1: History of Drug & Vax Development

Life expectancy + infant mortality in 1800

Life expectancy ~ 35 years

Infant mortality ~ 30% (1 in 3 children did not reach age of 5)

Life expectancy + Infant mortality in 1900

Life expectancy ~ 46

Infant mortality ~ 17%

Life expectancy + Infant mortality in 2020

Life expectancy ~ 83 years

Infant mortality ~ 0.3%

Main way people died in 1769

Smallpox

Main way people died in 1811

TB (consumption and cough)

First antibiotic + when was it introduced

Penicillin - 1946

What drugs existed before Penicillin was discovered

Sulfonamides (antimicrobials)

Why did 1st and 2nd world wars accelerate medical advancement

• High deaths from infection

• Wars lead to famine and poor hygiene

• Movement of people – move infections

• Increased funding during wars and the benefits after the war

1st recorded clinical trial

~550BC – King Nebuchachnezzar

o Comparison of carnivorous diet to herbivorous diet

First parallel arm trial

1747 – Dr James Lind

o Determination of treatment for scurvy – had 6 groups of 2 sailors with different treatments.

o Only the two that had citrus fruit recovered

First use of a placebo (2)

1801 John Haygarth – Perkins Tractors for rheumatism

1863 Dr Austin Flint – for rheumatism, used a herbal extract instead of established remedy

Which 2 breakthroughs accelerated the need for improved pharmaceutical development and production systems

1) Discovery of Insulin by Dr Frederick Banting 1922

2) Discovery of Penicillin by Alexander Fleming 1928 (originally discovered by Frenchman Ernest Duchesne)

Penicillin discovery - 3 important people / years / what they did

1897: First discovered by Ernest Duchesne - thesis ignored

1928: Alexander Fleming observed plates of his S. aureus contaminated with Penicillin nonatum w zones of inhibition where S. aureus were killed- but didn’t take it further

1938: Dr Howard Florey actually did the work to prove the concept and generate the antibiotic

What year was first patient treated and cured with penicillin

1942

Improvements in clinical regulation and management:

British Medical Research Council (MRC) officially recognized importance of

clinical trials and established the _____ in ___ to do what?

The Therapeutic Trials Committee in 1930 to advise and assist on trials

Example of a British committee aimed to Improve clinical regulation and management

The Therapeutic Trials Committee (1930)

History of Clinical Trials:

Bradford Hill Scheme

For Randomised patient selection and no researcher knew who was given the treatment

Placebo contrilled

First publicized randomized clinical trial

1946-1948

MRC Tuberculosis Research Unit led by Sir Geoffrey Marshall

• Efficacy of the drug streptomycin for treating pulmonary tuberculosis

19th century TB major cause of mortality in Europe

What % of deaths during this time were caused by this disease

Who did it effect

Tuberculosis

25% of deaths caused by TB in 1900s

Indiscriminate - killed predominantly young adults

First use of Bradford Hill randomisation

TB randomised clinical trial 1946-48

Testing efficacy of Streptomycin

Trial was both double blinded (researchers did not know who was on the drug) and placebo controlled

Is TB still a major cause of mortality globally

Yes

3 developments in ways to measure efficacy and safety before involving human subjects that accelerated drug development

1) Use of animal models to test novel compounds for efficacy and safety

2) Use of cell culture

3) Use of phenotypic measurements in cell culture, in tissues and in animal models

When was the introduction of molecular cloning and what did this lead to the emergence of

1970s

Emergence of public databases on proteins

When was a complete map of the human genome published

2003

History of Vaccine Development:

Variolation origins

Inoculating smallpox crusts from convalescent stage of mild cases of disease ground

up into powder and either taken as snuff or into the skin – practiced in India and China from 200BC

History of Vaccine Development:

British/European adoption of Variolation

1717: Lady Montagu (wife of British ambassador to Turkey) witnessed variation- failed to convince the British medical establishment to use it

1721: 7 prisoners were freed if they agreed to trial Smallpox variolation

Practice became common in Europe in 1700s , 2-3% died

History of Vaccine Development:

Leishmanisation

Ancient practice in Arabia and North Africa of ‘vaccinating’ against cutaneous leishmaniasis by

inoculating material from a lesion into the leg or buttock or exposed babies backsides to sandfly bites at night to cause a lesion on the backside and not the face

First vaccine (Western vax) was for the disease ___ and created by ___ in ___

Smallpox

Edward Jenner in 1796

Smallpox vaccine development

1796 Edward Jenner

- Inoculated 8 yr old boy with material from milkmaids cowpox lesion

- 3 months later he inoculated the boy again with material from a smallpox lesion

- No disease developed

-Jenner’s paper to Royal Society was rejected, published his own paper

First disease to be eradicated on planet

Smallpox

What was the second vaccine to be developed and when

Rabies vaccine by Louis Pasteur and Emile Roux (1885)

Rabies vaccine development key dates and people

1879: Louis Pasteur generated 1st animal vax for rabies

1880s: Pasteur tested vax on dogs - successful

1885: Pasteur and Emile Roux vaccinated 9 year old bitten by rabid dog - boy survived

Louis Pasteur: development of rabies vax for animals

His work on chicken cholera (Pasteurella multocida) = realised could weaken a pathogen by exposing it to adverse conditions - led to work on rabies/anthrax

– 1880s: Pasteur suspended the spinal cords of rabbits in air to dry and used the material to treat infected dogs. The dogs failed to develop rabies

– He used increasing concentrations of attenuated virus’ to treat the dogs

Anthrax vaccine development timeline

• 1879 – Anthrax epidemic in France

• Koch and Pasteur each independently proved anthrax bacteria were the cause of the disease.

• 1881 - Louis Pasteur used his knowledge of attenuation to make a weak version of anthrax

bacteria.

• He gave 25 sheep 2 shots of his attenuated live anthrax bacteria and 25 normal anthrax into 25 more sheep.

All the vaccinated sheep survived, all the control sheep died.

Who developed the anthrax vaccine

Louis Pasteur

BCG Tuberculosis Vaccine

Why has it been abandoned by most countries

Efficacy for TB between 0-80% depending on the population

In Malawi – 49% efficacy against leprosy but 0% against TB

Abandoned by most high income countries

Still given at birth in developing countries

Why might the BCG Tuberculosis Vaccine be re-introduced in developing countries

• BCG vaccine induces rapid production of G-CSF and increases neutrophils

• This reduces the chance of sepsis in infants due to other bacterial infections

Which physician was credited for first using a placebo when testing the efficacy of a treatment

A. Dr Lindt

B. Dr Flint

C. Dr Banting

D. Dr Flemming

B. Dr Flint

For rheumatism, used a herbal extract instead of established remedy

The TB study on the efficacy of streptomycin run in 1946 by Professor Geoffrey Marshall was notable for:

A. The first use of power calculations for patient numbers

B. The first use of drugs pre tested in animals

C. The first use of a placebo group for a potential fatal disease

D. The first use of fully randomized patient and placebo groups

D. The first use of fully randomized patient and placebo groups

Variolation is:

A. The use of weakened rabies virus to treat patients

B. The use of formaldehyde treatment to inactivate virus

C. The use of crushed up smallpox scabs to inoculate patients

D. The use of cowpox to protect against smallpox

C. The use of crushed up smallpox scabs to inoculate patients