On Tech Ethics Podcast – Modernizing Clinical Trials with ICH E6(R3)

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1. Introduction to the Episode (00:00:03) The host welcomes listeners and introduces Eric Kupferberg as a co-host.
2. Eric’s Background (00:00:14) Eric shares his role and experience with CITI Program and GCP curriculum revisions.
3. Introduction of Cindy Gates (00:00:39) The host introduces guest Cindy Gates and highlights her extensive background in research protections.
4. Purpose of ICH Guidelines (00:02:17) Cindy explains the International Council for Harmonisation and the significance of GCP guidelines.
5. Reasons for GCP Update (00:03:41) Cindy discusses the changes in clinical research prompting the update to the GCP guidelines.
6. ICH Guidelines Legal Standing (00:05:15) Cindy clarifies that E6(R3) is not law but important for drug approval processes.
7. New Responsibilities for Researchers (00:06:03) Cindy outlines updated expectations for researchers regarding oversight and documentation.
8. Changes in Informed Consent (00:08:29) Cindy elaborates on the new flexible approaches to obtaining informed consent.
9. Investigational Product Management (00:11:06) Cindy describes how investigational products are managed in decentralized trials.
10. Data Governance in E6(R3) (00:12:50) Cindy explains the new section on data governance and its implications for trials.
11. Impact of E6(R3) Updates (00:14:22) Cindy discusses the positive effects of the updated guidelines on clinical trials.
12. Resources for Learning About E6(R3) (00:16:39) Cindy recommends resources for further information on the changes in E6(R3).
13. Final Thoughts on E6(R3) (00:17:07) Cindy shares her optimistic view on the updates and their potential benefits for research.

Daniel Smith: Welcome to On Tech Ethics with CITI Program. I am joined today by my colleague and guest host Eric Kupferberg. Eric, can you tell us a bit about yourself?

Eric Kupferberg: Sure. I am the associate director of clinical research education. I’ve been at CITI Program for four years now, and recently been in charge of revising our curriculum from the GCP ICH E6(R2) to the GCP E6(R3). We’ve been very fortunate to have a number of authors and experts with us in this process, and I’m excited to be part of this podcast today.

Daniel Smith: Wonderful. Thanks, Eric. So our guest today is Cindy Gates, who’s an experienced leader in human subjects research protections and clinical research. Cindy has previously worked at WIRB, the University of California Davis, the University of Miami, the Houston Methodist Medical Center, and the George Washington University. Today we’re going to discuss the updated International Council for Harmonization Guideline for Good Clinical Practice, known as E6(R3), and what it means for researchers.

Before we get started, I want to quickly note that this podcast is for educational purposes only. It is not designed to provide legal advice or legal guidance. You should consult with your organization’s attorneys if you have questions or concerns about the relevant laws and regulations that may be discussed in this podcast. In addition, the views expressed in this podcast are solely those of our guest.

And on that note, welcome to the podcast, Cindy.

Cindy Gates: Oh, thank you, Daniel. I’m really happy to be part of this, and I’m excited about the new guidelines and can’t wait to talk about them.

Daniel Smith: Me as well. So I just very briefly introduced you, but for our listeners, can you just tell us more about yourself?

Cindy Gates: Okay. Well, I’ve been in human subject protections ever since I got out of law school. Before I became a lawyer, I was a nurse and I worked on the hospital floors, and I also served in management. But my first job out of law school was at WIRB, where I worked for 11 years, and I was the vice president for eight of those years. And like you said, I’ve been a leader in human subject protections at several institutions, so it’s been my life’s mission.

Eric Kupferberg: Fabulous. Cindy, can you provide us with a brief overview of the International Council for Hominization or ICH and the purpose of the ICH Good Clinical Practice guidelines?

Cindy Gates: Sure. The ICH or International Council for Hominization is a global partnership, and it’s made up of regulatory authorities and pharmaceutical industry groups. It was formed to ensure that drugs developed in one region of the partnership, could be approved and marketed in another regions without having to duplicate the trials in every region. And that’s where the Good Clinical Practice or GCP guidelines come in to make sure the trials are done correctly. They all want to follow the same guidelines.

And so these guidelines are the gold standard for how clinical trials should be designed, conducted, monitored, and reported. They’re all about protecting research participants’ rights and safety, while ensuring that the data we collect are reliable. In other words, the guideline provides standards that help balance ethics and the science.

Eric Kupferberg: It seems like it’s a wonderful organization with ambitious goals.

Cindy Gates: Oh, yes. Yes, it is, and E6 is just a small part of it. There are several other sets of standards for drug manufacturing and for the data reliability and stuff like that. So yeah, it’s always a work in process too.

Daniel Smith: So speaking of the guidelines, they have changed in the past and they just recently changed in light of technological advancements, regulatory changes, and evolving ethical considerations. So can you talk a bit about the specific reasons for the recent update to the ICH GCP guidelines?

