Thalidomide & Toxicology

Question 1

Lecture Outcomes

Answer 1

1) summarise social, commercial, and medical factors that contributed to
the 1960’s thalidomide disaster
2) summarise key factors and events in the botched development of
thalidomide by Chemie Grunenthal
3) describe thalidomide toxicity, its impact on newborn and elderly victims,
and the likely toxicological mechanisms
4) describe the global impacts of the thalidomide disaster and the main lessons
learned
5) list the current therapeutic use of thalidomide and its safer derivatives

Question 2

The Titanic & Thalidomide - the Two Major Technology
Disasters of the 20th Century

Answer 2

• Reveal the risks accompanying blind faith in new technologies

Question 2

Aim of Lecture

Answer 2

To explore the scientific and
historical aspects of the
worst drug-induced medical
tragedy of the 20th century.

Question 3

The Background to Thalidomide - I

Answer 3

 Chemie Grünenthal GmbH, personal products
company
 Founded in Germany in 1946
 Many former Nazis in company
 Successful antibiotic ventures
 First company to make penicillin in post-war
Germany
 1950s, wished to expand into lucrative
tranquiliser market

Question 4

The Background to Thalidomide - III

Answer 4

“The Baby Boom” and Sleep Disruption in Pregnancy
 The Baby Boom that occurred after WW-2 left
many mothers experiencing pregnancy
 Many complex physical, hormonal, psychological
changes in pregnancy
 Expectant mothers frequently experience
insomnia
 Occurs in all trimesters
 Nausea-related in trimester 1
 Severity often increases with gestational age
(e.g., backache, nocturia, etc
)

Question 4

The Infamous Grunenthal “Jiggle Cage”

Answer 4

Question 4

October 1, 1957 – Thalidomide on Sale

Answer 4

Sold as “Contergan” (Germany)
OTC in Germany + elsewhere
Massive marketing campaign
50 medical journals
250,000 letters to doctors
50,000 “therapeutic circulars”
1961, top-selling sedative in Germany (5X
nearest competitor)

Question 4

The Background to Thalidomide - II

Answer 4

 Barbiturate class of hypnosedatives (sleep
inducers) were developed late 19th C/early
20th
C
 Powerful sedatives but serious side-effects
 e.g., Nembutal: addiction, tolerance
 A low “margin of safety” → high risk of
overdoses

Question 5

Early Human “Trial” Results Thrill Grunenthal Executives

Answer 5

Early 1955, results from tests in
epileptic patients in Germany &
Switzerland
No anticonvulsant benefits but
apparent hypnotic effects
Recipients report long, deep sleep
No effects on motor activity
Lacked proof for hypnotic properties in
animal model

Question 5

“A New Drug in Search of a Disease”

Answer 5

 Wilhelm Kunz, Grunenthal chemist
 Discovered thalidomide (by-product while making
antibiotic peptides)
 Secured 20-year patent
 Commenced animal testing in rats, mice, guinea
pigs, etc
 No signs of toxicity (“nontoxic”)
 Inactive in classic sedative tests (e.g., “righting
reflex”)
 Structure (wrongly) suggested tranquilizer actions
to Kunz’s supervisor, so human trials begun

Question 5

Chemie Grunenthals’ Woefully Inadequate “Human Trials”

Answer 5

 No systematic, properly conducted human
trial of thalidomide
 No evaluation of thalidomide safety in pregnant
women
 Grunenthal simply distributed free packets
of thalidomide to doctors
 No proper follow-up or patient monitoring
 Also distributed free of charge to company
employees

Question 6

Thalidomide: A Global Success Story

Answer 6

 Rapid expansion into overseas markets
(2nd only to aspirin!)
 e.g., Europe, Asia, Africa, Americas (not
USA!)
 Sold under 37 different trade names
 In UK & Australia – distribution rights
sold to Distillers
 No pharmacologists or toxicologists on
staff – no further testing in UK!
 Marketed as “Distaval

Question 7

Not So Safe After All?

Answer 7

In 1st year of marketing, written complaints
from doctors:
 Dizziness
 Memory loss
 Blood pressure loss
 Cold hands and feet
 Numb hands & feet
 GI-tract pain & constipation
Met with denial by Muckter
Dec 1960, letter on peripheral neuritis in BMJ
Alexander Leslie Florence (Scottish doctor)

Question 7

A Worrying Christmas Present

Answer 7

1956, December 25, Stolberg, Germany
“Earless” daughter born to worker at
Grunenthal plant
Father had supplied free pills to his
expectant wife
Failed to draw link to drug
10 months before thalidomide
marketing began in Germany

Question 8

A Shocking & Mysterious Epidemic Unfolds

Answer 8

 Pediatric clinics across Germany report cases of
phocomelia
 Lit. “seal limbs” – absent or ill-formed upper or
lower limbs
 Amelia
– both upper and lower limbs affected
 Extremely rare condition (normally)
 Germany was the cradle of emerging disaster
 News slowly emerged of affected infants elsewhere
 Widukind Lenz [1919-1995] – University of
Hamburg paediatrician – November 1961 began
exploring likely role of thalidomide
 Nov 16, 1961, phoned Chemie Grünenthal to
express his concerns re: teratogenicity

