How do you know? The ultimate goal is to bring RDGL to the clinic. A brief intro from clinicians working with patients is appropriate. The FDA reviewers are not machines but human beings.

JHU probably doesn't have a rabbit colony. So they need to purchase them and acclimate them for at least 1 week. Now that they know how many rabbits they need they could get the process started. It all depends on their timetable to run the study.

JHU is not a CRO with SOPs in place so there needs to be some qualified oversight to ensure proper record keeping and data reporting. Thus the need for the independent quality assurance consultant.

I doubt this will be a strict GLP study but more "GLP-like". Non-clinical radiolabeled tissue distribution studies to support human studies are never GLP. This rabbit study isn't too different in scope. Only non-clinical chronic safety and some other toxicology studies need to be GLP.

The inoculation is IACUC approved so technically they could. But I don't think they will since the entire study has to be approved.

Mayo Docs are now key members of the RDGL team. They should be on the call.

I know some FDA reviewers personally. They don't think like you do.

"well as soon as we have an IDE application before us, you'll know within thirty days if human trials can proceed" doesn't sound like an FDA response.

The test will take 1.5-2 months from inoculation.

The study is now in JHU's hands. They may move much faster!

This is not how it works. It's up to the sponsor to submit the details of the protocol for review. Most likely RDGL proposed n=2-4 but the FDA want have more (n=5-6). This has no bearing on the timeline since all rabbits will be inoculated/treated at the same time.

You are wrong. If the FDA wanted to stop this they would not have suggested the EFS.

You seem to forget what happened:

- RDGL submitted draft IDE
- At meeting FDA requested an additional meeting to discuss containment and dosimetry
- RDGL most likely submitted all data available, maybe even from the Batelle days which may have taken some time to dig out (I have been involved in similar cases where we tried to make our point to the FDA by sending all we had).
- FDA did not considered the data to be good enough (not necessarily for the reason you keep bringing up ad nauseum) and requested more controlled data.
- RDGL worked out protocol with JHU
- RDGL submitted protocol and requested meeting
- FDA approved protocol

So where is the lack of focus? Some of the activities take time and Vivos is not Merck or Pfizer with nearly unlimited resources and personnel. Could they go faster? Probably. But I don't see a lack of focus.

Have you ever had a meeting with the FDA? You sound like you have.

If JHU submitted the protocol to the IACUC before Nov 1st it will be reviewed/approved on Nov 17th (https://web.jhu.edu/animalcare/). They could technically inoculate the following week. However, I doubt this will happen. Given that they need to hire an independent quality assurance consultant and the upcoming holidays I anticipate they won't start until beginning 1Q23, although they could inoculate the rabbits before Christmas and have tumors ready to be treated in January. In any case, the study should completed by end of 1Q23 with IDE submission shortly thereafter. I predict IDE approval June '23.

RDGL mentioned that they would use PET at dosing time and an unnamed very sensitive method at study termination to quantitate the amount deposited in the tumor. I assume it must be liquid scintillation counting after tumor solubilization. Before the broad application of Quantitative Whole Body Autoradiography (QWBA) we used do this in rats with excised tissues/organs for dosimetry calculations before conducting radiolabeled studies in human.

A good scientist always looks at the data first. It doesn't matter where it comes from. And you can't ignore anything. I've published on novel reaction mechanisms in top peer-reviewed journals based on very tiny signals that were indicative of something new or different. The same thing is going on here. There are too many reports to be ignored. The truth will come out. And some people will be very sorry they didn't pay attention.

You mean a credible peer reviewed primary medical journal like The Lancet?

Yeah, I recommend you watch this:

https://www.theepochtimes.com/from-wildfire-cancers-to-foot-long-clots-dr-ryan-cole-explains-the-dangers-of-the-spike-protein_4813813.html

Because they have never submitted anything to, or interacted with, the FDA. It's just their misinformed opinion.

Here ye go again, assuming that "old data on a prior version of Radiogel wouldn't fly". As I explained before, it may have nothing to do with the version of RDGL. And in the EFS paradigm the product version doesn't have to be final.

