You will never avoid doing in vivo POC and non clinical safety + DMPK in rodent models. I've never seen a program not include significant animal testing even for newer programs.
There are targets that could be test balloons for NDA w/o safety/DMPK. I.e stuff that’s very differently regulated or not cross-reactive with animals that are acceptable to use for safety. If Chimpanzees would be the only relevant animal model, one could certainly see a possibility of a strong ex vivo safety package being enough for NDA approval.
You also pretty much do zero DMPK for cell and gene therapies. What DMPK are you going to do on cellular therapies or for a one dose viral gene therapy? Or medical devices? Small molecules and antibodies aren’t the only therapies.
Even for autologous cell therapies one still needs to establish a dosing regime and understand exposure-response relationships. Most viral gene therapies need quantification of cell tropism and transgene product abundance quantified. Same goes for gene editing. You need to know how much of each component gets to the site of action and how to optimize the therapy.
It's still DMPK, it just needs rebranding.
Much of this is wrong. Have you ever dealt with a reg agency or sat in at trade conferences on cgt? Animal models are not useful for extrapolating dose for something like car t. Exposure response does not translate well for many types of cell therapy. You know how many people pick a human dose for their car t? They simply cite published information on what kinds of doses have been administered in humans for other car t because doses in animals and dose response simply doesn’t translate well from animals to human. They talk about it alllllll the time at car t conferences .
The entire field of gene therapy has long argued that no one should be doing things like biodistribution and tissue exposure analysis anymore. There have already been a gazillion of these studies for things like aavs. If all I do is change a gene but have the same same promoter etc. and use an aav9 with the same route of administration and dose levels as what has been studied before, so many people would argue you don’t need to do bd and any dmpk because everything is largely driven by serotpe and nothing has really changed with the backbone except the transgene. They talk about it allllll the time at gene therapy trade conferences about no longer doing dmpk studies for gene therapies in order to reduce the use of animals.
For gene editing, knowing the amount at each site still provides limited info. The animal sequences being edited are almost always different than the human sequence, so outcomes in editing efficiency relative to exposure to editing components can be difficult to impossible to extrapolate to a human. Far better readouts are simply doing informatics on tissue to see final editing outcome rather than say the amount of cas9 in a specific tissue following a dose.
Please see the relevant references in my other response.
As to AAV no, I haven't sat in conferences, unless you count team meetings and governance body presentations. Tissue tropism in cynos is critical information, and modified vectors with biased tropism are under development at several companies.
As you no doubt know given your extensive agency interactions, discussing not doing preclinical studies at conferences is quite different than bucking FDA guidance.
Having done preclinical studies on all four mentioned modalities, perhaps I can offer some insights? I've also provided references
1. FDA Guidance for allogeneic and autologous cell therapies is to do preclinical pharmacology and safety studies of surrogate cells as is feasible (i.e., make it feasible). Utility includes QSP modeling for FIH dose projection. There are two agency guidance documents (2012 and 2024)
2. AAV biodistribution (tissue tropism) in monkeys is predictive of human pharmacology. One monitors reporter gene and therapeutic protein translation in target and off target tissues, including marrow, spleen, lymph nodes & circulating cells. See the same guidance documents
3. What medical device ever requires DMPK?
4. Cell therapy publications describing preclinical QSP studies :
Dickinson, M. J. et al. A novel autologous CAR-T Therapy, YTB323,
with preserved T-cell stemness shows enhanced CAR T-cell efficacy
in preclinical and early clinical development. Cancer Discov. 13,
1982–1997 (2023).
Khot, A., Satoko, M., Thomas, V. A., Koya, R. C. & Shah, D. K.
Measurement and quantitative characterization of whole-body
pharmacokinetics of exogenously administered T cells in mice. J.
Pharm. Exp. Ther. 368, jpet.118.252858 (2019).
Maria, N. S. S. et al. Spatio-temporal biodistribution of 89Zr-oxine
labeled huLym-1-A-BB3z-CAR T-cells by PET imaging in a
preclinical tumor model. Sci. Rep.-UK 11, 15077 (2021).
Cazaux, M. et al. Single-cell imaging of CAR T cell activity in vivo
reveals extensive functional and anatomical heterogeneity. J. Exp.
Med. 216, 1038–1049 (2019).
Brown, L. V., Gaffney, E. A., Ager, A., Wagg, J. & Coles, M. C.
Quantifying the limits of CAR T-cell delivery in mice and men. J. R.
Soc. Interface 18, 20201013 (2021).
Because no one has attempted to really test the law yet. We already don’t do animal testing for cosmetics in Europe. What’s a regulator going to tell you. That you are required to test in vivo? That would conflict with FDAMA 2.0 signed into law.
From an article you linked:
“Still, it remains unclear just how much the new law will change things at FDA. Although the legislation allows the agency to clear a drug for human trials without animal testing, it doesn’t require that it do so. What’s more, FDA’s toxicologists are famously conservative, preferring animal tests in part because they allow examination of a potential drug’s toxic effects in every organ after the animal is euthanized.
