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The Process

Drug development is time consuming and costly. In principle, if all the processes are straight-forward, a drug can be developed in a seven year period. In practice, drug development takes in excess of twelve years. Procedures are tightly regulated both for safety and to ensure drugs are effective. Of the many compounds studied with the potential to become a medicine, most are eliminated during the initial research phases. Clinical trials follow extensive research using in vitro and animal studies. Even so, many drugs are withdrawn or fail, never becoming approved as medicines. Common reasons include side-effects, the drug proving less effective than hoped or lacking financial viability.

Computer Modelling

Drug development often begins with a design process. A target for the drug is identified and computers are used to show which structural features of a molecule are likely to have biological activity. Thousands of compounds are screened using simulations and modelling processes, of which around a few hundred compounds will be investigated to determine their potential as drugs.

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In vitro research

Initial tests are carried out to see the action of the compounds on individual cells containing the drug target. These studies are largely automated processes, which examine particular actions of a large number of different compounds on individual cells. From these tests the basic pharmacokinetic properties of each compound will be determined, and large numbers of the compounds developed during the design stage will be eliminated as unsuitable for drug development.

The remaining compounds are studied in single cells and in vitro tissue preparations in more detail by research teams to determine their biological activity in detail. Those which have a potential application as drugs are then developed more fully.

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Exploratory development

Of the thousands of potential drugs screened, only a few will reach the development stage. The effect of the drug on the systems of the body, rather than at the target site are investigated, using non-animal techniques such as computer modelling, further in vitro studies, and the first animal tests. These will investigate delivery systems, by which the drug will reach its target site within the body, further pharmacokinetic properties and pharmacodynamic properties of the drug. These initial tests will usually be carried out on rats or mice, unless the target for the drug is specific to a disease where particular models must be used. Even if drugs developed to this stage prove to have no therapeutic value, they may be useful as research tools, and developed for use in basic physiological studies.

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Full development

The purpose of this stage is to find out more about how the drug works, and its potential for use clinically. Drugs which have a potential therapeutic application undergo a thorough development process.

They are studied in several animal models, alongside continuing research into their effects in vitro. These two approaches to research complement each other, as in vitro studies can give information about the specific effects of a drug at a particular site, while in vivo animal studies give information about the effects of the drug on a whole, living system, and how it affects the interactions between different organs of the body. These studies will include a full assessment of drug delivery systems, preliminary safety testing, studies of possible drug interactions and other side effects.

Toxicity testing

Before a potential new drug can be tested on humans its safety must be assessed through toxicity testing. While these tests cannot predict how a human body will respond to the compound, they are used to determine the range of doses that will be used, which organs of the body the compound might affect, how it will be administered, how long and how frequently individuals should be exposed to the substance, and to what extent its chemical structure is intrinsically toxic. By law, these must be determined before it is considered reasonable to test a substance on human volunteers.

Microdosing

A microdose is defined as less than 1/100th of the pharmacologically active dose of a compound, as determined by pre-clinical animal testing. Pioneered in the EU, microdosing has recently been reviewed by the FDA as part of their critical path initiative, and guidance has been issued for its use in the US drug development process.

The tiny microdoses of a compound are given to human volunteers during the later stages of drug development and toxicity testing, immediately prior to clinical trials. This new development phase has been termed phase 0 human studies.

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Clinical Trials

Clinical trials are medical studies in humans, and may begin relatively early in the development process. The first trials are intended to verify the findings of previous studies in animals and models. They follow set protocols so that they can assess the actions of the drug in humans, with particular attention to how their physiology may differ from the animals used during the development process.

The drugs undergoing trials can have unpleasant, serious or life-threatening side effects, but the risk to those undergoing the trials is minimised as much as possible. The development process will have given detailed information on the drug, which gives a guide as to how the new drug is expected to behave.

Although the procedures are similar, the exact legislation governing clinical trial protocols varies by country. Approval for the planned trials must be obtained from the relevant regulatory body before they can go ahead. Once begun, trials are audited and amended for their duration.

Clinical trials are carried out in four phases, each of which is designed to answer different questions about the new drug:

Phase I trials aim to discover how humans react to and metabolise the new drug. Tests are carried out on a small group of healthy volunteers (usually around 20-80). They are carried out on female volunteers or patients when it is unlikely that testing in healthy male subjects will be informative. The drug is given in increasing doses to determine the safe dosage range and the pattern of side effects. The action of the drug, its metabolism, its distribution in the body will be determined, and the first comparisons of the drug’s effectiveness compared with placebo may also be made. 

Phase II of trials test the effectiveness and the safety of the drug in a larger group of people (100-300). This group consists of people with the condition being studied and healthy volunteers, so that a profile of the common short-term side effects can be built. The phase II trials are controlled studies, where the drug will be compared with a placebo to assess its effectiveness. Controlled trials are double blind studies, so neither the volunteers nor the researchers administering the drugs know which subjects received the drug candidate and which received the placebo.

Phase III trials are wider scale and consist of both controlled and uncontrolled studies. Measures of the drug’s effectiveness have already been obtained during phase II, and the benefits versus the risks of the drug are studied in detail. A larger group of patients in a wide variety of clinical settings will be studied. This phase collates the information which will be used for the packaging of the drug, and the advice which will be given to those administering the drug. Some uncommon side-effects may be identified at this stage.

Long-term phase IV human studies are carried out once a drug has been licenced. They continue to investigate longer term side effects, risks, benefits and the optimal use of the drug. Animal work investigating fundamental ways that the drug affects the body often form part of phase IV clinical trials. Rare side-effects are frequently identified during these trials. There may not have been enough people taking the drug to notice a harmful effect before. Serious side effects seen after-market in drugs will be confirmed in animal studies, so that advice on how the drug should be used can be adapted. On rare occasions severe side-effects are identified and on risk-benefit analysis the drug is withdrawn.

In the USA, approximately 11% of drugs that begin phase I clinical trails are eventually licensed.

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Licensing of medicines

Medicines which have completed research and development processes, and which have undergone successful screening in clinical trials must apply for a product licence. The application for licence must be submitted to the appropriate regulatory body for the country where the medicine will be sold. Each regulatory body has their own submissions and approval processes.

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