Pre-clinical Development - Science topic

Hi Rashmi Patil

This has been observed due to a phenomenon called as "historical bias" where male mice were used by default for the majority of studies and hormonal considerations were the major excuse.

Thanks,

Hi, there are lots of papers implying the role of sex hormones on mood regulation, and perceptual and cognitive performance. These effects would be more pronounced if the hormones also change significantly in a periodic manner like female cyclic alterations. So, when you select male samples you are accepting the role of sexual hormones but you are controlling for the fluctuations (which is another layer of variation). Rashmi Patil

Hi

There is no specific guidance by the FDA or guideline by EMA. But some information should be helpful:

and in general: https://www.fda.gov/search?s=organoid

Hope it helps

Best regards

Tomasz

Mimicking physiological conditions or clinical situations is critically important for the success of translational research. This is due to the fundamental premise of translational research: translating fundamental scientific discoveries into practical, clinical applications.

Accurate replication of the human body's environment helps ensure that the results obtained in the lab can be applicable to real-world scenarios. It enables us to understand the biological and molecular pathways that govern health and disease more accurately, which is essential for creating effective treatments and interventions.

For instance, cells behave differently under in vitro conditions compared to in the human body. Thus, research models that closely mimic human physiology provide a more realistic view of how cells function and interact, improving the reliability and accuracy of findings.

In drug discovery and development, understanding the precise physiological conditions can aid in predicting a drug's effectiveness and potential side effects. In vitro testing often lacks the complexity of the human body, which could lead to incorrect assumptions about drug safety and efficacy. By mimicking physiological conditions, we can better predict how a drug will behave in the body, increasing the likelihood of successful clinical trials.

Furthermore, considering the clinical situation can enhance the relevance of research outcomes. This takes into account the complexities of disease progression, comorbidities, patient lifestyle, and other factors that can influence treatment effectiveness.

In summary, mimicking physiological conditions and considering the clinical situation can enhance the realism, relevance, and potential success of translational research, bridging the gap between lab-based findings and clinical application.

There are a number of journals specifically for the publication of negative results.

You could also publish it as a preprint on a site like medRxiv, which would save you the process of having your negative results going through peer review and taking on any associated costs of publication.

Hi,

As you said in the question, the goal determines the type of model (pre-clinical). The type of clinical trial determines our choice. The key to the selection is whether the model is relevant. For example, another model we need when you aim to assess absorption by skin tissue only to show the difference between two SC formulations at the absorption phase of the drug which is approved and from 30 years on the market. Another model you need is when your drug candidate will go to First in Human study. Consequently, model/species selection depends on different contexts and could be different depending on future needs:

Pre-clinical means before clinical development. In the case of one drug development sometimes numerous models are used in one project across the whole development process good example is a therapeutic monoclonal antibody (Tysabri) where numerous studies were performed across the drug development process:

Single & repeated dose tox studies

Pharmacokinetics after a single dose and repeated dose

Toxicokinetics

Cardiovascular profile after a single dose

Reproductive toxicity

Carcinogenicity

PK linearity

Single dose PK/PD comparability study (different processes),

Single dose bioequivalence study (formulation buffers),

PK comparability between two different stages of drug development

Interactions with interferon PK/PD study

Reference for this example Pharmacology reviews package 1-6:

And the final conclusion:

“All models are wrong, but some are useful” as said George Box

and my :-)

Best regards

Tomasz

Paid software recommendations would be fine as well....

Dear Hakan,

normally and with very few exceptions, female animals always have to be included into regulatory acceptable preclinical studies. Exceptions are some in vivo genotox studies where male rats/mice have a proven higher susceptibility. If you refer to the respective ICH guideline documents, that is stated clearly. Some experimental work, especially in reproductive toxicology, ONLY can be conducted in females ;-).

Hope that answers your question.

All the best, Geertje

Hi

Generally, the BSA dosing paradigm has more than 50 years, and it's based on observations explained in FDA Guidance based on two papers:

"antineoplastic drugs, doses lethal to 10 percent of rodents (LD10s) and MTDs in nonrodents both correlated with the human MTD when the doses were normalized to the same administration schedule and expressed as mg/m²".

Allometric scaling (conversion) approaches suggested by different Authorities cover rather BW not BSA in relation to PDE. ICH, FDA, EPA, ECHA suggest BW^0.75 or BW^0.67 depending on species and approach. It is suggested that BW^0.67 correlates more closely with surface volumes and BSA. See the Sussman paper below:

Best regards

Tomasz

Have a look at this useful RG link.

