Daniel Sado takes us through the process of drug discovery

New drugs appear on the market all the time. One of the challenges facing us, as doctors to be, is to try to evaluate how good a new drug is likely to be. To attempt to critically appraise a new drug, it is important to understand the different stages that the drug has had to go through to reach the market.

Cost effectiveness

When considering whether to undertake a drug discovery programme, the first thought of any drug company is, "Will the drug be of economical benefit to us?" The cost of developing and testing a new drug can be as much as £125m. Discovery programmes suffer high failure rates and it is often difficult for drug companies to predict whether the new treatment will be commercially valuable when it hits the market. These uncertainties mean that drug companies will often undertake drug discovery programmes only if there will be a big market for the drug in developed countries. This is why there is not much interest in developing antimalarial treatments. Malaria is prevalent only in developing countries, and many of the countries that would benefit from new drugs would not be able to afford them. On the other hand, conditions such as hypertension and asthma are regularly targeted for new drugs because they are chronic and prevalent in developed countries.

Identifying a drug target

The next question is, "What might be a suitable drug target?" This will often require a good physiological, pathophysiological, biochemical, or even genetic understanding of the disease. The commonest sites to target a drug at are enzymes or receptors. An example of this is the recently licensed drug clopidogrel, which is an antiplatelet aggregation treatment. Before the clopidogrel discovery programme was undertaken, it had been shown that activation of the adenosine diphosphate receptors found on platelet cell membranes causes platelets to aggregate.

So the company Sanofi Winthrop decided to try to find a drug that would act as an adenosine diphosphate receptor antagonist. It was hoped that such a drug would not cause gastrointestinal bleeding, which was the major problem with the previous drug of choice in this area, aspirin. The theory that blocking the adenosine diphosphate receptor would decrease platelet aggregation was proved to be correct, and clinical studies suggest that clopidogrel may be slightly more effective than aspirin in the secondary prevention of the complications of peripheral vascular disease and as effective in the secondary prevention of stroke and myocardial infarction. Unfortunately, the side effect profile of this drug has not yet proved to be any better than that of aspirin.¹

Finding a drug

The company then needs to find a drug that will either potentiate or inhibit the target - an agonist or an antagonist. This is generally achieved using high throughput screening. Today drug companies can use various chemical methods to synthesise thousands of new compounds. These compounds are all stored in a massive chemical library.²

Once a suitable in vitro model of the drug target is developed, the use of robotic technology allows every compound in the chemical library to be tested for efficacy. The company hopes that this will result in the discovery of several leads that can be further investigated. Once a lead has been found, the medicinal chemistry department will play around with some of the chemical groups found on it to try to maximise the efficacy, solubility, and specificity. This process is called lead optimisation.

In vivo studies

Live animal studies provide toxicology data about the prospective drug (acute, chronic, reproductive toxicity, and carcinogenesis studies), pharmacokinetic studies (what the animal does to the drug), and pharmacodynamic studies (what the drug does to the animal). It is vital that a drug is shown to be safe in this phase of the drug discovery programme because in the next phase it will be administered to humans. After the thalidomide teratogenesis tragedy in the 1950s new laws were brought in to ensure that any new drug is thoroughly investigated toxicologically before it is given to humans. Even so possible reproductive toxicity is difficult to assess and much animal species variation may occur.³

A major problem with these animal studies is deciding how much information they actually provide about the effects that the drug will have in humans. Even so, if the drug is found to be acceptably safe and efficacious in the animal models of the disease, drug companies in the United Kingdom can apply for ethics approval to test it in humans. In other countries a regulatory authority has to be approached before the ethics committee.

Phase 1 studies

Early human studies on a prospective drug are called phase 1 studies. These studies are carried out on healthy volunteers in the laboratory. Cancer chemotherapy phase 1 trials usually use patients rather than volunteers since these drugs often have fairly high toxicity. At this stage the investigators are cautious and will begin by using single, low, slowly escalating doses of the drug in question. It will usually be given via the route ultimately intended for all patients. These studies will usually be double blind ones with placebos. The investigators will closely monitor bodily functions, such as heart rate and blood pressure. Biochemical monitoring will also usually be carried out via blood tests and urine analysis. The early studies may involve about 24 volunteers. If the drug is well tolerated the drug company will carry out further phase 1 studies at various doses (sometimes over 100) to assess in depth its pharmacokinetics, pharmacodynamics, and possible drug interactions.

If the results of the phase 1 studies show that there are no contraindications to administering the drug to patients the discovery programme moves on to phase 2.

Phase 2 studies

In phase 2 studies a small, but statistically significant, number of patients suffering with the disease in question are investigated. Phase 2 trials will usually be double blind, randomised, placebo controlled studies carried out in a hospital or laboratory setting. These studies provide the first evidence of the possible efficacy of the drug, because patients are being investigated. Again any adverse effects will be monitored and bloods and urine assessed. If the drug is shown to be acceptably safe with some efficacy the discovery programme will move to phase 3.

