RESEARCH 101

Session 1:

Research History and Background,

Evolution of Regulations and Guidance

Janie Gardner, MS, CCRP, CIM

Key Points

The Science - Clinical Trial Study Design

The Ethics - Protection of Human Subjects

U.S. Regulations and Guidance ---Study Conduct

Objectives:

Recognize the events in history that led to the drafting of ethical and regulatory guidelines for clinical
research in the U.S.

Explain the major provisions of the national Research Act of 1974 -

Include the impact on the ethical and regulatory considerations for
clinical studies.
 Clinical Research
is
Research involving Humans

v To examine physical, mental and/ or behavioral attributes of an

individual or group of people

v To collect information that contributes to our collective memory and

general knowledge about individuals and groups of people
 Clinical Trials

A special type of Clinical Research that evaluate the effects of an intervention on biomedical or
health–related outcomes.

The function of the controlled clinical trial is not the "discovery" of a new drug or therapy. The
function of the formal controlled clinical trial is to separate the relative handful of discoveries
which prove to be true advances in therapy from a legion of false leads and unverifiable clinical
impressions, and to delineate in a scientific way the extent of and the limitations which attend
the effectiveness of drugs.”

William Thomas Beaver, MD

PHARMA v. Robert Finch and Herbert Ley
1969
Contributions to “The Science”

These early physician /investigators through their

Curiosity, Observation, and Documentation
pioneered a rigorous research method for new
treatments.
Study Design
First Documented Clinical Study
Problem: Daniel and his friends cannot eat the food ordered by the king

(Daniel 1:5-16).
First Novel Therapy
Problem: Gunshot wounds (guns used in battle for the first time in 16th century)

Ambroise Pare
1537, Siege of Turin
First Controlled Clinical Trial
Although the benefits of citrus had been known for centuries, Lind’s
Problem: Sea Scurvy study confirmed the addition of citrus fruit to the diet as superior to
other remedies.
All were treated the same except for the tx
A common laxative
Vitriol is sulfuric acid
Published his finding on scurvy in a treatise in 1753
Navy did not adopt the changes for another 42 years

James Lind’s Experiment, 1747

Twelve sailors with same symptoms of scurvy; each
pair received one of the following interventions
• Quart of cider a day
• 25 drops vitriol 3x a day
• 2 spoons of vinegar 3x a day
• Half pint of sea water a day
• Paste of garlic, mustard seed, dried radish and
myrrh
• An orange and two lemons
First Double Blind Controlled Clinical Trial
Proble : The Common cold

British Medical Research Council- 1943 – 44

Multi-center study to compare Patulin to placebo.

Patulin a fungal metabolite (mycotoxin) from rotting apples

(Penicillium patulum) was compared to placebo

W. A. Hopkins, M.D.
Bradford Hill, M.D.
Army and Navy Trials

“An Apple a Day…”

First Randomized, Double–blind Controlled Clinical Trial
1948
Problem: Penicillin ineffective against Pulmonary Tuberculosis

… tuberculosis was the most important cause of death ( 50% mortality) of young adults in
Europe and North America. Study was to measure the efficacy of Streptomycin to treat
Pulmonary tuberculosis

Bradford Hill, M. D.
Phillip D’Arcy Hart

The randomized, double blind controlled trial is still considered the gold
standard for today’s clinical investigations.
“The Ethics” - Protection of Human Subjects

Prior to the twentieth century, research ethics were primarily governed by physicians’
conscience and professional codes of conduct.

In the previous examples “patients/subjects” were not informed that they were involved in
experimental treatments.

Patients expected that the treatment or intervention was for therapeutic purposes
Early U.S. Court Cases

Carpenter V. Blake, 1871

Earliest significant contribution to human subject protections

The Carpenter court held that a doctor who departs from the usual, established method of
treatment is liable for any resulting problems.

