Drug Development

Phase IV

Phase IV studies are long-term and typically conducted after regulatory agency approval (post-marketing studies). They are aimed at gathering additional information on safety, efficacy and new indications. In other words, Phase IV trials assess the drug’s real-world effectiveness in an extensive cohort and provide the opportunity of detecting unique AEs. In some cases, this might result in withdrawal of the drug from the market or restriction to particular uses. On the other hand, Phase IV studies may also open-up new markets by demonstrating effectiveness for new indications.

Discovery

Preclinical development starts with the identification of a target whose action can be modified with a particular agent (e.g. drug, antibody etc). Studies are then performed to investigate whether modulating this target can modify a disease. Once lead compounds against that target are obtained, their potential to interact with the target as well as their effect on the biological system is evaluated. Thousands of modifications and variations of these lead compounds are synthesised and tested during preclinical activities.

Clinical Trials

Once an optimised compound is identified, it becomes a candidate for clinical trials involving human subjects for the first time. Trials have 3 phases pre-appraisal. These investigate whether the drug candidate performs as expected (as determined in preclinical studies) and assess the safety and tolerance of the compound, determining its maximum tolerated dose and its most common and serious adverse effects (AEs). In addition, the compound’s pharmacological, pharmacodynamic, and pharmacokinetic properties are evaluated and eventually, its therapeutic efficacy and safety in the intended population patients is assessed.

Appraisal

Appraisal, or Marketing authorisation (MA) refers to the approval for a medicine to be marketed. In the European Union, a single application is submitted to the European Medicines Agency (EMA) for evaluation by the Agency’s Scientific committees. If the assessment is positive, a single marketing authorisation is issued by the European Commission. The Marketing Authorisation Holder can then legally begin to market the medicine in all EEA (European Economic Area) countries (EU member states and the three EEA EFTA States (Iceland, Liechtenstein, and Norway).

Phase IV

Phase IV studies are long-term and typically conducted after regulatory agency approval (post-marketing studies). They are aimed at gathering additional information on safety, efficacy and new indications. In other words, Phase IV trials assess the drug’s real-world effectiveness in an extensive cohort and provide the opportunity of detecting unique AEs. In some cases, this might result in withdrawal of the drug from the market or restriction to particular uses. On the other hand, Phase IV studies may also open-up new markets by demonstrating effectiveness for new indications.

Discovery

Preclinical development starts with the identification of a target whose action can be modified with a particular agent (e.g. drug, antibody etc). Studies are then performed to investigate whether modulating this target can modify a disease. Once lead compounds against that target are obtained, their potential to interact with the target as well as their effect on the biological system is evaluated. Thousands of modifications and variations of these lead compounds are synthesised and tested during preclinical activities.

In Focus

How are drugs developed and tested?

The identification, development and approval of drugs is a long, costly and difficult process. It is estimated that 9 out of 10 experimental drugs starting human clinical trials never gain final approval.

There are two main phases in drug development: pre-clinical development (discovery) and clinical development. Drugs are usually first developed in a university laboratory where researchers have undertaken basic or fundamental research to understand the processes behind a disease, often at a cellular or molecular level. It is through better understanding of disease processes and pathways that targets for new treatments are identified. A target might be a gene or protein instrumental to the disease process that a new treatment could interfere with.

Once a potential target has been identified, researchers search for a molecule or compound that acts on this target. Scientists are increasingly using knowledge gained from the study of genetics and proteins to create new molecules using computers. Thousands of compounds can be considered and whittled down to just 10 to 20 that could theoretically interfere with the disease process.

The next stage is to confirm that these molecules have an effect and that they are safe. Before any molecules are given to humans, safety and efficacy tests are conducted using computerised models, cells and animals. After this, they are tested in humans. In the EU, approval by the European Medicines Agency is required before any testing in humans can occur. The company will put in a clinical trial application, which will be reviewed by medical and scientific experts, who will decide whether or not sufficient preliminary research has been conducted to allow testing in humans to go ahead.

