Entries by Andrew Sonderfan

Tox to support intermittent dosing in clinical trial

Dear RTC -

A client is planning that a US IND will open with clinical dosing "1 or 2 or 3 doses every 1 or 2 or 3 months" (...yes, there are still some efficacy and PK/PD studies to be conducted!).

I'm hoping to find one or more examples of FDA new approvals for a small, non-oncology molecule - or to learn from RTCers how best (when the clinical regimen has been determined) to design the clinical-trial-enabling nonclinical safety.

I've found approval documentation for large molecules and for oncology NCEs, and I've found plenty of ANDA approvals for infrequently-administered compounds......but in each case the respective, earlier innovator-drug approvals included traditional, daily-dosing tox studies.

I realize this is a basic question. Can anyone point me toward guidance(s) or literature? Or toward an approval I can peruse?

Thanks; cheers,
Andy

Andrew J Sonderfan, PhD, DABT
Nonclinical Strategies, LLC
asonderfan@gmail.com
+1.978.505.7138

...

 

CROs: “Anyone who’d pay $50 for a cab would certainly pay $75”

Dear RTC -

 

I’m hoping for
a CRO recommendation or two. I’m disappointed with CRL and Labcorp after I was
contacted about a possible schedule slip for an in-life study start planned
(finally and not without some wrangling) for April 2022. I’d previously
encountered (and complained here about) delays to bio/ analytical work, but
I’ve always expected that animal-study schedules were inviolate. It looks like
I will be able to “fix” this particular study, but (as I plan a new program for
a different client) I’d like to have the benefit of RTCers experiences and cast
the net more widely.

 

For the program
I’m considering we need to conduct and report GLP 13-week tox in rats and dogs
along with Safety Pharmacology. I’d like to do all study work with one CRO (I’m
open to different locations but concerned that would complicate dose-formulation
analytics should any results be out of range). This endogenously-occurring
small molecule is relatively well-characterized (and, indeed, some ex-USA
clinical work may soon be conducted), but GLP study work is needed to support
the FDA submission. The studies will likely not be technically challenging and
(from my review of published/ available tox data) I’m not expecting a lot of
in-life adventure. I’m considering including respiratory and CNS endpoints in
the 13-week rat or dog studies (depending on the CROs expertise with one or the
other), and then doing stand-alone cardiovascular and hERG. Bioanalytical work
will be conducted at a 3rd-party Testing Site.

 

I’m hoping to
conduct this client’s work in North America or western Europe. I’ve had good, recent
experiences with Inotiv, Sequani, and ITR (I don’t know SP capabilities for any
of these, though). I haven’t worked with Altasciences or Sinclair.

 

Whom would you
approach about the work I’m describing?

 

My concern is
that the largest labs will book work later and later into 2022, and if they
don’t initiate as scheduled/ promised, what’s the recourse? Once on the hook
and contracts signed, we’re painted into a corner. Remember in “Planes, Trains,
and Automobiles”, the attorney Steve Martin’s character persuaded with cash to surrender
a taxi in rush-hour traffic? The attorney said “Anyone who’d pay $50 for a cab
would certainly pay $75”.

 

 

Thanks for your
help; best to all,

Andy

 

 

Andrew J Sonderfan, PhD, DABT

Nonclinical Strategies, LLC

asonderfan@gmail.com

+1.978.505.7138...

 

CROs: “Anyone who’d pay $50 for a cab would certainly pay $75”

Dear RTC -

I’m hoping for a CRO recommendation or two. I’m disappointed with CRL and Labcorp after I was contacted about a possible schedule slip for an in-life study start planned (finally and not without some wrangling) for April 2022. I’d previously encountered (and complained here about) delays to bio/ analytical work, but I’ve always expected that animal-study schedules were inviolate. It looks like I will be able to “fix” this particular study, but (as I plan a new program for a different client) I’d like to have the benefit of RTCers experiences and cast the net more widely.

