FDA Clinical Investigator Training Course: Day 2 Insights

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Hello, clinical researchers and clinical research educators!

We just concluded Day 2 of the FDA Clinical Investigator Training Course (CITC)! I would say after yesterday’s training, I have exposure to FDA regulations now. At the very least, I know where to locate FDA resources. If you’re in the same boat as me, I URGE you to read this post. I encourage you to also read FDA Clinical Investigator Training Course: Day 1 Insights if you didn’t attend yesterday’s session.

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.

In this post, I will cover what was discussed for Day 2 of the course:

DISCLAIMER: There was a seventh presentation, but I was unable to attend.

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Before you take a deep dive into these sections...

It would be helpful to have a strong chemistry background. I have very minimal experience in chemistry and could understand some terms. Again, like yesterday, I will highlight key takeaways.

I would love to further explore these topics with the appropriate subject-matter expert!

Chemistry, Manufacturing and Controls: Regulatory Considerations Through Clinical Development

First, we learned about pharmaceutical quality. Pharmaceutical quality assures safety, efficacy, and availability of every dose. With Chemistry, Manufacturing and Controls (CMC), we can assess pharmaceutical quality. CMC is involved throughout the whole product life cycle from the pre-clinical stage to marketing. 21 CFR Part 314.30 defines the difference between the following terms:

Drug Substance	Drug Product
An active ingredient that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the human body, but does not include intermediates used in the synthesis of such ingredient.	A finished dosage form, e.g., tablet, capsule, or solution, that contains a drug substance, generally, but not necessarily, in association with one or more other ingredients.

The presentation continued with IND requirements of both drug substances and drug products. There were also aspects of the Common Technical Document (CD) which must include the following for:

It's important to note that prior to submitting an IND, the FDA provides one pre-IND meeting. In this meeting, the FDA will assess the substance or product in your application. Here are some resources from the training (and a bonus link) related to this topic:

• 21 CFR Part 312.23: IND content and format
• Guidance for Industry M4Q: The CTD-Quality August 2001
• Bonus: FDA CMC and GMP Guidances

Pharmacology/Toxicology in the Investigator's Brochure

The Investigator's Brochure (IB) has four key elements of nonclinical information:

• Pharmacology
• Safety Pharmacology
• Pharmacokinetics
• Toxicology

Pharmacology provides proof of concept, data on the intended/primary and unintended/secondary targets, support toxicology species selection. Safety pharmacology assesses the potential effects on physiological functions on vital organ systems such as the cardiovascular system, central nervous system, and respiratory system. Pharmacokinetics refers to the drug's movement through the body as it passes through absorption, distribution, metabolism, and excretion (ADME). Lastly, toxicology determines if the proposed clinical study is safe and also identifies a starting dose for the drug. There were MANY guidance documents referenced in this presentation. If you search through the FDA guidance document database, you can search for the umbrella topics listed below:

• S1 Carciogenicity Studies
• S2 Genotoxicity Studies
• S3 Toxicokinetics and Pharmacokinetics
• S4 Toxicity Testing
• S5 Reproductive Toxicology
• S6 Biotechnology-derived Products
• S7 Safety Pharmacology Studies
• S8 Immunotoxicology Studies
• S9 Nonclinical Evaluation for Anticancer Pharmaceuticals
• M3 Nonclinical Safety Studies for the Conduct of Human Clinical Trials
• Oncology Pharmaceuticals: Reproductive Toxicity Testing and Labeling Recommendations

Why Clinical Pharmacology is Essential in Drug Development

Clinical pharmacology is the study of pharmacokinetics (PK) and pharmacodynamics (PD). From my understanding, both PK and PD measure what the drug does to the body. However, PK studies the concentration of the drug over time. While PD studies the effect of the drug over time. When we put these tools together (PK + PD), we can see the exposure/response relationship of the drug.

With this relationship, we can ensure the right patient receives the right drug at the right dosage and timing.