Fortner v. Koch, 1935

For the first time, the court recognized that some human experimentation must be permitted
– specifically , Therapeutic Research, experiments that could potentially benefit the patient.
The court imposed two important limits on such experimentation, namely that the subject
must consent and that the procedure not deviate too much from established practice.
 In the meantime – in Europe

The Berlin Code of Ethics, 1900

“Prussian Standards”

• First regulations by a state authority

for human experimentation
• Became a part of physician
employment contracts
• Binding under German law
 Guidelines for New Therapy and Human Experimentation'
“Reich Instructions”

1931
Expanded on the Berlin Code of Ethics

1) No experimentation on patients who were poor or socially disadvantaged.

2) Proportionality of risk and benefit must be respected, and

3) that experiments should first be done in animals.

4) Experimentation with dying persons not permissible, and

5) Made the head of the institution personally and professionally responsible for
the design, implementation and review of human experimentation
Rise of Adolf Hitler and the Third Reich, 1933
The earlier human protection directives were reversed and laws were passed to control
reproduction and achieve racial cleansing.

1. Sterilization Act of 1933 - Protect the Hereditary Health of the German People

2. Reich Citizenship law

3. Nuremberg Laws of 1935 - Safeguard Marital Health

Euthanasia Program - “life unworthy of life, ”1939

• This program authorized doctors to identify and destroy those who were “undesirable” in
the population.
• In Berlin, a state organization was formed, which allowed doctors to examine hospital and
clinic records.
• Between 1939 and 1941, doctors sentenced 70,000-100,000 Germans to death through their
experiments in “perfecting methods of group killings”
• Public forced a shut down of the domestic euthanasia program – Hitler set up the death
camps
Nazi Doctors’ Trial, 1946: USA vs. Karl Brandt, et al
Prosecution of 23 doctors and administrators participating in war crimes and crimes against
humanity in the form of medical experiments and medical procedures inflicted on prisoners and
civilians without their consent

The specific crimes charged included more than twelve series of medical experiments concerning
the effects of and treatments for high altitude conditions, freezing, malaria, poison gas,
sulfanilamide, bone, muscle, and nerve regeneration, bone transplantation, saltwater
consumption, epidemic jaundice, sterilization, typhus, poisons, and incendiary bombs.

“Permissible Medical Experiments” (Nuremberg Code)

Considered the basic text of modern medical ethics for human experimentation

First INTERNATIONAL document that advocated for informed consent and voluntary participation
and imposed limits on how experiments could be conducted.

Compliance and enforcement left to the investigator

Nuremberg Code
1. The voluntary consent of the human subject is absolutely essential

2. The experiment should aim at positive results for society that cannot be procured in some
other way.
3. It should be based on previous knowledge (like, an expectation derived from animal experiments)
that justifies the experiment.
4. The experiment should be set up in a way that avoids unnecessary physical and mental suffering and
injuries.
5. It should not be conducted when there is any reason to believe that it implies a risk of death or
disabling injury.
6. The risks of the experiment should be in proportion to (that is, not exceed) the expected
humanitarian benefits.
7. Preparations and facilities must be provided that adequately protect the subjects against
the experiment’s risks.
8. The experiment should be conducted only by scientifically qualified persons.
9. The human subjects must be free to immediately quit the experiment at any point when
they feel physically or mentally unable to go on.
10. Likewise, the medical staff must stop the experiment at any point when they observe that
continuation would be dangerous.
Post Nuremberg ---1947 – 1974
Novel therapies and experiments continued to be performed on unsuspecting US
populations by researchers without consent including those populations that we would
now consider “vulnerable”.

• Pregnant Women
• Children
• Mentally disabled
• Prisoners
• Military personnel
• Elderly
• Terminally ill
• Infants

Especially egregious were the experiments on the US population and military by the
Atomic Energy Commission.
First Federal Policy for Protection of Human Subjects
1953

The first U.S. Federal policy for the protection of human subjects was put into place for
research conducted at the Clinical Center, NIH.

This system is the model for the current IRB system.

NIH Policy, 1966

It required prospective review of human subjects research, taking into account the
rights and welfare of the subjects involved, the appropriateness of the methods used to
secure informed consent, and the risks and potential benefits of the research.
Declaration of Helsinki, 1964
Many in the medical community saw the Nuremberg Code as imposing strict legal obligation on
Doctors.

