Modified on March 5, 2026 to remove the “subscribe” option. This blog has been retired and replaced by the S.P.I.R.I.T. newsletter.
Tasha Mohseni
(Author)
Adnan Shaikh
(Author & Reviewer)
Good morning, good afternoon, and good evening Compliance Rockstars, Clinical Researchers, Ethics Educators, and Investigators from around the globe!
It’s hard to believe that January is coming to a close. It feels like just yesterday folks were sending their New Year wishes. It felt as though I was reviewing countless study submissions. I prefer to be on my toes than idle!
ICYMI, TikTok went dark on January 18, 2025 only to return on January 20, 2025. You can read about my insights here:
Now, back to today’s post. On January 6, 2025 the final version of the ICH GCP E6(R3) guidelines. Whether you’re a novice to clinical research (like me) or an expert, this is a HUGE deal. The last revision for ICH GCP E6(R2) was back in November 2016. Without writing this post, I could guess that there are significant differences. But I don’t like to guess…I like to know and understand why.
For background, I primary review IRB studies related to social, behavioral, and education research (SBER). I am extremely interested in learning more about clinical research ethics and clinical trials in general.
Therefore, I would like to thank Adnan Shaikh for his willingness to review and co-author this post!
In this post, we plan to describe in detail the differences between the E6(R2) version and the E6(R3) version. As a general disclaimer, these are our own interpretations of these guidelines. If you have any questions about these guidelines, you should always consult with your institution.
Tasha Mohseni’s POV on General Guideline Differences
Aside from document length, the table below summarizes the general differences between the guidelines:
ICH GCP E6(R2) Summary
ICH GCP E6(R3) Summary
1. Published in November 2016. 2. It emphasized updates needed to integrate modern technology and risk-based approaches into clinical trials. 3. Key updates included: A. Adoption of risk-based monitoring. B. Enhanced guidance on electronic records and data management. C. Emphasis on quality management systems tailored to clinical trial complexities.
1. Published in January 2025. 2. Introduced broader revisions across clinical trial design, oversight, and ethical conduct, emphasizing: A. Greater focus on patient needs and preferences. B. Enhanced data reliability and transparency mechanisms. C. Encouragement of adaptive and innovative trial designs. D. Modernized guidance for handling big data and novel analytical tools.
What Did ChatGPT Have to Say About The Guideline Differences?
I can’t even quantify how long it took me to summarize the general differences for the two documents. Though this was interesting to review, I found it difficult to sift through the information. This might be because I haven’t had exposure in this area. I likely should have completed the GCP CITI training course to provide a foundation. Alas, here we are!
Out of curiosity and efficiency, I decided to upload both guidelines to ChatGPT and asked for itemized differences. Below is a complete response from ChatGPT:
“To provide a detailed, itemized comparison of the ICH E6(R2) and ICH E6(R3) documents, I will identify key differences across major sections and topics in both documents. This will include updates, additions, and revisions. Here’s an itemized list based on their content:
Introduction and Scope
ICH E6(R2):
Introduced updates to integrate risk-based monitoring and electronic systems.
Focused on maintaining ethical principles while improving trial efficiency and data reliability.
ICH E6(R3):
Broader scope, emphasizing patient-centric approaches and advanced technologies like decentralized trials and real-world evidence.
Greater emphasis on stakeholder collaboration and global harmonization.
Quality Management
ICH E6(R2):
Introduced a risk-based quality management system.
Focused on identifying and mitigating risks to critical data and processes.
ICH E6(R3):
Expands the quality management framework to include:
Adaptive approaches.
Continuous quality improvement throughout the trial lifecycle.
Integration of advanced analytics and real-world data for monitoring.
Data Management
ICH E6(R2):
Introduced guidance on electronic systems and electronic data capture.
Added the requirement for an audit trail for all changes in electronic data.
ICH E6(R3):
Extends guidance on managing big data, artificial intelligence (AI), and machine learning (ML) tools.
Updates standards for data security, privacy, and transparency in decentralized trials.
Trial Design
ICH E6(R2):
Focused on traditional trial designs, with some flexibility for centralized monitoring.
ICH E6(R3):
Encourages adaptive, innovative, and patient-centric trial designs.
