Proposal for a Liver Safety Research Consortium - aasld.org 4B_5... · Proposal for a Liver Safety Research ... Just an example of the kin對d of data I think if we could even just
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Paul B. Watkins, M.D. April 15, 2013 Proposal for a Liver Safety Research Consortium
DR. REGEV: Okay. And for our last speaker for this session Dr. Paul Watkins is a professor of medicine, pharmacy and public health at the University of North Carolina. He's well known to everybody here. He's also the director of the Hamner Institute. And he is a well known and well published DILI expert. And he will talk about a proposal for a liver safety research consortium. Paul. DR. WATKINS: Great. Well thanks for everybody who's still here. And as last speaker and as last speaker I'd like to lead everybody in a round of applause for John and Lana. (Applause) DR. WATKINS: They nailed it once again. It's always the highlight of the year for those people interested in drug-induced liver injury. I know, John, it's a huge effort and a labor of love. And what I'm going to talk about is really an outcome of the great efforts that John has put into these meetings.
A “Liver Safety Data Warehouse” exists now:
more… from Ted Guo - FDA
Presenter
Presentation Notes
We heard about the ECG data warehouse. And actually in a sense a liver safety data warehouse exists as well. That's what John and Ted Guo really as renegades without any permission as far as I know just started doing in the FDA. But then it caught on because it was so brilliant and sensible. So there are now I'm told over 100,000 subjects with serial liver chemistries in the eDISH program, a variety of different drugs, a variety of different indications, comparators, placebos. And the eDISH program is becoming incorporated into other things like the HCB database that's being built. And the real issue is is this always just going to be something people behind the FDA firewall are going to tell us what they found, or is this data, is it possible as happened with the ECG warehouse, can this get the benefit of the best other minds in the world to think about what these data are showing us.
Figure from M. Merz
Baseline vs. Peak serum liver chemistries in a clinical trial
Presenter
Presentation Notes
I'm sorry you can't see this. I actually had a blowup slide but for some reason it didn't come out. This is actually Michael's slide version similar to one just showing the baseline ALT versus the peak ALT in a clinical trial, with alkaline phosphatase,and AST. And then down at the bottom, I know you can't see it very well, are the placebo treatments. So you're looking at the baseline liver chemistry versus the peak liver chemistry. Something simple with a small number of people I think has some interesting observations. So for instance, in the lower right quadrant you can see that first of all the upper limits of normal is the green line across there. In the placebo groups most people are within the upper limits of normal in this study. But of course the peak ALT will be higher than the baseline because in multiple measurements. It appears that the higher your baseline ALT the higher the increment to your maximum ALT. In other words, it isn't that if you start off at 40 your variance is still, say, 5 units and when you start off at 10 it's 5 units. If you start off at 10 it's a much lower increment. And I don't know what this is telling us but I have a feeling it's fascinating data. I mean is the actual content of ALT per liver cell? What's the variable that's a normal variation? Is it variation in clearance of ALT I would argue this is the kind of data that would support using full baseline versus full arbitrary upper limits of normal in assessing liver safety. Just an example of the kind of data I think if we could even just get the placebo arms from this database and start critically analyzing it there would be a lot of insights.
Conclusion
An unprecedented wealth of liver safety data is in eDISH The insights from analysis of these data could be substantial Access to the data in a precompetitive effort will require individual company approval (and maybe more).
Key Objectives of the Cardiac Research Safety Consortium
1). To facilitate focused pragmatic research that will inform regulatory processes with regard to cardiac safety. 2). To develop expert consensus around common nomenclature, standards, and key definitions, and to draft white papers in challenging areas, describing what is known and unknown, and proposing paths forward to address such knowledge gaps. 3). To develop knowledge and strategies intended to improve the evaluative sciences in relation to cardiac safety and product development. 4). To coordinate “think tanks” and other programs and public forums for open discussion and updates on topics in cardiovascular safety pertaining to drug and device development.
Presenter
Presentation Notes
This is right off the Cardiac Research Safety Consortium website, their four main goals. Facilitate focused pragmatic research that will inform regulatory processes with regard to cardiac safety -- liver safety -- develop expert consensus around common nomenclature standards, key definitions and to draft white papers in challenging areas describing what is known and unknown and proposing paths forward to address such knowledge gaps. To develop knowledge and strategies intended to improve the evaluative sciences in relation to cardiac safety and product development. To coordinate think tanks and other programs and public forums for open discussion and updates on topics in cardiovascular safety pertaining to drug and device development.
Think Tank Incubators launched for:
Safety of Atrial Fibrillation Ablation Initiative (SAFARI) Dual Anti-Platelet Therapy (DAPT) Study CSRC-HESI preclinical cardiac safety evaluation TransRadial Education And Therapy (TREAT) II Program Study of Access Site for Enhancement of PCI for Women (SAFE-PCI For Women) Diabetes Mellitus and Cardiac Safety CSRC Blood Pressure
Thirteen white papers published in the American Heart Journal.
