The Culture Wars Strike Clinical Trials

FDA purges material on clinical trial diversity from its site, showing stakes of Trump DEI ban

In recent years, the importance of diversity in clinical trials has gained significant attention in the medical research community. This focus is not just a matter of inclusivity; it’s a crucial scientific and ethical imperative that directly impacts the quality and applicability of medical research.

Why Diversity in Clinical Trials is Essential

Scientific Validity and Generalizability

Different populations may respond differently to the same treatment due to variations in genetics, lifestyle, and environmental factors. By including diverse participants, researchers can better understand how a treatment works across various groups, leading to more accurate and widely applicable results.

Addressing Health Disparities

Minority groups often experience poorer health outcomes in various diseases. Including these groups in clinical trials is a crucial step towards understanding and addressing these disparities, potentially leading to more targeted and effective treatments for underserved populations.

Innovation and Discovery

Diversity in clinical trials can lead to unexpected discoveries. For instance, the identification of PCSK9, which revolutionized our understanding of cholesterol homeostasis, was a result of studying variations in cardiovascular risk factors among different racial groups.

Alignment with ICH Guidelines

The International Council for Harmonisation (ICH) has recognized the importance of diversity in its updated guidelines, particularly in ICH E6(R3) and ICH E8(R1).

ICH E6(R3)

This guideline emphasizes the importance of including diverse patient populations in clinical trials. It encourages the use of innovative trial designs and technologies to enable wider participation and inclusion of diverse populations. The guideline also stresses the need for quality by design (QbD) and a focus on critical-to-quality factors, which inherently includes considerations of diversity to ensure the reliability of trial results.

ICH E8(R1)

ICH E8(R1) focuses on the general considerations for clinical studies and emphasizes the importance of engaging with a broader range of stakeholders, including patients and patient advocacy groups. This approach naturally leads to more diverse perspectives in trial design and conduct, potentially increasing participation from underrepresented groups.

The Impact of Recent Policy Changes

The recent purge of FDA pages on clinical trial diversity, as reported by STAT News, raises significant concerns about the future of inclusive clinical. This action, part of a wider executive order banning diversity, equity, and inclusion (DEI) initiatives, could have far-reaching consequences:

Reduced Guidance: The removal of these resources may leave researchers and pharmaceutical companies with less clear direction on how to ensure diverse representation in their trials.
Potential Setbacks: Years of progress in improving trial diversity could be undermined, potentially leading to less representative studies and, consequently, less generalizable results.
Health Equity Concerns: This move could exacerbate existing health disparities by reducing the focus on including underrepresented groups in clinical research.
Scientific Integrity: The quality and applicability of clinical trial data may be compromised if diversity is not actively pursued, potentially affecting the safety and efficacy of new treatments for certain populations.

Moving Forward

Despite this setback, the scientific and pharma community must continue to prioritize diversity in clinical trials. The principles outlined in ICH E6(R3) and E8(R1) provide a strong foundation for this effort. Researchers, pharmaceutical companies, and regulatory bodies should:

Continue to develop innovative recruitment strategies to reach diverse populations.
Engage with community leaders and organizations to build trust and awareness about clinical trials.
Design trials with flexibility to improve access for all populations, including the use of decentralized trial elements.
Maintain a focus on quality by design, ensuring that diversity considerations are built into trial planning from the outset.

It is important to remember that E6(r3) is the regulation in Europe, while it is a guidance in the US. So companies need to follow it for their EMA approval possibilities.

In conclusion, diversity in clinical trials is not just a matter of equity; it’s a scientific necessity that ensures the development of safe and effective treatments for all populations. While recent policy changes may present challenges, the medical research community must remain committed to this crucial aspect of clinical research, guided by international standards and ethical imperatives.

2024 FDA 483 Data

The FDA has published the 2024 Inspectional Observation Data Sets. I don’t think there are any surprise that on what the inspection observations data for fiscal year 2024 shows and what key GMP inspection themes emerge for drug manufacturers:

Quality Systems and Documentation

Inadequate Procedures and Documentation

Failure to establish or follow written procedures for various operations, including quality control, production, and process controls.
Lack of complete documentation for investigations, batch records, and laboratory testing.

Quality Control Unit Deficiencies

Inadequate responsibilities and authority of the quality control unit.
Failure to approve or reject components, products, procedures, or specifications.

Manufacturing and Process Controls

Equipment and Facility Issues

Inadequate design, maintenance, or cleaning of manufacturing equipment.
Deficiencies in facility maintenance, sanitation, and environmental controls.

