or where basic research is more closely tailored to clinical need with results used to quickly and appropriately guide the development of clinical research. We are now seeing further evolution of the research focus towards precision or stratified medicine. This involves identifying treatments that are most likely to be effective for individual patients or groups based upon bioinformatic and pharmacogenomic data aiming to increase the efficacy, safety and cost‐effectiveness of new treatments.
Preclinical development
The preclinical stage of drug development involves in vitro and in vivo studies in animals assessing safety and efficacy prior to use in humans.
In vitro studies
In vitro analyses performed in the early stages of drug discovery can permit extensive yet inexpensive testing of the effects of drugs on samples of tissues, cells or bacteria. They can also provide information on important aspects of drug development such as interactions, absorption, distribution, metabolism and excretion before and after testing in vivo.
In vivo animal studies of efficacy and toxicity
In vivo studies in animals are essential to assess a drug in development for desirable pharmacological properties and potential toxic effects before being studied in humans. Acute, and in most cases chronic, toxicity studies will be carried out in animals, using increasing doses, until clear toxic effects are noted, including a proportion of the animals dying. These studies provide ‘pointers’ to focus the safety assessments in human studies. In Europe, the guidelines require that the toxic effects of the drug should be assessed in two mammalian species (one non‐rodent) over 2 weeks of dosing before a single dose is administered to humans. Mutagenicity, carcinogenicity and the impact of drugs on reproduction are assessed and pharmacokinetic studies in animals can be used to help predict doses needed when first used in humans.
Clinical trials
Clinical trials form the main basis for determining drug safety and efficacy prior to regulatory approval and must be performed under highly regulated processes in order to minimise the risk to participants. This principle of protecting the rights of the trial subjects comes from the Declaration of Helsinki (initially agreed by the World Medical Association in 1964, with revisions made when needed since). The International Conference on Harmonization (ICH) brings together the regulatory authorities of Europe, Japan and the United States, with the aim of producing common guidelines relating to quality, e.g. manufacturing, safety and efficacy requirements. Their Good Clinical Practice Guidelines were established to provide a unified standard for clinical trials across the three main regulatory authorities maintaining safeguards on quality, safety and efficacy, and regulatory obligations to protect public health.
Phase I clinical trials
Usually in healthy volunteers they are designed to find out how the drug affects the human body and vice versa. This will be a combination of assessing the pharmacodynamics of the drug, including detailed safety screens and the pharmacokinetics. The results of Phase I clinical studies will determine whether there is potential for the drug to move towards the next stage of development. At this stage, the drug has to be shown to be relatively safe and, where feasible, for a reasonable signal of efficacy to have been established. This is easier in some disease areas (e.g. hypertension) than others (e.g. oncology). Usually less than 100 individuals are involved.
Specific types of Phase I clinical studies
First in human studies
A medicine may look safe and potentially efficacious in the laboratory, but a clinical trial will establish whether this is the case in humans. Studies will start with low, single doses, in just a couple of volunteers. The serious side effects experienced by volunteers taking part in the trial of TGN1412 in March 2006 at Northwick Park Hospital in London are extremely rare but highlights the need for thoroughly testing a treatment before widespread use. First in human studies may also provide evidence for proof of concept, for example a demonstration of inhibition of relevant enzyme systems.
Dose ranging studies
Healthy volunteer Phase I clinical studies can be used to start the process of predicting the optimal dose of a medication before it gets tested in large clinical trials. Single low doses initially will be used moving to multiple dosing with bloods taken for plasma concentrations of drug, and dose–concentration curves plotted. Pharmacodynamic responses to the drug, both desired and side effects, will be noted with the aim of selecting a dose range that will give you the desired effect but with few side effects. This range will then be taken into Phase II trials.
Interaction studies
There is a lot of potential for drugs to interact with other drugs or dietary factors. A lot of the potential for interaction occurs through the effect of drugs on enzymes in the liver, both induction and inhibition. A lot of these interactions can now be predicted from in vitro studies but if such studies suggest a clinically relevant interaction may exist, many regulatory authorities will require that the effect be quantified more accurately via a clinical interaction study. An example of this is when there are concerns that a drug may cause an interaction mediated through an effect on cytochrome P450 3A4. Midazolam is almost exclusively metabolised by this enzyme. If a drug in development is thought to interact through an effect on cytochrome P450 3A4, then dosing the drug with and without midazolam will allow you to quantify the effect. If the drug is an enzyme inducer, then the amount of midazolam measured in the plasma will be less and if an enzyme inhibitor, the amount of midazolam measured in the plasma will be greater.
Safety studies
Phase I studies can be used to look at specific safety issues in drug development. For example, based on pharmacology or toxicology results, a drug may be thought to have potential to cause QT interval prolongation on the ECG which may predispose to cardiac arrhythmias. A simple Phase I study using an escalating dose of drug with ECG recording can show whether there is any relationship between concentration of drug in the plasma and QT interval.
Phase II clinical trials
These studies, often called ‘proof of concept’, look at whether a drug works in the patient population that might benefit from the treatment. They are usually conducted by specialists in the field, in a relatively controlled environment, and are designed to assess efficacy or markers of efficacy and the dose–response relationship. A key goal is to decide whether the odds are acceptably good that the compound is effective, may have an acceptable benefit/risk ratio and, if so, to define a single dose to be taken into the Phase III trials. However, some disease areas have very limited markers of efficacy which can be measured in a short, small trial; therefore, in these cases, dose selection is significantly more difficult and sometimes more than one dose will be taken into Phase III. In addition to looking at markers of efficacy, this stage of development allows the identification of side effects in the target patient population. Phase II would normally involve designing a double blind randomised control trial against placebo and possibly also a study against a standard reference drug therapy as control. If the exploratory type II studies suggest good efficacy and acceptable results concerning safety, tolerance and pharmacokinetics, then the larger Phase III clinical trials can be planned. This decision has potentially large cost implications as the costs rise exponentially once you start Phase III clinical trials.
Phase
