How to Interpret and Implement FDA Guidelines for Biologics?
Emily Le:
Hi everyone I'm Emily Le from PEGS Boston Events. I'm really pleased to have the opportunity to speak with William Hallett, Product Quality and Immunogenicity Reviewer from the Center for Drug Evaluation and Research at the US Food and Drug Administration about updates on FDA guidelines for novel biologics, interpretation and implementation, who will be giving a talk in the implementation of regulatory guidelines session at the 14th Annual PEGS Boston Summit on Wednesday, May 2 in Boston.
Will, thank you for joining us.
William Hallett:
It's my pleasure.
Emily Le:
Can you outline what you consider to be some of the greatest obstacles to access immunogenicity of biologics?
William Hallett:
Sure. I would say that it's kind of old hat for most people who do assay development, but we still seem to have the biggest issues with assay sensitivity and drug tolerance. These seem to be the two most important characteristics of assay validation that seem to give our sponsors a lot of headaches. Probably right behind them is having an appropriate cut point, which includes both the method of determining the cut point and also making sure that the population used to generate the cut point is appropriately justified.
As many people know, our guidance for assay validation has changed recently, or is in the process of going through draft right now. Those are being lowered and that is causing a lot of people some heartache. But we're willing to work with people and talk about that a little bit more later.
But, assay sensitivity is really secondary to what the drug tolerance is, that many of these products have very long serum half-lives and they stay around for quite a bit of time in the sampling time points of the assays the samples are being drawn from. There's a lot of drug in the system and having a sufficient drug tolerance that we can feel confident that a negative result is truly a negative and not an inference from the on board drug is really important.
For the cut points, we've been, we've tried to be fairly consistent in the FDA about having a 5% false positive rate for the screening cut point with a 1% false positive rate for the confirmatory and neutralizing assays. And I would say that, for the most part, most sponsors are following that, be we still have a lot of people still using a 0.1% false positive rate. And it's not that that's wrong, there's nothing right or wrong about this, it's just that we feel that's it probably a little bit more space than is really needed to call things positive and so we're really asking sponsors to try to stick to that 1% rate for the confirmatory in the neutralizing assay.
Emily Le:
So, it's really interesting that you brought that up about the lower cut point in assays. Could you comment on what might be the reason behind the new requirement for a lower cut point in assays?
William Hallett:
Sure. It's a complex problem and we've seen some data from some sponsors that has shown that at levels around 100 nanograms per ml, that you can start seeing impacts on the administrate therapeutics. Changes in efficacy, changes in the PK can occur, even with very low levels of ADAs. So that's kind of where a lot of this started from. We know we're starting to see ... The goal of the AD assay to detect ADAs before they're a problem, not when they're already overtly a problem.
However, they're already almost a problem at the 100 nanograms, there could be argument to say go even lower. That's not a threat or anything but we are always trying to make sure that we're catching these ADAs before they become a problem. We're starting to see some impact of them, even at these low levels, as the assays gets more sensitive.
And that's kind of the other part of it, is when the old guidelines were written, the technology that we have today just didn't exist or wasn't as developed as it is now. As the technology has moved, a lot of our sponsors are getting down almost into the picogram level of sensitivity and from that we know that many of our sponsors have already been achieving these kind of rates for several years now. And so it's kind of more of an expectation that's not because something has changed in the science, but more just, it's what we're seeing that a lot of people are already kind of already there. And the people who are maybe, who are not there, were kind of asking them to target this type of sensitivity.
And that gets kind of into the most important part, the 100 nanogram is not a hard rule where if you're at 150, 250, 300 or 400, that you're going to be put on hold. It's kind of more of a target. This is where we'd like you to push your development team to try to see if they can get their assay down to this level. But if you've gunned the development and your assay just can't hit that kind of level, and you can provide us justification on why you've tried it, you've developed good controls and the controls aren't getting there, the technology is just not quite there that you're using, then higher sensitivities can be justified and we'll take that.
Emily Le:
So you have been a reviewer for many years, and so could you share with us some of the things that you've learned about the difficulties of reviewing different biologic platforms?
William Hallett:
Sure. I think at the FDA, especially in the Office of Biotechnology Products, we see, obviously, a lot of monoclone antibodies. And I think for the most part, we're getting now a pretty good handle on what to expect from these monoclonals, but there's always still new things that are kind of popping up about these molecules that maybe we didn't appreciate before that we're gaining a new appreciation for now.