Cindy Gates: Oh, yeah, that’s a great question. The recent update, which is known as E6(R3), as we said, it’s driven by the fact that clinical research has changed a lot in the last couple of decades. We’ve seen a huge rise in decentralized trials where the participants might not even step foot in a clinic, so everything is done remotely. Digital health technologies like wearables and electronic records have also had a big impact on clinical trials.

So the previous version of the guidelines, the E6(R2), it started to focus on these things, but it really didn’t truly address the new realities that we’re seeing in research. (R3) modernizes the guidance by promoting a more flexible, a risk-based approach to trial design and oversight. It also places more emphasis on quality by design. That means that researchers must build in quality from the very start before they ever enroll the first subject, rather than trying to fix the problems after they happen. In other words, they have to identify and address the risks of the research, and that’s the research itself or to the research participants, and the research glitches that might happen before the study ever starts so the trial goes much more smoothly.

Eric Kupferberg: It seems as though the new guidelines have the flexibility in mind for the current development of clinical trials. Can you tell us about the relationship between ICH guidelines and the FDA? Is E6(R3) law in the United States?

Cindy Gates: No. However, most sponsors would want investigators to follow the guideline if they want to get their drugs approved in the member countries. And so while it’s not law, there is this guideline and you should check your protocol in the contract to see if you’re required to follow it before you start your trial.

Eric Kupferberg: Thank you for providing that clarification. Can you tell us a little bit about the new responsibilities and requirements for the researchers under E6(R3)?

Cindy Gates: Researchers or investigators now have clear expectations around things like proportionate oversight, the way they delegate and train their research staff. And under (R3), they’re expected to focus their time and their resources on what really matters, the parts of the trial that may affect participant safety or data reliability. There’s also a bigger emphasis on documenting how responsibilities are delegated and ensuring staff are trained appropriately for their task. So it’s not just about being qualified, it’s about matching people’s skills to the complexity of the study and then being able to show that you’ve done all that.

And so another important update I think is to essential records and that’s very different than in (R2). These are the documents that support the trial’s conduct and the data’s reliability. (R3) broadens the definition, but then allows discretion in identifying the documents that fit within the definition of what’s now called essential records. It doesn’t give researchers just a list of documents that they have to have. Instead, it provides a list of considerations that help investigators identify the records they need to support the finding that the participants are protected and the data reliability. It helps investigators determine whether a specific document is an essential record too.

So (R3) emphasizes that records can be physical or they could be electronic, but it still stresses that they must be organized, they got to be traceable, version controlled, and secure. Investigators are expected to maintain clear documentation of where the records are stored. And they have to do that at the very beginning, and the sponsor has to have a copy of that. And that includes the electronic systems and the other documentation, so patient diaries, things like that. They have to assure that they’re accessible for monitoring and inspection. And it’s a more modern approach though, and it reflects how a trial really works today.

Alexa McClellan: I hope you’re enjoying this episode of On Tech Ethics. If you’re interested in hearing conversations about the research industry, join me, Alexa McClellan, for CITI’s other podcast called On Research with CITI Program. You can subscribe wherever you listen to podcasts. Now, back to the episode.

Daniel Smith: So I know another significant change in (R3) from (R2) are some of the new stipulations for informed consent. So can you elaborate a bit on that for us as well?

Cindy Gates: Sure. Informed consent gets an upgrade in (R3), especially when it comes to flexibility. The new guidelines acknowledge that consent can be obtained in different ways, including remotely, electronically, or in person, as long as it’s meaningful, concise, and understandable. The new (R3) kind of mirrors the updated common rule that you need to make sure the consent has the information that a reasonable person would need to decide whether or not to participate in the trial. There’s a stronger focus on tailoring the information to the participant by using plain language and even visual aids where appropriate. It emphasizes the need to document the consent process too, to demonstrate how the person conducting the process ensured that the participant understood the research at the time of consent.

We’ve always required the person obtaining consent to sign the document. That’s an ICH requirement, it’s not a regulation, but (R3) finally explains the rationale for obtaining that signature from the person conducting consent. It’s an attestation that the informed consent was freely given by the participant or their LAR, and the consent information was accurately explained and apparently understood. E6(R3) stresses the need to make sure that you have the right person. So you need a policy really on how to identify the participant, but you should document how the participant’s identification was confirmed to how the participant’s understanding that the research was assessed.

Eric Kupferberg: That’s fabulous. It seems like there’s a number of changes there. I always wondered, does the participant need to be physically in the same room as those that are conducting the informed consent?

Cindy Gates: No. Under ICH E6(R3), remote consent is allowed, and it can also happen, especially with these decentralized trials. Of course, the IRB needs to approve that remote process, and there’s also FDA guidance for people in the US that the way the consent should be handled remotely.

Eric Kupferberg: That’s a terrific innovation. Speaking of innovations, what are the new guidelines for the investigational product management? That is the study drug, biologic, device under research.

