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2.1 Professional Practice > Clinical Trials > Flashcards

Clinical Trials Flashcards

1
Q

Define tissue culture

A

In-vitro cultivation of organ tissues and cells in a favourable artificial growth situation

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2
Q

Give some examples of where tissue cultures would be used

A

Vaccine research
Cancer research
Protein therapeutics

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3
Q

What are the two types of tissue culture?

A

Primary cell lines
Secondary cell lines

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4
Q

What are primary cell lines?
(2)

A

Primary cells are directly prepared from an organism’s tissues

These grow and proliferate a finite number of times

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5
Q

What are secondary cell lines?

A

These are derived from clinical tumours or created from transforming primary cells with viral oncogenes or chemical treatments

These will grow indefinitely

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6
Q

What are some benefits of primary cell lines over secondary cell lines?
(3)

A

They more closely represent the tissue of origin

They are similar to the in vivo state and exhibit normal physiology

They provide excellent model systems for studying

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7
Q

How can primary cell lines provide excellent model systems for studying
(2)

A

They can be used for the normal physiology and biochemistry of cells e.g. metabolic studies, aging, signaling studies

They can be used to display the effects of drugs and toxic compounds on the cells

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8
Q

What types of cells are used in primary cell cultures?
(8)

A

Epithelial cells
Fibroblasts
Keratinocytes
Melanocytes
Endothelial cells
Muscle cells
Hematopoietic stem cells
Mesenchymal stem cells

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9
Q

Write a note on transformation
(3)

A

Cultures are initially heterogeneous and can be maintained in vitro only for a limited period of time

Transformation can occur spontaneously or can be chemically or virally induced

Transformation is the the process whereby cells divide indefinitely and become an immortalised secondary cell line

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10
Q

List the advantages of primary cells overall
(3)

A

Use of primary cells avoids many ethical objections raised against animal experiments

The use of primary cells provides more relevant results than cell lines

They are cost-effective as they help reduce the expenditure on animal models required for in vivo studies

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11
Q

What are the challenges of primary cells?
(6)

A

Take more time to grow than other cell lines

Have limited growth potential even under optimal growth conditions and eventually senesce and die

Cells from different donors behave differently in response to pro-inflammatory cytokines. The growth of metabolic regulatory mechanism that exist under in vivo conditions are absent in culture conditions

Cost of isolation and culture is often high and prohibitive through cheaper than animal models

The tissue culture may not be always possible

Characteristics of cells may change with each subsequent passage if optimum culture conditions are not maintained

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12
Q

Give some applications of primary cell lines
(8)

A

3D Cell Culture
Cancer Research
Virology
Drug Screening and Toxicity Testing
Vaccine Production
Genetic Engineering
Tissue or Organ Replacement
Stem Cell Therapy

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13
Q

Give an example of a culture collection

A

The American Type Culture Collection (ATCC) Cell Biology Collection

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14
Q

What does the ATCC contain

A

Over 3,600 cell lines from over 150 different species

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15
Q

What cells are often used in research in place of primary cells?

A

Immortal cell lines

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16
Q

Give some examples of immortal cell lines

A

3T3
HeLa
COS

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17
Q

What is 3T3

A

Mouse embryonic fibroblast

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18
Q

What is a Mouse embryonic fibroblast used for

A

Robust and easy to handle
Contact inhibited
Stops growing at very high densities

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19
Q

What is a HeLa cell

A

From cervical cancer in a human patient named Henrietta Lacks

May contaminate other culture cell lines

Able to grow in suspension

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20
Q

What are COS cells

A

Monkey Kidney cells

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21
Q

What are Monkey Kidney cells
(2)

A

Efficiently transfected

Commonly used as an expression system for high-level, short-term expression of proteins

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22
Q

List the advantages of immortal cell lines
(5)

A

Cost effective
Easy to use
Unlimited supply of material
Bypass ethical concerns associated with the use of animal and human tissue
Provide a pure population of cells

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23
Q

List the limitations of immortal cell lines
(4)

A

Genetic manipulation may alter their phenotype, native functions and their responsiveness to stimuli

Serial passage of cell lines can further cause genotypic and phenotypic variation over an extended period of time

Cell lines may not adequately represent primary cells and may provide different results

Contamination with other cell lines and mycoplasma

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24
Q

Write a note on HeLa Cells
(5)

