SPS Webinar on SP with Oncology Drugs. Toxicology Standards?
August 19, 2009 8:37 am Education, Government, ScienceWebinar
I found the Webinar on ICH S9 very interesting and informative. The Panel discussion was particularly interesting to me. There seems to be a preference for rolling large molecule work into the Toxicology studies. Here are my questions.
1) If we perform Cardiovascular, CNS and Respiratory studies in toxicology studies, should the model all be tested with positive controls to indicate that the study design would detect an effect if it was present?
2) Are the standards for sensitivity the same for these add-ons to Toxicology studies the same as for safety pharmacology?
3) What would be a reasonable positive control study to show the sensitivity and specificity?
I look forward to your insights.
October 16th, 2009 at 6:14 am
The webinar on S9 was very good from a content standpoint; very timely too. Within my company, we have adopted previously a modified strategy to assess safety pharmacology endpoints for small molecule oncology drugs (e.g., during candidate selection: hERG evaluation; rat telemetry to assess overt hemodynamic effects; pre-FIH stage: integration of SP endpoints into toxicology studies) as decribed during webinar.
In regard to positive controls in a toxicology study, I think it would be considered a good practice to evaluate various positive controls in a toxicology study paradigm, to assess and establish sensitivity to detect a signal (QTc, blood pressure, respiratory rate, behavioral). This would mean that multiple positive controls may need to be assessed, per endpoint of interest. It would great to know if any SPists have worked with their tox colleagues, to run reference compounds thru tox protocols.
Speaking of detecting a signal, it would be equally important to assess statistical power in tox study designs, given dose group sizes, endpoint variability, etc, to establish sensitivity. Guth et al (Journal of Pharm Tox Methods 60:107-116, 2009) provided an excellent perspective on ECG collection in SP & tox studies, and outlines experimental design considerations, issues, and improvements that can be used to optimize ECG collection in both SP & Tox studies, including power assessment. The views shared in this article can assist preclinical safety scientists in understanding the pros/cons of integration SP endpoints into non-rodent toxicology studies. They principles described can also help assessment, potentially, of other endpoints (CNS/Respiratory).
Other views?