Developing drugs: from digitalis to clinical trials

William Withering and digitalis

In the 18th century, William Withering investigated a folk herbal remedy (a 'soup' or tea of many herbs) used to treat dropsy, the swelling (oedema) often caused by heart failure. He identified foxglove (Digitalis purpurea) as the active ingredient.

He tried different doses on his patients: too little had no effect, too much was poisonous. In 1785 he published his results from 163 cases. His approach was trial and error on patients, without controls, which would not be accepted today.

Modern drug testing

• Pre-clinical testing: on cells, tissues and often animals, to check the drug works and is not toxic.
• Phase 1: a small number of healthy volunteers: is it safe, what are the side effects, how is it absorbed and broken down, what dose is safe?
• Phase 2: a small number of patients with the condition: does it work, and at what dose?
• Phase 3: a large number of patients (often thousands): compared with an existing treatment or a placebo, to confirm effectiveness and detect rarer side effects.

Placebos and double-blind trials

• A placebo looks identical to the drug but has no active ingredient. Comparing with a placebo group shows whether improvement is due to the drug or to the placebo effect (patients feeling better because they expect to).
• In a double-blind trial neither the patients nor the doctors know who receives the drug, so expectations cannot bias the results.
• Patients are randomly allocated to groups. Where a good treatment already exists, the new drug is compared with it instead of a placebo, because withholding treatment would be unethical.

Worked example

Explain why phase 3 trials use thousands of patients.

1. Larger samples reduce the effect of chance.
2. Rare side effects are more likely to be detected.
3. Results are more reliable and can be generalised.

Answer: To make results reliable and to detect rarer side effects.

Check yourself

1. Which plant did William Withering identify as the active ingredient in a remedy for dropsy?
   • Willow
   • Garlic
   • Opium poppy
   • Foxglove
   Show answer

   Foxglove. Foxglove gives the drug digitalis.

2. Who takes part in phase 1 trials?
   • Thousands of patients
   • A small number of healthy volunteers
   • Only animals
   • A small number of patients only
   Show answer

   A small number of healthy volunteers. Phase 1 tests safety in healthy people.

3. What is the main purpose of phase 3 trials?
   • To test the drug on cells in a dish
   • To find whether it is safe in a few healthy people
   • To work out the chemical formula
   • To compare the drug with a placebo or existing treatment in a large number of patients
   Show answer

   To compare the drug with a placebo or existing treatment in a large number of patients. Phase 3 confirms effectiveness on a large scale.

4. What does double-blind mean?
   • Neither patients nor doctors know who receives the drug
   • Patients are blindfolded
   • Two drugs are given at once
   • Only doctors know who gets the placebo
   Show answer

   Neither patients nor doctors know who receives the drug. This removes bias from both sides.

5. Why is a placebo used?
   • To make the drug work faster
   • To reduce side effects
   • To see whether improvement is due to the drug or to patients' expectations
   • To treat a different disease
   Show answer

   To see whether improvement is due to the drug or to patients' expectations. It controls for the placebo effect.

6. Why might a new drug be compared with an existing treatment instead of a placebo?
   • Withholding an effective treatment would be unethical
   • Placebos are too expensive
   • Placebos always work better
   • Existing drugs have no side effects
   Show answer

   Withholding an effective treatment would be unethical. Patients should not be denied effective treatment.

7. What was a weakness of Withering's method by modern standards?
   • He used too many patients
   • He used animals only
   • There was no control group or placebo
   • He did not record his results
   Show answer

   There was no control group or placebo. Trial and error on patients without controls.

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Sources

• Pearson Edexcel International Advanced Level in Biology specification (XBI11/YBI11, first teaching 2018)
• Britannica: William Withering
• Linda Hall Library: William Withering (Scientist of the Day)

Last updated 7 November 2026. Spotted a mistake? Tell us.