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How Changes in ICH E6 (R3) Guidelines are Changing the Future of Clinical Trials

ICH E6 (R3) Guidelines for Good Clinical Practices (GCP) have been a work in progress to put forward changes to the previous R2 version.  The overall purpose is to revise principles that account for ethical trial conduct, participant safety, and clinical trial outcomes that may be reliable. The ICH E6 R2 Guidelines for GCP consists of three key components:

  1. The overarching principle that will apply across the board
  2. Annex 1
  3. Annex 2

Annex 1 currently reflects the principles in E6 (R2), with necessary updates and modifications. While Annex 2 contains additional information that should be considered in the case of non-traditional interventional clinical studies that are not included in Annex 1.

Besides Annexes 1 and 2, the modifications in R3 consist of 12 major principles.  These 12 principles heavily focus on conducting clinical trials based on ethical principles, designing and conducting research that ensures patient rights, safety, and well-being.

Moreover, the principles highlight the need to acquire informed consent where participants are aware of all the trials. Subjecting the clinical trial to an objective review is another critical principle, along with ensuring that all trials adhere to the requirements based on the latest scientific knowledge.

Additionally, the principles highlight the importance of conducting the trial by an expert within the field and the necessity to include it in the scientific and operational design and execution of clinical trials. There is also an emphasis on designing the trial so that it’s comparative to patient risk and trial results while also ensuring that it’s clear and concise.

R2 vs. R3 What is The Difference?

R2

R3

Risk-based approach – The focus of E6 (R2) was on a balanced, risk-based approach to clinical trial design and execution.

Risk-based approach -ICH E6 R3 is intended to promote this notion while also encouraging interested parties to incorporate this approach.

Technology – E6 (R2) isn’t entirely equipped to deal with new technology.

Technology – The rising usage of electronic data sources and risk management procedures is addressed in E6 (R3).

Principle/Annex – R2 consisted of the overarching principle and annex 1.

Principle/Annex – R3 has revised the overarching principle and annex 1. Moreover, there is an addition of annex 2.

Is Clinical Research Industry Going to Face New Challenges?

Any change can bring about challenges; however, the gravity of the challenges depends on the quality design of the trial(s) currently in place. There is an evident need to ensure the reliability of clinical trial results. Without this, all the resources used to accomplish the findings would result in a loss of millions of dollars. This is precisely why the ICH E6 R3 has emphasized using Risk-Based Quality Management (RBQM) and Risk-Based Monitoring (RBM).

Many of the methods and technologies that researchers are already using in clinical trials will be simplified by the new ICH advice, especially when it comes to risk-based monitoring (RBM). The industry may anticipate guidelines on remote evaluation and observation, as well as a technical design that is flexible enough to accommodate both existing platforms and future developments, assuring trial integrity while removing the effort of confirming non-critical evidence.

Conclusion

Although many clinical researchers have yet to get accustomed to the ICH E6 R3 or implement it, the clinical importance of applying these guidelines will streamline research and produce more accurate and reliable results. Moreover, ICH E6 R3 will ensure inspection readiness ensuring no hindrance to clinical trials, which is why immediate implementation of ICH E6R3 guidelines are truly beneficial.

The process of building quality into the design of a trial can be arduous without the sound quality management system (QMS) in place.  Don’t have the time to ensure your system has the quality that exceeds compliance to the ICH E6 R3 standards?  Contact us and let us help you implement compliance strategies and a streamlined process for your QMS prior to the rollout! 

 

References

CITI Program. 2021. ICH Releases Draft Principles for GCP | CITI Program. [online] Available at: <https://about.citiprogram.org/blog/ich-releases-draft-principles-for-gcp/> [Accessed 15 March 2022].

ICH, 2019. Final Business Plan ICH E6(R3): Guideline for Good Clinical Practice. [online] Available at: <https://database.ich.org/sites/default/files/E6-R3_FinalBusinessPlan_2019_1117.pdf> [Accessed 15 March 2022].

ICH, 2021. ICH-E6 Good Clinical Practice (GCP). [online] Available at: <https://database.ich.org/sites/default/files/ICH_E6-R3_GCP-Principles_Draft_2021_0419.pdf> [Accessed 15 March 2022].

Mauri, K., 2021. Rewriting the Rules: How to Prepare for ICH E6 (R3). Pharmaceutical Outsourcing, [online] Available at: <https://www.pharmoutsourcing.com/Featured-Articles/579132-Rewriting-the-Rules-How-to-Prepare-for-ICH-E6-R3/> [Accessed 15 March 2022].

MY EXPERIENCE AS AN FDA INVESTIGATOR

I have been asked so many questions about my FDA career and what it was like working with the FDA.  I thought it would be best to write about my experience in an interview-based article according to the most frequently asked questions.

 How were you introduced to the FDA?

