Dose Range Finding (DRF) Studies: The 3 Things That Shape Your GLP Program — Transcript

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1. 0:00Your DRF study can literally tip your whole program and make it fall down
2. 0:05like a ton of bricks. I personally believe that the DRF study is actually
3. 0:09the unsung hero of an entire GLP program.
4. 0:12This is arguably the pivotal point.
5. 0:15GLP studies, I know, they say are the pivotal studies,
6. 0:18but your DRF, I think, is literally what bridges your research,
7. 0:22early-stage, top-level research, your MTDs,
8. 0:24your PK studies, and it bridges that to your GLP study and ultimately your
9. 0:28IND submission. And if you get this wrong,
10. 0:30it has so many consequences down the line that it can literally upend your
11. 0:35IND. So, let's talk about why this is,
12. 0:38right? Your dose range finding study,
13. 0:40it's your, essentially your 7-day, your 14-day study,
14. 0:43the study that gets run after your PK and before your GLP study.
15. 0:48So, what are the major things that we can do in these DRF studies
16. 0:52to make sure that they're properly designed and they give us the data that
17. 0:55we need to be able to design our GLP study accurately enough to have
18. 0:59a defensible IND submission? Well, the first thing is dose selection.
19. 1:03Dose selection is by and far one of the most important things for a
20. 1:06dose range finding study. If you don't design a dose range finding study with
21. 1:11the right doses, you're not going to have well-informed GLP doses.
22. 1:14And this means that your PK studies have to be on point,
23. 1:17your species selection has to be on point,
24. 1:20meaning your MET ID or your TCR have been conducted and they're well executed,
25. 1:24and you can pick your species, and that you understand essentially where your exposure
26. 1:29margins are going. to be compared to your modeled human AUC,
27. 1:32which are going to be modeled off of your early efficacy or pharmacology studies.
28. 1:37The next thing that's super important are your target organs.
29. 1:40The DRF is essentially a study that allows you to see your target organs
30. 1:44before you run your GLP study. It allows you to prepare for the IND
31. 1:48and your narrative and your story and be able to be able to anchor
32. 1:51that to your exposures and your safety margins.
33. 1:54so in your DRF if you're missing the endpoints that allow you to understand
34. 1:57target organs Then your design is off.
35. 2:00Missing your endpoints in your DRF can prevent target organ ID.
36. 2:04And I just saw this actually with a client of mine where they had
37. 2:08a particular compound, it had a pharmacology that elicited a certain response and
38. 2:13they omitted those particular tissues that were affected in their histopath
39. 2:18of their dose range finding study. As a result they thought that their dose
40. 2:22levels were going to be higher than it actually was.
41. 2:25They went into the GLP, they actually had mortality at their mid and high
42. 2:28dose based on pharmacologically relevant effects from
43. 2:33the test article that would have been caught if they had included those tissues
44. 2:38in the histopath of the dose range finding study.
45. 2:41So that was a major thing. Your target organ identification doesn't have to be
46. 2:45during your GLP study, it can absolutely be during your DRF.
47. 2:48a third and final major part of a DRF study is your TK profile.
48. 2:52Profile,
49. 2:57which doesn't allow you to one, understand exposure margins anchored to your human AUC,
50. 3:02understand your exposure margins anchored to your target organs and be able to come
51. 3:06up with an adequate IND narrative that's defensible in relation to your clinical protocol.
52. 3:11And so your TK profile, this stems a lot from your PK study where
53. 3:15you run an entire PK study with the right species,
54. 3:18the right doses, and you understand the time profile,
55. 3:21you understand your clearance, your half-life, your c-max,
56. 3:24and your t-max, and you use that to adequately add these TK endpoints
57. 3:29into your system. Your DRF study, this correlates along with one,
58. 3:32your dose selection and two, your target organs.
59. 3:34So all of these things, they work together.
60. 3:38They go back and forth with each other. And so if you don't have
61. 3:41the right TK endpoints, you're not going to understand exposure or c-max or t-max
62. 3:46in comparison with your target organs that you have,
63. 3:49in comparison with the dose levels that you have.
64. 3:51And this is going to create a huge gap in your DRF study that
65. 3:54doesn't allow you to design a proper GLP study.
66. 3:57And then this is where we get to is that your GLP study doesn't
67. 4:01get designed well enough to allow you to present the data that you need
68. 4:05to the FDA to show that your drug is safe enough to go into
69. 4:08humans. All of these pieces are important.
70. 4:10And if any one of them is missing, that's a red flag too.
71. 4:13That can absolutely create a gap in your submission that the FDA could potentially
72. 4:16question, put you on an IR or clinical hold,
73. 4:19and need you to be able to justify that before you are able to
74. 4:23move into the clinic. So all of these things,
75. 4:27these can all tip the whole program in terms of a DRF study.
76. 4:30Your dose selection, your target organs,
77. 4:34and your TK profile. The DRF is not a warm-up.
78. 4:37It's where the program gets shaped. So you want to make sure that you
79. 4:40have it well designed, it's based off of data that you've run beforehand,
80. 4:44and it supports data that you're going to get in the future.
81. 4:46And if you want more content like this, check out my course,
82. 4:49The Complete Guide to Non-Clinical Development. There's 12 plus modules,
83. 4:52plus two bonus modules, three tiers for your experience.
84. 4:55The link is in the comments.