With ICH E6(R3) Draft Due in Early 2022, FDA Official Fields Questions from Impatient Industry
After months of speculation that the public draft version of ICH E6(R3) would land in January 2022, an FDA official confirmed that ICH is on target to meet that timeline despite months of COVID-19 delays. M. Khair ElZarrad, FDA’s acting director of the Office of Medical Policy and the agency’s rapporteur for the revision, said last week that the long-awaited guideline will be out in early 2022.
ICH E6(R3), along with E8(R1), will usher in a large-scale shift toward greater efficiency and a focus on quality in trials when the guidelines are finally released and implemented by regulators globally, ElZarrad said.
More than 130 people attended last week’s session on the pivotal, highly anticipated guidelines at the 4th Annual WCG Metrics Champion Consortium Clinical Trial Risk and Performance Management Collaborative vSummit. CenterWatch Weekly selected the most compelling questions that ElZarrad tackled during that session:
Q: Are there any plans to establish a platform for FDA to share some examples and lessons learned after implementation of ICH E6(R3) begins and the agency starts looking at programs/conducting inspections?
A: We are working really close with our colleagues at [the FDA’s] Office of Scientific Investigations. Around our discussion on implementation, we believe that engagement and sharing information is going to be critical … for mutual learning. There are multiple venues we can explore for that, but that’s definitely part of the discussion. We believe implementation is going to require a very solid engagement and mutual learning, so yes, I think that’s a focus of ours.
Q: One of the areas from ICH E6(R2) that the agency has struggled with is quality tolerance limits (QTLs). Will R3 help the industry with approaching QTLs, their definition and their use?
A: That’s another topic we’re looking into as well. You have to keep in mind that what I’m saying here is [for] a draft document that is continuing to evolve, but that topic did come up, and I think … you have to look at it in the context of E6 as a certain high-level document. The question is, where can we touch on [QTLs]? How can we provide a little bit better clarity on QTLs in general? Yes, it’s part of the discussion, and I’m hoping we can be helpful in that area. I cannot say for sure, being one member of the [working group], [but] the topic itself is something we’re considering.
Q: Will ICH E6(R3)’s concept of proportionality apply to simplifying the informed consent form (ICF) documentation both for initial consent and even more for updated consent?
A: I think it’s going to depend. I think we use proportionality to be an umbrella term across all processes to highlight that you really have to have that proportional approach, you know, any kind of measures that make that correspond to the risks to participants and the risk to data. I think that’s the overarching umbrella here. I think … the risk to participants is paramount, probably the No. 1 thing you have to think about.
Q: Do you have any comment for sponsors who believe their studies are too small to benefit from a risk-based approach?
A: This is something we generally discuss in-depth, too. If you’re saying your study is too small for a risk-based approach, that might be the case. It depends, [but] isn’t that by itself a risk-based approach? I think that’s something we’re very conscious of. I think what we need to think about is, did you consider the risks for the trial and how do you address those risks? That’s, I think, the proportionality aspect here, and the way I see it, if you determine that your trial is too small … and you made that calculation, that’s also an indication of a risk-based approach, at least to me.
Q: Can you explain what constitutes trustworthy, medically sound and reliable data, especially in the context of the rapidly evolving digital ecosystem and the growing ways we are generating evidence?
A: We mention reliability of results quite a bit and we had quite a bit of discussion here. I want to separate that from a larger discussion on trustworthiness, especially with the use of real-world data, for example. I think we have a ways to go defining what we mean by ‘trustworthiness’ with the use of different data sources. I think E6 is going to touch on some elements here, but … it’s not going to be everything for everybody. I think building the parameters better around what we mean by trustworthiness, the reliability, I think that’s the critical aspect.
Q: Many companies are investing a lot into implementing and improving risk-based monitoring (RBM) on the backend of their trials, but what isn’t changing rapidly is the protocol and electronic data capture (EDC) system design. What other guidances can be provided on simplifying both? Is there enough guidance for protocol writers and EDC designers to achieve that?
A: Maybe we don’t have enough guidance, enough clarification around that, and I will take that back [to the group]. I think we’re … touching on a global issue here on how to see the full picture, full spectrum, and address all parts of it at the same time. I do agree, I think we need more of a connection across the process, including the EDC design aspect. I need to talk to my colleagues, probably, to see what areas we’re already identifying vs. what we may need more clarity on. The investment in RBM, it fits within the larger context of E6(R3), but we need to do a better job of connecting the dots, linking the process.