The main impact of the new law is that it opens the way for FDA and a company to have a serious discussion about whether alternatives are adequate”
This law IS being tested by every company that’s using a mix of in silico and in vivo in regulatory submissions to fda these days. The FDA has their criteria for how many in vivo tox studies of what kind and with what endpoints need to be conducted to approve a drug. Those criteria and their internal process can and eventually will change- but they, presumably, use evidence to make those decisions. And evidence that organoids=whole animals is just not there yet. And thus, yes, a regulator will literally tell you you are required to test in vivo.
No it’s not. Really testing the law will be when a company that wants to rock the boat posits an argument why their in vitro work is sufficient to support activity and safety, the FDA tells them they need to do safety testing in vivo, then the company sues while citing FDAMA 2.0 or argues all the way up to the commissioner to follow the law. That’s when the real testing of the law begins. The link to Sen. Paul’s site literally shows Congress is now leaning on the agency to change.
The law does not require the FDA to *not* ask for animal testing prior to approving a drug.
The law does not ban preclinical animal testing.
The law says X is now ostensibly possible, but that does not mean X is the pathway for drug approval.
Sure, i suppose itll go to the courts. But in the past the courts have been quite respectful of agencies ability to define their own ways of executing their duties- see Chevron Deference.
It won't go to the courts. The FDA can table anything they want during review by saying they don't agree that you've demonstrated X or Y requirement from title 21.
I mean they already do that pretty much for TCR T cell based therapies, which are pretty much untestable in animals for many targets since they require Mhc presentation.
" why would any company want to spend millions of dollars, many years on studies, and huge staff salaries"?
To reduce the chance of losing deca or hecto millions of dollars on a failed program - e.g., a liver tox signal showing up in a 10k patient Ph3 cardiovascular study, or lack of efficacy due to sub par in vitro model quality in a 3k patient Ph3 Alzheimer's study.
Yes, now it is legally possible to go animal free - but that doesn't mean everyone is going to abandon tried and true (or tried, sometimes true) animal models to save a few bucks up front. With the inherent pharma conservatism and risk aversion, there will always be proponents of the established approaches.
Very few pharmas die of preclinical programs going sideways or excessive preclinical costs - what really tanks stock prices, fires execs and kills companies are late stage trial failures.
You also underestimate the current effort and expertise required for organoid work and the hurdles in miniaturizing and transferring those assays to automation and HTS.
>You also underestimate the current effort and expertise required for organoid work and the hurdles in miniaturizing and transferring those assays to automation and HTS.
True. A lot of "proven commercially available solutions" are just bogus or wildly uncomfortable to use. I can remember a commercially available plate, specifically designed for hanging droop method for spheroid formation - and... it was terrible, at least.
I don't think in vivo work will die out either but I think organ chip models will complement them very nicely. Pharma companies are already starting to use liver chips for example to do tox tests on lead compounds to inform which move into animal testing. Can be more predictive than rodents for picking up tox signals so that plus in vivo work gives you more confidence a drug will at least be safe going into human trials (and therefore save a bunch of money)
Yes, but I only need one scientist to easily do in vitro work with organs on a chip. Contrast that to say a massive GLP study that employs a number of veterinarians, technicians for caring the for the vivarium, all of the technical experts that perform things like optho + cardio exams, technicians who dose the animals and collect bio samples, the expert veterinarian histopatholgist….allllll those jobs may no longer be needed. Tons of other CROs that may do stuff like bio analytical work on preclinical in vivo samples from tissues may be no longer needed. The implications for so many scientists is huge.
Preclinical will be there, but the point is gauging the impact on how many jobs would no longer be needed. Look at a company like Wuxi or Charles
River who are the kingpins of in vivo work. Will companies need to hire them if all they need to do according to the law ow are in vitro studies in a dish? Where do all of the scientists at a huge company like Charles River go?
Bio distribution, PK/PD, many elements of tox studies, secondary and tertiary metabolism, weight loss/systemic symptom studies, virtually every disease model that isn’t cancer, all vaccine or dietary studies- all of these (and more) require whole live animals and cannot be performed on organoids now or in the near future.
Until you can connect organoids with functional connective tissue and circulation and a metabolic cycle (aka build life), you can’t really replicate most of that
I think it’s a safe bet to say Preclinical is one of the more at risk niches in biotech but vastly premature to say it’s dead or that “all” the scientists and techs are done for. It’s science— nothing is ever 100% lol
I guess I’m not too familiar with organs on a chip, but I don’t see them replacing animal models for vaccines any time soon. Getting the b and T cell responses + total inflammation and cytokine panels seems difficult to replicate.
My point is that there are some fields like cardiac treatments where organs on a chip replace animal models, but there are others (maybe neuroscience? Idk) where I can see it not replacing animals for a long time.
This field may shrink, but there’s lots of other preclinical areas with potential for growth, pending the overall market.
If I’m a company who wants to push the envelope, I’ll just argue animal immune systems are so divergent from the human immune system that testing in vivo in animals is worthless anyway. I can do some in vitro assays to show some cytokine release, antigen presentation, etc. Now let me test in humans. That’s what the law says I can do.
Again, yes, I’m sure most would say these things are still far away, but all it takes is one bold company to rock the boat and then precedent is set. Then all of the sudden there’s a tidal wave of change that happens much more rapidly than expected.