To me, when thinking about those words and their common uses, I have them divided up in my head a certain way. Your mileage may vary, but here's how I use them.

Acclimation and acclimatization are the same thing-- getting used to life at a different place than the animal producer. I like acclimation better as acclimatization just seems....extra.

Habituation is getting used to something happening--animals are habituated to restraint, they are habituated to a behavioral testing apparatus.

And finally, adaptation is a longer-term event occurring at the species level to permanent changes--the rats are adapted to living at altitude; the mice have adapted to desert life.

I think it would also depend on the variability of the results so far. You may need to increase the number of animals, dosage range etc.

if you have statistically significant results already in one model then extension to another model would be valuable.

What market are you referring to?

If in the EU, the former MDD, and now the new Medical Device Regulations (MDR) state sufficient clinical evidence must be provided commensurate with the risks of the device. Integral to this aim is having a very clear and robust Risk Management process. This would involve of course having an intimate understanding of the use, benefits and risks associated with the device from various resources (eg, background education, literature, user discussions, adverse event analysis, etc.). If a clinical investigation is deemed appropriate, then you should be sure it addresses the risk and supports the claims of intended use.

You should hire a consultant if you are uncertain about this.

Dear Jean,

Best source of preclinical data you can find at accesdata FDA site (keywords for google: "accesdata", "FDA", "drug name"). Of course its work if such data exist.... in your case I cant find any pdf's with data. Not agree with Tomas that humanisation excluding from animal testing. Huge group of monoclonals (including fully human guselkumab, binds selectively to IL-23 ) are tested in different phases of preclinical works using animal models even if they are fully human. Of course humanisation is source of immune responce and antihuman antibodies production. If they are neutralizing then high clearance can affect the study but in general this feature not excluding such drugs from preclinical development with animal models. Key problem for applicability of animal model is not humanization but question how relevant is the model. Is it only PK relevant or PD relevant too (affinity to the target). But even if affinity is much lower than in humans preclinical animal studies are still approved and still useful (The affinity of certolizumab to cyno TNF is 44 x lower than for human, affinity of ranibizumab to rabbit VEGF is 40 x lower than for human, but cyno and rabbit are approved by Health Authorities as models). Some nice citations below could be useful for your future works,

https://www.ema.europa.eu/en/documents/scientific-guideline/ich-s6r1-preclinical-safety-evaluation-biotechnology-derived-pharmaceuticals-step-5_en.pdf

Guidance for Industry Scientific Considerations in Demonstrating Biosimilarity to a Reference Product FDA 2012

Best regards

Tomasz

Dear Chenxiao Tang,

To check what is the role of MTD in FIM studies please download FDA guidance:

https://www.fda.gov/media/72309/download

Sense of dose/response studies explain next FDA guidance:

https://www.fda.gov/media/71277/download

" This exposure-response guidance focuses on human studies, but exposure-response information in animal pharmacology/toxicology studies is also a highly useful component of planning the drug development process (Peck 1994; Lesko 2000). "

" Biomarkers can also be useful during the drug discovery and development stage, where they can help link preclinical and early clinical exposure-response relationships and better establish dose ranges for clinical testing."

" Exposure-response data can be derived from these clinical studies, as well as from other preclinical and clinical studies, and provide a basis for integrated model-based analysis and simulation (Machado et al. 2000; Sheiner and Steimer 2000)."

" It emphasizes the importance of conducting an integrated analysis of all clinical and preclinical exposure-response data that forms the foundation for dose and dosing regimen determinations and dose adjustments for subpopulations. "

Hope it helps,

Best regards,

Tomasz

Hello everybody,

I know this would be a delayed response, but I just now came across this question. And if you haven't came across with any of the better solutions yet, this could potentially assist you.

Firstly, I suggest you rather than looking for some specific pre-clinical studies database, I would recommend you to go with MEDLINE, NLM, NIH, NCBI etc. As these all databases has separate entity for pre-clinical studies (animal studies), you can just do this by adding filter to your search.

Secondly, yes! There exists a registry for pre-clinical studies which comprises of protocols. (www.preclinicaltrials.eu)

Finally, as far as my knowledge concerned, GOSTAR doesn't deal with pre-clinical stuff. (As one of the researchers mentioned about it)

I hope, I have answered your question and assumes this could aid you.

Regards.