A

Epithelial cells from the cervix of Henrietta Lacks

She died in 1951 dur to an aggressive cervical cancer

While she was being treated doctors had taken samples of her cancerous cells

Her tissue was shared with researches without her knowledge or consent

Her cells have an extraordinary capacity to survive and reproduce - immortal

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25
Q

What contributions were made by HeLa Cells?
(4)

A

Contributed to many medical breakthroughs

Used in research on the effects of zero gravity in outer space

Used in the development of polio and COVID-19 vaccines

Used in the study of leukaemia, the AIDS virus and cancer worldwide

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26
Q

Define clinical studies?
(2)

A

Research studies that evaluate new ways to improve treatments and quality of life for people with diseases

It involves research using human volunteers/participants that is intended to add to medical knowledge

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27
Q

What are the two types of clinical research studies?

A

Clinical trials
Observational studies

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28
Q

What is the aim of clinical trials?

A

The results help to develop New Drugs, New Procedures, New Research

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29
Q

What are the four uses of animal models

A

To advance scientific knowledge

To study disease and develop medicines

To assess the safety of chemicals

Teaching

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30
Q

How are animal models used to advance scientific knowledge?

A

Used to learn about the ways animals and humans develop and function biologically

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31
Q

How are animal models used to study disease and develop medicines?
(2)

A

Animals are used as models to understand disease processes and to develop new vaccines and medicines e.g. RA, polio, Hep C

Genetically modified animals e.g. mice are used to study the role of genes in disease processes

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32
Q

How can animal models be used to assess the safety of chemicals?

A

Animals are used in toxicological studies to test the safety of substances that could be harmful to animals, humans or the environment (e.g. household/industrial chemicals, fertilisers, food additives)

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33
Q

Give four examples of animal models

A

Yeast
Zebra fish
Mouse
Macaque Monkey

34
Q

What yeast species is used in animal models

A

Saccharomyces cerevisiae

35
Q

What fish species is used in animal models?

A

Danio rerio

36
Q

What species of mouse is used in animal models?

A

Mus musculus

37
Q

What species of monkey is used in animal models?

A

Macaca mulatta

38
Q

What are the benefits of using yeast in animal trials?
(3)

A

Single celled eukaryotes which can be grown in vitro

Replicates quickly

Genes are easy to manipulate

39
Q

What are the benefits of using zebra fish in animal trials

A

Embryos and larvae are transparent
Can use fluorescence as visual tool
Useful in transgenic models

40
Q

What are the benefits of using mice in animal trials?
(3)

A

Genetically similar to humans
Inbred colonies have limited diversity
Nude strains are immunodeficient

41
Q

What are the benefits of using macaque monkeys in clinical trials?
(3)

A

Genetically similar to humans
Similar immune responses to humans
Useful for longitudinal studies

42
Q

Write a note on Dolly the Sheep
(5)

A

First mammal cloned from an adult somatic cell

Cloned at the Roslin institute in Scotland

Used the process of nuclear transfer from a cell taken from a mammary gland

Her cloning proves that a cloned organism could be produced from a mature cell from a specific body part

Successful cloning led to widespread advancements within stem cell research including the discovery of induced pluripotent stem cells.

43
Q

Write a note on Macaques and HIV
(3)

A

The only animal species susceptible to HIV viruses are non human primates

Macaques infected with viruses close to HIV-2 (SIVmac) are the most commonly used

Almost identical pathophysiological features of HIV-1 pathogenesis

44
Q

What are the pros of animal models
(5)

A

Test many hypothesis

Most similar to humans

No human genetic ethical dilemma

Genetically modified

Shortens length of study

45
Q

What are the cons of using animal models

A

Creating a representative phenotype is difficult

Ethical dilemma

Expensive

Difficult to replicate

46
Q

What are the cons of using animal models

A

Creating a representative phenotype is difficult

Ethical dilemma

Expensive

Difficult to replicate

47
Q

What were the three aspects of the directive of 2010/63/EU of the European Parliament on the protection of animals used for scientific purposes

A

Replacement
Reduction
Refinement

48
Q

The directive of 2010/63/EU introduced a replacement aspect for animal models, what does this mean?