Includes guidance for decentralized clinical trials (DCTs) and the use of real-world evidence (RWE).
Investigator Responsibilities
ICH E6(R2):
Detailed investigator obligations, focusing on protocol adherence and oversight.
Introduced responsibility for supervising delegated tasks.
ICH E6(R3):
Expands the investigatorโs role to ensure oversight in remote and virtual settings.
Adds accountability for new roles introduced in decentralized models (e.g., telemedicine).
Monitoring
ICH E6(R2):
Introduced risk-based monitoring (RBM) for the first time.
Emphasized centralized monitoring over traditional on-site monitoring.
ICH E6(R3):
Refines RBM principles and promotes greater use of AI-driven monitoring systems.
Integrates remote monitoring for decentralized trials.
Patient-Centric Approaches
ICH E6(R2):
Focused primarily on data integrity and participant safety.
ICH E6(R3):
Strong emphasis on patient engagement, including:
Simplified informed consent processes.
Participant-centered trial design.
Use of digital tools to enhance patient experience and access.
Ethical Considerations
ICH E6(R2):
Rooted in the principles of the Declaration of Helsinki, with updates for vulnerable populations.
ICH E6(R3):
Expands ethical considerations to include:
Diversity and inclusion in clinical trial participation.
Enhanced protection for participants in decentralized and global trials.
Use of Technology
ICH E6(R2):
Introduced electronic systems, requiring validation and audit trails.
ICH E6(R3):
Extends to newer technologies like AI, blockchain, and wearable devices.
Requires validation and traceability for advanced digital systems.
Regulatory Harmonization
ICH E6(R2):
Harmonized standards for the EU, U.S., and Japan.
ICH E6(R3):
Broader harmonization efforts, including additional regions (e.g., Canada, Switzerland).
Greater emphasis on mutual regulatory acceptance of trial data.
Risk-Based Approaches
ICH E6(R2):
Introduced risk-based approaches for trial management and monitoring.
ICH E6(R3):
Refines risk-based approaches with continuous risk assessment throughout the trial lifecycle.
Incorporates new methodologies to address emerging risks in decentralized and digital trials.
Terminology and Glossary Updates
ICH E6(R2):
Updated glossary to include terms like “risk-based monitoring” and “certified copy.”
ICH E6(R3):
Expands glossary to include modern terms like “decentralized trials,” “real-world data,” and “validation of AI systems.”
These itemized differences highlight the evolution of clinical trial guidelines from E6(R2) to E6(R3), reflecting advancements in technology, trial design, and ethical considerations. Let me know if you want a deeper analysis of any specific section!”
At face value, this seems to be an impressive comparative analysis.
You might be wondering why I said the word “seems”.
I say this because I am acknowledging that I am not a subject-matter expert. I can’t even say that I have direct experience with this other than reading the guidelines themselves. I can’t necessarily validate if ChatGPT assessed the information correctly. I could have done more iterative prompting to receive an even more detailed response…but for what? This is why it is so important to have the expertise to verify the information is correct. Whether you become knowledgeable or collaborate with someone who has the expertise. Let’s see what Adnan Shaikh has to say about ChatGPT’s analysis!
Adnan Shaikh’s POV on the ChatGPT Analysis (in his own words)
Hey everyone! I hope you’re enjoying reading Tasha’s content.Here’s my take on the ICH GCP E6(R2) versus ICH GCP E6(R3).
The adoption ICH GCP E6(R3) introduces a transformative update to the principles and practices of clinical research:
The ICH GCP E6(R2) guidelines were more focused
They adhered to the protocol and followed the traditional approach in clinical trial studies, that has an impact of โone size fits all”
While ICH GCP E6(R3) is more modern and advanced approach for clinical trial, it encourages โfit for purposeโ
Which means that proportionality and risk-based approaches focus on the quality of clinical trials
This is critical and fundamental to the safety of participants and the reliability of participants results
I humbly recognize that I am not as expert and that I am still learning
However, to summarize the overall concept of ICH GCP E6(R3), it focuses on the following:
Emphasize proportionality risk-based approach,
Incorporates innovative technologies, and
Promotes adaptability to modern clinical trial design.
