: What to Expect During an FDA Inspection

FDA’s Use of Alternative Approaches to Evaluate GCP Compliance

First, the presentation defined Remote Regulatory Assessments (RRA). As cited in the guidance, an RRA is an examination of an FDA-regulated establishment and/or its records, conducted entirely remotely, to evaluate compliance with applicable FDA requirements. RRAs assist in protecting human and animal health, informing regulatory decisions, and verifying certain information submitted to the Agency. RRAs are NOT inspections. You can read this guidance if you want to learn more about RRAs: Conducting Remote Regulatory Assessments Questions and Answers Draft Guidance for Industry. International collaboration for clinical trials was also discussed. Foreign collaborations can enable efficiency use of resources and improved inspection coverage. Lastly, the evaluation of GCP with respect to innovative technologies was discussed. The following resources were shared for this last topic:

• Integrating Randomized Controlled Trials for Drug and Biological Products Into Routine Clinical Practice Draft Guidance for Industry
• Conducting Clinical Trials With Decentralized Elements Guidance for Industry, Investigators, and Other Interested Parties
• Digital Health Technologies for Remote Data Acquisition in Clinical Investigations Guidance for Industry, Investigators, and Other Stakeholders

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Thank you for bearing with me during this highly intensive training! I hope you learned as much as I did. Again, I encourage you to bookmark this post (and the two previous posts). These posts provide a great overview of FDA resources and clinical trials.

Don’t forget to leave a comment about your favorite session covered during the training!