What is a clinical trial?

A clinical trial is a rigorously controlled test designed to examine the safety and effectiveness of medicines, devices, treatments, or preventive measures in humans.

Clinical trials follow a strict protocol. The protocol describes the aims, design and organisation of a clinical trial. It also provides information on the background and reasons for a trial and outlines the study plan for that trial. The plan must be carefully designed to ensure the safety of the participants as well as answer specific research question(s).

There are several phases to clinical trials:

Phase 1

In Phase 1, the safety and pharmacology of a candidate drug is tested in a small group of healthy volunteers. Small doses of the compound will be administered to a group of 20 to 100 healthy volunteers who are closely supervised. At least half of compounds will usually be considered safe enough to progress to phase 2 trials.

Phase 2

Phase 2 is designed to look at the efficacy of a compound in volunteer patients who have the condition the drug is intended to treat. The aim of phase 2 studies is to determine the most effective dose and method of delivery (for example, oral or intravenous), the appropriate dosing interval and to reconfirm product safety. Most drugs that fail during clinical trials do so at Phase 2 because they turn out to be ineffective, have safety problems or intolerable side effects.

Phase 3

Those candidates that make it through phase 2 are then tested in a much larger population of patients across multiple international sites. The aim of these phase 3 trials is to reconfirm the phase 2 findings in a larger population and to identify the best dosage regimen. In doing this, the drug company needs to generate sufficient safety and efficacy data to demonstrate an overall risk-benefit for the medicine to allow a submission to be made for a licensing application to the regulatory authority. Despite the rigorous testing that has already taken place, approximately 10% of medicines will still fail at this stage.

When does a drug enter the market?

The process of drug development and marketing authorisation is similar across the world.

In Europe, for drugs that make it through phase 3, pharmaceutical companies usually make a central application to the European Medicines Agency (EMA) in order to obtain marketing authorisation for the whole of Europe, to avoid having to make multiple applications to individual countries.

The submission contains preclinical and clinical information obtained during testing, including information about the chemical makeup and manufacturing process, pharmacology and toxicity of the compound, human pharmacokinetics, results of the clinical trials, and proposed labelling.

If a licence is granted, that is not the end of the process and each country will have its own process for medicines to reach patients. 

Clinical trials may also continue. Regulatory authorities may insist on Phase 4 trials for post-marketing safety surveillance (pharmacovigilance), when new side effects or risk factors may be identified that had not been previously recorded.

This Phase 4 is also part of the continued monitoring of the effectiveness of the drug in their target patients.

Patenting

Pharmaceutical companies will patent any molecule that shows promise early in the development process.

Patenting prevents other companies copying it for 20 years and covers many aspects of the intellectual property of a drug, including its manufacture, formulation and, in some cases, its use.

The purpose of a patent is to enable the pharmaceutical company that developed it to recoup their development costs and to make a profit to cover the development costs of drugs that failed during the testing process, as well as to invest in the development of future innovative drugs. By the time a drug has undergone the required testing and been licensed, half the patent period will usually have expired.

Once a patent on a drug has expired, generic versions of the drug can be manufactured and marketed.

Naming of drugs

Drug names usually start as a string of letters and numbers, a name used to identify it in the laboratory.

As the drug advances through testing, it gets a generic name, or non-proprietatry name, which must be approved by the World Health Organisation (e.g. for SMA approved drugs: onasemnogene abeparvovec, nusinersen, risdiplam). The name often reflects the drug's chemical class and use. A group of medicines that have similar actions often have similar sounding generic names. For example, penicillin, ampicillin, amoxicillin and flucloxacillin are in one group of antibiotics.

The brand name, or proprietary name, is chosen by the manufacturer, usually on the basis that it can be recognised, pronounced and remembered by health professionals and members of the public (e.g. for SMA approved drugs: Zolgensma, Spinraza and Evrysdi). The brand name must be unique to protect the trademark and not sound or look too much like any other drug name to avoid medical errors.

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