In the recent times, AI is claimed to be one of the best tools in helping with clinical research.
Now, I would like to share my POV on ChatGPT.
It is helpful in many ways, for example:
Preparing document with little to no grammatical errors,
Providing information on particular drug molecules, and
Providing information on ICH GCP guidelines
When I prompted ChatGPT about the difference between ICH GCP E6(R2) vs ICH GCP E6(R3), I received the following graphical explanation:
Image of ChatGPT’s graphic representation of the differences between ICH GCP E6(R2) and ICH GCP E6(R3)
As you can see, this further illustrates my point that ICH GCP E6(R3) highly focuses on modern adaptation. By implementing this concept, it can provide more flexibility in clinical research studies. In the era of AI and emerging technologies, itโs important to adapt the modern techniques in clinical trials. It is also criticial to note that this must be done without compromising confidentiality. We must adhere to ethical standards for the responsible use of these emerging technologies.
I am expressing my sincere gratitude to Tasha for involving me in this post. I ‘m looking forward to working with her on future projects!
We hope you find the content useful and thought-provoking! What do you think about current guidelines? Please lead the discussion and leave a comment below!
Again, thank you Adnan Shaikh for your invaluable expertise! For those who would like to learn more about him, you can follow him on LinkedIn and read his brief biography below.
Adnan Shaikha is a Pharm.D (Doctor of Pharmacy) candidate. He is completing his clinical pharmacy internship at New Civil Hospital. His degree will be from the Shree Dhanvantary Pharmacy College, Kim, Surat, Gujarat, India. He is expecting to graduate with his PharmD degree in June 2025. Additionally, he is doing a certification course on medical writing in clinical research.
We wish you the best of luck on this exciting endeavor and soon-to-be new chapter in your life!
Modified on March 5, 2026 to remove the “subscribe” option. This blog has been retired and replaced by the S.P.I.R.I.T. newsletter.
Author
Tasha Mohseni
Good morning, good afternoon, good evening IRBers, Clinical Research Educators, and Investigators from around the world!
I’m so excited about sharing the very first Show-and-Tell post within a highly educational series!
I’m sure by the title you can tell what this post is going to be about. But first…
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And then…
I want to tell you about my methodology of assessing 17 social, behavorial, education research (SBER) IRB protocol templatesfrom various institutions.
Being in the compliance field, I am also passionate about research. More importantly, passionate about doing research ethically and in a reproducible way. I am briefly going to summarize how I analyzed 17 SBER IRB protocol templates from various institutions for commonalities:
I went to Google and typed in “IRB Templates”.
From here, I only reviewed templates with the following keywords:
“SBER”
“Social/Behavioral”
“Social/Behavioral/Educational”
My initial plan was to stop once I browsed through 10 pages. Which I did and was hoping to have 50 records for review.
But…I encountered obstacles:
Some institutions had templates for consent and recruitment, but not for the protocol (perhaps this is an internal document in the electronic IRB submission system)
Some institutions relied on Federal agency templates (which is completely fine, but I said I would do my search on institutions)
Some institutions only had one type of protocol template (i.e., no difference between SBER or biomedical research) – again this is completely fine depending on the nature of the research at your institution
Some institutions required an institutional login to access their templates (hear, hear for additional security!)
Some institutions had protocol templates based on review type (exempt, expedited, vs. full board) – this is interesting to me because I wonder how these institutions have trained their investigators to know which template to use
Some institutions may have had SBER protocols, but I was limited by the keywords I selected
Could I have assumed that surveys/focus groups/observations fall under SBER? Sure…but how do I know they aren’t also applicable to a biomedical component? Further, I set my keywords and that does not fit the criteria
After going through 20 (LONG) pages of results, I decided to stop once I reviewed 17 institutions’ SBER protocol templates.
As I reviewed each template, I gathered the following data points:
A link to their PDF for future reference
Their institution only to avoid duplicate values (once I had 19 unique values – this column was deleted)
Sections within their protocol template
Then, with iterative prompting in my personal ChatGPT-4 account, the GPT summarized the recurring themes within the protocol templates.
If you would like to review any of my references, please leave me a comment or email me at tmohseni@renovationinirbeducation.org.