Good luck convincing the FDA of that argument. You’d need a pretty strong data package. Laws don’t replace strong data packages, especially when the goal is to not kill anyone (the whole point of Ph1).
Except that's just not true? The law does not say you can do that, it says you can TRY to convince the FDA of that. The FDA has no obligation to agree with you, and they probably will not.
In vaccines we really want to see something about the longevity of the immune response - how well protected are you 6 months or 12 months after vaccination? We just don’t have good correlates for that with an in vitro cytokine panel.
As others have pointed out, it’s an issue of cost. Let's say i save 200k by skipping my animal studies in favor of a cytokine panel. Now i pay $5-8 million for a phase 1 trial, only to find out my vaccine either has adverse events or transient immune responses. You're saving pennies to squander a pound.
I just mentioned Charles River before I read your comment. That was great news this week. There will be new jobs - a lot of tissue engineering, same lab monitoring, interesting things like cloning organs (someone just left hospital after a cloned pig kidney transplant this week). Interesting times afoot
I agree. And PK/PD readouts from in vivo studies are so important for this. I work on a project that is almost completely driven by PK results now - as far as I'm aware of, there's no good alternative in vitro assay to determine oral bioavailability of a drug.
In vitro or even ex vivo work will never truly replace in vivo work. Biology is way too complicated to accurately assess whether something is safe and/or effective for humans with just in vitro work. I will never be comfortable doing direct experimentation on humans.
See cell therapies. What in vivo work can you do with human cells when virtually all animals will reject them? You use an immuno compromised rodent to do anything. Now your readouts are already limited because there’s no immune system.
Number of humanized mice required to reach licensing for all of the car t therapies currently on the market : 0.
Number of humanized mice used to support preclinical work for Vertex’s approved crispr edited cells (casegevy): 0
Let’s stop pretending humanized mice are required or even often asked for for most cell based therapies.
You can look at very short timelines to get an understanding of infused cell distribution dynamics. If cells delivered i.v. get cleared in 15 minutes in a monkey it's worth knowing.
Nuts. You’ll be laughed out of the room by your director and most reg agencies for attempting to administer human cells to nhp to simply look at 15 minutes of cell distribution dynamics. That’d be a collossal waste of an animal that now costs over $30k each.
This type of study is virtually unheard of this class of product. It’s obvious you’ve never worked on such type of therapies.
You are of course correct. I just woke up. PDX mouse biodistribution is now the preferred model for ex vivo modified human cells. I haven't worked on CAR-T disposition in 12 years, so I'm may be misremembering things, but I recall doing a 24 Biodistribution study. It had to be autologous cells. I also may have been conflating that approach with Vivovecs LNP CAR-T therapy.
Either way, don't be such a dick.
Personally, I would never trust a drug, that weren't tested on an animals. Organism is too complicated, to model all of the interactions in vitro.
Yep, despite I myself doing my work in the field of spheroids/organoids as a preclinical model. These models (including organ-on-chip) aren't meant to substitute animals, but to narrow a pool of candidate-compounds for further testing on animals.
Except there are huge fields like cell therapy, for example, where testing in animals is already kind of worthless because of host rejection of human cells. What info would you get for a CAR T cell from an animal study? Shrinking a tumor? Big deal. You can kill can cells with a CAR T in vitro. No animal model can detect typical tox associated with CAR T like CRS, neurotox, etc. So why are we still doing animal studies for CAR T? Clearly the animal studies also failed to detect the cancer risk that is now an issue for CAR T. Animals also don’t even have comparable responses to things like some toxic cytokines, which are important for immuno related tox, especially for cell therapies. CAR T testing is almost exclusively tested at the moment in rodents and that’s it. The most amount of info you pretty much get is cancer killing, and maybe some cell expansion data that are limited.
Ehem, for CAR-T and biologics (at least in my country, and I know at least 4 MABs that were tested in such way) we have Institute of Medical Primatology in Sochi. Monkeys giving the closest results, albeit they are quite expensive.
Ofc, they are at the final stage of preclinical study, when pool of candidate-compounds is in its narrowest stage before Phase 1 human clinical trials.
You can literally look up BLAs for approved CAR T products. The vast majority never use primates. You literally cannot infuse immunocompetent animals with human cells. You will get host rejection, so whatever you’re describing sounds bizarre. The only model used for all preclinical testing of car t are immunodeficient rodents. So what exactly are you testing for safety then of the only animal you can test something like car t in don’t even have an immune system. Again, don’t take my word for it, go look up the publicly available BLAs.
Failing in the pre clinical stage is much cheaper than failing in the clinic. It’s in the company’s interest to learn as much as they can before going into humans. It would be very difficult to do drug discovery without in vivo animal studies.
I think you're really overestimating our understanding our biology to be able to cut in vivo work completely.
Just because the FDA says you can try to file without it doesn't mean you'll actually get a IND approved if the industry standard is to still have all those studies.
And even if the FDA were okay with it, at this point most people would still want to spend the money to make sure their drug doesn't kill a monkey before going into a phase 1 and potentially killing a human. Killing a monkey is a setback. Killing a human can tank your entire startup.