Cindy Gates: Because of decentralized trials, a lot of times the investigational product goes directly to a clinic that’s outside of the research center, or it may go directly to the participant’s home and could be given to the participant by a contracted provider, not necessarily the normal research staff. So the management of investigational products now has to be a risk-adapted approach depending on where the product is going, how it’s being transmitted there, and who’s going to dispense it or administer it to the participant. If a product though was already well understood and approved for other indications, routes, or populations, the investigator might not need the same level of monitoring. So again, it’s risk based on the drug, where the drug’s being transmitted, and whether or not the drug already has safety data behind it because it’s been already approved.

The guidelines clarify responsibilities around storage, labeling, accountability, and shipping in these decentralized or hybrid trials where the product isn’t delivered, but it could be delivered directly to the participant’s home. In these cases, the researchers need clear procedures to maintain the integrity and safety of the product that’s being dispensed and administered. Like if you have a contracted provider, the investigator must have access to the documentation from that contractor, and that’s something that needs to be contractually established.

Eric Kupferberg: Cindy, there’s an addition to (R3), this section on data governance. Can you tell us a little bit about what data governance is and what it means for (R3)?

Cindy Gates: Oh, sure, yeah. The data is what you need as the result of the trial. That’s what regulators look at to ensure that the trial was done correctly and the data reliable, the participants were protected according to the ethical principles. And so it used to be, and it still is somewhat, the issues to consider about the data were in the investigator section, the sponsor section, et cetera. But now there is a section solely on data governance, and it talks about the life cycle of the trial and what data you need to support the trial and how you maintain it.

And it really goes into computerized systems, and it talks about how you implement a system, what standards you need to follow in the system, and you have to have validation. It’s similar to 21 CFR Part 11, but it’s easier to understand and read. I think it’s a big benefit that they’ve added this section. That with the section on essential records is very clear about what the data should look like, how it should be maintained, and how people should access it.

Daniel Smith: So Cindy, these updates are meant to provide more flexibility to investigators, particularly as clinical trials have evolved and technology has evolved and provided them with more options. So broadly, what impact do you think this will have?

Cindy Gates: I believe the positive impact is going to be, again, some of the flexibility, but the list of considerations that investigators should have when they’re developing their SOPs or their procedures for a specific study. E6(R3) now describes the ways to secure the data, whether it be a paper format or electronic format. And it also describes the life cycle of the data. And that is some guidance that I think that investigators have struggled with is how do you maintain all this data and have it ready for the regulators, and especially when we’ve gone to electronic data? So I think that’s a really big plus with this version of E6.

And also, I think the additions to the consent process and to the training. It gives the investigator so much flexibility with training where E2 said you needed a qualified doctor or dentist to attend to the medical needs of the subjects to treat AEs and et cetera. Now it says, “Or other healthcare professional.” So it recognizes PAs, ARNPs, and other professions that can take care of participants when they have adverse events.

Again, like I said, it’s the flexibility, but with the list a considerations, things that we should consider. And there’s a lot of new principles at the beginning of the E3 that provides, here’s what the standard really is, and then later in the guidance, it kind of gives you some ways to meet that standard. So again, the main benefit is that it provides you a list of principles that you’re supposed to meet and follow, and then it gives you the considerations and other points that you need to meet that ethical principle.

Daniel Smith: Certainly. You’ve done a really wonderful job today of succinctly summarizing the changes for investigators and also the positive impacts that these changes will have on their work. But for our listeners who are interested in learning more, do you have any recommendations for additional resources that they can check out to learn more about E6(R3) and the changes we’ve discussed today?

Cindy Gates: Oh, definitely. The ICH website, it’s a good place to start. They’ve published the full E6(R3) guidance along with background materials and some of the public comments, but that really is a lot of reading. For more in-depth training, I really think CITI has a great resource that it breaks down all of these complex topics into much more practical guidance.

Eric Kupferberg: Cindy, do you have any final thoughts that we’ve not touched on today?

Cindy Gates: Well, just one, I guess. These updates really are a good thing, and I know that change can be a little daunting for everyone, especially when it comes to compliance. But E6(R3) is really about making research better, making it more efficient, more ethical, and more inclusive. It’s encouraging research to focus on what truly matters rather than checking boxes like we’ve been doing. And if we can make more trials more participant centered and easier to run, we’ll get safer treatments to the people who need them faster. So I believe it’s progress, and I think it’s exciting.

Daniel Smith: And that is a wonderful place to leave our conversation for today. I also invite everyone to visit citiprogram.org to learn more about our courses, webinars, and other podcasts. Of note, you may be interested in our new ICH E6(R3): An Introduction course, which further examines how the changes affect the responsibilities of investigators, sponsors, and institutional review boards. In addition, as Eric mentioned earlier in this conversation, we’ll be rolling out E6(R3) updates to our Good Clinical Practice and other content in July of this year.

And that is all for today. A special thanks to our line producer, Evelyn Fornell. Production and distribution support provided by Raymond Longaray and Megan Stuart.