CSRC Accomplishments
Presenter
Presentation Notes
And so what they've been able to do with these think tanks has gone far beyond just the analysis of data and the ECG warehouse. You can see the Safety of Atrial Fibrillation Ablation Initiative, dual anti-platelet therapy, a study CSRC-HESI, pre-clinical cardiac safety evaluation. I won't go through them. But they've obviously gone far beyond just looking at the ECG warehouse. And there have been 13 papers now published that are sort of position papers in the American Heart Journal and I think have had very significant impact.
Introductions, opening statements and presentations
Introduction, expectations towards liver safety best practices
Paul Watkins, Hamner IDSS Michael Merz, Novartis
Chairs: Neil Kaplowitz, USC Arie Regev, Eli Lilly
08:30 - 08:40
FDA's approach to liver safety assessment: current status and challenges
John Senior, FDA Mark Avigan, FDA 08:40 - 09:15
Comments from the FDA Guidance on DILI
Arie Regev, Eli Lilly 09:15 - 09:20
Liver injury causality assessment: US and European perspectives
Leonard Seeff, FDA Guru Aithal, Nottingham U
09:20 - 09:50
Linking phenotypes to biosamples: biobanking issues
Paul Watkins, Hamner IDSS 09:50 - 10:15
Introduction to breakout groups Paul Watkins, Hamner IDSS Michael Merz, Novartis
10:15 - 10:25
Coffee break
Parallel breakout sessions
Data elements essential to assess clinical liver safety, data standards, data acquisition
Chairs: Mark Avigan, FDA Einar Björnsson, Reykjavik U
Methodology to manage liver safety data (eDISH, others)
Chairs: Paul Watkins, Hamner IDSS Michael Merz, Novartis
Methodology to assess liver safety from data with special considerations (cancer, hepatitis trials)
Chairs: Neil Kaplowitz, USC Dominique Larrey, Montpellier U
10:40 - 12:25
Lunch break Report from breakouts, discussion, next steps
All Chair:
Paul Watkins, Hamner IDSS
13:10 - 14:55
Closing remarks Paul Watkins, Hamner IDSS Michael Merz, Novartis
14:55 - 15:00
Boston Meeting November 9, 2012
Presenter
Presentation Notes
You saw this before, the program put on in Boston on November 9th. I apologize that not everybody was aware of it. The original plan was to do this with approval of the American Association for the Study of Liver Diseases that was having their annual meeting there. It was a convenient time when experts were meeting in Boston, but unfortunately the president told Michael and me that there were only two ways to do that: One, to pay them $50,000 so that it could be advertised through the AASLD, and the other was to request formally this to be a program on the AASLD agenda, the earliest that could come about would be in fall of 2014. We weren't willing to wait so long, so we did it anyway but we had to find a place -- actually a room in the basement that we had to do it. One issue was to just get at the data that already exists, which may require companies to agree to send their placebo or comparative data in parallel fashion, as it goes to the FDA. It may not be possible to directly get this from the FDA. Ted Guo, John and I about two years ago went to the SAS company, which you may know has a great interest in developing software to analyze large clinical databases, and proposed that they support eDISH and support a liver safety data warehouse. At the time they weren't interested; it may be different now. I think now that they're developing a commercial product that might be an option for us. In any event, I think their reasons and my own particular interest go beyond that, which is really the necessity to standardize across the industry collection and management of phenotypic data for drug-induced liver injury and connect it in a standard way to biospecimen collection.
Presenter
Presentation Notes
The first thing is DNA, and this is the guidance that just came out in January from the FDA on pre-market evaluation. It says of early-phase clinical studies, but actually appears to be for all clinical development phases, with recommendations for labeling and clinical pharmacogenomics.
Excerpt from Guidance
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Presentation Notes
It says that because historically many pharmacogenomic relationships have been identified several years after the drug has been marketed, DNA should be retained in the event that new genomic issues arise after the completion of studies, when possible under applicable laws, regulations and ethics committee policies. Samples should be retained for a time period that will permit post-market analysis should the need arise, that is, at least 15 years. So that's the current recommendation.
Examples where retrospective analysis of banked DNA bank revealed DILI risk alleles
Ximelagatran - Kindmark, A., et al., Pharmacogenomics J, 2008. 8(3): p. 186-95
Lapatinib - Spraggs, C.F., et al., J Clin Oncol, 2011. 29(6): p. 667-73 Lumiracoxib - Singer, J.B., et al., Nat Genet, 2010. 42(8): p. 711-4.
