Many reasons Tox delayed in past, but future…?
I agree 7 or whatever years promising Tox is inexcusable, but the question now is whether they are close to actually starting the next IND-enabling Tox phase now - now that they have produced material for the range-finding Tox in September.
I am pretty much in agreement with BK on the CMC requirements and large quantities being the reason for the present holdup (see #5 below). But I think there may be a little more to the early delays.
Conjecture on my part, but relying on a bit of understanding of industry and human nature.
#1 Early on, I think lack of experience with this novel drug made them overconfident thinking that it would be easy.
#2 They started bringing on board Regulatory experts and getting better understanding, but there were still unknowns with this novel drug.
#3 They were guided by the experts to get a Pre-IND meeting with the FDA to get a better understanding of all that would be needed to get into Tox studies and clinical trials.
#4 They learned a lot in the Pre-IND meeting of March 2012 on what the FDA would require for IND for a novel drug of this nature:
- What needed to be specified for Batch Release requirements.
- What Analytical and Characterization tests would need to be developed and validated.
- That they needed assurance of consistency of process and batches to bridge from GLP studies to clinical studies.
- That they needed to do process development and scale-ups to understand and control the consistency at each batch size. And probably other things I am not aware of.
#5 March 2012 - Sept 2013:
- They worked to develop and validate the tests for specs and characterizations.
- They made multiple batches, ran DOE's, RSM's and process optimization experiments to understand the product and process.
- They set specifications and justified them.
- They ran confirmatory batches at the process settings and conditions to assure consistency.
- Finally produced enough small batches to run the range-finding Tox study in Sept. 2013.
NOTE: this early range-finding Tox study is standard practice in industry to avoid wasting money finding your maximum dose in the more expensive, GLP constrained, IND-enabling Tox Study.
#6 Sept 2013 - ???: They are now working to produce enough materials for the IND-enabling GLP Tox Study with scaled up production equipment in the existing facility.
- Because of the extremely low toxicity (a very good thing that may enable accelerated FDA review path), they need a great deal of material.
- And there are not only mice, but dogs for the testing as well.
- And both male and female of both species will need to be tested with multiple animals for each dosage level.
- This means much more drug product needs to be made for all the animals and doses.
- [Edit-Add] Also, enough material must be made to run a concurrent stability study where all the stability-indicating batch release requirements must be tested over multiple time points to confirm the batches in the study are stable and still potent without degradation, consistent, etc.
- In addition, all material must pass batch release testing and chemical characterization confirmation to be released to the study.
- And it is possible that the specifications set may be relatively tight. Just one tight spec may make the process difficult to dial in to meet that spec and all the others.
- Batches not meeting requirements must be scrapped. (These process and batch specification controls are the CMC requirements mentioned by BK).
In the end, whether you believe the next Tox testing is just around the corner now depends on whether you believe they have finally worked through the difficulties with validating tests, setting specs, and refining their process.
To me, I think the fact that they have completed the range-finding Tox tests in September means that they have resolved all of the big issues and now just need to make enough material at spec to begin the IND-enabling GLP Toxicity testing. I was hoping for timeline upside that hasn't come about. But I do still think they will come through in the next 0-3 months.
