Just 5% of therapies tested in animals end up as as human drugs, new study shows. CLL research has particular challenges due to the TME

[AussieNeil]

There's a long and challenging journey from microscope observations of cancer cells hopefully dying while exposed to candidate therapies, that is, 'in vitro' testing, to successful in vivo human studies, clinical trials and eventual approval. Not only does the therapy need to kill the cancer cells with negligible damage to healthy cells (acceptable side effects, adverse events), it needs to be delivered to the cancer cells. That's particularly difficult with oral delivery, because digestion might destroy the therapy, or it can be poorly absorbed into the blood stream and then rapidly metabolised by the liver, so that it's impossible to achieve a killing concentration. Curcumin from turmeric is a classic example here. Then there's the protective effect of the tumour micro-environment established by the cancer cells, not present in in vitro testing, which needs to be overcome. healthunlocked.com/cllsuppo...

Adrian Esterman, Professor of Biostatistics and Epidemiology, University of South Australia covers why "in a study published today doi.org/10.1371/journal.pbi... , we find out how few of these therapies tested in animals receive regulatory approval for use in humans and end up on the market."

New drugs are generally tested on animals such as mice and rats before being tested on people. (Mouse model studies are commonly used for CLL research - Neil) The results of these animal studies are often reported in the media, perhaps raising hope these “miracle”, “promising” or “dramatic” findings will one day be replicated in humans and lead to a new drug. (My emphasis)

:

The Swiss and UK researchers found just 5% made the grade and for those that were successful, the process took an average ten years.

Here’s why so few drug candidates in animal trials end up as human therapies.

theconversation.com/just-5-...

We think of CLL as a leukaemia, but CLL/SLL (Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma), is the most commonly diagnosed adult Non-Hodgins Lymphoma. The CLL expression of CLL/SLL presents in the blood and in the nodes, spleen and bone marrow, as well as the blood. With the SLL expression of CLL/SLL, little to none of the CLL/SLL cells are present in the blood. See healthunlocked.com/cllsuppo...

CLL/SLL actively grows in the nodes and bone marrow, where it sets up a protective tumour micro-environment (TME). CLL cells are in their dormant stage in the blood, so while leukaemia cancer research has the huge benefit of providing easy sampling access to tumour cells through blood sampling, assessing the impact of therapies on CLL cells removed from blood samples is misleading regarding their effectiveness.

Back to the article, where the authors "assessed the quality of the included studies using a meta-analysis (which combines the results of several studies) to work out whether positive outcomes in animal studies translated into positive outcomes from human studies.", with my emphasis of issues of specific relevance to CLL;

What they found

Overall, the researchers found that of 367 therapeutic interventions tested in 54 human diseases:

- 50% progressed from animal studies to human clinical trials

- 40% progressed to randomised controlled trials (large, clinical phase 3 trials, the ones generally needed before regulatory approval)

- 5% received regulatory approval.

Their meta-analysis showed 86% of positive results in animal studies were translated into positive results in subsequent human trials.

For animal studies that progressed, the researchers found it took an average:

- five years for animal studies to reach any human study

- seven years to reach a randomised controlled trial

- ten years for regulatory approval.

Why the gap?

The authors found many of the animal studies were not well designed, making their results less valid.

For example, most did not include blinding, where the investigator does not know which animal received each treatment, or randomisation of animals to treatments.

Many animal studies also involved too few animals to provide reliable evidence of whether the treatment was successful.

Animal studies often involve young, healthy animals, while human patients may have multiple health conditions and be older. Animal studies often focus on how a drug works on a molecular level, while human studies prioritise the drug’s overall effectiveness.

Finally, the outcomes measured in animal studies might not always reflect the most important clinical outcomes for patients.

This post explains why randomisation is so very important when conducting clinical trials:

healthunlocked.com/cllsuppo...

Blinding, ideally double blinding, is also a very important part of good clinical trial design in avoiding bias.

The article encouragingly ends with some promising news about how researchers may be able to increasingly avoid the ethical dilemma of animal research.

Neil

[Shepherd777]

Very enlightening. Ten years of research to produce 5% of drugs that work. No wonder the drugs are so expensive. My guess is without an early profit or return on their investment they are not as likely to put themselves out for another 10 years to find a newer drug with less toxic effects.

Also, I wonder how they determine side effects like headache or muscle aches in the mice. I suspect many side effects are unknown until the humans studies are complete. Humans obviously can better communicate with the researches than the mice. I'm not saying all of this is true...just my thoughts.

[Spark_Plug]

Although it's a great article, now I can't stop thinking, "Three blind mice, three blind mice...".

[Agiledog]

Neil, Thanks for bringing this to us with credible stats. Do we know what percent of preclinical research is supported by public money before drug companies take it into trials?

Bud

[AussieNeil Partner Administrator in reply to Agiledog]

That's a very good question, but unfortunately I haven't seen any reports on this and how it varies by country.

[Agiledog in reply to AussieNeil]

Thought I’d ask Chat gpt:

“ As of the latest available data, approximately two-thirds (about 67%) of preclinical drug research is funded by public money, which includes government grants and funds from nonprofit organizations. This indicates a significant reliance on public funding for the initial stages of drug research before private investment typically increases in later clinical trial phases.”

Gave no references, however.

I’ve been thinking that taxpayers are largely the venture capitalists for pharma. But we don’t get a piece of the action it seems.

Cheers

[SeymourB in reply to Agiledog]

Agiledog -

Hard to say whether that result is an AI hallucination. I think funding depends a lot on which country. What was your prompt? Here are some tips:

zdnet.com/article/how-to-ma...

Also, I imagine that the amount of funding has changed over time. Drugs coming to market now were probably researched as far back as a decade ago.

I asked Microsoft Copilot several times, and got different answers each time even with identical wording of the question. They do give references, but the references were often 10 or more years old.

I'm not a fan of AI because of these and other verifiability issues. I'm sure that constructing the query properly by anticipating sources of data will help. But it still will seldom be properly verfiable. GPT AI is a stunt monkey.

=seymour=

[AussieNeil Partner Administrator in reply to Agiledog]

There's definitely valid concerns about the cost of access to papers produced from taxpayer funded research, but keep in mind that "just 5% of therapies tested in animals end up as as human drugs" and pharmaceutical companies would cover most of the clinical and post-approval R&D costs.

This paper COSTS OF PHARMACEUTICAL R&D

knowledgeportalia.org/costs...

states that "Breaking down the total costs between preclinical and clinical stages, the estimated preclinical out-of-pocket costs are $430 million and $1,098 million capitalized and for clinical stage out-of-pocket costs are $965 million and $1,460 million capitalized. Therefore, preclinical costs were estimated to represent 32% of total out-of-pocket costs and 42% of total capitalized costs. The study also provides an estimate of post-approval R&D costs at USD$312 million after capitalization, which would increase the cost estimate to USD$2,870 million (2013 dollars) if included."

Neil

[Felixgratus]

Thanks very much, Neil!!

[Big_Dee]

Hello AussieNeil

So, the upside to this a lot of new pesticides? 😁