Drug testing was in the news on Friday – though this time it wasn’t the usual sports doping headlines, but instead news of the clinical trial of a drug gone tragically wrong in France. Of the 90 people given the drug in a phase 1 clinical trial, one has been left with permanent brain damage, and another five are still hospitalised. What is a phase 1 clinical trial? That’s what this graphic aims to explain, as well as outlining the whole drug discovery process.
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 marketing 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.
This goes some way towards explaining the large numbers of stories in the media which tout the discovery of drugs that can treat particular diseases or conditions. Often these are reporting on drugs which are still at some point in the development process, and this process is full of pitfalls which can spell the end for drugs that may have initially seemed full of promise. 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. This target could be a protein or pathway in the body which has been implicated in a particular disease or condition. 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.
Researchers will try to be as sure as possible that a target is involved in some way in the disease or condition before proceeding. Once a target has been identified, it goes through a process known as ‘target validation’; this can involve a range of techniques, such as developing ‘knockout’ animals which lack certain genes, and seeing if the disease proceeds in the same manner in these animals.
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. At this stage, it’s unlikely that the perfect candidate will suddenly present itself, but compounds that show promise will be identified. These compounds can then be tweaked by medicinal chemists to attempt to improve their potency against the target. This is known as ‘lead optimisation’.
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. This can be useful in determining the degree of the drug’s efficacy, and can also give information on its toxicity, though it doesn’t give information on all the ways in which it might affect organisms; that’s where in vivo testing comes in.
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. In vivo testing can tell us how the drug behaves in the body of an organism; it might have some unpredictable effects, so this is important to know.
Of course, animals aren’t the perfect models for humans either. Generally, mammals that provide relatively good models are used, such as rodents. However, regulatory bodies usually require tests to have been carried out on at least two different mammalian species, including one non-rodent species, before the drug can be permitted to start human clinical trials. The hope is that these animal tests can detect any serious side effects before humans are exposed to the drug.
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. As such, their primary purpose is to establish what side effects the drug induces in humans. Usually, any potential for serious side effects will have been spotted previously during animal studies, but as we’ve seen in France, sometimes effects can be seen that were not seen in these studies. The dosages used in these studies start small and gradually increased, to reduce the chances of the serious side effects seen in the French study. The phase 1 trials can also give researchers useful information on how quickly the drug is absorbed, and how quickly it breaks down in the body.
Phase 2 trials involve a larger number of subjects, usual 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 the drug emerges successful from the phase 2 trials, it will pass into the phase 3 trials, the goals of which are much broader. A much larger number of people are tested (usually several thousand), with the areas researchers are examining 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. Approval involves the regulatory body examining the evidence and considering 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. Probably the most famous example of a drug that reached manufacture and distribution but was later found to have serious side effects is that of thalidomide. Marketed as a medication to relieve morning sickness in pregnant women, it also caused terrible birth defects, the discovery of which led to its withdrawal. It is still in use today, but now as a treatment for some cancers, and leprosy complications.
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. Medicinal chemist Derek Lowe has an interesting article where he considers the probability of a medicinal chemist discovering a drug that makes it to market, and suffice to say that it’s a pretty low figure. That the drug involved in the trials in France has clearly fallen at the phase 1 hurdle isn’t necessarily in itself a surprise, then, though the magnitude of the side effects experienced is.
The drug involved in France was initially reported as being a cannabis-based painkiller, but that’s since been refuted by the French government. Of course, since it’s a drug that’s still in development, details are still hazy, so it’s difficult to speculate on the cause of the damage to those involved in the trials. Derek Lowe (again) has a page where he’s been keeping track of updates to the story, which is likely one of the better sources on the story at present.
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References & Further Reading
- Principles of early drug discovery – J P Hughes & others
- The drug development process – Food & Drug Administration
- Regulatory road map for the development of human medicinal products – Research Quality Association