There’s a reason why 90% of drugs fail clinical trials, and we can fix it.

(ORDO NEWS) — It takes 10 to 15 years to develop one successful drug, and it takes about 1 billion US dollars. Despite this significant investment of time and money, 90 percent of drugs in clinical trials fail.

Because of inadequate treatment for the disease they are targeting, or because of too severe side effects, many applicants never make it to the approval stage.

As a pharmaceutical scientist working in drug development, I was disappointed by this high failure rate. For the past 20 years, my lab has been studying ways to improve this process.

We believe that starting from the earliest stages of development and changing the way we select potential drug candidates can lead to improved success rates and ultimately better drugs.

How is drug development going?

Over the past few decades, drug development has been carried out according to the so-called classical scheme. Researchers start by looking for a disease-causing molecular target, such as an overproduced protein that, if blocked, can stop cancer cells from growing.

They then check the library of chemical compounds to find potential drug candidates that act on that target. Once a promising compound is selected, the researchers optimize it in the lab.

Drug optimization primarily focuses on two aspects of a drug candidate.

First, it must be able to strongly block its molecular target without affecting irrelevant targets. To optimize potency and specificity, researchers look at the structure-to-activity ratio, or how the chemical structure of a compound determines its activity in the body.

Secondly, it must be “drug-like,” that is, capable of being absorbed and transported through the blood, in order to act on its intended target in the affected organs.

If a drug candidate meets the researchers’ optimization requirements, it is tested for efficacy and safety, first in animals and then in human clinical trials.

Why do 90 percent of clinical drug development fail?

Only one in 10 drug candidates successfully passes clinical trials and receives regulatory approval. An analysis in 2016 identified four possible reasons for this low success rate.

The researchers found that 40 to 50 percent of the failures were due to a lack of clinical efficacy, meaning the drug failed to have the desired effect on people.

About 30 percent were due to unmanaged toxicity or side effects, and 10-15 percent were due to poor pharmacokinetic properties, that is, how well a drug is absorbed and eliminated from the body. Finally, 10 percent of failures are due to a lack of commercial interest and poor strategic planning.

This high failure rate makes one wonder if there are other aspects of drug development that are being overlooked. On the one hand, it is difficult to really confirm whether the chosen molecular target is the best marker for drug screening.

On the other hand, it is possible that the current drug optimization process does not lead to better candidates for further testing.

Drug candidates that make it to clinical trials must strike a delicate balance: give enough of the drug to have the desired effect on the body without causing harm. Optimizing a drug’s ability to pinpoint and act strongly on its intended target certainly plays an important role in how well it achieves this balance.

But my research team and I feel that this aspect of drug efficacy is being overemphasized. Optimizing the ability of a drug to reach diseased parts of the body in sufficient quantities while avoiding healthy parts of the body – its effect on tissues and selectivity – is equally important.

For example, scientists can spend many years optimizing the potency and specificity of drug candidates so that they act on their targets at very low concentrations.

But this can come at the expense of ensuring that enough of the drug reaches the right parts of the body and does not harm healthy tissues. My research team and I believe that such an unbalanced drug optimization process can skew the choice of a drug candidate and affect its final results in clinical trials.

Improving the drug development process
Over the past few decades, scientists have developed and implemented many successful tools and strategies to improve every step of the drug development process.

These include high-throughput screening, which uses robots to automate millions of tests in the lab, speeding up the process of identifying potential candidates; drug development based on artificial intelligence; new approaches to prediction and testing of toxicity; more accurate selection of patients in clinical trials.

However, despite all these strategies, the success rate still hasn’t changed much.

My team and I believe that new strategies that target the earliest stages of drug development, when researchers are screening for potential compounds, can help increase success.

This can be done with new technologies such as the CRISPR gene-editing tool, which can more rigorously validate a disease-causing molecular target and determine if a drug is actually targeting it.

It can also be done with the new STAR system that my research team and I have developed to help researchers better strategize how to balance the many factors that make a drug optimal.

Our STAR system makes missed tissue exposure and drug selectivity as important as potency and specificity. This means that the ability of the drug to reach diseased parts of the body at a sufficient level will be optimized to the same extent as how accurately it is able to act on its target.

To do this, the system groups medicines into four classes based on these two aspects as well as recommended dosages. Different classes will require different optimization strategies before the drug is subjected to further testing.

For example, a Class I drug candidate will have high potency/specificity as well as high tissue exposure/selectivity. This means that it will only need a low dose to achieve maximum efficacy and safety and will be the most desirable candidate to move forward.

A Class IV drug candidate, on the other hand, will have low potency/specificity as well as low tissue exposure/selectivity. This means that it is likely to have insufficient efficacy and high toxicity, so further testing should be stopped.

Class II candidate drugs have high specificity/potency and low tissue exposure/selectivity, requiring a high dose to achieve adequate efficacy, but may have unmanageable toxicity. These candidates require more careful evaluation before moving on.

Finally, class III drug candidates have relatively low specificity/potency, but high tissue exposure/selectivity, which may require a low or medium dose to achieve adequate efficacy with controlled toxicity. These candidates may have high clinical success rates but are often overlooked.

Realistic expectations in drug development

Getting a drug candidate into clinical trials is a big deal for any pharmaceutical company or academic institution developing new drugs. It’s a shame when years of effort and resources spent trying to promote a patient candidate so often results in failure.

Improving the process of optimization and selection of drugs can significantly increase the success of a candidate.

While the nature of drug development does not make it easy to achieve 90 percent success rates, we believe that even modest improvements can significantly reduce the cost and time required to find a cure for many human diseases.

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