Understanding drug discovery

07 Oct 2016
Written by
Andy Brunning

Andy Brunning is a chemistry teacher based in Cambridge, UK. He also writes Compound Interesta site that aims to take a closer look at the chemical compounds we come across on a day-to-day basis. It also provides graphics for educational purposes, both for teacher and student use.

As a consumer, it’s easy to be oblivious to the amount of time, work, and money that goes into the development of a drug. The cost of developing a drug that goes on to gain market approval was estimated to be $2,558 million in 2014, and the process can commonly last longer than a decade. Additionally, the chances of success are low: it’s estimated that only around 1 in 5,000 identified drug candidates eventually reaches approval and widespread use.

So what are the steps involved in this process?

Research & Development

Before a drug can even begin to be tested, it must first be researched. This will often start not with the drug itself, but with the identification of a possible target for a drug to act upon. Diseases and conditions that we know more about are easier to determine targets for; conversely, those where we’re still not sure about the precise manner in which the ailment develops are tougher to work with.

Once a target has been identified and validated, the search to find entities that can have an effect on it then begins. This will involve the laboratory testing of a huge number of compounds, often 10,000 or more, to determine which show some activity against the target.

Preclinical Studies

Commonly only around 250 compounds from those initially considered will pass through to more rigorous preclinical studies. These can involve both in vitro and in vivo experiments. In vitro is Latin for ‘within glass’ and involves tests on cells or molecules outside of their usual biological surroundings. In vivo is Latin for ‘in the living’. In vivo testing involves the use of animals to test drugs. Although efforts are being made to reduce the amount of animal testing, it is still used because it can give information about the effects of drugs that in vitro testing cannot. 

Of course, animals aren’t the perfect models for humans either. Generally, mammals that provide relatively good models are used, such as rodents.

Clinical Trials

Clinical trials are those involving human volunteers. Drugs must receive a clinical trial authorisation (CTA) in the EU, or submitted to the FDA as an investigational new drug (IND) in the US, before they can begin clinical trials. These trials are divided into three categories: phase 1, phase 2, and phase 3.

Phase 1 trials are the first tests of the drug involving human participants, and commonly involve up to 80 subjects. Their primary purpose is to establish what side effects the drug induces in humans.

Phase 2 trials involve a larger number of subjects, usually several hundred, and at this point it’s the drug’s efficacy that’s under the microscope. Researchers will carry out controlled trials to compare the drug to a placebo, in order to determine how effective it is in humans. This point is often a stumbling block for new drugs, as the efficacy seen in earlier animal studies or in vitro testing may not manifest in humans.

If phase 2 is successful, it will pass into phase 3 trials. A much larger number of people is tested (usually several thousand), with the areas examined including dosage and efficacy (both in general and versus other existing drugs that treat the same condition). They also continue to monitor the safety of the drug in the larger number of test subjects.

It’s worth noting that a number of each phase of trial will take place; each drug will likely go through tens of clinical trials before the researchers feel they have enough evidence for its efficacy and safety to apply for approval.

Many drugs, however, do not make it through this process. The FDA estimates that whilst 70% of drugs successfully make it through the phase 1 trials, only around a third of these candidates pass through phase 2 trials successfully, and 25-30% of these get through the phase 3 trials. This all takes time – often up to seven years, though for some drugs this figure can be even higher.

Review & Approval

Once researchers feel the evidence they have for the drug’s efficacy is compelling, they will apply to the relevant regulatory body for approval. A regulatory body examines the evidence and considers whether the drug’s benefits outweigh its risks. No drug is absolutely safe, and what the regulatory body decrees to be an acceptable risk will often depend on what the drug is designed to treat. For example, drugs used in the treatment of terminal diseases are likely to have a higher acceptable level of risk that simple painkillers.

Some drugs are given priority in the approval process over others. Drugs which provide a treatment which did not previously exist will be fast-tracked over drugs which are similar to drugs that already exist on the market.

If the regulatory body is satisfied that the benefits of the drug are significant enough to make the risks worthwhile, it will meet with approval, a process that usually takes around a year. The FDA claims that around 75% of the approval requests it receives are granted, though this includes those which are initially rejected, then approved after further evidence is provided.

The drug reaching the market isn’t the end of the road for the process, however. Its use in the general population is still monitored, because it’s still entirely possible that rare side effects might come to light that were not observed in clinical trials.

It’s clear that developing a successful drug is a long and painstaking process, and one that meets with failure more often than it meets with success.


This is a shortened version of an article that appeared originally on Compound Interest, along with the graphic.