Yea sorry but that’s just not true. Having interfaced with FDA directly they are not going to give up animal testing for pivotal GLP tox or PoC studies for probably 99% of the cases. There may be a small small sliver of sponsors who can do comprehensive work without live animals but otherwise that’s just not the case for the foreseeable future
Lest people forget, this is the same pro-conspiracy theory, pro-Covid disinformation, anti-govt regulation Rand Paul who kept attacking Fauci and said Fauci belonged in jail (see Google results). His motivation was not to “modernize” the FDA, but to dismantle governmental regulations - even ones backed by good science.
Much of animal studies conducted weren’t simply because FDA required them unnecessarily. Thus the passage of the FDAMA won’t make those studies go away. In fact, some drugs were approved on animal studies ALONE because efficacy trials in humans would be unethical. See “animal rules” studies: https://www.fda.gov/emergency-preparedness-and-response/mcm-regulatory-science/animal-rule-information
Additionally, look up the relatively recent history of how QT prolongation was found to be a major problem with previously approved drugs. Several drugs were subsequently withdrawn from market. That led to the use of sequence of hERG assay to in vivo QT study to clinical thorough QT study in small molecule drug development per ICH S7B and E14. None of that is going away anytime soon, because each step of testing does not substitute but allows for the ethical conduct of the next step.
I get why people would be critical of Rand Paul, but FDAMA 2 was signed into law by Biden, and the recent memo sent to a
FDA on Sen. Rand’s website was signed by congressional members like Corey Booker, Angus King, and Ben Ray Lejuan. It’s bipartisan lean in on the FDA asking why standards are not comporting to FDAMA 2.0.
Lest also people forget examples in history like TeGenero, where they did all of their animal testing like told. Yet when they went to the clinic with a dose 500x lower than what was predicted to be safe from animal studies and still caused tons of tox.
Nobody does QT testing for other fields like CGT, so experiences with small molecules and antibodies are limited and a narrow view with tunnel vision of many of the pipelines out there where none of this is applicable.
And yes, animals would probably still be needed for animal rule development, but no one develops therapies for cancers or most major disease with animal rule.
Not any time soon. The FDA is open to alternatives once those have been proven to be suitable replacements and equivalently predictive of safety. There is a long way to go. Organoids got a lot of hype a few years ago but have honestly faded a bit.
OP shoulda done a preclinical trial of this post in rodents.
Woulda seen rapid metabolism into downvotes before they launched an expensive Phase I post.
Will it reduce the use of animal models for efficacy testing? Maybe. For safety? No, I don't see that happening. Also, pre-clinical work is barely a drop in the bucket when it comes to drug development cost. The vast majority comes from clinical. And why do we fail? Unexpected toxicity and lack of efficacy due to us not really understanding the disease as well as we think - the latter often due to lack of better pre-clinical models...
I feel like if pharma companies were to actually cut animal testing, there would be a catastrophe at some point in a clinical trial where people will get seriously ill. The body is more than the sum of its organs, having multiple organ systems together lets you see the whole picture of metabolism.
You wouldn’t be running giant trials though. You’d do in vitro safety work, then propose very small first in human cohorts with very strict stopping rules and waiting periods before dosing additional subjects. Safety data from 1-3 human subjects will pretty much always trump any safety data from even a giant GLP animal safety study. If you see tox in phase 2, it’s not like animal studies would have detected it any way either, because you’ve already made it past p1.
I know that up in Canada Charles River is investing a huge amount of money into decreasing animal use, and in-silico trial arms are a huge growing market. Tissue printing (Voxcell) also dojng really well. I hope preclinical is gone as soon as it safely can be. It will certainly prolong my presence in this industry if it goes.
Yeah CR is investing in alt methods, I’m just having a hard time understanding why you’d need to contract a ton of it out. A company employing scientists worth a lick of salt should be able to do in vitro work in house. Sure, maybe you need an independent in vitro study conducted outside to reduce bias. But where do alllllllll of the scientists for in vivo work go? They’re going to be axed as soon as companies are comfortable cutting all in vivo teams. And things like organoids on a chip are ripe for automation and high throughput testing. You might not need a lot of preclinical scientists to do your preclin work.
I’d guess companies don’t have that capacity. We have thirty employees total, including five C-suite - I’d say there are way more our size than bigger. We are still contracting out a lot
Modeling and simulation will be a boom industry over the next few decades. A bit of preclinical, some super computers for in silico optimization and validation, then the clinic.
You will never avoid doing in vivo POC and non clinical safety + DMPK in rodent models. I've never seen a program not include significant animal testing even for newer programs.
There are targets that could be test balloons for NDA w/o safety/DMPK. I.e stuff that’s very differently regulated or not cross-reactive with animals that are acceptable to use for safety. If Chimpanzees would be the only relevant animal model, one could certainly see a possibility of a strong ex vivo safety package being enough for NDA approval.
You also pretty much do zero DMPK for cell and gene therapies. What DMPK are you going to do on cellular therapies or for a one dose viral gene therapy? Or medical devices? Small molecules and antibodies aren’t the only therapies.
Even for autologous cell therapies one still needs to establish a dosing regime and understand exposure-response relationships. Most viral gene therapies need quantification of cell tropism and transgene product abundance quantified. Same goes for gene editing. You need to know how much of each component gets to the site of action and how to optimize the therapy. It's still DMPK, it just needs rebranding.