A

This involves the acceleration of the development and use of models and tools, based on the latest science and technologies, to address important scientific questions without the use of animals

i.e. avoid using animals as much as possible or bypass animal testing if possible

49
Q

The directive of 2010/63/EU introduced a reduction aspect for animal models, what does this mean?

A

This refers to methods that minimise the number of animals used per project or study consistent with the scientific aims

50
Q

The directive of 2010/63/EU introduced a refinement aspect for animal models, what does this mean?

A

This refers to methods that minimise the pain, suffering, distress or lasting harm that may be experienced by the animals, and which improve their welfare

51
Q

Where are clinical studies used
(6)

A

New drugs or new combinations o f drugs

New ways of doing surgery

New medical devices

New ways to use existing treatments

New ways to change behaviours to improve health

New ways to improve the quality of life for people with acute or chronic illness

52
Q

When was the first experiment carried out to resemble clinical trials?

A

500 BC

53
Q

What happens in a clinical trial?
(4)

A

Participants receive specific interventions according to the research plan or protocol created by the investigators e.g. changes to participant’s behaviour e.g. diet, procedures e.g. surgery or medical products e.g. drugs or devices

An attempt to determine the safety and efficacy of the intervention by measuring certain outcomes in the participants

Clinical trials may compare new medical approaches to old ones or placebos

Clinical trials may compare two interventions that are already available to each other

54
Q

What happens in observational studies
(3)

A

Investigators assess health outcomes in groups of participants according to a protocol or research plan

Participants may receive interventions, which can include medical products, such as drugs or devices, or procedures as part of their routine medical care, but participants are not assigned to specific interventions by the investigator

Cohort study

55
Q

What are the six phases to clinical trials
(6)

A

Preclinical + approval for clinical trials

Phase 1 (20-80 participants)

Phase 2 (100-300 participants)

Phase 3 (1,000 to 3,000 participants) + application for regulatory approval

Regulatory review process (assessment of safety and efficacy) + regulatory approval

Phase 4 (1,000+ participants)

56
Q

What happens in phase 1 trials
(4)

A

Clinical pharmacology and toxicity

To determine if the drug can safely be given to humans, and what dosage levels can be given without causing serious side effects

Usually conducted on volunteers

20-80 normal volunteers

57
Q

What happens in phase 2 trials?
(6)

A

Initial clinical investigation for treatment effect

Small number of closely-monitored patients receive the drug

Safety and effectiveness evaluated

Determines if the new treatment has an effect on the disease

Used to see how the new treatment affects the body and fights disease

Involves 100-200 patients

58
Q

What happens in phase 3 trials
(3)

A

Controlled evaluation of treatment

Compares the new treatment to the current ‘best practice’ treatment(s) in a substantial number of patients

Often simply called clinical trials or controlled clinical trials

59
Q

What happens in the regulatory review process?
(3)

A

The decision about the value of the new treatment will rest on the clinical trials

Vital that these are conducted so that the possibility of bias is minimised

Approved by regulatory bodies such as FDA or EAM

60
Q

What happens in phase 4 trials?

A

Postmarketing surveillance

Monitoring of adverse reactions and long-term consequences of use

Refine prescribing indications by documenting rare complications, subgroups of patients with poor response

Long term follow-up of drug reactions

61
Q

What are four key methodological features of a clinical trial
(4)

A

Controlled - treatment is evaluated against a defined alternative

Randomised - patients allocated treatments at random ensuring comparability

Blinded - to reduce bias

Intention-to-treat analysis - analysis based on treatment allocation, not adjusted for compliance

62
Q

What is a control
(5)

A

The control group

Used as a baseline for comparison

Allows clear interpretation of results

Control group receives the same treatment as the intervention group except for the intervention being assessed

Compensates for Hawthorn effect and for unusual intensity of treatment during trials

63
Q

What is the Hawthorn effect?

A

Alteration of behaviour due to being observed

64
Q

What is randomisation
(4)

A

Random allocation of patients to treatments

No characteristic of the patient can influence the treatment they receive

Ensures comparability of treatment and control groups

But does not allow for patient preference -> which may be important in determining treatment sucess

65
Q

What are the different types of blinded testing and what is the point?

