Drug Development

From natural sources to medicines

Humans used substances from living organisms as remedies long before their active chemicals were understood. Traditionally, useful drugs were extracted from plants and microorganisms. The heart drug digitalis originates from foxgloves, while the painkiller aspirin originates from willow. Penicillin was discovered by Alexander Fleming after he observed the effects of the microorganism Penicillium, a mould.

A natural origin does not automatically make a substance safe, effective or suitable at every dose. A useful chemical must be identified, purified and investigated. Most new drugs are now synthesised by chemists in the pharmaceutical industry, although the starting point may still be a chemical first extracted from a plant. Synthesis can provide controlled quantities of a substance and allows chemists to develop potential medicines from promising chemical structures.

What a potential medicine must prove

A promising chemical cannot be prescribed immediately. New medical drugs must be extensively tested and trialled to investigate three connected questions:

• Toxicity: is it harmful, and what side effects does it cause?
• Efficacy: does it produce the intended medical effect?
• Dose: how much should be given to achieve the effect without causing unacceptable harm?

These questions are linked. A drug might work at a high dose but cause serious side effects, or be safe at a dose too low to be effective. Testing therefore seeks an optimum dose that produces the desired benefit while keeping risks acceptably low.

Preclinical testing in the laboratory

Testing begins preclinically, before the drug is given to people. Researchers test it in a laboratory using cells, tissues and live animals. These tests provide early evidence about its effects and toxicity and help researchers judge whether it is suitable to progress to human trials.

Each model supplies different information: cells and tissues allow effects to be studied under controlled conditions, while tests involving a whole living organism can reveal effects that depend on interacting organs and body systems. Promising preclinical results do not prove that a drug will be safe and effective in humans, so clinical testing is still necessary.

Clinical trials in people

Clinical trials use healthy volunteers and patients. At the start, very low doses are given. Healthy volunteers can provide evidence about safety and side effects without an illness obscuring the results. Starting with a very low dose limits potential harm when the response in humans is still uncertain.

If the drug is found to be safe enough, further trials involve patients who have the condition the drug is intended to treat. Researchers can then investigate whether it is effective, continue monitoring side effects and compare different doses. Evidence from these trials is used to find the optimum dose.

This is a progression rather than a single test: evidence of acceptable safety allows the next stage to proceed, while later and larger trials give stronger evidence about benefits, side effects and dose.

Placebos make a fair comparison

Symptoms can change naturally, and people may report improvement simply because they expect a treatment to help. To distinguish these changes from the drug's genuine effect, some patients in a trial may receive a placebo—a treatment that resembles the real one but contains no active drug. The outcomes of the drug group can then be compared with those of the placebo group.

Patients should be allocated to comparable treatment groups so that other differences do not systematically favour one treatment. If the drug group improves more than the placebo group, this provides evidence that the active drug caused the additional effect.

Why trials are double-blind

In a double-blind trial, neither the patients nor the doctors assessing them know during the trial who receives the active drug and who receives the placebo. This reduces two possible sources of bias: patients' expectations are less likely to alter how they describe symptoms, and doctors' expectations are less likely to affect how they assess or record outcomes. Treatment identities can be revealed after the results have been collected so that the groups can be compared.

A placebo and double-blinding do different jobs. The placebo supplies a comparison, while double-blinding reduces the influence of expectations on that comparison.

From evidence to published findings

Results from testing and trials are analysed to decide whether the evidence supports the drug's safety, efficacy and chosen dose. The results are published only after scrutiny through peer review, in which other scientists examine the methods, evidence and conclusions. Peer review can identify weaknesses, unsupported claims or bias, although it does not guarantee that research is perfect.