World Medical Association prepared recommendations as a guide to every physician in

biomedical research involving human subjects.

Informed consent requirement based on whether the research was considered Therapeutic or
Non-therapeutic.

Obedience to Authority Study

Stanley Milgram
Yale University
Deception in Research
"Tuskegee Study of Untreated Syphilis in the Negro
Male,” 1932- 1972
Based on finding of the Oslo Study of the natural history of 2000 cases of untreated syphilis
1890 – 1910 and follow up 1921 – 1928

National Research Act, 1974

Three major provisions

1. Office of Protection from Research Risks (OPRR) in the NIH

2. Promulgated 45 CFR 46 Public Welfare Regulations for the Protection of Human Subjects
3. National Commission for the Protection of Human Subjects of Biomedical and Behavioral
Research*
- Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research
45 CFR 46
Public Welfare, Protection of Human Subjects
National Research Act required DHEW to adopt the 1966 NIH policy for protecting human
subjects as part of the public welfare regulations.

The 1974 regulations at 45 CFR 46 were amended and re-issued in 1981 with provision that
they only applied to federally funded research

Oversight of federally funded human research was assigned to

Office of Protection from Research Risks in the NIH

1991
45 CFR 46 subpart A was adopted by 17 federal agencies – called the “Common Rule”
Regulations & Guidance: Good Clinical Practice
v Is comprised of the FDA Regulations and guidance documents, the ICH guidelines for good
clinical practice and ethical codes of conduct in clinical trials such as the Declaration of
Helsinki and the Belmont Report

v Is a standard for the design, conduct, performance, monitoring, recording, analysis and
reporting of clinical trials

v Ensures the rights, safety and welfare of subjects are protected and the integrity of the
study data is maintained
Good Clinical Practice in Clinical Trials
Concurrent to the drafting of ethical guidelines and regulations , authorities began to
recognize the need for controlling medical therapies early in the 20th Century

Predecessor office to the current Food and Drug Administration (FDA) was the
Chemistry Division, a scientific department, in the Department of Agriculture
established in 1862.

Major function was to test pesticides and other agricultural products

(included preservatives in foodstuffs)
FDA consumer oversight function of food and
drug products began in 1906
The role of the FDA as a consumer protection agency has evolved and expanded

“FDA is responsible for protecting the public health by assuring the safety, efficacy,
and security of human and veterinary drugs, biological products, medical devices, our
nation’s food supply, cosmetics, and products that emit radiation.”

Turn of the Century in the United States - 1900

“Adulterated Foods”

“Patent Medicines” trade

Publication of “The Jungle”

Adulterated Foods
Chemistry Division, Department of Agriculture

“…investigate the character of food

preservatives, coloring matters, and other
substances added to foods, to determine their
relation to digestion and to health, and to
establish the principles which should guide their
use."

Common Additives/ Preservatives

§ Borax
§ Copper Sulfate
§ Sulfuric Acid
§ Potassium Nitrite
§ Benzoic Acid
§ Alum
§ Formalin
The Patent Medicine Trade
Outrageous Advertising - “Secret” Ingredients
“Brain Tonic”
The Jungle

Sinclair wrote how

diseased, rotten, and
contaminated meat
products were processed,
doctored by chemicals, and
mislabeled for sale to the
public.

…how workers would

process dead, injured and
diseased animals after
regular hours when no
meat inspectors were
around – or paid them off
The Pure Food and Drug Law of 1906

LANDMARK LEGISLATION

The federal government assumed permanent and comprehensive ( law

enforcement) responsibility for the health and safety of the American food and
drug supply for the first time.

