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
Zanubrutinib-Gazyva Shows Promise for CLL/SLL