Novel biomarkers could also include wide range of biomolecules such as micro RNAs, long-non coding RNAs and circular RNAs. you could always start through cancer cell lines beside computational validation.

Thank you!

I am going to check the paper

Best wishes

Hello Gertje Lewin,

Your answer was helpul, I found some articles linked to this purpose.

The hardest part seems to coordinate the biologists' manipulations to the study designs.

Sorry for the delay of answer.

thank you

Sorry I could not find any paper or published article on it.

Thank you for your good critical thinking in preclinical experiments and I agree with your conclusion.

Hi. (Systemic) absorption and bioavailability are often used interchangeably. However, there may be a difference between absorption and bioavailability. This can occur in particular in the case of  liver first pass: the compound is absorbed from the gut into the portal vein but is metabolized extensively by the liver before it reaches the site of sample collection (usually a venous return). In other words good absorption is required for good oral bioavailability but good absorption does not always guarantee good bioavailability.

You may realize this for example by dosing radioactive compound and observe that radioactivity is well absorbed, despite poor bioavailability assessed by a specific bioanalytical assay. Let's say you saw this in the rat.

This could be of relevance for clinical development. You may for example expect absorption in human to be as good as in your rat experiment (other data is indicative of passive absorption). If humans are expected to have slower hepatic metabolism than the rat (e.g. quantitative assessment based on in vitro rat and human liver microsome or hepatocyte data), then liver first pass could be  expected to be low in human and both absorption and bioavailability may be high in human. Best.

I think I have had good effects, particularly when combined with R-lipoic acid.

Thanks Michal, very helpful. Much appreciated

Meta-analysis can be done for any sort of statistical result.  If you have several studies of a similar topic, it is possible that a meta-analysis will be useful. This is true for randomized trials, other randomized studies, observational studies and anything else.

Indeed, they may be even more helpful for observational studies than for experiments.

A meta-analysis serves at least two functions:  1) Increasing power  and 2) Reducing bias.  In a meta-analysis of several experiments, there should be relatively little bias to reduce. 

Hi Jim, thanks for the tips. I agree, a good drug would impact food motivation only, rather than bringing about any counter-obesity effect through some other effect such as on affective state in general. I think the binge eating model is very interesting and useful in many ways, though I wonder how closely it reflects human binge eating, where I suspect periods between binges are driven partially by guilt in addition to satiety. 

Dear Hans Christoph and Klena danke and obrigado for your responses.

Best Regards,

As the others already stated, from a regulatory point of view, don't take OECD 423. Have you tried careful tracheal instillation and using the inhalation guidelines as a surrogate? Or if you don't now about the first pass effect mediated degradation yet, I would suggest to do some preliminary kinetic work, you will need the data anyway later on.

Usually all the infusion pumps are periodically calibrated and the variation can be less than 2%. Having said that, for a given application  if the infusion time is less than, say 3 hrs, the variation can be +/- 3.6 min. that is not a significant variation. However if the infusion time is more than 12 hrs, hope you can imagine the large variation that could lead a significant difference in dosage administration.

Dear Rossana, 

Elena Ardini here on RG is the one who can answer your question

Hi Alexandra,

I found pyrantel dosage in this book "Flynn's Parasites of Laboratory Animals" where they have dose for rodents: Pamoate formulation: 50 mg/kg PO.

The book is also avalaible on-line.

Ivan

Hi, 

Your question is way too generic.

Here a few things you might consider before asking:

- What is the target compound/s (from chemical classification down to specific moieties of interest)

- What is the matrix (blood, plasma, tissue, specific organ or part of it, cells, bacteria whatever..)

- Has anyone done it before? What is the state of the art? (search with whatever tool you want).

When you have answers to these 3 questions, build a first draft for your method. Then you might consider asking around for help.

But the question you ask is so generic that no one can really give you an answer.

I worked on anthracyclines for PhD back in 1995-1997. At the time I synthesized three derivatives, 2 were very potent. My supervisor used to test the compounds at the Christie hospital (http://www.christie.nhs.uk/). I suggest you contact them.

All the best!

Dear Thad Wadas,

Send your quires to us, www.gmrfoundation.com  , we can able to provide  lyophilized herceptin, if you need any other specification also inform us, For only R&D use, not for any human use.,

Good Luck & Regards

R.Selva.....