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We know there are example where very latent development or even post-marketing severe liver injury liabilities have been discovered in drugs, and only because the company was saving DNA and archiving it was it then possible to go back and find genetic associations, risk alleles for more minor liver injuries. In some cases that was actually not felt to be a significant problem. And then show in those few cases post-marketing where they could get DNA that the risk factors identified in the clinical trials actually were present, the risk alleles, in the people with severe liver injury. And other things that we mentioned before like the actual phenotype of the mild injuries mirrored the phenotype of the severe injuries later. That was certainly true with lumiracoxib where they actually used this risk allele to propose reintroduction on the market. It was also true for ximelagatran, although the drug was dead. And lapatinib was actuallyapproved in Europe,,then discovered to cause idiosyncratic liver injury, after which genetics were done in ongoing studies.
Future DILIN (SAE) genetics paradigm
Cases of severe DILI captured in networks. Company has archived DNA from Phase 3 Clinical trial allowing genetic analyses guided by biomarker changes
Presenter
Presentation Notes
The Drug-Induced Liver Injury Network has of course for 10 years now been collecting clinically important cases of drug-induced liver injury. Raul Andrade and others internationally are doing similar things. We will find your severe liver cases. We have six Ketek severe cases, including two of the three original liver failures that were in the Annals of Internal Medicine. I think the NIH-funded academic program is probably going to have a lot easier time finding these cases. It's been a lot easier for us to get complete phenotypic information including the ability to re-contact these individuals and offer them additional studies. So we will be doing what happened with lumiracoxib. And it's your job to see that you have saved the DNA in an organized, standardized fashion linked to the appropriate phenotypic data to easily do genetic studies.
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eDISH – evaluation of Drug-Induced Serious Hepatotoxicity
Drug Safety,34(3)243-52, 2011
Presenter
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And the potential is really enormous. What's going on with some of the software companies right now is building in statistical packages for clinical trial analysis. They have copuied the ability in the eDISH plot to just point to individual points and actually see serial liver chemistries over time. The new programs can actually draw a loop around them and use for controls of people whose ALT never went over upper limits of normal, press a button and do a statistical analysis on, say, CYP2D6 genotype, or ultimately whole genome sequencing or genotyping in a GWAS format.
Time Course of Liver TestsPatient #1234, caucasian male 80, Drug X
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Courtesy John Senior
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This is an example. Of course if you click on an extreme case, and it's a famous case from John, the drug X where the patient obviously developed a delayed severe hepatocellular injury. And I like this case because it points out the dangers of Hy's Law. Because this particular patient didn't show Hy's Law alert criteria, at first; the bilirubin didn't rise until a couple of weeks after he actually had stopped taking the drug, and the patient died in less than two months.. So following people's ALT in a clinical trial waiting for the bilirubin to go up is generally safe, but not always safe. And so there's an argument that the dual bilirubin-ALT is not just a biomarker of potential for serious liver injury. It may be life-threatening liver injury.
Time Course of Liver TestsPatient #1234, caucasian male 80, Drug X
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Courtesy John Senior
Hy’s Law
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The only reason I say this is there's no alternative now but there's intense interest in finding biomarkers that you could use earlier in the course of the liver injury or possibly even before it to tell whether a drug has this potential or not. And that's what Mark was talking about. There's great effort. The IMI has the SAFE-T Initiative, around a 35 million Euro effort, to come up with robust assays for a variety of novel biomarkers including mechanistic biomarkers that can be done in small volumes of serum. And the problem is in order to qualify and validate these things is going to be a very large effort. It will take looking at a lot of different patient populations, drugs that are safe but cause ALT elevations, those that cause ALT elevations that aren't safe. And so the important thing will be to standardize across the industry how do you manage the data, again the right phenotypic data, and not just link it to DNA specimens but link it to archived at least serum collections for it. For instance, you could imagine that you would know very easily going back even years later that you have stored serum at various times on the graph.
Summary A Liver Safety Research Consortium is being established aided by the Duke Clinical Research Institute that manages the CSRC It will have parallel goals to the CSRC. Like the CSRC, it will require modest resources.
Presenter
Presentation Notes
In summary and in closing, a Liver Safety Research Consortium is being established. Duke, which runs the Cardiac Research Safety Consortium initially had agreed to support this and actually have it together organizationally with the Cardiac Research Safety Consortium, but their attorneys decided there wasn't anything in it for Duke. But they've agreed to share all the lessons learned and the legal document templates for access to data. I think the goals will be parallel to the CSRC. It will require modest resources. Michael and I learned that you can avoid peer review if you're willing to pay $17,000 to the Journal of Drug Safety for a supplement. That way you can get everything all in one journal and the target is this fall. But obviously resources are required to do this. And to do it right it will take human resources from companies willing to put in the effort to be part of working groups and to generate future white papers. So with that I'll quit. (Applause)
