We had a great webinar session last week on presenting safety parameters for early detection of potential organ toxicity. Based on the participation level and types of questions, it was clear that this topic resonates throughout the clinical trials industry. We have highlighted some of the insightful responses Dr. Botham and Dr. Patru provided during the Q&A portion of the webinar:
Is there any guideline or defined limit of ALT/AST level beyond that there could be risk or safety issue?
Essentially it’s ATs 3x ULN (3 times the upper limit of normal). The FDA will ask how many were at 3x ULN in a study, and also 5 and 10x ULN. The main issue isn’t just one patient, but an increase in frequency between patients – that’s a real signal that there may be a risk of toxicity associated with that drug. We encourage you to access the FDA guidance document, which provides valuable information on these parameters.
What percentage of patients in the active group should have elevations in transaminases above 3x ULN to consider it as a signal for liver damage?
Unfortunately there’s not a clear answer for that because it depends entirely on the specific trial within the patient group. Sometimes 3x ULN is not useful if the patient population already has elevated liver profiles. In those cases, it is necessary to look around two times the baseline levels. Primarily, we would be looking at combined increases of the amino transferase and bilirubin across the patient population. One case of that showing in the database is indicative, but the appearance of two cases where there no other cause for these signals essentially means there will be a frequency of DILI that will result in pre-marketing withdrawal of that drug.
In study data analysis, how significant is mild and transient (one time lab value, non repeatable) transaminase elevation compared to a repeatable one?
This depends on the patient, circumstances and the extent of elevation. We find people broadly fall into, three groups: tolerators, who even in the case where a drug may be toxic, will appear absolutely fine; adapters who will initially show a very transient increase and then drop off and return to normal; and then lastly, there are those who are susceptible. Depending on how toxic the drug is, people may move between those groups, and it will be weighted in one direction or another. What we find is that more than 3x ULN should be flagged as an issue, especially when combined with the increase in bilirubin over 2x ULN. With most DIOT, what you can do is rule it in, and spend the rest of the time trying to rule everything else out.
What types of biomarker panels are offered by ACM Global?
The front line testing to be used to monitor for different forms of DIOT are as follows:
• Liver: Alanine amino-transferase, aspartate amino-transferase, alkaline phosphatase, bilirubin, g-glutamyl transferase
• Kidney: Serum creatinine, blood urea nitrogen, GFR/creatinine clearance, serum cystatin C
• Bone Marrow: Hemoglobin, platelet count, absolute neutrophil count
• Heart: Troponin, B natriuretic peptide, CK-MB, hs-CRP
Should any of these monitoring panels display signals conducive with toxicity, ACM Global can work with you in performing follow up testing to aid in identifying the route of the signals.
Have Dr. Botham’s and Dr. Patru’s responses covered some of the questions you had about DIOT? Please leave a comment with any of your questions about DIOT and suggestions for upcoming webinars. Visit the Xtalks website to access the webinar archive.