history & tragedies in clinical research

8/2/2019 History & Tragedies in Clinical Research

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Historical Background Adulteration and misbranding of foods & drugs

have always been a problem in the U.S.

The problem increased by the late 19th C.

Drugs such as Quinine were cut with fillers to

increase profit

Sufferers of serious illnesses were sold worthless

drugs or therapies

Preservatives added to foods & drugs were useless

or worse toxic



Harvey Washington Wiley, chief chemist concerned

about chemical preservatives, initiated "poison

squad" experiments

Healthy volunteers consumed varying amounts of

questionable food additives to determine their

impact on health

Officially designated the “Hygienic Table.”

Chemicals fed to the young men included borax,

salicylic, sulfurous, and benzoic acids, &

formaldehyde



Wiley became convinced that chemical

preservatives should be used in food only when

necessary

That the burden of proving safety should fall on the

producer

That none should be used without informing the

consumer on the label

Wiley unified a variety of groups behind a federal

law to prohibit the adulteration and misbranding

of food and drugs



No regulations for pharmaceutical products until

1906



Food and Drugs Act of 1906 First nationwide consumer protection law made it

illegal to distribute misbranded or adulterated

foods, drinks and drugs across state lines

Offending products could be seized & condemned;

persons could be fined & jailed

Drugs had either to abide by standards of purity

and quality set forth in the UNITED STATES

PHARMACOPEIA & the NATIONAL FORMULARY

Presence & quantity of alcohol or certain narcotic

drugs had to be stated on proprietary labels



Sulfanilamide Tragedy

A disaster in 1937 prompted Congress to act

A Tennessee drug company marketed a form of the

new sulfa wonder drug that would appeal topediatric patients, Elixir Sulfanilamide

The solvent in this untested product was diethylene

glycol

Over 100 people died, many of whom were children



Elixir Sulfanilamide

http://www.fda.gov/cder/about/history/Graphics/sulfanilamideLrg.jpg



Food, Drug, and Cosmetic Act

in 1938• required pre-market review of safety in a New Drug

Application (NDA) and specified labelingrequirements

• It also began marking study drugs with the phrase, “forinvestigational use.”

• It also gave the FDA the authority to inspect sponsor

drug manufacturing plants and gave them moreenforcement power.

• The requirement of proving effectiveness was stillmissing.



NAZI MEDICAL EXPERIMENTS• Nazi human experimentation was a series of

controversial medical experiments on large

numbers of prisoners by the German Nazi regime in

its concentration camps during World War II.

• Prisoners were coerced into participating: they did

not willingly volunteer and there was never

informed consent.

http://en.wikipedia.org/wiki/Human_experimentation


http://en.wikipedia.org/wiki/Germany

http://en.wikipedia.org/wiki/National_Socialist_German_Workers_Party

http://en.wikipedia.org/wiki/Concentration_camp

http://en.wikipedia.org/wiki/World_War_II

http://en.wikipedia.org/wiki/Coercion

http://en.wikipedia.org/wiki/Informed_consent

http://en.wikipedia.org/wiki/Informed_consent

http://en.wikipedia.org/wiki/Coercion

http://en.wikipedia.org/wiki/World_War_II

http://en.wikipedia.org/wiki/Concentration_camp

http://en.wikipedia.org/wiki/National_Socialist_German_Workers_Party

http://en.wikipedia.org/wiki/Germany





Typically, the experiments resulted in death,

disfigurement or permanent disability.

At Auschwitz and other camps, under the direction

of Dr. Eduard Wirths, selected inmates weresubjected to various experiments which were

supposedly designed to help German military

personnel in combat situations, develop new

weapons, aid in the recovery of military personnelthat had been injured, and to advance the racialideology backed by the Third Reich

http://en.wikipedia.org/wiki/Disfigurement

http://en.wikipedia.org/wiki/Auschwitz_concentration_camp

http://en.wikipedia.org/wiki/Eduard_Wirths

http://en.wikipedia.org/wiki/Third_Reich

http://en.wikipedia.org/wiki/Third_Reich

http://en.wikipedia.org/wiki/Eduard_Wirths

http://en.wikipedia.org/wiki/Auschwitz_concentration_camp

http://en.wikipedia.org/wiki/Disfigurement



Dr. Aribert Heim conducted similar medical

experiments at Mauthausen. After the war, these

crimes were tried at what became known as the

Doctors' Trial, and revulsion at the abusesperpetrated led to the development of the

Nuremberg Code of medical ethics.

http://en.wikipedia.org/wiki/Aribert_Heim

http://en.wikipedia.org/wiki/Mauthausen-Gusen_concentration_camp

http://en.wikipedia.org/wiki/Doctors'_Trial

http://en.wikipedia.org/wiki/Nuremberg_Code

http://en.wikipedia.org/wiki/Medical_ethics

http://en.wikipedia.org/wiki/Medical_ethics

http://en.wikipedia.org/wiki/Nuremberg_Code

http://en.wikipedia.org/wiki/Doctors'_Trial

http://en.wikipedia.org/wiki/Mauthausen-Gusen_concentration_camp

http://en.wikipedia.org/wiki/Aribert_Heim



Nuremberg Code -1948• first formal statement on medical ethics

• 10 standards for physicians to conform to when

carrying out experiments on human participants.

