Clinical trials: A history

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Clinical trials A history

• Group C presentation, July 2006

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First clinical Trial
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Nebuchadnezzar II

• Instructed courtiers to follow strict diet of
  wine and meat
• Jewish courtiers refused to eat meat offered to
  idols and were allowed to eat vegetables, bread
  and water
• Daniel and colleagues were healthier than those
  on the meat and wine

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Ambroise Parè 1537

• Ran out of traditional dressing compound
• Mixed oil of rose, turpentine and egg yolk and
  dressed wounds with this
• Following day wounds dressed with his compound
  were healthier
• Unintentional

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James Lind 1747

• Controlled trial of crews in British navy
• 1 Crew given lemon juice
• 1 Crew normal diet
• No scurvy in treated crew
• First controlled trial

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19th century

• Placebo- literally I Will Please developed in
  clinical trials

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Austin Bradford Hill 1947

• Streptomycin used in first double blind,
  randomised, placebo controlled clinical trial.
• Use of streptomycin already proven in advanced
  disease
• Pulmonary tuberculosis not always fatal so
  placebo considered ethical
• This trial was organised by the group that became
  the MRC Clinical Trials Unit

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Ethical Considerations

• Following WWII, after atrocities carried out by
  Nazi doctors, the Nuremberg code (1947) was
  developed.
• voluntary consent
• Avoidance of unnecessary suffering
• High scientific standards

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Tuskegee

• Observational study of men with syphilis
• Started in 1932
• Despite availability of penicillin from early
  1950s, study participants were observed without
  treatment until 1972

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Declaration of Helsinki

• Statement of ethical principles for medical
  research first issued in 1962
• Most recently revised 2000
• Has legal force in most countries
• Embodied in EU good clinical practice guidelines
  since 1990

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Declaration of Helsinki

• Fundamental ethical principles
• Respect for Persons
• Beneficence
• Justice

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Stages of testing a new drug
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Pre clinical trials

• Drug development
• Promising substances tested on animals
• Trials on human cells often also take place
• 0.1 of substances pass this stage

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Phase 1 studies

• First exposure to humans
• 20 100 subjects
• Healthy volunteers
• Investigates pharmacokinetics and adverse effects
  with increasing doses
• Takes 1-2 years
• 70 go on to Phase 2

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Phase 2

• Several hundred patients
• First exposure to Patients
• Trials to study Efficacy of drug, dosage and
  frequency
• Also likely to show common side effects and risks
• 50 will pass on to phase 3

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Phase 3 studies

• Hundreds to thousands of patients
• RCTs
• Huge cost
• Designed to show benefits and effectiveness
  compared to other treatments and adverse
  reactions
• 70 90 are marketed after phase 3

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Phase 4 (Post marketing)

• Compare drug with others already on the market
• Look at cost effectiveness compared to other
  therapies
• Gain experience and monitor safety in real life

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