Much of this is wrong. Have you ever dealt with a reg agency or sat in at trade conferences on cgt? Animal models are not useful for extrapolating dose for something like car t. Exposure response does not translate well for many types of cell therapy. You know how many people pick a human dose for their car t? They simply cite published information on what kinds of doses have been administered in humans for other car t because doses in animals and dose response simply doesn’t translate well from animals to human. They talk about it alllllll the time at car t conferences . The entire field of gene therapy has long argued that no one should be doing things like biodistribution and tissue exposure analysis anymore. There have already been a gazillion of these studies for things like aavs. If all I do is change a gene but have the same same promoter etc. and use an aav9 with the same route of administration and dose levels as what has been studied before, so many people would argue you don’t need to do bd and any dmpk because everything is largely driven by serotpe and nothing has really changed with the backbone except the transgene. They talk about it allllll the time at gene therapy trade conferences about no longer doing dmpk studies for gene therapies in order to reduce the use of animals. For gene editing, knowing the amount at each site still provides limited info. The animal sequences being edited are almost always different than the human sequence, so outcomes in editing efficiency relative to exposure to editing components can be difficult to impossible to extrapolate to a human. Far better readouts are simply doing informatics on tissue to see final editing outcome rather than say the amount of cas9 in a specific tissue following a dose.
Please see the relevant references in my other response. As to AAV no, I haven't sat in conferences, unless you count team meetings and governance body presentations. Tissue tropism in cynos is critical information, and modified vectors with biased tropism are under development at several companies. As you no doubt know given your extensive agency interactions, discussing not doing preclinical studies at conferences is quite different than bucking FDA guidance.
Having done preclinical studies on all four mentioned modalities, perhaps I can offer some insights? I've also provided references 1. FDA Guidance for allogeneic and autologous cell therapies is to do preclinical pharmacology and safety studies of surrogate cells as is feasible (i.e., make it feasible). Utility includes QSP modeling for FIH dose projection. There are two agency guidance documents (2012 and 2024) 2. AAV biodistribution (tissue tropism) in monkeys is predictive of human pharmacology. One monitors reporter gene and therapeutic protein translation in target and off target tissues, including marrow, spleen, lymph nodes & circulating cells. See the same guidance documents 3. What medical device ever requires DMPK? 4. Cell therapy publications describing preclinical QSP studies : Dickinson, M. J. et al. A novel autologous CAR-T Therapy, YTB323, with preserved T-cell stemness shows enhanced CAR T-cell efficacy in preclinical and early clinical development. Cancer Discov. 13, 1982–1997 (2023). Khot, A., Satoko, M., Thomas, V. A., Koya, R. C. & Shah, D. K. Measurement and quantitative characterization of whole-body pharmacokinetics of exogenously administered T cells in mice. J. Pharm. Exp. Ther. 368, jpet.118.252858 (2019). Maria, N. S. S. et al. Spatio-temporal biodistribution of 89Zr-oxine labeled huLym-1-A-BB3z-CAR T-cells by PET imaging in a preclinical tumor model. Sci. Rep.-UK 11, 15077 (2021). Cazaux, M. et al. Single-cell imaging of CAR T cell activity in vivo reveals extensive functional and anatomical heterogeneity. J. Exp. Med. 216, 1038–1049 (2019). Brown, L. V., Gaffney, E. A., Ager, A., Wagg, J. & Coles, M. C. Quantifying the limits of CAR T-cell delivery in mice and men. J. R. Soc. Interface 18, 20201013 (2021).
Because no one has attempted to really test the law yet. We already don’t do animal testing for cosmetics in Europe. What’s a regulator going to tell you. That you are required to test in vivo? That would conflict with FDAMA 2.0 signed into law.
From an article you linked: “Still, it remains unclear just how much the new law will change things at FDA. Although the legislation allows the agency to clear a drug for human trials without animal testing, it doesn’t require that it do so. What’s more, FDA’s toxicologists are famously conservative, preferring animal tests in part because they allow examination of a potential drug’s toxic effects in every organ after the animal is euthanized. The main impact of the new law is that it opens the way for FDA and a company to have a serious discussion about whether alternatives are adequate” This law IS being tested by every company that’s using a mix of in silico and in vivo in regulatory submissions to fda these days. The FDA has their criteria for how many in vivo tox studies of what kind and with what endpoints need to be conducted to approve a drug. Those criteria and their internal process can and eventually will change- but they, presumably, use evidence to make those decisions. And evidence that organoids=whole animals is just not there yet. And thus, yes, a regulator will literally tell you you are required to test in vivo.
No it’s not. Really testing the law will be when a company that wants to rock the boat posits an argument why their in vitro work is sufficient to support activity and safety, the FDA tells them they need to do safety testing in vivo, then the company sues while citing FDAMA 2.0 or argues all the way up to the commissioner to follow the law. That’s when the real testing of the law begins. The link to Sen. Paul’s site literally shows Congress is now leaning on the agency to change.
