Anatomy and physiology of clinical research

Question 1

Objectives

Answer 1

Be familiar with the main components of clinical trials, including research questions, background significance, design, subjects, variables and statistical issues

Question 2

Anatomy sequence of a clinical trial

Answer 2

Research question
Background significance
Design
Subjects
Variables
Statistical issues

Question 3

Design

Answer 3

clinical trials and clinical studies

Question 4

Subjects

Answer 4

selection criteria and sampling design

Question 5

Variables

Answer 5

Predictor and outcome

Confounding

Question 6

Statistical issues

Answer 6

Hypothesis
Sample size
Analytical approach

Question 7

Learning objectives of lesson 1

Answer 7

Know how a research question is approached.

Know some characteristics of a good research question.

Know the codes of medical ethics.

Appreciate and understand the applications of the abovementioned points to real-world scenarios.

Question 8

Research definition

Answer 8

Research is a systematic investigation designed to discover or contribute to a body of generalizable knowledge

Question 9

How is a project of study considered research?

2 reasons

Answer 9

• is conducted with the purpose of making conclusions with general applications
• uses a widely-accepted scientific method.

Question 10

The scientific method defintion

Answer 10

Research uses a process called the scientific method to solve problems or to resolve previously unanswered questions.

Question 11

What are the 6 fundamental components of a scientific method

Answer 11

Research purpose
hypothesis
experimental
interpretation
conclusion
theory formulation

Question 12

Clinical trials

Answer 12

Clinical trials fall under clinical research,
Clinical trials is a primary method used by clinical researchers to find if a new treatment is safe and effective to people.
Clinical trials are research studies performed in people that are aimed at evaluating a medical, surgical, or behavioral intervention
Often a clinical trial is used to learn if a new treatment is more effective and/or has less harmful side effects than the standard treatment.

Question 13

4 phases in clinical trials

Must all clinical trials be competent with Good Clinical Practices

Answer 13

There are FOUR (4) phases in a clinical trial.
Based on Food, Drug & Administration (FDA) requirements, only the first three (3) phases are required to determine if the treatment (or drug) is safe for use.

All clinical trials must be compliant with Good Clinical Practices.

Question 14

GCP good clinical practices

Answer 14

Good Clinical Practices are ethical and scientific quality standard for the design, conduct, performance, monitoring, auditing, recording, analyses & reporting of clinical trials.

Question 15

Phase 1 clinical trial

Answer 15

Involves normal, healthy people
Small group size (~20 – 80)
Evaluate drug safety and safe dose range.

Question 16

Phase 2 clinical trial

Answer 16

• Involves a small scale of patients
• Larger group size than Phase 1 (~100 – 300)
• Evaluate drug effectiveness on patients with existing conditions.

Question 17

Phase 3 clinical trial

Answer 17

• Involves a larger scale of patients.
• Larger group size than Phase 2 (~300 – 1000)
• Confirm drug’s safety and effectiveness.
• If results from Phase 3 are positive, FDA will approve the treatment.

Question 18

Phase 4 clinical trial

Answer 18

• Usually takes place after FDA approval
• Monitoring the drug’s effectiveness and safety over a large and diverse population (used to uncover findings not addressed in Phase 3.)

Question 19

Research question

What question will the research study address?

Answer 19

This contains the objective of the study, the uncertainty that the researcher wants to resolve.

The research question often begins with a general concern that must be narrowed down to concrete, researchable issue e.g.

Question 20

5 important qualities of a good research question

Answer 20

Feasibility, interesting, novel, ethical and relevant

Question 21

Find the
- general concern,
- narrow and focus
(the concrete researchable issue?)

Answer 21

If you’re allergic to dairy, lactose intolerant or you just aren’t crazy about the taste of dairy milk, reach for soy milk as a comparable alternative. Soy milk has become increasingly popular as a beverage and also has a number of nutritional advantages.

general concern - reach for soy milk as a comparable alternative

narrow and focus (the concrete researchable issue) - increasingly popular as a beverage and also has a number of nutritional advantages

Question 22

Difference between general concern and narrow and focus

Answer 22

Narrow & focus addresses more in-depth and specific issues in the research question (e.g. working population with diabetes, link between exercise and blood sugar levels).

Question 23

Feasibility

Answer 23

What are the practical limits and problems studying such a question? Can we actually carry this out?

It is important to know the practical limits and problems of studying a question early on, before wasting much time and effort along unworkable lines

Question 24

Number of subjects, part of feasibility

Answer 24

Many studies do not achieve their intended purpose because they cannot enrol sufficient subjects.

