The 5-Question Flowchart for Adverse Tox Findings — Transcript

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1. 0:00Adverse effects can literally make or break your program.
2. 0:05Today we're talking about how we decide whether finding in a tox study is
3. 0:09adverse or not. So I have a little flowchart here that you can see,
4. 0:13and we're going to go through it. There are typically about five things you
5. 0:16can see here that we use to decide whether an effect is adverse.
6. 0:21And when we talk about an effect or a finding,
7. 0:24we're talking about a test article related finding.
8. 0:27So within a tox study, you might have no findings,
9. 0:31or you might have some findings that aren't test article related.
10. 0:34They might be, just a smaller incident or species specific or animal
11. 0:39related. and then we have test article related findings that are directly related to
12. 0:43the drug, the drug is causing these effects. And then we have adverse effects,
13. 0:46which means that those effects that the drug is causing are adverse enough that
14. 0:51it alters essentially the physiology and the biological function of that animal.
15. 0:56And so adverse effects are what we use to determine NOAELs
16. 1:00and that correlates with our exposures,
17. 1:03which correlates then to how we determine our starting dose in the humans.
18. 1:07And then ultimately how we determine if our drug is safe enough to
19. 1:12go into humans by using, you know, adequate margins and,
20. 1:15understanding where that, that safety fold lies.
21. 1:18There are other videos, that I have out there on Nonclinical Academy on YouTube
22. 1:24that talks about, TK profiles, exposure, interpreting findings,
23. 1:26things like that. so check them out. But today we're gonna focus on adversity
24. 1:30and how we decide, with the study director and or the pathologist,
25. 1:34what which findings are adverse really
26. 1:39is a conversation. it is a discussion between the sponsor,
27. 1:43which could be you, the CRO or the study director,
28. 1:45which also could be you, depending on what your role is,
29. 1:47the pathologist, which could be you. and so it's,
30. 1:49it's really a discussion, about how we would decide what's adverse,
31. 1:53what's not adverse. And there are a lot of, a lot of different papers
32. 1:55and literature out there that discuss this as well,
33. 1:58but we'll go through this flow chart. This kind of breaks it down to
34. 2:01a simpler flow to understand what we're thinking about,
35. 2:03why we're thinking about that So let's start at the top,
36. 2:07right? A finding came back in your study and we're going
37. 2:12to ask you to ask these questions. Is there a dose response?
38. 2:16It's question number one. basically is that finding become more severe
39. 2:20as dose increases and as exposure increases,
40. 2:24or is it a flat response where the finding you see it across every
41. 2:29dose? and so if there is not a dose response,
42. 2:32then it's likely not adverse. There's no dose relationship.
43. 2:35it's usually incidental, document it and sort of move on.
44. 2:39In the cases that this is not adverse would be if it's a one-off
45. 2:43finding. You see two animals in the mid-dose that have it or you see
46. 2:47one animal in the low dose, one animal in the high dose,
47. 2:49and there's no dose response.
48. 2:52There's no linear connection between the findings across doses.
49. 2:56The finding itself doesn't increase in severity.
50. 3:00it doesn't increase in effect.
51. 3:02And so that's when it would likely not be adverse.
52. 3:05When it would be adverse is if there's no dose response because it is
53. 3:10a very toxic, potentially fatal finding at all doses.
54. 3:14that kind of flat dose response, that's a clear adversity.
55. 3:19So let's say that there is. a dose response, right? So we see this
56. 3:21finding, increasing in severity, across increasing doses.
57. 3:24So we're going to go down to the next one. Is it reversible in
58. 3:28recovery animals? If it's not reversible in recovery animals,
59. 3:33then it's likely adverse. full stop. Typically what happens is we'll,
60. 3:37we'll dose animals in life for a certain duration and then we'll stop dosing
61. 3:41after, you know, for example, a 28 day study,
62. 3:44we'll stop dosing at day 28 and then we'll go into a recovery period
63. 3:48to see if there's any findings that we saw in the dosing phase if
64. 3:51those continue in recovery and if those are reversible,
65. 3:54meaning that those findings actually go away,
66. 3:56if they don't go away, then this is likely adverse.
67. 4:00so non-reversible findings are a serious regulatory signal.
68. 4:04The FDA will absolutely scrutinize your clinical dose say you have an enlarged liver
69. 4:08with elevated liver enzymes.
70. 4:11And that doesn't mean that it doesn't recover in your recovery animals,
71. 4:15meaning that dosing has stopped after four weeks,
72. 4:18those livers are still enlarged and you still have elevated liver enzymes,
73. 4:21that's a clear, ah, liver toxicity response and that's something that the FDA
74. 4:26is definitely going to flag. So that would definitely certainly be adverse.
75. 4:30Okay, so is it reversible in recovery animals?
76. 4:32Yes, it is. Okay, so, is there histopathological evidence?
77. 4:35this is something that we take very seriously in terms of that you could
78. 4:39have elevated liver enzymes, but no histopathological changes within the liver.
79. 4:44And this lack of correlation usually means that a finding may not
80. 4:49be adverse. Now, there are different scenarios,
81. 4:52you know, every, every program is different. So if you have elevated liver enzymes
82. 4:55that increase in severity, like we said,
83. 4:58overdoses, then and that could potentially be an adverse finding.
84. 5:02But if you have some elevated liver enzymes that don't correlate to any enlarged
85. 5:07liver, there's no gross path findings,
86. 5:09there's no histopath findings, and no changes in the tissues,
87. 5:12then it's then this could just be adaptive,
88. 5:14could be something that is a discussion, likely a discussion,
89. 5:17of whether or not you would call that, it's definitely probably pointing to liver
90. 5:21toxicity, but whether you would call that adverse versus just test article related,
91. 5:26that is a conversation that you're gonna have to have with the study director
92. 5:28and the pathologist so everybody can kind of weigh in together.