• the result of judgment by an American military war

crimes tribunal conducting proceedings against 23

Nazi physicians and administrators for their willing

participation in war crimes and crimes against

humanity.

• The doctors had conducted medical experiments on

concentration camp prisoners who died or were

permanently affected as a result



Nuremberg Code -1948 was developed in response to the judicial

condemnation of the acts of Nazi physicians, and

did not specifically address human subject research

in the context of the patient-physician relationship. Nuremberg Code establishes the need for

informed consent in human research



Nuremberg Code -1948 Briefly the 10 standards of the Nuremberg Code:

Volunteers freely consent to participate

Researchers fully inform volunteers concerning

the study

Risks associated with the study are reduced

where possible

Researchers are responsible for protecting

participants against remote harms

Participants can withdraw from the study at any

time



Nuremberg Code -1948 Qualified researchers conduct the study

Cessation of the study if adverse effects emerge

Society should benefit from study findings

Research on humans, should be based on

previous animal or other previous work

A research study should never begin if there is a

reason to believe that death or injury may result.



Thalidomide tragedy-

1957 to 1961 Thalidomide – the active ingredient of an hypnotic

agent which was sold in Germany

under the trademark Contergan – triggered a global

tragedy. & remains part of the corporate history of Grünenthal. Even now, after almost 50 years,

Thalidomide was developed by Grünenthal in

1954.

The substance had a sedative effect and was usedto promote sleep was prescribed to women in early

pregnancy to overcome the unpleasantness of

morning sickness



Thalidomide tragedy-

1957 to 1961 Unlike other hypnotics of that period it was not

associated with dependency and

it appeared to be particularly well tolerated. In line

with the pharmacological and toxicologicalinvestigations carried out in rodents AT THAT TIME

THE STD.PRACTICE



The deformities



The culprit drug



Thalidomide tragedy Thalidomide, the nightmare drug responsible for

over 10,000 human birth deformities and many

more-born throughout the world as\ phocomelics,

deformed, some with fin-like hands grown directly on the shoulders; with stunted or missing limbs;

deformed eyes and ears; ingrown genitals; absence

of a lung; a great many of them still-born or dying

shortly after birth; parents under shock, mothersgone insane, some driven to infanticide

is an Example Of Animal Research Misleading

Science. OR too little animal experimentation



WHO TO BLAME? Thalidomide campaigners argue that the

thalidomide tragedy is not an example of an

animal-tested drug that proved disastrous for

humans, but of the dishonesty and sharppractices of the pharmaceutical industry.

An Observation that the animal tests carried out by

the inventor of the drug, the West German

pharmaceutical company Chemie Grünenthal, werevery superficial and incomplete, and their clinical

trials were hastily done and questionable



What went wrong? Prior to the introduction of thalidomide Grünenthal

did not carry out animal tests specifically to

demonstrate teratogenic (malformation causing)

effects. The unacceptable truth unfolds that the human

birth deformities caused by thalidomide was the

result of misleading results from animal

experimentation as well as the dishonesty andruthless behavior of drug companies.



What about Legal

aspect? thalidomide apologists defend that the thalidomide

tragedy could not have been predicted, mainly

because the drug had not been tested specifically

for birth defects before being marketed, as at thetime it wasn't required by law.

Adverse drug reaction of peripheral neuritis

revealing thalidomide's the toxic effects on the

nervous system of user reported in 1957, soon afterlaunching Contergan (thalidomide) in West

Germany



Criminal Negligence the fact that despite thousands of cases of

peripheral neuritis and that a growing number of

cases of deformities were being reported the drug

firms resisted moves to withdrawal their products.

Also, the new animal tests could not duplicate the

deformities, company had no reason to remove the

drug. Only until the evidence was overwhelming didChemie Grünenthal finally take Contergan off the

market.



Criminal Negligence Also, in other countries around the world including

Brazil, Italy, Japan, Sweden and Canada drugs

containing thalidomide were not withdrawn till

a year or longer after Grünenthal's withdrawal of the drug.