Question 9

1961: An Aussie Doctor Draws the Link

Answer 9

 1960, William McBride, Sydney gynaecologist, gave
thalidomide to pregnant patients
 Early 1961, several phocomelia babies
 Drug removed from hospital pharmacy
 Began testing in pregnant mice and guinea pigs
(unsuccessful)
 Sept 1961, 2 more affected babies
 Dec 1961, famous letter published in The Lancet
 Short-lived fame (later disgraced)

Question 10

Extent of the Global Tragedy

Answer 10

 Grunenthal eventually bowed to inevitable
 Drug withdrawn from all global markets
 Not marketed in US – Dr Frances Kelsey
 1957-1962: ~10,000 malformed babies worldwide
 Excludes miscarriages & stillbirths (occurred when
mothers took drug outside “window of susceptibility”)
 High mortality rate in newborns
 40% died by 1 y.o.

Question 11

Scope of Thalidomide Prenatal Toxicity

Answer 11

 Phocomelia “Window of Susceptibility”:
 Day-20 to Day-36 post-fertilization
 Day 34 to Day 50 after last menstrual cycle
 1 pill sufficient within this period
 Non-phocomelia malformations:
 Eyes (e.g. small)
 Ears (e.g. small or absent)
 Hearing loss
 Heart
 Kidneys
 GI-tract
 CNS (autism & low IQ in some victims)
 Abnormal genitalia (Vargesson, 2009)

Question 12

Scientific Puzzles I – Species Selectivity

Answer 12

Question 12

60 Years Later: Disability Issues in Ageing Thalidomiders

Answer 12

Question 13

Scientific Puzzles II – Mechanisms?

Answer 13

Question 14

Things We Learned from the Thalidomide Tragedy

Answer 14

 High level care needed when developing new drugs
 Must assess drug toxicity systematically (birth of modern
toxicology)
 Need for global and national drug laws &
pharmaceutical industry oversight
 Drug companies must be accountable for the harm their
products cause
 New uses have emerged from knowledge of
thalidomide effects

Question 16

Thalidomide’s Comeback

Answer 16

 Used to slow down body wasting in leprosy victims  Used to prevent weight loss & mucocutaneous ulcers in HIV-infected patients  Used to treat some types of cancer:  e.g., multiple myeloma, glioma  Safer thalidomide-based drugs, e.g., lenalidomide  Also used to limit vomiting [antiemetic] in some cancer chemotherapy patients

Question 17

Key Question: Is the Drug Safe?

Answer 17

* Since thalidomide, toxicologists have been key members of drug discovery and development teams in Big Pharma companies –Oversee toxicological evaluation of new molecules as they move along the drug discovery and development conveyor belt * Toxicologists are also employed by federal regulatory agencies where they review scientific data in dossiers submitted by pharmaceutical company sponsors.

Question 17

Further Reading

Answer 17

Question 18

Lecture Outcomes

Answer 18

Question 19

Aim of Lecture

Answer 19

To review the scientific strategies used and the questions that are asked during the evaluation of new pharmaceuticals for toxic potential.

Answer 19

Question 20

Key Questions in Early “Preclinical” Toxicity Testing - I

Answer 20

Question 21

Methods Used during each Phase of Toxicological Assessment

Answer 21

Discovery Phase Preclinical Testing * Metabolism studies * “In vitro” cell-based toxicity assays * Animal-based safety and toxicity testing Development Phase Clinical Testing * Conducted in human volunteers * Small scale pilots and large-scale trials * Pharmacokinetics, metabolism & safety

Question 22

Paracetamol – A Classic Example of Drug Bioactivation in the Body

Answer 22

Very safe at recommended doses, but at high doses (i.e., overdose conditions), paracetamol is converted to a toxic metabolite

Question 22

The Example of Ketotifen (“Zaditen”)

Answer 22

Question 23

Establishing the Metabolic Profile of Drugs in Cells and Tissues of Human & Animal Origin

Answer 23

 Mass spectrometry is key enabling technology during metabolic studies  Aim is to identify any metabolites with toxic potential  Knowing metabolic profiles in humans is most important  Need to identify any differences between humans & animals during the metabolism of new drugs  Cultured cells expressing human drug metabolising enzymes are widely used in industry

Question 24

Key Questions in Early “Preclinical” Toxicity Testing - II

Answer 24

Question 25

Ethical Factors in Animal-Based Drug Testing

Answer 25

 Animal use in medical research and pharmaceutical testing is a privilege that is subject to strict oversight  e.g., legislation, government regulators, vets, welfare groups, etc  Animal suffering kept to a minimum  3R’s of animal use:  Reduce  Refine  Replace

Question 26

Toxicological Issues that are Assessed in Animals

Answer 26

Short-term toxicity (e.g., limited doses) Accumulation in body tissues Ability to cause allergies (sensitisation) Long-term toxicity (repeated dosing) Toxicity to unborn animals Cancer-causing ability (“carcinogenicity”)

Question 27

Which Animal Species?

