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From could to can – the long road to drug approval

We see it all the time in the media; “new drug could cure cancer”, “novel therapies have the potential to save millions of lives” and “serendipitous finding may unlock the key to curing all illnesses”. Perhaps the last one is a bit of an over exaggeration, but you get the point. The use of non-committal verbs allows news outlets to spam us with the latest reports on new discoveries which may or may not reshape modern medicine. This article is not intended to play down the developments we see in science every day, instead it will hopefully provide a bit of a reality check and start to put the right value on our discoveries.

If a drug shows promising results in early, pre-clinical cellular models there is still just a small chance it will go on to become a product for sale in major markets. Furthermore, if the drug progresses to phase I, phase II or even phase III clinical trials (figure 1), the chances of gaining regulatory approval for sale on the markets are still just 7, 15 and 25%, respectively (1). These chances are very low, even if the molecule reaches the later stages of clinical development. The stages of drug development will be explained in more detail later.

Case Study

T cells are white blood cells which, among other things, break down old or damaged cells by engaging with cell surface proteins (figure 2). Cancer is commonly caused by cells gaining the ability to evade these T cells and continue dividing uncontrollably (2). MR-1 is a cell surface protein often found on cancer cells which is linked to erroneous cell division within the tumour (3). Recently, Crowther et al (4) from Cardiff University discovered a T cell that targets MR-1. This white blood cell has the potential to treat any cancer made up of cells expressing MR-1 on their surface – as the BBC quite rightly says in their article reporting on the discovery. However, as discussed above, just because it has the potential, it doesn’t mean it will. The chance of the T cell therapy getting to market is still very low as it is yet to be tested in the clinic. Perhaps the T cell will eventually be used to treat millions of cancer patients the world over, but more likely is that it won’t.

So why is it so difficult for a new drug to become available for doctors to use for treating patients?

Firstly, drug development costs a lot of money, which means companies developing drugs need to have confidence they will work. The drug must therefore provide convincing evidence from an early stage in cell models. Cell models are cells grown in a lab that aim to model a disease. For example, we may use cells that have been modified to grow like cancerous cells to test how well a drug inhibits this growth. Often, however, these cell models are not ideal for showing whether drugs will have a clinical benefit, so a drug that would work in patients may not show efficacy in cell models. Such drugs would never realise their full potential as continuing development is considered too risky. Nonetheless development can only progress based on evidence that can be generated.

Once the cell model hurdle has been overcome the drug must then prove its worth in animal models. In the wild the animals used may not develop the disease being tested. Even if they do, for the purposes of testing we usually induce disease-like states which probably don’t mimic the human disease perfectly. For example, a Guinea pig model for idiopathic fibrosis, a disease which affects the lungs, is forced to inhale noxious fumes to build up inflammation in the lung. A molecule can then be tested to examine its effects on dampening this inflammation (5). Animal testing is done primarily to see any early signs of safety issues which may be encountered in human trials.

Finally, when all the pre-clinical mountains have been climbed, we have the toughest test of all – clinical development (figure 1). Clinical development takes many years, sometimes spanning more than a decade. After initial testing in smaller cohorts successfully shows safety and effectiveness the drug can finally be trialled in a large group of patients. In these larger phase III studies the drug must show statistically significant and clinically meaningful results – two very loaded phrases. Statistical significance is the phrase that turns the non-committal verb into the committed form – ‘from could to can’. To say a drug shows statistical significance in reducing disease activity, measures must be taken in the analysis of data to ensure we are 95% sure the results we are seeing are not due to chance. There are many examples of such measures, the details of which are beyond the scope of this article – stay tuned!

However, statistical significance is only part of the story. A drug could show a statistically significant reduction in disease activity, yet this difference may be insignificant for the patient – who wouldn’t notice a difference. For example, hypothetically a drug for asthma may statistically significantly increase lung capacity by 10mL, but in reality a difference of 100mL is required for the patients to feel a difference in their ability to breathe. It is therefore often prespecified that a drug must show a certain level of effect for it to be clinically meaningful to the patient. And finally, to be deemed truly effective in the eyes of health regulators around the world, drugs often must show statistically significant and clinically meaningful results in two separate trials.

Despite all the stringent steps above, if there is a sniff of evidence at any point during development that the drug has any negative effects these have to be taken into consideration when weighing up the benefits and risks of taking it. Taken together, pre-clinical and clinical development provides an obstacle course like no other which, if completed successfully, ensures only the best drugs are approved for sale in markets around the world.

To conclude, the journey from media reports suggesting a new molecule could treat many patients successfully to said new molecule actually treating many patients successfully is a long and arduous one. Next time you see a news article making bold claims it is worth reading the words carefully. A drug could do many things: treat respiratory illness, help us wake up in the morning, it may even allow us to fly – but what are the actual chances it can and will reach the market for general use? As said at the beginning I am not trying to downplay the small discoveries we make every day, all scientific discoveries contribute to our understanding and play their part in the development of new medicines. Moreover, I am not trying to downplay the system. I have no better solution for the path of drugs to patients. However, I am perhaps providing some context as to why we still haven’t cured disease in all forms as the media often suggests we might. It’s difficult!


(1) Dowden, H. and Munro, J. (2019). Trends in clinical success rates and therapeutic focus. Nature Reviews Drug discovery 18; 495-496

(2) Töpfer, K., Kempe, S., Muller, N., Schmitz, M., Bachmann, M., Cartellieri, M., Schackert, G., Temme, A. (2011). Tumour Evasion from T Cell Surveillance. Journal of Biomedicine and Biotechnology 2011; 1-19

(3) Lu, R., Sun, M., Feng, J., Gao, X., Guo, L. (2011). Myofibrillogenesis regulator 1 (MR-1) is a novel biomarker and potential therapeutic target for human ovarian cancer. BioMed Central Cancer 11; 270

(4) Crowther, M.D., Dolton, G., Legut, M., Caillaud, M.E., Lloyd., A et al., (2020) Genome-wide CRISPR-Cas9 screening revels ubiquitous T cell cancer targeting via the monomorphic MHC class I-related protein MR1. Nature Immunology 21; 178-185

(5) Tashiro, J., Rubio, G.A., Limper, A. H., Williams, K., Elliot, S.J., Ninou, I., Aidinis, V., Tzouvelekis, A., Glassberg, M.K. (2017) Exploring Animal Models That Resemble Idiopathic Pulmonary Fibrosis Frontiers in Medicine 4; 1-11

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