So while we're pretty comfortable with monoclonals, what we're less comfortable with are these new therapeutic things like bi-specific antibodies, anti-drug conjugates, nanobodies. Some aspects of these molecules fit really nicely into our expectations for ADAs, but there are a lot of nuances of these products. Like their degradation profiles, how ADAs, anti-drug antibodies, impact these molecules that we're still kind of learning on a case by case basis.
So what would be helpful to us in the FDA is, often the sponsors have a ton of development data about these products and they might be able to share some insight with us. And so, while what we've seen so far, compared to things that monoclonals, we haven't seen that much. And so, these new, novel, molecules are something that we're still learning from and are eager to get more information on.
Emily Le:
So in the world of biosimilars, how do you think we can start accelerating biobetters to the market?
William Hallett:
Biobetters are certainly a really complex issue to handle. In biosimilar space, things that we're looking for that are a really well thought out analytical similarity plan, is really helpful when you're trying to compare it to another molecule. There are obviously many characteristics that you could look at for whatever molecule it is, but when you're doing your comparison, you're going to put into which tier, which type of analysis you're going to do. If you've got that development already squared away before you come to us, it'll really speed things up as opposed to us having to go back and forth trying to negotiate what the right assessment is.
From an immunogenicity perspective, having an assay that's sufficiently sensitive with really good tolerance and sufficient sampling time points is very helpful. If you're doing a comparative study where you have, for instance, maybe just a single dose and maybe only one sampling time point post administration, and you have high onboard drug and you have a lot of samples that are inconclusive at the time of sampling, it's gonna be really hard for us to talk about how the product is from a bio-similarity perspective. And so, having good assays with a good drug tolerance and having sampling time points that are sufficiently far out and multiple time points that if one is not good, maybe they rely on other ones, to look for data between the two products would be very helpful.
Emily Le:
So, what kind of advice do you have for the industry in biologic development to accelerate FDA approval?
William Hallett:
Well I'm happy that all of our sponsors do a really excellent job of getting all their data together. But all of them also have kind of a very different approach to how they like to lay out their data. And I think it's maybe hard to understand is that it can be very difficult for the reviewers to find the information they need because they could be found in many different parts of the application. Especially in immunogenicity, where you have assays over here, and you have the clinical results over there. And they don't always reference each other as clearly as they could. So, with that in mind, a well laid out BLA or exceptionally clear meeting package really goes a long way to making sure that we understand exactly what questions you're asking, what the relevant information is, what the important factors you want us to consider are.
If we have to go hunting for things, we're probably going to miss things. And that will result in miscommunication, it'll result in additional meetings, more communications and will just slow your process down. So, with that in mind, a comment that we've been giving to some of these sponsors that were, have been talking about it at some of these conferences recently, is this whole idea of an integrated summary of immunogenicity, which asks the sponsor to develop their own integrated summary that talks about all the various factors of immunogenicity, including things that ... And it'd be a living document that you could have from early development all the way through licensure and it would talk about the, usually the risk of the product, details on the tiered strategy that you're using in your clinical program, have all the links to the method development validation reports for any assays that used throughout development. Your sampling plan for which studies and immunogenicity assessments performed as part of them. Summaries of the results for all of the clinical studies, including the impacts on PK, PD, ethically safety. And finally, the traceability of drug products that are used.
And having this all in one place really helps the immunogenicity reviewers, which includes multiple disciplines. It includes clinical reviewers, the assay reviewers, the clinicalpharm reviewers. We're all kind of looking at the same data, different parts of it. So having it all in one place where we can all see all the relevant information in one place has been extremely helpful. And some of the sponsors who are doing it, it works great for us.
Emily Le:
Alright. Well those are all great recommendations. Will, thank you for your time and insights today.
William Hallett:
Your welcome.
Emily Le:
That was William Hallett, Product Quality and Immunogenicity reviewer from the Center for Drug Evaluation and Research at the FDA. He'll be speaking in the immunogenicity assessment and regulatory approval of biologic track at the PEGS Boston event this May. If you would like to hear him in person, go to pegsummit.com for registration information and enter the key code “PODCAST”. I'm Emily Le. Thank you for listening.