Answer 27

Rats and mice are preferred: Affordable to maintain Convenient lifespan Genetically defined Large database of drug effects Similar to humans in drug handling – i.e., ADME (pharmacokinetic properties)

Answer 27

Some Animal Species Predict the Human Toxicity of Drugs Better than Others (Cancer Drugs Only)

Question 28

Animal Toxicity Data Can Sometimes Halt Drug Development Programs

Answer 28

 Novo Nordisk, Danish drug company  2002, dropped diabetes drug ragaglitazar during final-stage human trials  Due to finding unexpected bladder tumours in rats and mice  Millions of $$$$ lost

Answer 29

Question 30

“Organs on Chips” - Emerging Alternatives to Animal-Based Drug Safety and Toxicity Testing

Answer 30

In vitro 2D cultured cells long used to test drugs  Poor reproduction of rich multicellularity and 3D complexity of whole organs Now many labs are studying microfluidic models as alternatives to animals/2D cultures Allow multiple cell types to be grown in artificial environment that mimics intact tissue Can use induced pluripotent stem cells (iPSCs) e.g., Liver on Chip, Kidney on Chip, etc Body on Chip – hook up multiple organ chips Not yet fully accepted by drug regulatory bodies Key companies: Mimetas, Emulate, etc

Answer 31

The Transition from Drug Discovery to Development Occurs when a Promising Molecule is Judged Safe and Effective and Worthy of Human Testing

Question 32

Key Questions in “Clinical” Drug Testing - I

Answer 32

Question 33

The 5 Phases of Clinical Testing

Answer 33

Question 34

Phase 0 Clinical Testing

Answer 34

 Enabled by advances in mass spectrometry equipment that allow detection of tiny amounts of drugs in blood or urine  A recent addition to modern clinical drug testing protocols  Also called “Pre-Phase 1” testing  Assess human safety of drug and obtain preliminary PK and PD data  Is the molecule suitable as a drug?  Small groups: 10 to 12 healthy volunteers  Tiny doses used (“microdoses”)  Measure drug concentrations in blood, urine, etc

Question 35

Phase 3 Clinical Testing

Answer 35

 Main purpose is large-scale testing of drugs (1 - safety & 2- effectiveness)  Normally conducted in >2000 disease-affected patients  Recruited in different cities, countries (= “multisite trial”)  Takes 3-5 years, complex organisation

Question 36

Phase 1 Clinical Testing

Answer 36

 Main purpose is to assess human safety of expected drug doses  Normally conducted in 10 to 100 healthy volunteers  Dose starts low, may increase with study progression  Measure drug concentrations in blood, urine, etc

Question 37

Phase 2 Clinical Testing

Answer 37

 Main purpose is to assess effectiveness of drug in target population  Normally conducted in 50-500 disease-affected patients  Controls may have received existing drug in current use  Success rate ~30%

Question 38

Phase 4 Clinical Testing

Answer 38

 Purpose is to monitor drug safety under “realworld” use patterns  AKA “post-marketing surveillance”  Can involve 50,000+ subjects (sometimes 1 million+)  Reporting system uses doctors, pharmacists, patients to report side-effects  Also assesses quality of life measures & economic considerations

Question 39

Lecture Conclusions

Answer 39

 Attentive toxicity testing has likely helped to make drugs safer but high caution is still needed  Combination of in vitro cell-based, whole animal and human testing methods  Important to identify any tendency for metabolic bioactivation (associated with organ damage)  Animal models allow comprehensive study of drug-induced toxicity  Short term, long term, multigenerational, etc  Human studies allow preliminary confirmation of drug safety, but vigilance needed upon human release of any drug

Question 40

Further Reading

Answer 40

1) Burcham, PC (2013) The emergence of modern toxicology, Chapter 1 in An Introduction to Toxicology, Springer (UK). 2) Cairns, R et al (2019) Paracetamol poisoning-related hospital admissions and deaths in Australia, 2004–2017. Medical Journal of Australia, 211, 218-223 3) Gallo, MA (2013) "History and Scope of Toxicology." Casarett and Doull's Toxicology: The Basic Science of Poisons, Eighth Edition Ed. Curtis D. Klaassen. New York, NY: McGrawHill. 4) Hill, RG & Rang, HP (2013) Drug Discovery & Development: Technology in Transition, Churchill Livingstone. 5) Erickson MA & Penning TM (2018) Drug toxicity and poisoning. Chapter 4 in Goodman & Gilman’s The Pharmacological basis of Therapeutics, 13th ed. McGraw Hill.