Common side effect of

thalidomidesedation peripheral neuritis, drowsiness, mood

changes dizziness, tremor, Gastrointestinal

constipation, increase appetite, hypotension,

hypertension, bradycardia deep venous thrombosis,pruritus, skin rash, neutropenia, eosinophilia, dry

mouth, oedema, altered temperature sensitivity



Could have been

prevented? Neither the original animal tests by Chemie

Grünenthal nor several European countries,

including England and Sweden, the licensees of

thalidomide carried out their own animal tests,independently from the German firm, show

indications of this unexpected and serious side-

effect.

If the tests had predicted peripheral neuritis and if the firms acted upon the results in a responsible

manner, the drug would not have been released in

the first place and a major disaster would have

been avoided



FDA stand Based on peripheral neuritis symptoms in adults

Lady Officer of the Food and Drug Administration,

wasn't satisfied that the drug would be safe to take

during pregnancy. rejected the drug firm'sapplication to market Kevadon (thalidomide) in the

United States,.



Obstetrician Dr William McBride, first warned

against thalidomide in 1961, has called on doctors

to study children of victims and report back to

determine the scale of the tragedy. Concern raised about second generation victims in

Germany, Japan and Bolivia as well as Britain.



The court case

1968 - 1970 The proceedings, which were held before the Grand

Criminal Court of the Landgericht Aachen, became

the longest and most costly case in German legal

history up to that time.

It was recognized that the employees of Grünenthal

had adequately tested the sedative and hypnotic

drug in accordance with the guidelines then in

force. After the first detailed, justified suspicion that

thalidomide might be responsible for producing

deformities in the unborn child, Grünenthal had

reacted within 12 days and had withdrawn its



The consequences Comprehensive medical act 1976

an amendment to the Medicines Act of the Federal

Republic of Germany in 1964, the comprehensive

Medicines Act of 1976

Act made it compulsory for new medicines to

undergo astringent licensing and assessment

procedure.

Since that time companies have to submit to theregulatory authorities extensive experimental

results



The consequences confirming the efficacy, safety and sufficient

quality of medicinal products before a medicine

can be licensed for sale for the first time.

Special tests to detect any risk of malformationhave become standard practice.



Kefauver-Harris Drug

Amendment The earlier law (the Federal Food, Drug, and

Cosmetic Act of 1938) was passed in response to a

tragic error made in formulating a cough syrup for

children

In the USA, proof of efficacy of pharmaceuticals was

required for the first time with the passage of the

Kefauver- Harris Drug Amendment



Kefauver-Harris

Amendments

(1962) Efficacy as well as safety must be demonstrated in

studies before a drug is marketed

First US law requiring researchers

to:

– Inform subjects of experimental nature of a drug

– Obtain consent before starting the trial.



research1966rewrite:

– Consent required except in cases of emergency or

experimental therapeutic treatment with children or

similar situations

– Documentation of consent in writing Inform

subjects that they may receive a placebo



Tuskegee Institute

Syphilis Study 1932 Study the natural course of untreated

syphilis:

– Was originally scheduled to end after assessing

what health effects had occurred

– In the beginning, there was no intent to deny

anyone treatment on a lonTgu-

stkeegremebInasstiitsute,

399 African-American men matched against 201uninfected subjects (controls)

Men were not informed about their disease

Were not informed that the research would not

benefit them



Tuskegee Institute

Syphilis Study they did not receive the proper treatment needed to

cure their illness. In exchange for taking part in the

study, the men received free medical exams, free

meals, and burial insurance.



Syphilis Study

• 1943- penicillin accepted as treatment for syphilis

1951- Penicillin was widely available but was

withheld from the subjects.

Subjects were never given the choice about

continuing once penicillin became available

1972- Study exposed. Public outcry

March 1973- Study Stopped

1997- President Clinton apologizes to subjects and

their families



What changed unethical

researchEstablishing Proof of Efficiency

In the 1960s and 1970s, governments began to

require that clinical trials be performed to establish

that drugs worked before they could be marketedby the pharmaceutical industry.

Establishing Proof of Safety

One of the main catalysts that led to this

development was the tragedy of infants being bornwith deformities to women who took the drug

thalidomide during pregnancy in the late 1950s

and early 1960s



Summary Catalyst Event

Sulfanilamide Tragedy

Nazi Physicians Trial

Thalidomide Tragedy

Syphilis Study



Tragedies changed the

practices Regulatory Milestone

Food, Drug, and Cosmetic Act

Nuremberg Code

Kefauver-Harris Amendments

National Research Act

history & tragedies in clinical research

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