I was introduced to the FDA in my last year of college at Rutgers University.  As I was prepared for graduation and entering the workforce, I also attended as many job fairs as possible. I thought that submitting my resume to as many companies possible would increase my chances of getting hired after graduation.  Of all the numerous job fairs I attended, FDA was only present at one of them.   I met the FDA representative, who was also the District Director, had a great conversation with her and handed her my resume which was added to the stack of resumes from hundreds of other candidates.

How did you get hired to work for the FDA?

Getting hired to work for the FDA was not easy.  After graduation, I was determined to have a career relative to biology or similar scientific field and the FDA was one of top companies I wanted to work for.  I was very persistent in having my name and resume stand out from the others.  For months, I called the District Director every other day to check in and see if she reviewed my resume.   My persistence paid off.  A couple of months later, I finally received a call from the district office to come in for a face-to-face interview.

What was the hiring process like?

The hiring process was pretty rigorous.  The interview was a few hours long.  It included an overview of FDA and discussion about me and my experience (although very limited as a college grad). It also included a long list of case-based scenarios along with questions on how I would handle each case.  The purpose of these questions was to test my moral character, sound judgement and ability to protect confidential information. 

After being considered a potential candidate, I moved on to the next phase where there was the typical drug test, credit check and a detailed background check.  The background check not only included a criminal history check but a thorough investigation on me as person.  Not only were my past and current employers contacted and visited, but all of my neighbors from my current and past addresses as well!  

What was a typical day in the life of an FDA Investigator?

A day in the life of an FDA Investigator primarily involves preparing for and conducting inspections according to your specialty (Pharmaceuticals, Devices, Foods, Biologics).

Inspections can be as short as a few hours or as long as a few weeks depending on the size of the firm and complexity of the inspection.  Other tasks include handling and investigating customer complaints and recalls in addition to attending meetings and continuous training sessions. Overall, the job entails a lot of travel, but the majority of it is local. 

What’s the difference between FDA investigator and Inspector?

FDA Investigators (or Consumer Safety Officer -CSOs) differs from FDA Inspectors (or Consumer Safety Inspectors- CSI) in that Investigator positions requires a Bachelor of Science (BS) degree (usually in science or engineering) whereas the CSI position does not.

In addition, the role and responsibilities of an Investigator and Inspector are different.  Investigators are responsible for conducting domestic & international inspections and investigations in the areas of food/imports, pharmaceutical, biologic, BIMO and medical device; whereas Inspectors are responsible for performing import work which includes physically inspecting imported products in the aforementioned areas.   GCP/BIMO inspections, will always be conducted by an FDA Investigator.

Why did you leave the FDA?

Leaving the FDA and my colleagues was bittersweet.  I enjoyed working at the FDA but compensation was low (GS-5 which is $25K a year) as is expected for a government position.  At the time, there were so many opportunities in the industry looking for someone with my experience paying 2-3x as much, I could not say no.  I was curious to see what the industry had to offer.

Any regrets leaving the FDA?

Initially, I had regrets and wanted to kick myself for leaving, but as I started working in the industry and gaining more experience with CROs, pharmaceutical and medical device companies, my regrets started to dissipate.  I realized how valuable it was to work on “the other side” as it only diversified and enhanced my knowledge and experience.  If anything, continuing to work with the FDA would have limited me from seeing and understanding both perspectives.  Having the experience of seeing both sides (industry vs FDA) is truly priceless.

Have more questions? Feel free to contact me at info@2kclinicalconsulting.com

FDA vs EMA in Terms of GCP Inspections

The national and global regulations for conducting clinical trials involving human participants are known as Good Clinical Practice (ICH-GCP). They include not only quality criteria, but also regulatory guidelines to ensure that all newly created pharmaceuticals and medical devices have been clinically shown to benefit the health of the public.  The FDA and the EMA are two of the most important regulatory authorities involved in ensuring patient safety and data integrity, and here is some information about both.

FDA vs EMA

The United States Food and Drug Administration (USFDA) is a division of the United States Department of Health and Human Services. All investigative product and approved products  (drugs and devices) sold in the United States are reviewed, approved, and regulated by the FDA both domestically and internationally. The European Medicines Agency (EMA), on the other hand, controls the drug development process for all European Union member countries.

How do the FDA and EMA work differently?

Inspection Focus:

FDA Investigators will spend some time looking at generic processes, but their main focus will be on research activities. The overall approach will be to follow the Bioresearch Monitoring Program guidelines and check conformity on each study. While the EMA will analyze study details in their trial master file (TMF) review, their Subject Matter Expert (SME) interview will focus mostly on general processes.

Trial Master Files (TMF):

There is no particular FDA mandate for organizations to develop a trial master file in the United States, but if the regulatory body wants ICH GCP to be followed, then a trial master file must be created and maintained.