First U.S. Consumer Protection law of the 20th Century

Sulfanilamide Disaster, 1937
“…to realize that six human beings, all of them my
patients, one of them my best friend, are dead
because they took medicine that I prescribed for
them innocently, and to realize that that medicine
which I had used for years in such cases suddenly
had become a deadly poison in its newest and most
modern form, as recommended by a great and
reputable pharmaceutical firm in Tennessee: well,
that realization has given me such days and nights
of mental and spiritual agony as I did not believe a
human being could undergo and survive”
A.S. Calhoun, MD
Food, Drug and Cosmetic Act of 1938
The only remedy for such a situation ( Sulfanilamide Disaster) is the enactment by
Congress of an adequate and comprehensive national Food and Drugs Act which will
require that all medicines placed upon the market shall be safe to use under the
directions for use. ...“

Required
“substantial” evidence that a new drug was safe for use and be reported to the FDA*
Required a FDA approval of new drug for market

*Doesn’t specifically require animal testing in the law: however animal testing has
become the default standard for the FDA and the agency will generally ask for toxicity
test results using at least two species of animals
Thalidomide Tragedy, 1957 – 1961

Synthesized in Germany and marketed over the counter in 1957 as a

sedative under the trade name Kevadon.

Distributed in 46 countries -------wildly popular as the only non-

barbiturate sedative available

An Australian obstetrician discovered that the drug also alleviated

morning sickness. He started recommending this off-label use of the
drug to his pregnant patients, setting a worldwide trend.
Thalidomide Tragedy
• In 1960 the FDA was petitioned to approve distribution in the US.
• Dr. Francis Kelsy held up the application for over a year –by then reports of the birth defects
were being associated with Thalidomide use.
Kefauver – Harris Amendment to the Food Drug and
Cosmetic Act, 1962
For a new drug application: the amendment

v Required Manufacturers to provide substantial proof of “Efficacy” through well

controlled clinical trials
v Codified the informed consent requirement
v Set the rules for investigations
v Required the FDA specifically approve marketing applications
v Required adverse events be reported

Laid the ground work for the New Drug Regulations

Investigational Drug Regulations, 1963

21 CFR 312 - IND Application Regulations

21 CFR 314 - New Drug Application for market approval

Food Drug and Cosmetic Act
Many other amendments through the years (24)
1951 Durham Humphrey Act
1976 Medical Device Amendments
1983 Orphan Drug Act
1992 Prescription Drug User Fee Act
2003 Pediatric Research Equity Act

1981
FDA and OHRP regulations were harmonized to the extent allowed by statute.
1991
45 CFR 46 Subpart adopted as the “Common Rule”

Helpful to Remember!
OHRP has regulatory oversight clinical research funded or supported by the federal government. (45 CFR 46)
FDA has regulatory oversight of clinical investigations of FDA regulated products regardless of the source of
funding.
21 CFR 11, 50, 54, 56, 312, 314, 812, 814
International Conference on Harmonization Guidance
Documents , 1996
International Conference on Harmonization
Guidance Documents
Efficacy (E) - 20 Guidelines
Concerned with the design, conduct, safety and reporting of clinical trials.

E8 GENERAL CONSIDERATIONS FOR CLINCIAL TRIALS

The Guideline provides an introduction to clinical development, quality design of clinical
studies and a focus on those factors critical to the quality of the studies.

E6 (R2) GOOD CLINCIAL PRACTICE

Outlines expectations of all participants in the conduct of clinical trials, including investigators,
monitors, sponsors and IRBs. GCP E6 covers aspects of monitoring, reporting and archiving of
clinical trials, and incorporates addenda on Essential Documents and on the Investigator's
Brochure. The revised guidance updates and improves approaches to clinical trail design,
conduct, oversight, recording and reporting including standards regarding electronic records
and essential documents.

E2 PHARMACOVIGILANCE
E2A – Clinical Safety Data management: Definitions and Standards for Expedited Reporting
Useful Resources

Nuremburg Code
Declaration of Helsinki
Belmont Report
https://www.hhs.gov/ohrp/international/ethical-codes-and-research-standards/index.html

Compare OHRP and FDA regulations

https://www.fda.gov/science-research/good-clinical-practice-educational-materials/
comparison-fda-and-hhs-human-subject-protection-regulations

Milestones in FDA History

https://www.fda.gov/about-fda/fdas-evolving-regulatory-powers/milestones-us-food-and-
drug-law-history