As for the path forward, it is very clear: Run the containment study and submit IDE.

Please give me examples.

Why is "humans next" a bold statement? Isn't that what is going to happen?

It is not a matter of chance but execution. You don't get that far with the FDA to get rejected. It just doesn't happen. The only scenario that could derail RDGL is not enough containment for thyroid cancer as an entry indication, although the FDA could decide to still approve the IDE but lower the maximum allowable dose to reduce risk to neighboring tissues.

I agree, particularly if resorption is slow.

Where did you read this? I remember another dog who died from an infection.

I don't think the cause of Whoudini's death was reported. Could have been old age.

Whoudini was 14 years old, with a large tumor. He did fine post treatment.

I don't mind the transparency. This is exciting!

Same concept but different gel and radionuclide. Given the differences between I-131 and Y-90 applications may not be completely overlapping. Time will tell. The Duke group is way behind but they could progress much faster than RDGL.

Dr K submitted a draft IDE on Sep 2021. How do you know it wasn't a "serious" draft? Could you explain to all of us what you mean by "serious"?

se·ri·ous (/'sire?s/):

adjective

1. (of a subject, state, or activity) demanding careful consideration or application.

2. acting or speaking sincerely and in earnest, rather than in a joking or halfhearted manner.

"he only entered into pre-submission discussions to determine what's required for a serious IDE application in Sept. 2021" Are you serious?

I hadn't seen your response before sending mine. We are in complete agreement!

"Failed" breakthrough applications are not uncommon. It even happens to companies like Merck that have no shortage of resources to submit gold-plated applications. It has to do with the perception of novelty and effectiveness. Acceptance criteria can be found here: https://www.fda.gov/medical-devices/how-study-and-market-your-device/breakthrough-devices-program. In the Jan. 19, 2021 PR Dr K quoted part of the FDA response: “The FDA does believe that RadioGel™ meets criterion #2a: Device represents breakthrough technology. Your device does meet this criterion because it is a novel application of a brachytherapy device outside of the liver.” This means that the FDA felt that RDGL does not meet criterion #1 (and possibly criteria #2b-c) to be granted BDD at this time. RDGL can resubmit an application after it has obtained clinical data showing that it meets criterion #1, which, if accepted, could speed up marketing application and review. Voila.

To be clear, the BDD gets a faster review of the IDE submission, not a guaranteed approval.

BDD and IDE approval are unrelated. IMO they should have submitted the BDD after IDE approval and first clinical data.

Once the IDE is approved in the US it will open many doors. There is a huge opportunity for RDGL in India (https://pubmed.ncbi.nlm.nih.gov/25337139/). Imagine what it will do to the SP when Dr K announces some (licensing) deal with an Indian party.

You don't have this many interactions with the FDA and get your application rejected. Most of my clients have a single pre-IND meeting and that's it. The sub-dime days for RDGL will be over soon.

From this publication (https://pubmed.ncbi.nlm.nih.gov/25853660/), "the hind limb VX2 rabbits required an average of 19.6 ± 5.4 days to reach approximately 4–5 cm in diameter (palpable nodules)". Assuming they inoculate before Nov 11 the containment study should be completed by Christmas.

RDGL's plan is to use PET and an other method on excised tumors/tissues (which they haven't specified in their communication). I assume it must be liquid scintillation counting which would be much more sensitive than PET.

Have you ever filed anything serious with the FDA?

This is a non-clinical study in non-rodent. N=5-6 is probably what the FDA would like to see.

Here's a potential reasonable timeline:

Oct 17: Meeting with FDA. I am assuming they come to an agreement.
Oct 21-Nov 1: Inoculate rabbits
Nov 21-Dec 1: Rabbits ready to be treated
Dec 1 - Dec 15: Samples collection, processing and counting (assuming they wait 4 half-lives)
Dec 15- Jan 15: Data analysis and draft report
Jan 15 - Feb 15: Final report + request meeting with FDA
Mar 15 - Apr 15: Meeting with FDA
Apr 15 - Jun 15: IDE submission and approval 30 days later.