I agree with Robert that your question needs details but when considering mouse models you have to keep in mind that there are at least three major types: genetically-engineered mouse models (GEMMs), patient-derived xenograft models (PDXs), and cell line xenograft models.  Like all experimental platforms, they all have pros and cons.  The GEMMs are nice because you can study pathogenesis and drug response in an intact animal (microenvironment, intact immune system, etc.).  The PDXs are nice because they are human tumor cells growing in a mouse.  The hope is that PDXs will be more predictive than cell line xenograft models which have been the mainstay for decades.  I hope this helps.

To be used in clinical studies needs more evaluation

A brilliant question. How I wish I had ResearchGate to ask this in 1970.

My first thought would be to follow my father's advice - looking after patients is the most rewarding thing and keeps you sane while the research is slow. Doing both is hard but perfectly possible and I would not have wanted to miss out on either. Moreover, looking after patients shows you what the real problems are - the ones worth spending twenty five years on.

Doing clinical work and research together successfully has always been a question of breaking the rules. If you follow the rules you will be stuck in treacle. Taking your own path can be lonely and frightening at times but you have to stick to the motto of the Royal Society 'Nullis in verba' - never believe what someone else says. So there is no way to advise on 'which department to work for' or 'which area to target'.

Which brings me to the next point which is my advice to find your very own question to ask and answer. Forget what everyone else is asking, find your own question. If you cannot think of your own question then you have to wonder if you are suited to research. (Unfortunately research is full of people who cannot think of their own question.) And be prepared to keep asking one question for thirty years. What you should not do is stick to the same answer for thirty years - that is the sign of failure. Wisdom is discovering you were wrong, and wrong again, and again.

Now for the knock-out point. Forget systems biology and emergent behaviour. Systems biology is just a meaningless fad. It is bad science. The body has no systems. Everything dovetails with everything. The protein that lubricates joints comes from the same gene as megakaryocyte stimulating factor. As my hero Leibniz pointed out there are no systems in nature. The current fashion for systems thinking is a march back into the middle ages. It imposes presuppositions that stop you thinking. And I have no idea what emergent behaviour is really supposed to be but I am fairly sure it does not exist in complex dynamic patterns with parts. The idea is used by people to bullshit mostly - to give the impression you have an explanation when you do not. Something like emergence does appear in terms of the partless units of quantum field theory but that is another story.

So in summary my advice is to find your own question - based on talking to people with illness. I found my question talking to people with rheumatoid arthritis. You might find it with Parkinsonism or multiple sclerosis - both well worth a lifetime's effort. And learn to forget fads like systems biology. They have nothing to do with productive research.

The biggest and most interesting problem of all is how we come to have thoughts. And why thoughts go wrong in schizophrenia is perhaps the most worthy question. Mental illness is worse than hell for the sufferer and their family. I am too old to solve this one but you might look at http://www.ucl.ac.uk/jonathan-edwards if you are brave enough to break some rules and think some different thoughts!!

Hallo,

this is an extremely interesting question, since BACE1 inhibitors are being discussed for the therapy of Alzheimers disease for years now. Unfortunately preclinical studies (e.g. in mouse "models" for AD or in drosphila) were quite disappointing because of BACE-related undesired effects (off-site effects and /or off-target effects). These included -amongst others- retinal pathology and myelinisation abnormalities. In a clinical Phase II study hepatotoxicity was observed (which is not necessarily related to a reduction of BACE activity)When assessing toxicity you should not only look for behavioral deficits (which are unlikely to occur) but specifically for lesions in the peripheral nervous system. An extensive phenotyping may be necessary. The literature is confusing, since BACE1 KO mice were reported to be entirely "normal".

Good luck for your research and your zebrafish!

Just

Could you be more specific? Are you talking about synthesis in which one of the reagents is methotrexate? or in vitro studies?

Yes, my company offers services around Life Sciences. Personally Pre-clinical space is quite new for me though I have mostly worked on Bio-banking. I use research-gate to add on to my knowledge with the help of community . And I feel thats the best way because the community uses all these softwares and It helps me to understand their needs.

I am still looking for the answer to my questions? and being an Industry expert I would be happy to hear from you.

We have prostate cancer subcutaneous models for drug development. We find that the PC-3 line grows well in nude mice, but the LNCap and DU145 do much better in SCID mice

Yup crude herbal extracts cannot be given iv . Not acceptable because of suspended particles.

But it has been seen that herbal extract formulation, when administered intravenously, could potentially alter the pharmacokinetics of its active ingredients. There are studies where herbal extracts have been given iv. Here are the links below:

I think after sufficient purification and filtration (0.45 microns followed by 0.22 microns), it is acceptable.

Regards