Phase 3 studies

Phase 3 studies are large patient studies that may investigate the effects of the drug on thousands of patients. They will nearly always be randomised and double blind trials but unlike in phase 2 studies they will usually compare the new drug with the previous drug of choice for the disease in question rather than with a placebo. The main aims of the phase 3 studies are to investigate the safety and potency of the new drug. The big sample size of these studies means that the majority of the possible adverse effects of the drug will be seen. The severity and frequency of such adverse effects will also be assessed. The most important factor is that the drug is shown to be acceptably safe. If it has some efficacy for treating the disease as well the company will apply to get it licensed for use.

Getting a drug licence

The Committee on the Safety of Medicines (CSM) decides whether a drug will or will not be granted a licence in Britain. If a drug is not licensed for use in a particular condition it does not mean that doctors cannot prescribe it, but if they choose to do so they risk legal problems if anything goes wrong. Thus all drug companies will apply to get their new drugs licensed for use for specific diseases.

The CSM looks at several factors when deciding whether or not to grant a new drug a licence. Firstly, it looks at the pre-clinical data on the drug. It is particularly interested in acute, chronic, carcinogenic, and reproductive toxicity studies. Secondly, it assesses the pharmaceutical data on the drug. It looks at the manufacturing processes and whether the preparations consistently contain the correct amount of drug. Thirdly, the CSM assesses the human pharmacological data on the drug. It will look at the pharmacokinetic and pharmacodynamic data obtained in the phase 1 and 2 studies.

The committee also assesses the efficacy, side effects, and route of administration that the drug has shown in phase 3 studies and compares it with the previous drug of choice for the disease in question to decide whether the new medicine will be of benefit in any or all of these areas.

Lastly, the CSM needs to see a leaflet from the drug company showing a summary of product characteristics. Overall, the CSM needs to see evidence that the new drug is safe, efficacious, and will be correctly manufactured. In effect, it assesses a theoretical risk to benefit ratio for the drug in question.⁴

National Institute of Clinical Excellence (NICE)

The CSM has no interest in deciding whether a drug is cost effective to prescribe on the NHS. Once a drug has been licensed, NICE makes a decision as to whether it is economically viable to allow a drug to be made available on the NHS.

An interesting example was the Glaxo-Wellcome drug, zanamivir (Relenza). This drug was given a licence by the CSM to treat influenza. But NICE decided that the preliminary studies carried out on the drug were not good enough because they looked only at young patients, rather than the older generation that would benefit more from the drug. Thus NICE decided that it was not cost effective to allow the drug to be prescribed on the NHS.⁵

It has now reversed the decision for specific groups of patients in the light of new evidence.⁶

Phase 4 studies and postmarketing surveillance Phases 1 to 3 of a discovery programme will often not provide a great deal of information about the new drug's action in specific population groups, such as the young, old, and those who are pregnant. Some of this data can be obtained from phase 4 studies, which are usually open trials that are carried out after the drug has been licensed. The aim of these studies is to provide further information about the efficacy and toxicity of the new treatment. The results of these studies are often difficult to interpret but they are important because they replicate more closely the general clinical situation in which the new drug is being used than the phase 3 studies.

It is the responsibility of doctors to report any side effect that occurs in the patients for whom they prescribe a new drug for two years after the drug hits the market. This is done via a yellow form that can be found in the British National Formulary. The reporting of adverse effects caused by a new drug has been shown by numerous studies to be woefully inadequate and probably only about 10% of side effects are reported. This is because most junior and senior doctors do not realise that yellow card reporting exists or are too busy to complete the cards.⁷

Conclusions

If a drug has been licensed for use by the CSM and NICE has decided to allow it to be made available on NHS prescription this provides some evidence that the drug should be fairly safe and should show some efficacy in the treatment of disease. Unfortunately, the evidence that the early studies provide is not always conclusive. A good example of this was the drug practolol, which was designed to be a selective b1 antagonist. This drug showed good results in the preliminary studies, but after it had been on the market for a few years, it was found that a musclo-ocular-cutaeneous syndrome was occasionally occurring in some patients. As this syndrome was fairly rare, the phase 3 study on the drug did not have enough patients for it to be seen. This side effect caused the drug to be taken off the market.⁸

Even so, it is vital to look at the preliminary data published on a new drug before deciding whether it will benefit your patients. In particular, the phase 3 study on the drug will provide you with the most relevant information to help you make your decision. Daniel Sado, fourth year medical student, University of Southampton Dan_sado@yahoo.com

I would like to thank the lecturers on the drug design course at University College London. Most of the information contained in this review is a summary of their lectures.