Poll created in LinkedIn to determine an investigator’s problem area when creating a SBER protocol.
Though only one person voted (thank you!), they gave me some great insight. This is a common issue I see. Providing too little detail doesn’t give the IRB reviewer an idea of what the proposed research is about. More importantly, by providing little detail, you lose the significance behind your very important research!
Now, let’s take a deep dive into the various sections of a SBER protocol template. At the end, I will have a list of of applicable Office of Human Research Protections (OHRP) guidance documents and Secretaryโs Advisory Committee on Human Research Protections (SACHRP) recommendations. You should consult with your institution’s IRB if you have any questions about the resources provided at the end of this post (or the recommendations within this post to ensure it is applicable to your institution):
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Title
This should hopefully be one of the easiest parts of your SBER IRB protocol! The title of your protocol should give the IRB reviewer a sense of what your IRB protocol will be about.
Is there a grant associated with your study?
If so, I recommend reviewing sponsor requirements. Some sponsors may require that your protocol title must be the same title as your grant.
Principal Investigator (and Study Team)
The institution must know who is the lead investigator (i.e., the principal investigator (PI)) for the SBER study. This is typically a faculty or staff member. If the research is student-led, then the student should check with their institution to see if they can be listed as the PI. Some institutions may be fine with this, but require a faculty member to be listed on the protocol as well. The protocol should also list all study team members associated with your study. Whether they are affiliated with your institution or an external collaborator, IRBs want to ensure that everyone has received the proper IRB/human subjects research training.
Institution Team Members
These are team members that are affiliated with your institution.
External Collaborators
These are team members that are not affiliated with your institution. If the collaborator is affiliated with an institution, they will need to reach out to their IRB. The collaborator’s IRB may require that the collaborator submit a study for review. Conversely, the collaborator’s IRB may not considered them engaged in research. You may not know this, but institutions have flexibility in how to apply the regulations.
Stay tuned for an upcoming post that will discuss the reliance process and the single IRB mandate!
Background and Objectives
This is also known as:
The study significance and rationale (i.e., purpose) for the proposed research
The study aims and hypothesis
This is where you briefly introduce the purpose of your proposed study. If your research is funded, the study aims should be consistent with your grant. This is also where you would include your research question(s) and hypothesis. You should also provide a summary of research currently available (i.e., publications) to provide justification for the proposed study. I caution you here to avoid any technical terms or jargon. Remember, IRB reviewers aren’t as connected to your project as you are.
Therefore, this section should be written in a way that anyone can understand:
The main idea of the proposed research
Any published research that is related to the proposed research
Any current studies that are related to the proposed research (i.e., the ID number of any active studies related to the proposed research)
This helps IRB reviewers when they are making a determination for your study with respect to risk (i.e., no greater than minimal risk or above minimal risk)
Inclusion and Exclusion Criteria
As the section heading implies, this is where you would describe:
Criteria that makes the individual eligible for the proposed study
Criteria that makes the individual ineligible for the proposed study
Special Populations
If not obvious, you want to provide the scientific rationale for any exclusions of special populations. Special populations under The Common Rule (45 CFR 46) are:
There are other examples of special populations that aren’t covered in the regulations. An individual can be part of a special population if they can be considered vulnerable in the research:
Individuals with impaired decision-making capacity
Economically or educationally disadvantaged persons
Socially disadvantaged
Terminally ill or very sick
Racial or ethnic minorities
Institutionalized persons (e.g., persons in correctional facilities, nursing homes, or mental health facilities)
Dual role relationships (the investigator could be a manager or professor to the employee and/or student participant)
What is “vulnerability” in a research setting?
Below is a summarized table of when vulnerability can occur in a research setting:
Undue Influence
Coercion
Misusing a position of power to influence others to make a decision they would not normally make
A way to force or control someone
Number of Participants
In this section, you would indicate the number of anticipated participants you plan to enroll in your proposed study.
Recruitment Methods
Here, I like to take the “Five W’s” approach:
Who are you recruiting?
Why are you recruiting these potential participants?
What materials will be used for recruitment?
Where will potential participants be recruited?
When will recruitment begin?
Let’s look at these components one piece at a time.