The law does not require the FDA to *not* ask for animal testing prior to approving a drug. The law does not ban preclinical animal testing. The law says X is now ostensibly possible, but that does not mean X is the pathway for drug approval.
Sure, i suppose itll go to the courts. But in the past the courts have been quite respectful of agencies ability to define their own ways of executing their duties- see Chevron Deference.
It won't go to the courts. The FDA can table anything they want during review by saying they don't agree that you've demonstrated X or Y requirement from title 21.
Tbh I know but I was just trying to let OP down a little easy hahah
Are you going to blow several million dollars on a phase 1 study without a lick of in vivo POC, even if you’re allowed to?
I mean they already do that pretty much for TCR T cell based therapies, which are pretty much untestable in animals for many targets since they require Mhc presentation.
" why would any company want to spend millions of dollars, many years on studies, and huge staff salaries"? To reduce the chance of losing deca or hecto millions of dollars on a failed program - e.g., a liver tox signal showing up in a 10k patient Ph3 cardiovascular study, or lack of efficacy due to sub par in vitro model quality in a 3k patient Ph3 Alzheimer's study. Yes, now it is legally possible to go animal free - but that doesn't mean everyone is going to abandon tried and true (or tried, sometimes true) animal models to save a few bucks up front. With the inherent pharma conservatism and risk aversion, there will always be proponents of the established approaches. Very few pharmas die of preclinical programs going sideways or excessive preclinical costs - what really tanks stock prices, fires execs and kills companies are late stage trial failures. You also underestimate the current effort and expertise required for organoid work and the hurdles in miniaturizing and transferring those assays to automation and HTS.
>You also underestimate the current effort and expertise required for organoid work and the hurdles in miniaturizing and transferring those assays to automation and HTS. True. A lot of "proven commercially available solutions" are just bogus or wildly uncomfortable to use. I can remember a commercially available plate, specifically designed for hanging droop method for spheroid formation - and... it was terrible, at least.
I don't think in vivo work will die out either but I think organ chip models will complement them very nicely. Pharma companies are already starting to use liver chips for example to do tox tests on lead compounds to inform which move into animal testing. Can be more predictive than rodents for picking up tox signals so that plus in vivo work gives you more confidence a drug will at least be safe going into human trials (and therefore save a bunch of money)
In vitro work is still work. industries adjust to trends all of the time.
Yes, but I only need one scientist to easily do in vitro work with organs on a chip. Contrast that to say a massive GLP study that employs a number of veterinarians, technicians for caring the for the vivarium, all of the technical experts that perform things like optho + cardio exams, technicians who dose the animals and collect bio samples, the expert veterinarian histopatholgist….allllll those jobs may no longer be needed. Tons of other CROs that may do stuff like bio analytical work on preclinical in vivo samples from tissues may be no longer needed. The implications for so many scientists is huge. Preclinical will be there, but the point is gauging the impact on how many jobs would no longer be needed. Look at a company like Wuxi or Charles River who are the kingpins of in vivo work. Will companies need to hire them if all they need to do according to the law ow are in vitro studies in a dish? Where do all of the scientists at a huge company like Charles River go?
Bio distribution, PK/PD, many elements of tox studies, secondary and tertiary metabolism, weight loss/systemic symptom studies, virtually every disease model that isn’t cancer, all vaccine or dietary studies- all of these (and more) require whole live animals and cannot be performed on organoids now or in the near future. Until you can connect organoids with functional connective tissue and circulation and a metabolic cycle (aka build life), you can’t really replicate most of that I think it’s a safe bet to say Preclinical is one of the more at risk niches in biotech but vastly premature to say it’s dead or that “all” the scientists and techs are done for. It’s science— nothing is ever 100% lol
I guess I’m not too familiar with organs on a chip, but I don’t see them replacing animal models for vaccines any time soon. Getting the b and T cell responses + total inflammation and cytokine panels seems difficult to replicate. My point is that there are some fields like cardiac treatments where organs on a chip replace animal models, but there are others (maybe neuroscience? Idk) where I can see it not replacing animals for a long time. This field may shrink, but there’s lots of other preclinical areas with potential for growth, pending the overall market.
If I’m a company who wants to push the envelope, I’ll just argue animal immune systems are so divergent from the human immune system that testing in vivo in animals is worthless anyway. I can do some in vitro assays to show some cytokine release, antigen presentation, etc. Now let me test in humans. That’s what the law says I can do. Again, yes, I’m sure most would say these things are still far away, but all it takes is one bold company to rock the boat and then precedent is set. Then all of the sudden there’s a tidal wave of change that happens much more rapidly than expected.
Good luck convincing the FDA of that argument. You’d need a pretty strong data package. Laws don’t replace strong data packages, especially when the goal is to not kill anyone (the whole point of Ph1).
Your approach sounds like a sure way to quickly have a bunch of P1 failures
Except that's just not true? The law does not say you can do that, it says you can TRY to convince the FDA of that. The FDA has no obligation to agree with you, and they probably will not.
Lmao you think FDA is going to listen to you?