A

It eliminates bias

Single blinded (either subjects of assessors blind)

Double blind (both subjects and assessor blind)

Triple blind (subject, assessor and data analyst is blind)

66
Q

What are open label trials or non-blinded trails
(2)

A

Participants are aware which treatment they have been allocated to

Used to compare treatments or gather additional information about the long-term effects in the intended patient population

67
Q

What is intention to treat analysis
(4)

A

All persons randomised to a treatment are counted in the analysis not just those who complete it or comply with it

This means we are evaluating the treatment policy

Analysing those who complete treatment is called ‘per protocol’ analysis

Useful if treatments are long e.g. TB drugs

68
Q

What three principles/responsible in good clinical practice

A

Good Clinical Practice (GCP) Principles 2.1 and 2.8

Investigator Responsibility 4.1.3

69
Q

What are the good clinical practice principles
(3)

A

Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory requirement

Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s)

The investigator should be aware of, and should comply with, GCP and the applicable regulatory requirements

70
Q

What does regulation 24 of the Regulations for Clinical Trials on Medicinal Products for Human Use State

A

A person shall not conduct a clinical trial otherwise than in accordance with the conditions and principles of good clinical practice

71
Q

List some ethical issues

A

Consent
Reduced capacity
Fair distribution of benefit

72
Q

Write a note on consent
(3)

A

Patient may receive treatment which turns out to be inferior, or may simply get a placebo

They will have to forego their right to know their treatment

For these reasons, informed consent is vital

73
Q

Write a note on reduced capacity
(2)

A

Some patients will have reduced capacity to understand the issues or to give consent

Their interests require special protection

74
Q

Write a note on fair distribution of benefit
(3)

A

The people in the trial must stand to benefit - not necessarily as individuals but at least as a group

Altruism: doing things for the good of others, is a right

Doing research on captive populations or groups who are unlikely to benefit is unethical

75
Q

Define clinically significant

A

The treatment must produce a worthwhile effect in terms of the patient’s health - a drug that lowers cholesterol by 2% is no actual use!

76
Q

Define statistically significant

A

The treatment benefit must have been so large that it is unlikely to have occurred by chance in a patient group as big as the one being studied.

77
Q

What percentage of new therapeutic products that reach clinical testing are not approved or reach commercialisation adn why?
(40

A

90%

52% of these are due to lack of efficacy i.e. the treatment doesn’t work in the proposed dosage or formulation

24% due to safety issues i.e. adverse drug reactions

24% due to various technical or commercial reasons

78
Q

Give three examples of clinical trials that went wrong

A

Thalidomide - 1960s
The University of Minnesota Seroquel Experiment 2003
The Elephant Man Trial 2006

79
Q

Write a note on the thalidomide scandal (4)

A

Originally intended as a sedative or tranquiliser but was soon used for treating a wide range of other conditions including colds, flu, nausea and morning sickness in pregnant women

Researchers tested the drug on animals but neglected to observe the effects on their offspring

Deemed safe as impossible to die from overdose

William McBride discovered the link between Thalidomide and the deformities in children and mothers who took the drugs -> children born with shortened limbs or loss of limbs particularly arms

80
Q

Write a note on the university of minnesota Seroquel experiment 2003

A

In 2003 Dan Markingson was diagnosed with schizophrenia and admitted to the University of Minnesota Medical Center

He was put into a clinical trial testing three types of medications including Seroquel

Daily 800mg of Seroquel worsened his delusions

His mother attempted to remove him but the school blocked his removal as participation was worth 15,000 to the school

1/5 people on trial attempted suicude

2 people died by suicide - Dan was one of these

81
Q

Write a note on the university of minnesota Seroquel experiment 2003
(6)

A

In 2003 Dan Markingson was diagnosed with schizophrenia and admitted to the University of Minnesota Medical Center

He was put into a clinical trial testing three types of medications including Seroquel

Daily 800mg of Seroquel worsened his delusions

His mother attempted to remove him but the school blocked his removal as participation was worth 15,000 to the school

1/5 people on trial attempted suicude

2 people died by suicide - Dan was one of these

82
Q

Write a note on the Elephant Man Trial 2006
(6)

A

Clinical Trial testing a new cancer treatment called TGN1412

Preclinical trials performed in Macaque monkeys whose DNA is a 94% match to humans

Shortly after taking dose all patients began writhing in pain and vomiting

One patient lost his fingers and toes

Another had his foot partially amputated

One participants head swelled up ‘Elephant Man’

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