The first question should be a concise statement of your inclusion criteria. When IRB reviewers ask who you will be recruiting, they aren’t looking for specific names. They are looking for the population of interest that will help answer your research question(s).
The second question is aiming towards providing justification for the population of interest. How will this particular population help you answer your research question(s)? What is it about this population that would benefit from the proposed research?
For the third question, IRB reviewers are trying to understand what materials you will be using to recruit participants. Will potential participants be contacted via email? What about social media? Do you plan to do in-person recruitment where you will distribute fliers related to your study?
Typically, the fourth and fifth questions are a combined statement. Something to keep in mind is in-person recruitment. Say you are going to an event where you plan to distribute recruitment fliers for the proposed research. Do you have permission to distribute recruitment fliers for research purposes? You will want to make note of any site permissions you have obtained for the proposed research. The IRB reviewer will likely want to review the site permission documentation as well. Be sure to include any explicit permissions within your submission.
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Informed Consent
The consent process should outline key information from the investigator that should be provided to participants. The key information here should facilitate the participantโs comprehension and voluntariness of potential participation in your study. Though there are standard required elements of consent (and additional requirements depending on your study), at minimum, your consent form should include:
The study activities
The duration of time the activities will take
Explanation of risks and benefits
Compensation and any limits to receiving it
Protections and limits of confidentiality
Stay tuned for a blog post describing the consent process in MUCH greater detail!
Risk and Benefit Assessment
Risk
Remember when I said IRB reviewers look at previous applications similar to the proposed research?
To reiterate, IRB reviewers when they are making a determination for your study with respect to risk (i.e., no greater than minimal risk or above minimal risk). Minimal risk (as defined by 45 CFR 46.102(j)) means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests. When the proposed research has risks, the investigator must have risk mitigation measures in place.
Let’s look at the example below:
Say you are conducting an anonymous survey regarding the mental health of college students. The IRB reviewer will review the survey questions to see if any of these questions could cause distress to participants. Then, the IRB reviewer will look at your protocol to see if:
The possibility of distress from answering these survey questions was disclosed
Distress mitigation measures (e.g., a list of mental health/therapy resources)
The key here is that any potential benefits (whether direct or indirect) should outweigh the proposed study’s risks.
Direct Benefit and Indirect Benefit
First, let’s define direct benefit and an indirect benefit:
Direct Benefit
Indirect Benefit
Refers to a positive outcome that directly results from the intervention being studied and is experienced by the research participants themselves
A positive outcome that arises from the research process but is not directly related to the intervention itself, often benefiting society at large or future research, rather than the individual participant in the study
Now, let’s look at a couple of examples:
Direct benefit: In a behavioral intervention testing a new stress relieving technique, a direct benefit would be the participant experiencing symptom relief from applying said technique to their daily routine
Indirect benefit: In a study on a new educational program, an indirect benefit could be the increased awareness of the topic among the wider community due to the research dissemination
It is also important to note that compensation is not considered a benefit.
Study Design and Procedures
The IRB reviewer should be able to read and understand exactly what you are proposing to do with participants. Let’s pretend you’re wanting to conduct a survey to see how folks feel social media impacts their mental health. This section should include the following details:
A statement of how the survey will be disseminated (paper or electronic)
If electronic, indicate if the collection of IP addresses or email addresses will be disabled (as this is identifiable information)
A statement regarding how long it should take to complete the survey
A statement of whether participants are allowed to skip questions they are not comfortable answering
Stay tuned for the blog post related to online research considerations for a more detailed explanation of this!
For all study procedures, consider the five questions below:
Who on the study team is conducting the specific procedure?
What is the specific procedure?
How will the specific procedure occur?
When will the specific procedure occur?
Where will the specific procedure occur?
It is only important to note how the data collected from the specific procedures will be analyzed.
Compensation
As mentioned above, compensation is not a benefit. Rather, compensation is a token of appreciation for participating in the research. It is not required to provide compensation. If you do not plan to offer compensation, you would simply include a statement regarding this. If you do plan to offer compensation, ensure the following details are included:
The amount of compensation
The form of compensation (e.g., if it is a gift card, identify where the gift card is to)
The justification for the amount of compensation
When and how compensation will be provided to participants
It is important to note that IRBs are not reviewing the amount of compensation to determine if it’s “enough”. IRBs review compensation amounts to ensure the amount is not coercive. As we know from the section above, coercion can make any individual vulnerable in research.