Inspectors from the EMA, on the other hand, will conduct a thorough and comprehensive assessment of the TMF and, with rare exceptions, will prepare to browse without assistance. TMF review will normally take up major time during the inspection. Moreover, these organizations anticipate that the majority of study documents will be accessible directly within the TMF and will be recorded in a timely manner. If a TMF is ready for an EMA inspection, it is probably ready for any other significant agency as well.

Document Review:

According to the EMA’s inaugural documents, the agency’s main goal was to recognize the importance of improving patient-reported health-related quality of life (HRQOL). The EMA’s patient-reported outcomes (PRO) advice focuses on numerous domains for generalized HRQOL assessment, whereas the FDA’s focus is on symptom-specific measurements. This distinction can be seen in the pazopanib approval documentation. While the EMA included HRQOL data from pazopanib phase III studies in its assessment, the FDA statement makes no mention of this objective.

Conclusion

The two most influential regulatory agencies, USFDA and EMA, assure us that we can trust the industry as their respective accomplishments become more transparent in improving current processes and safeguarding patients and the clinical industry’s future.

 

References

CTA. (2019, January 11). Observations from GCP sponsor inspections. Clinical trials arena. Retrieved October 11, 2021, from https://www.clinicaltrialsarena.com/comment/how-to-prepare-for-gcp-sponsor-inspections.

EMA. (2021, August 10). European Medicines Agency. Retrieved October 11, 2021, from https://www.ema.europa.eu/en.

NCBI. (n.d.). FDA in PMC. National Center for Biotechnology Information. Retrieved October 11, 2021, from https://www.ncbi.nlm.nih.gov/pmc/funder/fda/#:~:text=FDA%20is%20responsible%20for%20protecting,manufacturing%2C%20marketing%2C%20and%20distribution%20of.

NIRH. (n.d.). Trial Master File. Trial master file. Retrieved October 11, 2021, from https://www.ct-toolkit.ac.uk/routemap/trial-master-file/.

Shalby, M. (2018, August 3). Good clinical practice: FDA vs. Ema. LinkedIn. Retrieved October 11, 2021, from https://www.linkedin.com/pulse/good-clinical-practice-fda-vs-ema-michaela-shalby/.

3 Surefire Ways your TMF can extend your Inspection

The Trial Master File (TMF) is the backbone of the clinical trial. It consists of essential documents which not only enable the conduct of a clinical trial, but also enable the evaluation of the quality of data produced.

One of the questions asked at the beginning of an inspection is: “Where and how are your documents stored?”.  It is expected that all responsible parties know the location(s) of all paper/hybrid, and electronic documents that comprise the TMF.  Most importantly, it is expected that the TMF is readily accessible and audit-ready.

The reality is…this is not always the case.  In most cases, the TMF is often forgotten and becomes a disorganized “pile of files”.  As a result, inspections can be extended for this reason.

In fact, MHRA stated that that 35% of inspections were extended and required extra days particularly due to critical findings of TMFs.

Three (3) critical findings and surefire ways a TMF can extend your inspection are:

1. Lack of Access – The majority of time, the full TMF is not readily available or accessible to inspectors causing a delay in document review.

2. Poor Indexing – Oftentimes, the person designated to the TMF has issues locating documents during inspections due to poor indexing.

3. Incomplete/Missing Files – This is self-explanatory. Files that are inaccurate, incomplete or missing/misfiled can certainly cause a delay. Furthermore, uploading last minute documents to the eTMF (electronic Trial Master File) is a red flag as inspectors can see the download date and time of each document.

Sounds familiar?

Well, this can all be prevented with proper planning, as noted in our article Planning for TMF Success, and effective QC measures as discussed in the following Trial Master File training sessions:

The “Audit-Ready” TMF: Concepts & Strategies (basic)
The “Audit-Ready” TMF: Tools &Techniques to effective QC Reviews (intermediate)- COMING SOON
The TMF Challenge: Part of the IRS (Inspection Readiness Survival) Series (advanced)-COMING SOON

Inspection Preparation Concepts for Clinical Research Sites

The first thought that typically comes to mind when you hear about an upcoming FDA inspection at your site is the logistics– where to meet, document review, and your facility’s condition.  There are however, other factors to keep in mind for both on-site and remote inspections.

This article will briefly cover the basic principles of a GCP inspections and what clinical site staff should expect and keep in mind for future inspections.

FDA Investigators (commonly known as Inspectors) regularly visit clinical research sites to conduct inspections and ensure GCP requirements are being followed.  In fact, according to FDA’s inspection metrics, almost 800 BIMO or Bioresearch Monitoring  inspections are conducted  at clinical research sites every year (with the exception of the pandemic in year 2020).

What to expect

Whether an FDA Investigator conducts an on-site or remote inspection, he/she will need to show his/her credentials and show an FDA-482 prior  to discussing the inspection’s purpose, scope and  number of days according to the size and complexity of the trial(s) being inspected.