93. 5:33So moving back down to the chain, if,
94. 5:35is there histopathological evidence? Yes there is,
95. 5:38so let me move back down. Is the magnitude biologically significant.
96. 5:43So if, if it is not biologically significant,
97. 5:46then it's likely adaptive, meaning the animal is basically compensating,
98. 5:50the animal is doing what it needs to do to be able to,
99. 5:52adapt to the changes that are happening based on the drug,
100. 5:56these are usually small, within normal variability,
101. 5:58they have a known background, you can document the rationale.
102. 6:01This also, is where historical control data comes into play,
103. 6:04meaning that if you have a finding that is not biologically significant,
104. 6:09and it is likely adaptive, it's likely because you're able to show that it's
105. 6:14within the normal range of that animal using historical control data.
106. 6:18And we use this a lot, but especially with the Tox species that we
107. 6:21have, there are a wide range of databases out there for historical control data,
108. 6:25and so if we have a finding in a particular animal,
109. 6:27in a particular dose, we can go back and look and see,
110. 6:30okay, what's the normal range that this finding,
111. 6:32would be found within this species and or sex of the species,
112. 6:36if it's within that range, then we wouldn't typically call it a drug-related finding.
113. 6:40Or even adverse, because,
114. 6:42it is just part of the species' biology.
115. 6:46is the magnitude of the finding biologically significant?
116. 6:49Let's say, yes, it is. We'll go down to the last one.
117. 6:53Is it consistent across sexes and or species?
118. 6:55This is a big one. This is probably one of the most major ones
119. 6:58aside from a dose response and or correlation.
120. 7:01If it's not consistent across sexes or species then you can do a little
121. 7:05bit more. More investigation, it could be species specific,
122. 7:08it could be sex specific, it could be, exposure differences that are causing this,
123. 7:12however, if it is consistent across sexes and species,
124. 7:16that's a big indicator that it's an adverse effect,
125. 7:19that it is going to be translatable to humans,
126. 7:21and that's why it's so massive is that it's, it's translational strength increases
127. 7:26if you see it across males and females and if you see it across
128. 7:29rodents and non-rodents, then that is definitely an indicator that you're probably going to
129. 7:33see it in the clinic and you have to be able to mitigate that
130. 7:36whether that's mitigating it through dosing and exposure,
131. 7:39mitigating it through clinical trials. Clinical monitoring, but you can see that yes,
132. 7:43it is consistent across sexes and species, then it's an adverse finding.
133. 7:46You want to document it, characterize it, and build your safety argument around it.
134. 7:50And now note here, even with this flow chart,
135. 7:52right? If you have an adverse finding,
136. 7:54that doesn't mean that your program is dead. That doesn't mean that,
137. 7:57your drug isn't going anywhere. That just means that you have to understand and
138. 8:01justify one, why is it adverse?
139. 8:03Where is it becoming adverse at?
140. 8:06you know, what exposures are driving it to be adverse?
141. 8:09Is it exposure? Is it Cmax driven? Is it species-specific?
142. 8:13There are a lot of species-specific findings that are adverse that don't relate to
143. 8:17humans. They're irrelevant to humans. Understanding that justification is critical.
144. 8:22And so an adverse finding, yes,
145. 8:24it drives your NOAEL, it drives your,
146. 8:26animal exposures and your exposure margin, and it drives your,
147. 8:29your human starting dose in the implications within the clinic in terms of clinical
148. 8:33monitoring and your clinical protocol, but it's not the end all be all of
149. 8:37your program not being able to move forward.
150. 8:40Ultimately what you want in a tox study is you want tox.
151. 8:43You want toxicity. That's how we understand where the ceiling is to be able
152. 8:47to understand where we can go and how we get there in the clinical
153. 8:50setting. And so having an adverse effect,
154. 8:52that's how we find our NOAEL. If you don't have any adverse effects and
155. 8:56you don't have a NOAEL, then your NOAEL will be above your high dose
156. 9:00essentially. And it's not necessarily that you didn't dose high enough to find it.
157. 9:04You might not have an adverse effect if you have a safe drug.
158. 9:08This is sometimes very common with biologics.
159. 9:10but being able to understand then what findings are drug related,
160. 9:14test article related, and what those exposures are and then potentially being able to
161. 9:18understand if there is a range of exposure that
162. 9:23would cause these effects to be more severe that would potentially go into
163. 9:27adversity. But as long as you've built your program around a
164. 9:32well-justified sequence of studies,
165. 9:35meaning that you've run your PK, then you've run your non-GLP,
166. 9:39you did a well-designed,
167. 9:41well-executed MTD study and or DRF study,
168. 9:45you chose your doses, you narrowed them down for your GLP,
169. 9:48you ran your GLP studies, you executed it well,
170. 9:50As long as that is all justified and you can thoroughly put
171. 9:55together a defensible regulatory narrative,
172. 9:58that regulatory story, then you should be in good hands.
173. 10:00you know, this is, this is something, as long as the science is there,
174. 10:03as long as the science is sound, you don't,
175. 10:05you might not necessarily have adverse effects on a study,
176. 10:08but if you do, you know, it's something that warrants a discussion,
177. 10:12particularly with the study director,
178. 10:14the CRO, the pathologist, the sponsor,
179. 10:18And then ultimately, would the FDA within your IND or any regulatory agency that
180. 10:22you submit to. so this is all about adversity,
181. 10:25and we do a much deeper dive into my course,
182. 10:27The Complete Guide to Nonclinical Development. I'll pin it here.
183. 10:30You can also, click the link in the description to shoot over there and
184. 10:34take a look at it. And I hope I see you in the next
185. 10:37video.