For the program I’m considering we need to conduct and report GLP 13-week tox in rats and dogs along with Safety Pharmacology. I’d like to do all study work with one CRO (I’m open to different locations but concerned that would complicate dose-formulation analytics should any results be out of range). This endogenously-occurring small molecule is relatively well-characterized (and, indeed, some ex-USA clinical work may soon be conducted), but GLP study work is needed to support the FDA submission. The studies will likely not be technically challenging and (from my review of published/ available tox data) I’m not expecting a lot of in-life adventure. I’m considering including respiratory and CNS endpoints in the 13-week rat or dog studies (depending on the CROs expertise with one or the other), and then doing stand-alone cardiovascular and hERG. Bioanalytical work will be conducted at a 3rd-party Testing Site.

I’m hoping to conduct this client’s work in North America or western Europe. I’ve had good, recent experiences with Inotiv, Sequani, and ITR (I don’t know SP capabilities for any of these, though). I haven’t worked with Altasciences or Sinclair.

Whom would you approach about the work I’m describing?

My concern is that the largest labs will book work later and later into 2022, and if they don’t initiate as scheduled/ promised, what’s the recourse? Once on the hook and contracts signed, we’re painted into a corner. Remember in “Planes, Trains, and Automobiles”, the attorney Steve Martin’s character persuaded with cash to surrender a taxi in rush-hour traffic? The attorney said “Anyone who’d pay $50 for a cab would certainly pay $75”.

Thanks for your help; best to all,
Andy

Andrew J Sonderfan, PhD, DABT
Nonclinical Strategies, LLC
asonderfan@gmail.com
+1.978.505.7138
...

 

CROs: “Anyone who’d pay $50 for a cab would certainly pay $75”

Dear RTC -

I’m hoping for a CRO recommendation or two. I’m disappointed with CRL and Labcorp after I was contacted about a possible schedule slip for an in-life study start planned (finally and not without some wrangling) for April 2022. I’d previously encountered (and complained here about) delays to bio/ analytical work, but I’ve always expected that animal-study schedules were inviolate. It looks like I will be able to “fix” this particular study, but (as I plan a new program for a different client) I’d like to have the benefit of RTCers experiences and cast the net more widely.

For the program I’m considering we need to conduct and report GLP 13-week tox in rats and dogs along with Safety Pharmacology. I’d like to do all study work with one CRO (I’m open to different locations but concerned that would complicate dose-formulation analytics should any results be out of range). This endogenously-occurring small molecule is relatively well-characterized (and, indeed, some ex-USA clinical work may soon be conducted), but GLP study work is needed to support the FDA submission. The studies will likely not be technically challenging and (from my review of published/ available tox data) I’m not expecting a lot of in-life adventure. I’m considering including respiratory and CNS endpoints in the 13-week rat or dog studies (depending on the CROs expertise with one or the other), and then doing stand-alone cardiovascular and hERG. Bioanalytical work will be conducted at a 3rd-party Testing Site.

I’m hoping to conduct this client’s work in North America or western Europe. I’ve had good, recent experiences with Inotiv, Sequani, and ITR (I don’t know SP capabilities for any of these, though). I haven’t worked with Altasciences or Sinclair.

Whom would you approach about the work I’m describing?

My concern is that the largest labs will book work later and later into 2022, and if they don’t initiate as scheduled/ promised, what’s the recourse? Once on the hook and contracts signed, we’re painted into a corner. Remember in “Planes, Trains, and Automobiles”, the attorney Steve Martin’s character persuaded with cash to surrender a taxi in rush-hour traffic? The attorney said “Anyone who’d pay $50 for a cab would certainly pay $75”.

Thanks for your help; best to all,
Andy

Andrew J Sonderfan, PhD, DABT
Nonclinical Strategies, LLC
asonderfan@gmail.com
+1.978.505.7138
...

 

Bioanalytical/ analytical delays in Mattawan – you too?

