Discovering new medicines

1. A drug changes the way the body works, and a medicine is a drug that is used to prevent or treat disease or to relieve its symptoms.
2. Many of the first medicines were found in plants, which make chemicals to defend themselves against pathogens and animals.
   1. Digitalis, which slows and strengthens the heartbeat in people with heart failure, comes from foxgloves.
   2. Aspirin, a painkiller, was developed from a chemical found in the bark of willow trees.
3. Other medicines have been found in microorganisms.
   1. In $1928$ Alexander Fleming noticed that a mould called Penicillium had killed the bacteria growing around it on a Petri dish.
   2. The substance released by the mould was the antibiotic penicillin.
   3. Penicillin was not produced in large amounts until the early 1940s, when Howard Florey and Ernst Chain found a way to purify it and test it on patients.
4. Most new medicines are now made, or synthesised, by chemists in the laboratory.
5. Scientists first identify a target, such as a protein that a pathogen needs or a protein that is not working properly in a disease.
6. Computers are used to model the shape of the target and design molecules that might bind to it.
7. Huge libraries of chemicals, containing hundreds of thousands of compounds, are also tested automatically against the target to find any that have the right effect.
8. A compound that looks promising is called a potential new medicine, and it must now be tested thoroughly before it can be given to patients.
9. Most potential medicines fail during testing, and only a very small proportion of the compounds first identified ever reach patients.

Preclinical testing

1. Preclinical testing is carried out in the laboratory before a potential medicine is given to any human.
2. It checks three things about the medicine.
   1. Its toxicity, which is whether it is harmful to cells and to the body.
   2. Its efficacy, which is whether it has the effect it is meant to have.
   3. The dose that is likely to be effective without being harmful.
3. The medicine is first tested on cells and tissues grown in the laboratory.
   1. These tests are quick and cheap, and they show whether the medicine damages living cells.
   2. They cannot show how the medicine affects a whole body, with its many organs working together.
4. It is then tested on live animals, usually mice or rats, and in the UK a second species of animal is normally used as well.
   1. Animal tests show how the medicine is absorbed, carried around the body, broken down and removed.
   2. They show whether it harms any organ, such as the liver or kidneys.
5. Animal testing has limitations and raises ethical questions.
   1. The bodies of animals differ from human bodies, so a medicine that is safe in mice may still harm humans.
   2. Some people believe it is wrong to cause animals harm or suffering to test medicines.
   3. UK law requires animal tests to use as few animals as possible and to reduce any suffering.
6. Only medicines that pass preclinical testing are allowed to move on to testing in humans.

Clinical trials

1. Clinical trials test the potential medicine on human volunteers, and they are carried out in phases, each involving more people.
2. In the first phase the medicine is given to a small number of healthy volunteers, often between $20$ and $100$ people.
   1. It starts at a very low dose, which is then increased slowly.
   2. The aim is to check that the medicine is safe in humans and to find any side effects.
   3. Healthy volunteers are used because the aim is only to test safety, and a person who is already ill might react badly to an untested drug.
3. In the second phase the medicine is given to a small number of patients who have the disease.
   1. This tests whether the medicine works in people with the illness.
   2. Different doses are compared to find the optimum dose, which is the dose that works best with the fewest side effects.
4. In the third phase the medicine is given to a large number of patients, often several thousand, in many different hospitals.
   1. The medicine is compared with a placebo or with the best existing treatment.
   2. The large number of patients means that rare side effects are more likely to be found and that the results are more reliable.
5. A clinical trial can be stopped at any point if the medicine causes serious side effects or clearly does not work.
6. The whole process from discovery to a medicine being available often takes more than ten years and costs a very large amount of money.

Placebos and blind trials

1. People often feel better after taking any treatment simply because they expect it to help, and this is called the placebo effect.
2. To show that a medicine really works, the patients are split at random into two groups.
   1. One group receives the medicine being tested.
   2. The other group, called the control group, receives a placebo, a dummy tablet or injection that looks the same but contains no active drug.
3. If the group taking the medicine improves more than the placebo group, the difference must be caused by the medicine itself.
4. Patients are placed in the groups at random, so each group has a similar mix of ages, sexes and severity of illness.
5. In a blind trial, the patients do not know which group they are in, so their expectations cannot affect the results.
6. In a double-blind trial, neither the patients nor the doctors know who is receiving the medicine and who is receiving the placebo.
   1. This removes bias from the doctors as well, because a doctor who knows which patient has the medicine might treat them differently or judge their improvement more favourably.
   2. The information about who received what is held by a third party and revealed only when the trial ends.
7. It can be unethical to give a placebo to a patient with a serious illness, because it means withholding a treatment that could help them.
8. In these cases the new medicine is compared with the best existing treatment instead of a placebo.

Approval and publication

1. When a trial is finished, the scientists write up their methods and results and send them to a scientific journal.
2. Before it is published, the work goes through peer review, in which other scientists who are experts in the same field check it.
3. Peer review checks that the methods were suitable, that the results support the conclusions, and that no mistakes or false claims have been made.
4. Publishing the results allows other scientists to repeat the work and check that they get the same results.
5. In the UK a medicine can only be sold once the Medicines and Healthcare products Regulatory Agency, the MHRA, has examined all the trial data and granted a licence.
6. Doctors continue to report side effects after the medicine is licensed, because very rare side effects may only appear once millions of people have taken it.