A preliminary calculation of the sample size requirements of the study early on can be very useful

An estimate of the number of subjects likely to be available for the study should be made by excluding those participants who refuse to participate and the number that would be lost to follow up. Even with such an estimate, sometimes the numbers may still be overly optimistic

Question 25

Technical expertise, part of feasibility

Answer 25

The investigator must have the skills, equipment and experience needed for designing the study, recruiting the subjects, measuring the variables and managing and analysing the data

Help can be acquired from consultants outside of the research team for procedures which are unfamiliar to the researcher, but for major areas of the study, it is better to have an experienced colleague who can be steadily involved as a co-investigator.

Members with different expertise are often required e.g. it will be wise to include a statistician as a member of the team from the beginning of the planning process.

The use of familiar and established approaches should be considered over developing new methods and skills as these are time consuming and uncertainties are plenty.

Question 26

Cost in time and money, part of feasibility

Answer 26

It will be important to estimate the costs of each component of the project, bearing in mind that the time and money needed, will generally exceed the amounts projected at the onset

If the projected costs exceed the available funds, the options are to consider

A less expensive design

Develop additional sources of funding.

Early recognition of a study that is too expensive or time consuming can lead to modifications or abandonment of the plan before expending a great deal of effort

Question 27

Scope, part of flexibility

Consider a less expensive design.

Develop additional sources of funding.

Early recognition of the heavy costs and time involved the study, which can lead to modifications or abandonment of the plan before implementation.

Answer 27

Problems often arise when an investigator attempts to accomplish too much, making many measurements at repeated contacts with a large group of subjects in an effort to answer too many research questions.
The solution is to narrow the scope of the study and focus only on the most important goals

Question 28

Interesting, aside from feasibility

Getting to the truth of the matter, which appears to be interesting and of primary concern to the investigator, provides a source of motivation for conducting research.
This will provide the intensity of effort needed for overcoming the many hurdles and frustration of the research process.

Answer 28

One of the motivations for conducting a research include getting to the truth of the matter appears to be interesting and of primary concern to the investigator

This will provide the intensity of effort needed for overcoming the many hurdles and frustration of the research process.

It would be wise to speak to mentors and outside expertise before devoting substantial energy to develop a research plan or grant proposal as you might find the question interesting, but to peers and funding agencies, the question at hand, is dull and of little interest

Question 29

Novel, aside from feasibility

Good clinical research contributes new information and a study that merely reiterates what is already established is not worth the effort or cost.
In other words, good clinical research uncovers new findings that are not repeated from previous studies !!!

Answer 29

Good clinical research contributes new information and a study that merely reiterates what is already established is not worth the effort or cost.
Although novelty is an important criterion, a research question need not be totally original. For example,
It might be worthwhile to ask whether a previous observation can be replicated

If the findings in one population can also apply to other populations

Whether improved measurement techniques can clarify the relationship between known risk factors and diseases.

A confirmatory study is particularly useful if it avoids the weakness of previous studies

Question 30

Ethical

Answer 30

If the study poses unacceptable physical risk or invasion of privacy, the investigator must seek other ways to answer the question.

Question 31

Relevance

How will the outcome of this research be and how will it impact scientific knowledge, influence practice guidelines, health policies or guide further research

Answer 31

This is one of the most important criteria in a good research question.

How will the outcome of this research be and how will it impact scientific knowledge, influence practice guidelines, health policies or guide further research

Question 32

How recruitment process works

Answer 32

Unfortunately, falling short in the rate of recruitment is one of the most common problems in clinical trials.
Recruiting enough subjects is critical in obtaining valid data in clinical research.

Recruitment of subjects involve contacting populations not well known by the research team (to minimise reporting bias)

An experienced member of the research team to contact the prospective subjects will be helpful.

Question 33

the work of john franklin enders

Answer 33

Develop the vaccines for poliomyelitis in 1952
Highly infectious viral disease which mainly affects young children
His work earned him the title of father of modern medicines

Question 34

Poliomyelitis (polio)

Answer 34

Polio is caused by the poliovirus, which spreads mainly through the faecal-oral route and multiplies in the intestine, from where it can invade the nervous system and can cause paralysis.

Contracted predominantly by children, can lead to permanent paralysis of various body parts and can ultimately cause death by immobilizing the patient breathing muscles

Question 35

The work of john franklin enders continued

Answer 35

The Polio Vaccine was introduced in 1955.
There were 13,850 cases of paralytic polio that year

The number of polio cases today have dropped by > 99% since 1988, where 350,000 cases were reported back then as compared to 22 cases today.

