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Hello, clinical researchers and clinical research educators!
I’ve been so excited to attend the FDA Clinical Investigator Training Course (CITC) this week. I have no experience with clinical research or FDA regulations. If you’re in the same boat as me, I URGE you to read this post.
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. I plan to bookmark this post myself as reference as I prepare for the CIP certification.
In this post, I will cover what was discussed for Day 1 of the course:
FDA Legal Framework and Guidance Documents
Title 21 CFR is the FDA regulation. At first glance, this is quite intimidating! I personally had no idea of all the FDA regulations out there. I was only aware of 21 CFR Part 50 and 21 CFR Part 56 (as these relate to human subjects research). I am extremely thankful that the FDA has guidance documents for these! The FDA has a repository of guidance documents to assist with interpreting the regulations. You can browse by topic or by product. If you are interested in seeing FDA guidance documents related to clinical trials, you can review them here: Clinical Trial Guidance Documents
FDA Applications
An Investigation New Drug (IND) application allows for interstate shipping of products statewide. INDs also allow for the initiation of clinical studies in humans. There are three types:
- Investigator
- Emergency Use
- Treatment
Before submitting an IND application, investigators should see if they meet the IND exemption criteria. The FDA can place a clinical hold on IND application to delay or suspend the investigation. Clinical holds are placed based on specific criteria. These criteria also vary depending on the phase of your clinical investigation.
The next two types of applications are marketing applications that tell the product’s story. The application can be related to marketing for a new product. These applications are also required for adding more information to a product currently on the market.
- The New Drug Application (NDA), as the name implies, is the application required for introducing a new drug the market.
- Subchapter C is the FDA regulation related to drugs.
- The Biologics License Application (BLA) contains specific information on the manufacturing processes, chemistry, pharmacology, clinical pharmacology and the medical affects of the biologic product.
- Subchapter F is the FDA regulation for biologic products.
Clinical Trial Design Basics and Statistics
The remaining sections should have their own posts dedicated to them. There is nothing basic about this. Clinical trial design is an intricate process. I plan to only highlight key takeaways (so you are not as overwhelmed as I was with this information). If you are interested in having me explore any of these topics in depth, please leave a comment!
The purpose of conducting clinical investigations of a drug is to distinguish the effect of a drug from other influences, such as spontaneous change in the course of the disease, placebo effect, or biased observation.
eCFR :: 21 CFR 314.126 — Adequate and well-controlled studies.
I want to highlight this regulation as this serves as the foundation in designing adequate and well-controlled studies. To meet this, study teams must have:
- Defined objectives and a summary of methods within the protocol
- Permits a valid comparison with a control to provide a quantitative assessment of drug effect; there are five types of controls:
- Placebo
- Dose comparison (i.e., comparing the product at different dosages)
- No treatment
- A different active treatment
- Historical
- Adequate selection of participants and assignment to treatment/control groups to minimize bias
- Adequate measures to minimize biases on subjects, observers,
and analysts - Well-defined and reliable assessment of subjectsโ responses
- Adequate analysis of results to assess the effects of the drug
The presentation also discussed aspects of enrichment, study arm assignment, endpoints, and other design considerations. The next presentation also emphasized the importance of clinical study design. Focusing on a solid study design and conduct will make statistical analyses straightforward. Study design, conduct, and analyses all have common goals (that may conflict with one another):
- To address a specific clinical question
- To minimize bias and minimize variability
- To ethically, safely, and feasibly conduct the trial
Statistical principles discussed were related to bias, bias types, variability, z-statistic, sample size, and multiplicity.
Drug Safety Considerations
This is a humbling moment for me. I’ve been struggling trying to summarize what was discussed here. Again, all of these sections could have their own posts. However, I rather speak to a subject-matter expert (SME) related to this topic. I want to ensure I am providing you all accurate information. If I come across a SME, I will be sure to share key considerations for this aspect! I do have some resources below related to the topic from the course. This can serve as background for this highly complex subject area:
- Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers
- S7A Safety Pharmacology Studies for Human Pharmaceuticals
- M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals
- 21 CFR Part 312.32 IND safety reporting
- 21 CFR Part 314.80 Postmarketing reporting of adverse drug experiences
- 21 CFR Parts 312 and 320: Investigational New Drug Safety Reporting Requirements for Human Drug and Biological Products and Safety Reporting Requirements for Bioavailability and Bioequivalence Studies in Humans
- Safety Reporting Requirements for INDs (Investigational New Drug Applications) and BA/BE (Bioavailability/Bioequivalence) Studies
- Sponsor Responsibilities – Safety Reporting Requirements and Safety Assessment for IND and Bioavailability/Bioequivalence Studies (DRAFT)
- Investigator Responsibilities โ Safety Reporting for Investigational Drugs and Devices (DRAFT)
- Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials
- IND Application Reporting: Annual Reports
Special Populations
The “TL;DR” version:
- Though pregnant women aren’t considered a “vulnerable population” under the Common Rule, they still require additional protections.
- Education in regulatory definitions is essential to appropriately applying federal regulations.
For those who still wish read about my journey:
The main, and dare I say, most controversial highlight was related to pregnant women in clinical trials – or so I thought. You may be aware that 2018 Common Rule, Subpart B provide additional protections for this special population. At first, I thought I misheard what I’m about to tell you. I took a look at the slides just to be sure. Within the presentation, it was noted that the Common Rule has removed the reference of pregnant women being “vulnerable”. This raised all kinds of red flags for me:
- What do you mean pregnant women aren’t vulnerable?
- What about the HHS update from October 2024?
- Doesn’t a vulnerable population by default have additional protections under the Common Rule?
I know the “TL;DR” version may have spoiled this for you. However, I want to take the time here to stress an important concept here. Having a fundamental understanding of regulatory definitions is essential. This might be attributed to me only being in research compliance since January 2022. When I heard that pregnant women weren’t considered a vulnerable population, I thought this meant that there are no longer additional protections for this special group. My head was spinning. I thought to myself, I need to connect with my team right away; THIS IS HUGE.
Before I rushed to send an email, I decided to do take a moment and breathe. I wanted to pause to collect my thoughts. Federal regulations can be tricky to interpret. I wasn’t sure who to ask to confirm this information (or how to search on Google). Then, I remembered the sacred texts of human subjects research: Institutional Review Board: Management and Function: Management and Function 3rd Edition. I originally purchased this textbook to help me prepare for the CIP. However, I find myself referring to this textbook on a daily basis.
I went to chapter 9-4 of the textbook where additional protections for pregnant women are discussed. The text indicates that in the pre-2018 Common Rule, pregnant women (along with other special groups) were considered vulnerable. For a special group to be considered vulnerable:
- The individuals within this group will have a compromised ability in providing consent., or
- The individuals within this group are at special risk of exploitation.
Another way of saying this: special groups of this nature are vulnerable to coercion and unduly influence. I decided to review the Annotated Comparison of the Pre-2018 Common Rule with the Revised Common Rule. Whether you are new to the field or a seasoned professional, I strongly encourage you all to review the annotated comparison. It’s really nice because you can see additions and deletions to the Revised Common Rule. Within the annotated comparison, I read an excerpt where vulnerability was discussed. The excerpt confirmed my understanding of the annotated comparison and of the text. I’m really glad I decided to pause and educate myself before taking action with my team. It’s true what they say, think before you speak (or act).
Thank you for bearing with me on this long and informative post! I can’t believe all this information was covered in four hours. And to think there’s two more days of training to go! Stay tuned for more updates on the FDA clinical investigators course.
Don’t forget to leave a comment about your favorite session covered during the training!