Clinical pharmacology studies occur from the point of initial submitting an IND (first-in-human) up until the post-approval phase. Clinical pharmacology studies can include:

• First-in-human studies
• ADME studies
• Bioavailability studies
• Food effect studies
• Hepatic impairment studies
• Renal impairment studies

Though specific references weren't shared for this presentation, I would like to share a bonus link: Model-Informed Drug Development Paired Meeting Program. Through this program, sponsors can meet with FDA reviewers to assess:

• Dose selection or estimation
• Clinical trial simulation
• Select appropriate response measures, predict outcomes, etc.
• Predictive or mechanistic safety evaluations

New Trends in Trial Designs: Digital Health Technologies and Decentralized Trials

Decentralized clinical trials (DCTs) are trials where some or all of the trial-related activities occur at locations other than traditional clinical trial sites. In other words, these decentralized elements allow trial-related activities to occur remotely at locations convenient for trial participants. This can promote:

• Accessibility to patients (especially those with rare diseases or mobility issues)
• Promotes patient convenience and trial efficiency

The presentation also shared investigational products suitable for DCTs, investigator oversight, safety assessments, sponsor's responsibilities, and other DCT considerations. It was also discussed that in context of clinical trials, the FDA is interested in digital health technologies (DHT) such as:

• Wearables,
• Interactive applications, and
• Instruments placed in the patient's environment that measure clinical features of interest in a clinical trial

When using DHTs in DCTs, study teams should consider confounders of measurement. An example of a confounder would be if the DHT provided different measurements depending on how the patient is wearing the device. The four references below were shared during the presentation. I also found a bonus reference that complements the topic discussed.

• Conducting Clinical Trials With Decentralized Elements
• Integrating Randomized Controlled Trials for Drug and Biological Products Into Routine Clinical Practice
• Digital Health Technologies for Remote Data Acquisition in Clinical Investigations
• Electronic Systems, Electronic Records, and Electronic Signatures in Clinical Investigations: Questions and Answers
• Bonus: The Evolving Role of Decentralized Clinical Trials and Digital Health Technologies

Informed Consent and Ethical Considerations in Clinical Trials

You might be familiar with the presentation if you attended FDA's webinar, Informed Consent – More than Just Another Document to Sign. on November 8, 2024. For today's event, I'm going to share with you resources from this presentation. I will also share two bonus links related to the FDA webinar that was held in November:

• 21 CFR Part 50.20 and 50.25
• FDA Proposed Rule: Protection of Human Subjects and Institutional Review Boards
• Clinical Trials Transformative Initiative (CTTI) Informed Consent
• Use of Electronic Informed Consent Questions and Answers
• Informed Consent: Guidance for IRBs, Clinical Investigators, and Sponsors
• Electronic Systems, Electronic Records, and Electronic Signatures in Clinical Investigations Questions and Answers
• Key Information and Facilitating Understanding in Informed Consent Guidance for Sponsors, Investigators, and Institutional Review Boards
• Use of Electronic Informed Consent in Clinical Investigations – Questions and Answers
• Bonus: Video: Informed Consent – More than Just Another Document to Sign
  • This is especially a treat because it will be like you attended today's session!
• Bonus: Transcript: Informed Consent: More than Just Another Document to Sign

mRNA Vaccines

The presentation started with a timeline of vaccination milestones. Next, different types of vaccine platforms were discussed. Some advantages of an mRNA vaccines relate to:

• Speed of manufacturing
• Speed of delivery
• More sophisticated immune response

There was also discussion revolving around the biosafety and biodistribution of mRNA vaccines. There are no resources to share in relation to this presentation.

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I'm so excited to see how the FDA wraps up our training course! There is so much great information in here. I am certainly glad I had an overview of this topic. I was sweating studying the FDA regulations for the CIP. I'm still sweating it a bit, but at least I'm better off than when I started! I at least know where to go to find these resources in preparation of the exam. I hope you find this content useful!