However, despite the progress, there is currently NO CURE for polio, but only PREVENTED by vaccines which can protect the child from contracting polio.

Question 36

Ethics

Answer 36

There are a number of codes of medical ethics which emphasize the personal responsibility of physician/investigator to provide subjects with adequate and appropriate information.

These impart principles of ethical conduct for experiments in humans.

These ethical issues revolve around the safety of the participating individual.

Question 37

Numbering code (ethical)

Answer 37

The voluntary consent of the human participant is absolutely essential.

Question 38

Belmont report (ethical)

Answer 38

Respect for Persons
Beneficence
Justice

Question 39

Declaration of helsinki

Answer 39

The health of my patient will be my first consideration.

Question 40

Nuremberg code history

Answer 40

The Nuremberg Code was created based on the verdict traced back in August 1947 (almost two years after World War II ended).

The trial was known as “The Doctors’ Trial” that occurred in the Nuremberg Military Tribunals in Nuremberg, Bavaria, Germany.

23 physicians from the German Nazi Party carried out atrocious medical experiments against the will of the prisoners-of-war (POW) “subjects” in concentration camps.

The cruel and inhumane practices experienced by the prisoners at the concentration camps led to the development of the Nuremberg code in the same year.

Question 41

What is nuremberg code history

Answer 41

Nuremberg code is a set of TEN (10) ethical principles to follow when conducing any experiments on humans, to protect human subjects from the torture the prisoners experience.

Question 42

Significance of Nuremberg Code

Answer 42

It laid the foundation for 2 things

GCP - the ethical principles of the Nuremberg Code influenced the principles of GCP

Belmont report and declaration of Helsinki - the ethical principles of the Nuremberg Code were expanded to form the Belmont report and declaration of Helsinki

Question 43

Tuskeegee alabama case study: Syphilis

Answer 43

Syphilis is a sexually-transmitted disease (STD) caused by the bacteriumTreponema pallidum.

In 2016, there were 88,042 new cases reported.
Benzathine penicillin is the recommended treatment for patients infected with Syphilis

Benzathine penicillin is the recommended treatment for patients infected with Syphilis

Beta-lactam ring in penicillin inhibit the peptidoglycan synthesis in bacteria (important in prokaryotic cell wall)

Question 44

Case Study:Syphilis Study (1932 – 1972)

Answer 44

Research project conducted by the U.S, where free medical examinations were given to 600 low-income participants (all of them are African-American Males).
The medical examination was conducted WITHOUT the consent of the patients.

Participants were neither told that the medical examinations were meant for a study, nor informed about their disease.

Out of 600 participants, 400 of them were infected with syphilis.

Participants were denied treatment, despite that a proven cure (penicillin) can be used to cure syphilis.
The study, initially projected at 8 months, continued for 40 years.

Throughout its study, MANY participants have died from the disease.

Question 45

More details on Case Study:Syphilis Study (1932 – 1972)

Answer 45

Free medical examinations were given; however, participants were not told about their disease.

Even though a proven cure (penicillin) became available in the 1950s, the study continued until 1972 with participants being denied treatment.

In some cases, when participants were diagnosed as having syphilis by other physicians, researchers intervened to prevent treatment.

Many participants died of syphilis during the study.
The study was stopped in 1973 by the U.S. Department of Health, Education, and Welfare only after its existence was publicized and it became a political embarrassment. In 1997, under mounting pressure, President Clinton apologized to the study participants and their families

Question 46

According to the Nuremberg code, which of the 10 principles were not fulfilled?

Answer 46

The panel found that the men had agreed freely to be examined and treated. However, there was no evidence that researchers had informed them of the study or its real purpose. In fact, the men had been misled and had not been given all the facts required to provide informed consent.

The men were never given adequate treatment for their disease. Even when penicillin became the drug of choice for syphilis in 1947, researchers did not offer it to the subjects. The advisory panel found nothing to show that subjects were ever given the choice of quitting the study, even when this new, highly effective treatment became widely used.

Question 47

Nuremberg code vs Belmont report vs The Declaration of Helsinki

Answer 47

While the Nuremberg Code lays the foundation for all the other ethic codes, it mentions that voluntary consent of the human participant is essential but may not be considered first.

The Belmont Report mainly involves the three principles: Respect for Persons, Beneficence and Justice.

The Declaration of Helsinki is the code of medical ethics that emphasizes the health of the patient to be their first consideration when recruiting patients for a clinical study