In general, the first day of inspection will also require the review of pre-inspection records, site files and subject files.  Interviews will also be conducted with the study personnel, such as the study coordinator(s) and the Principal Investigator to determine compliance to the regulations, protocol/investigational plan and other study-related procedures.

At the end of each day, the inspectors will do a summary of findings, as well as a general verification of their checklist to confirm if inspection criteria were fully covered and all requested documentation received.

The most important aspects that FDA Investigators  focus on are patient safety and data integrity. They will look at patient consents, adverse event/experience reporting, and anything that could potentially jeopardize the patient’s safety. They also ensure data integrity by confirming the absence of data transcription errors  and compliance to  the regulations, protocol and other study requirements according to CPGM (Compliance Program Guidance Manual) for Clinical Sites.

What to keep in mind

  • Plan Accordingly – Keep a checklist available to ensure documents are inspection-ready. site staff are adequately prepared and technology is properly working for provided access and sharing documentation (especially for remote inspections).
  •  Practice Interview Skills –During the interviews, it is important to inform your staff about the Do’s and Don’ts of interviewing including how to answer the questions asked by the inspectors. For example, all site staff should be prepared to discuss topics such as:
    • Training – Safety-related, Protocol, Case Report Form
    • Delegation of study-related tasks/PI Oversight
    • Subject recruitment
    • Informed consent process
    • Source documentation
    • Data entry
    • Investigational product or device handling

Interviewees only need to answer the question directly with no additional information. Moreover, if you don’t know the answer to a certain question, it is acceptable to say that you don’t have access to that information at the time and that you will get back to them with an answer later.

  • Don’t get defensive/ask questions – Be sure that none of your staff are getting defensive with the FDA inspector as this might come back to haunt you.
  • Ask for Clarification – If you need clarification or have questions about the findings reported by the FDA inspector, it is totally acceptable to point them out. However, defensive behavior is never a good idea.

Key Takeaway

Inspections are an important aspect of clinical research trials.  A proactive approach and consistent preparation from clinical site personnel at the start of a trial, results in a successful inspection at the end.

Need an Inspection Preparation checklist for your site?  Feel free to download our free Inspection Preparation Checklist as a preparation tool.

 

 

 

Location Matters…

What’s wrong with this picture?

On a typical workday, you may see nothing wrong with this picture…but place an FDA Investigator or other regulatory Inspector in this room, and you may it see differently. I’ve had the opportunity to work as an FDA Investigator working in the GxP (primarily GMP) world.  I left that career and transitioned over to the industry (AKA ” the other side”) in GCP starting out as a Clinical Research Associate (CRA).  

As an FDA Investigator inspecting all types of manufacturers, I was accustomed to reviewing documents in immaculate, spacious conference rooms.  When I became a CRA monitoring clinical sites, however, I had a rude awakening and was quickly humbled by my designated monitoring space. There were no spacious conference rooms…sometimes no room at all.  With some sites, I was placed in a small cubicle.  With other sites, I sometimes shared the busy desk of either the Principal Investigator, Sub Investigator or Study Coordinator. 

But the most memorable experience was when I was placed in the break room /copy/printer room where I shared a table with documents and binders from other trials and was entertained by interesting (and sometimes incriminating) conversations from site staff. 

At that point, I couldn’t help but reminisce on my prior career as an FDA Investigator thinking “Boy, would I have a field day if I were an FDA Investigator placed in this room!”

 But I’m no longer an FDA Investigator…I’m on the “other side” now, training others on audit/inspection readiness and providing tips on how they should prepare and set up appropriately for an inspection. 

Important tips to know when it comes to set up is to adequately prepare your staff and facility including inspection and support rooms.

FACILITY AND STAFF PREPARATION

When preparing the facility, for an on-site audit or inspection, select a private area, or conference room that has a phone and, a copy machine for document requests.  It is important that other areas such as work areas and printing rooms are clean and free of loose documents. 

Finally, support areas or affiliated departments such as the pharmacy and or laboratory should be assessed to ensure all documents and staff are inspection-ready.

Also post designated signs throughout nearby areas notifying others of the inspection to ensure all nearby conversations are minimized during the inspection.

INSPECTION ROOM VS SUPPORT/WAR ROOM

The Inspection Room should be a quiet, private and paper-free located near the Support/War Room.  This room should also be set-up with computers and screens for the FDA Investigator to review records and electronic systems used in the trial.

The Support/War Room which is a combination of clinical site and sponsor support, should be equipped with working electronics (such as email, printer, Instant Messaging) and dedicated to providing all needed documentation for the inspection.

KEY TAKEAWAY

In order to fully prepare for an audit or inspection, you must consider the rooms in your facility as part of readiness planning and preparation.  After all, LOCATION MATTERS!