Dear RTC colleagues -

I’ve been running into scheduling challenges for analytical/ bioanalytical work at CRL in Mattawan – more than once it’s been months-long delays to initiate (I’m not talking long lead-time [which I’m encountering – here and elsewhere], I’m talking delay of previously-scheduled starts).

To be clear, technical performance has been excellent.

I’ve had discussions that include client-services supervisors and I’ve gotten some accommodation on price, but no schedule improvement; supervisor has shared that they have not encountered this degree of resource challenge in almost 2 decades (not sure if their experience is at multiple sites). I’ve had validation packages moved to another CRL site – I’ll let you know how that goes. And – because this particular client has a couple of largish programs in Mattawan – it looks like I need to go back to the client about a second validation study and say this one is going to be late too.

Are others seeing this? At Mattawan? At CRL? Across service providers? It would be helpful to know. I’m having good success (technical performance AND schedule) elsewhere.

I think I understand some of what’s behind the long lead-time to initiate large-animal general tox studies, but these bioanalytical delays….a couple of months….now a couple more months….have been frustrating.

Thanks!
Andy

Andrew J Sonderfan, PhD, DABT
Nonclinical Strategies, LLC
asonderfan@gmail.com
+1.978.505.7138
...

 

Experience with rhabdomyolysis?

Hi RTC colleagues -

A client with whom I just began working has a compound in their library that appears to elicit rhabdomyolysis. They're curious about the mechanism, and whether it's an on- or off-target effect, as they consider whether this may be an anticipated liability should they pursue other compounds with similar structure or function.

Anybody seen much of this, and/ or have insights to share? I'd be happy to connect you directly (I'm sure I'd learn something from the discussions).

Thanks; best wishes,
Andy

Andrew J Sonderfan, PhD, DABT
Nonclinical Strategies, LLC
asonderfan@gmail.com
+1.978.505.7138

...

 

Reminder – RTC Business Practices Survey (closes Friday, June 11)

Dear Membership -

Thanks to all who have completed the survey - around 50 respondents so far which is encouraging.

If you haven't already, please take a few moments to provide your input - it's helpful to everyone.

To complete the Survey, lease (1) log in to the RTC website and then (2) follow this link to access the survey:

www.toxconsultants.com/eforms/2020-rtc-business-practices-revenue-survey/25/

Thanks for your participation!

Andy Sonderfan
For the EC
...

 

[14C]-AME in rats. Covance Madison or… (?)

Hi RTC -

It's been several years since I conducted a radiolabeled study (with QWBA, metabolite ID, etc.), and that study was at Covance Madison (they did an excellent job).

Prior to that it was several years between similar studies, but the previous study was also at Covance Madison (and was well done).

Now I'm planning to obtain proposals for a [14C] study - definitely I'll contact Madison. I can't recall other CRO(s) where I may have earlier obtained competitive quotes. Whom would you recommend?

Thanks,
Andy

Andrew J Sonderfan, PhD, DABT
Nonclinical Strategies, LLC
asonderfan@gmail.com
+1.978.505.7138

...

 

IND with draft; final report within 120 days for…..SAFETY PHARMACOLOGY?

Dear RTC experts -

I have a client that earlier completed GLP toxicology (but not Safety Pharmacology) to enable a first-in-human study outside the ICH regions. The completed tox will suffice for the limited-scope clinical program to be undertaken when the US IND is filed toward the end of this calendar year. Here's the question - we're conducting Core Battery SP studies to be included in the IND submission, and the client asked "Can we submit the IND with draft SP reports, and then finalize them within 120 days?"

I'd never encountered this question (when performed together, SP studies are always finalized ahead of the repeat-dose tox, so the situation never arose). I checked out FDA's (2000) Guidance, and it seems specific to "toxicology report" (which may be submitted as a draft, though with signed pathology as a later-added but well-understood stipulation).

Draft Safety Pharm reports? Your experiences and advice are welcome!

Thanks,
Andy

Andrew J Sonderfan, PhD, DABT
Nonclinical Strategies, LLC
asonderfan@gmail.com
+1.978.505.7138

...