Privacy, Confidentiality, Data Management, and Future Use of Data
Privacy and Confidentiality
First, let’s define the difference between “privacy” and “confidentiality”:
Privacy
Confidentiality
Refers to the right to control access to ourselves and our personal information
Refers to agreements made between investigators and participants, through the consent process, about if and how researchers will protect participant’s information
Now, this section of a research protocol is vital for ensuring ethical standards are upheld and participant trust is maintained. Below are key elements researchers should address to create a robust plan for protecting participant data:
Outline how participant privacy will be safeguarded throughout the project
For instance, provide private and secure environments for interviews or survey completion
Specify where and how all data typesโpaper, electronic, or multimediaโwill be stored and managed
Data must be stored securely, such as in password-protected databases or locked filing cabinets in restricted-access areas
Highlight additional security measures like data encryption for electronic records
Clearly state who will have access to the data, limiting it to essential study personnel to minimize risk
For studies involving audio or video recordings, specify the retention period and handling procedures
For example, recordings may be deleted after transcription and verification or within six months of collection
During retention, secure storage methods, such as encrypted drives or locked cabinets, should be employed to prevent unauthorized access
If a master list or key is used to link participant identities to data, describe its management
Explain how it will be securely stored separately from study data (e.g., on a different encrypted server or in a separate locked cabinet)
Identify who will have access to the master list and ensure access is limited to essential personnel
Additionally, specify when the master list will be destroyed
State the minimum retention period for study data, typically three years after project completion, as per regulatory requirements
Except for master lists or keys and audio/video recordings, which should be destroyed at the earliest opportunity, all other data should be securely retained until the retention period ends
To maintain confidentiality, include methods for secure destruction, such as shredding paper files or securely wiping electronic data
If data will be shared or moved outside your institution, provide a detailed plan (such as a data use agreement)
Specify the type of data that will be shared, the recipient(s), the circumstances under which sharing will occur, and the timeline for these actions
Include any additional security measures to ensure data confidentiality during transfer
Data Management
For this aspect, the IRB reviewer will look for:
A statement of the types of study data collected
A statement of who has access to study data
A statement of how data will be stored
A statement of when data will be destroyed
A statement of how study data will be de-identified (if applicable)
A statement of how identifiable study data will be managed
Stay tuned for a future blog post regarding methods on how to de-identify your study data!
Future Use of Data
This section requires explanation only if you plan to share data outside of your institution. The investigator should provide a plan for any data movement or sharing outside of their institution. This section should also specify what data will be provided, to whom, under what circumstances, and when. This should also be disclosed in the consent form.
Withdrawal of Participants
If a participant requests to withdraw from the study, the investigator should describe:
The scenarios under which they will be able to delete the participantโs data
The scenarios under which they will not be able to delete the participantโs data
Let’s look at a couple of examples:
If you are conducting an anonymous survey, you likely would have no way of identifying the participantโs individual responses. Therefore, when a participant opts to withdraw, there would be no way to delete their data (i.e., their responses).
If you are conducting interviews, you could delete a participantโs interview transcript when a master list is in existence. However, you may not be able to do so until after the master list is destroyed.
I hope you found the first post of this blog-series helpful! Did you find this post informative for your SBER IRB protocol application? If so, please scroll on down and leave a comment below!
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:
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:
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 โsubstantial evidenceโ to support the claims of effectiveness for new drugs.
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:
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!
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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:
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:
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:
FDAโs 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:
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!
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!
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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:
Drug substances:
Source
Complexity
Characterization
Impurities
Drug products:
Specification
Stability
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:
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
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.
Informed Consent and Ethical Considerations in Clinical Trials
You might be familiar with the presentation if you attended FDA's webinar, Informed Consent โ 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:
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.
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!
Modified on March 5, 2026 to remove the “subscribe” option. This blog has been retired and replaced by the S.P.I.R.I.T. newsletter.
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.
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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:
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.
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.
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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:
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?
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!
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