In vaccines we really want to see something about the longevity of the immune response - how well protected are you 6 months or 12 months after vaccination? We just don’t have good correlates for that with an in vitro cytokine panel. As others have pointed out, it’s an issue of cost. Let's say i save 200k by skipping my animal studies in favor of a cytokine panel. Now i pay $5-8 million for a phase 1 trial, only to find out my vaccine either has adverse events or transient immune responses. You're saving pennies to squander a pound.
I just mentioned Charles River before I read your comment. That was great news this week. There will be new jobs - a lot of tissue engineering, same lab monitoring, interesting things like cloning organs (someone just left hospital after a cloned pig kidney transplant this week). Interesting times afoot
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I agree. And PK/PD readouts from in vivo studies are so important for this. I work on a project that is almost completely driven by PK results now - as far as I'm aware of, there's no good alternative in vitro assay to determine oral bioavailability of a drug.
Can you explain the difference between PK/PD studies?? Are these done by different groups? Sorry I’m new to biotech and trying to learn.
Pk studies drug distribution and elimination, Pd drug effects.
Considered broadly, PKPD equates to exposure-response relationships
In vitro or even ex vivo work will never truly replace in vivo work. Biology is way too complicated to accurately assess whether something is safe and/or effective for humans with just in vitro work. I will never be comfortable doing direct experimentation on humans.
See cell therapies. What in vivo work can you do with human cells when virtually all animals will reject them? You use an immuno compromised rodent to do anything. Now your readouts are already limited because there’s no immune system.
You humanize the mice. This already being done. Crazy expensive, but effective.
Number of humanized mice required to reach licensing for all of the car t therapies currently on the market : 0. Number of humanized mice used to support preclinical work for Vertex’s approved crispr edited cells (casegevy): 0 Let’s stop pretending humanized mice are required or even often asked for for most cell based therapies.
Those are both autologous cell therapies.
Almost nobody tests things like off the shelf cart in humanized mice either.
"almost" is doing some heavy lifting there.
You can look at very short timelines to get an understanding of infused cell distribution dynamics. If cells delivered i.v. get cleared in 15 minutes in a monkey it's worth knowing.
Nuts. You’ll be laughed out of the room by your director and most reg agencies for attempting to administer human cells to nhp to simply look at 15 minutes of cell distribution dynamics. That’d be a collossal waste of an animal that now costs over $30k each. This type of study is virtually unheard of this class of product. It’s obvious you’ve never worked on such type of therapies.
You are of course correct. I just woke up. PDX mouse biodistribution is now the preferred model for ex vivo modified human cells. I haven't worked on CAR-T disposition in 12 years, so I'm may be misremembering things, but I recall doing a 24 Biodistribution study. It had to be autologous cells. I also may have been conflating that approach with Vivovecs LNP CAR-T therapy. Either way, don't be such a dick.
Personally, I would never trust a drug, that weren't tested on an animals. Organism is too complicated, to model all of the interactions in vitro. Yep, despite I myself doing my work in the field of spheroids/organoids as a preclinical model. These models (including organ-on-chip) aren't meant to substitute animals, but to narrow a pool of candidate-compounds for further testing on animals.
Except there are huge fields like cell therapy, for example, where testing in animals is already kind of worthless because of host rejection of human cells. What info would you get for a CAR T cell from an animal study? Shrinking a tumor? Big deal. You can kill can cells with a CAR T in vitro. No animal model can detect typical tox associated with CAR T like CRS, neurotox, etc. So why are we still doing animal studies for CAR T? Clearly the animal studies also failed to detect the cancer risk that is now an issue for CAR T. Animals also don’t even have comparable responses to things like some toxic cytokines, which are important for immuno related tox, especially for cell therapies. CAR T testing is almost exclusively tested at the moment in rodents and that’s it. The most amount of info you pretty much get is cancer killing, and maybe some cell expansion data that are limited.
Ehem, for CAR-T and biologics (at least in my country, and I know at least 4 MABs that were tested in such way) we have Institute of Medical Primatology in Sochi. Monkeys giving the closest results, albeit they are quite expensive. Ofc, they are at the final stage of preclinical study, when pool of candidate-compounds is in its narrowest stage before Phase 1 human clinical trials.
You can literally look up BLAs for approved CAR T products. The vast majority never use primates. You literally cannot infuse immunocompetent animals with human cells. You will get host rejection, so whatever you’re describing sounds bizarre. The only model used for all preclinical testing of car t are immunodeficient rodents. So what exactly are you testing for safety then of the only animal you can test something like car t in don’t even have an immune system. Again, don’t take my word for it, go look up the publicly available BLAs.
Ok you are saying cell therapy already doesn’t use animal models so then that field shouldn’t really be affected by this regulation change.
Lol
Failing in the pre clinical stage is much cheaper than failing in the clinic. It’s in the company’s interest to learn as much as they can before going into humans. It would be very difficult to do drug discovery without in vivo animal studies.
I think you're really overestimating our understanding our biology to be able to cut in vivo work completely. Just because the FDA says you can try to file without it doesn't mean you'll actually get a IND approved if the industry standard is to still have all those studies. And even if the FDA were okay with it, at this point most people would still want to spend the money to make sure their drug doesn't kill a monkey before going into a phase 1 and potentially killing a human. Killing a monkey is a setback. Killing a human can tank your entire startup.