Process Validation and Control

Lack of adequate process validation, especially for sterile drug products.
Insufficient control procedures to monitor and validate manufacturing processes.

Laboratory Controls

Inadequate Laboratory Practices

Failure to establish scientifically sound laboratory controls.
Deficiencies in test methods validation and stability testing programs.

Component Testing

Inadequate testing of drug components and reliance on supplier certificates without proper verification.

Sterile Drug Manufacturing

Aseptic Processing Deficiencies

Inadequate procedures and validation for sterile drug products.
Deficiencies in environmental monitoring and control systems for aseptic processing areas.

Training and Personnel

Inadequate Employee Training

Insufficient training of employees in GMP and specific job function.

Complaint Handling and Product Quality Reviews

Deficient Complaint Procedures

Inadequate procedures for handling product complaints.

Annual Product Quality Review

Failure to conduct adequate annual product quality reviews.

Equipment Related

Out of the 365 observations that mention equipment, 277 are from just 5 regulations. Let’s take a deeper look.

Reference Number	Short Description	Long Description	Frequency
21 CFR 211.63	Equipment Design, Size and Location	Equipment used in the manufacture, processing, packing or holding of drug products is not [of appropriate design] [of adequate size] [suitably located] to facilitate operations for its [intended use] [cleaning and maintenance]. Specifically, ***	85
21 CFR 211.67(a)	Cleaning / Sanitizing / Maintenance	Equipment and utensils are not [cleaned] [maintained] [sanitized] at appropriate intervals to prevent [malfunctions] [contamination] that would alter the safety, identity, strength, quality or purity of the drug product. Specifically, ***	76
21 CFR 211.67(b)	Written procedures not established/followed	Written procedures are not [established] [followed] for the cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing or holding of a drug product. Specifically, ***	60
21 CFR 211.68(a)	Calibration/Inspection/Checking not done	Routine [calibration] [inspection] [checking] of [automatic] [mechanical] [electronic] equipment is not performed according to a written program designed to assure proper performance. Specifically, ***	30

Improper design and qualification, improper cleaning, improper calibration and inspections. Yes these take work, but these are all areas that effort can improve.

Limiting and Delaying Inspections – Brands International as Example

I think many of us have been discussing the blatant obstruction demonstrated in the December 2024 Warning Letter to Brands International Corporation, a drug manufacturer located in Ontario, Canada, citing it for limiting and delaying FDA’s inspection. Which it is important to remember congress has said is a big no-no.

I just want to stress that the Quality Manager there had a really bad day, week, month, year.

Good writeup of what to do around building your procedure for interviewing of employees during an inspection over at FDA Law blog.

FDA Inspections: Lesson 1 – Interviewing Employees

FDA Continues the Discussion on AI/ML

Many of our organizations are somewhere in the journey of using AI/ML some where in the drug product lifecycle, so it is no surprise that the FDA is continuing the dialogue with the recently published draft of “Considerations for the Use of Artificial Intelligence to Support Regulatory Decision-Making for Drug and Biological Products.”

This draft guidance lays out a solid approach by using a risk-based credibility assessment framework to establish and evaluate the credibility of AI models. This involves:

Determining if the model is adequate for the intended use
Defining the question of interest the AI model will address
Defining the context of use for the AI model
Assessing the AI model risk based on model influence and decision consequence
Developing a plan to establish model credibility commensurate with the risk
Executing the plan and documenting results

I think may of us are in the midst of figuring out how to provide sufficient transparency around AI model development, evaluation, and outputs to support regulatory decision-making and what will be found to be acceptable. This sort of guidance is a good way for the agency to further that discussion and I definitely plan on commenting on this one.

FDA Draft Guidance on “Considerations for Complying with 21 CFR 211.110”

Usually I expect the FDA to publish some basic primer material as a webinar, so I was a little surprised when “Considerations for Complying With 21 CFR 211.110” was recently published as a draft. I’ve been rereading it, looking for what is actually worthy of a guidance here, and quite frankly, struggling.

It literally is a refresher course on 21CFR211.110. Maybe I should read it as “No we were serious about ICH Q8 and critical quality attributes.” Or maybe it is just the result of one too many bad Type C meetings lately.

Anyway, good refresher on product quality, in-process controls and samples. Still I think this would be better as a webinar with some graphics. Maybe I’ll better understand why this was published based on what sort of crazy comments are made and I can scratch my head and wonder what shenanigans some of these companies are up to.