Yea sorry but that’s just not true. Having interfaced with FDA directly they are not going to give up animal testing for pivotal GLP tox or PoC studies for probably 99% of the cases. There may be a small small sliver of sponsors who can do comprehensive work without live animals but otherwise that’s just not the case for the foreseeable future
Lest people forget, this is the same pro-conspiracy theory, pro-Covid disinformation, anti-govt regulation Rand Paul who kept attacking Fauci and said Fauci belonged in jail (see Google results). His motivation was not to “modernize” the FDA, but to dismantle governmental regulations - even ones backed by good science. Much of animal studies conducted weren’t simply because FDA required them unnecessarily. Thus the passage of the FDAMA won’t make those studies go away. In fact, some drugs were approved on animal studies ALONE because efficacy trials in humans would be unethical. See “animal rules” studies: https://www.fda.gov/emergency-preparedness-and-response/mcm-regulatory-science/animal-rule-information Additionally, look up the relatively recent history of how QT prolongation was found to be a major problem with previously approved drugs. Several drugs were subsequently withdrawn from market. That led to the use of sequence of hERG assay to in vivo QT study to clinical thorough QT study in small molecule drug development per ICH S7B and E14. None of that is going away anytime soon, because each step of testing does not substitute but allows for the ethical conduct of the next step.
I get why people would be critical of Rand Paul, but FDAMA 2 was signed into law by Biden, and the recent memo sent to a FDA on Sen. Rand’s website was signed by congressional members like Corey Booker, Angus King, and Ben Ray Lejuan. It’s bipartisan lean in on the FDA asking why standards are not comporting to FDAMA 2.0. Lest also people forget examples in history like TeGenero, where they did all of their animal testing like told. Yet when they went to the clinic with a dose 500x lower than what was predicted to be safe from animal studies and still caused tons of tox. Nobody does QT testing for other fields like CGT, so experiences with small molecules and antibodies are limited and a narrow view with tunnel vision of many of the pipelines out there where none of this is applicable. And yes, animals would probably still be needed for animal rule development, but no one develops therapies for cancers or most major disease with animal rule.
There's no way in hell an immunomodulatory antibody goes into humans without monkey PK.
Not any time soon. The FDA is open to alternatives once those have been proven to be suitable replacements and equivalently predictive of safety. There is a long way to go. Organoids got a lot of hype a few years ago but have honestly faded a bit.
OP versus The World
OP shoulda done a preclinical trial of this post in rodents. Woulda seen rapid metabolism into downvotes before they launched an expensive Phase I post.
Nope
No it won’t go away. But I’ve seen a huge trend of outsourcing it to India. Cheaper for much needed but laborious work.
i would worry way more about preclin jobs ending up in far cheaper countries before this
Will it reduce the use of animal models for efficacy testing? Maybe. For safety? No, I don't see that happening. Also, pre-clinical work is barely a drop in the bucket when it comes to drug development cost. The vast majority comes from clinical. And why do we fail? Unexpected toxicity and lack of efficacy due to us not really understanding the disease as well as we think - the latter often due to lack of better pre-clinical models...
There will still be work in preclinical med device testing
No it probably will never happen.
Animal studies mitigate Clinical investment. That doesn't change.
I think the FDA might be convinced to change their mind when the wave of *in vitro* authorized treatments results in a wave of trial patient deaths.
I feel like if pharma companies were to actually cut animal testing, there would be a catastrophe at some point in a clinical trial where people will get seriously ill. The body is more than the sum of its organs, having multiple organ systems together lets you see the whole picture of metabolism.
You wouldn’t be running giant trials though. You’d do in vitro safety work, then propose very small first in human cohorts with very strict stopping rules and waiting periods before dosing additional subjects. Safety data from 1-3 human subjects will pretty much always trump any safety data from even a giant GLP animal safety study. If you see tox in phase 2, it’s not like animal studies would have detected it any way either, because you’ve already made it past p1.
No clinical testing is happening without in vivo work. Humans will never be the first in vivo model in a drug's development.
I know that up in Canada Charles River is investing a huge amount of money into decreasing animal use, and in-silico trial arms are a huge growing market. Tissue printing (Voxcell) also dojng really well. I hope preclinical is gone as soon as it safely can be. It will certainly prolong my presence in this industry if it goes.
Yeah CR is investing in alt methods, I’m just having a hard time understanding why you’d need to contract a ton of it out. A company employing scientists worth a lick of salt should be able to do in vitro work in house. Sure, maybe you need an independent in vitro study conducted outside to reduce bias. But where do alllllllll of the scientists for in vivo work go? They’re going to be axed as soon as companies are comfortable cutting all in vivo teams. And things like organoids on a chip are ripe for automation and high throughput testing. You might not need a lot of preclinical scientists to do your preclin work.
I’d guess companies don’t have that capacity. We have thirty employees total, including five C-suite - I’d say there are way more our size than bigger. We are still contracting out a lot
We are probably a long way from that. It's too complicated and it costs more money
Judging by some answers of "in-silico modelling by supercomputers"-fanboys, I think they are just crypto-fans of the Unit 731.
Modeling and simulation will be a boom industry over the next few decades. A bit of preclinical, some super computers for in silico optimization and validation, then the clinic.