Strand B Flashcards
What is a clinical trial?
A research study in which one or more human subjects are prospectively assigned to one or more interventions to evaluate those interventions on health-related biomedical or behavioural outcomes
What is a clinical study?
A study involving using human volunteers that is intended to add medical knowledge, interventional and observational
What is the difference between a clinical trial and study?
Study - interventional and observational
Trial - interventional only
What is the history of clinical trials?
562 BCE - ‘first’ clinical trial
1537 - first trial of 2 medical treatments
1747 - one of the earliest controlled clinical trials
1940s - first double blind clinical trial
1948 - first ‘true’ randomised control trial
What are the different types of clinical trials?
Mechanistic
Exploratory/development
Pilot/feasibility
Other interventional
Behavioural
Basic experimental (BESH)
What are the differences between experimental and observational studies?
Experimental - Randomised control trials (RCTs)
Non-randomised control trials (nRCTs)
Observational - Cohort studies
Case-control studies
Cross-sectional studies
Ecological studies
What are randomised control studies (RCTs)?
Used to find effectiveness of new treatment while eliminating as many biases as possible
Randomised to one of two or more groups to test specific drug, treatment, etc (e.g. intervention used vs placebo)
Groups are followed up to see how effective
Outcomes measured at specific times and different responses are assessed statistically
What are non-randomised control studies (nRCTs)?
People allocated to different interventions using methods that are not random
Purely observational, non-randomised interventional studies, and single-arm trials with external control
What are cohort studies?
Observational study using defined groups while being followed over time
People with similar characteristics
Why are cohort studies used?
Examine associations between different interventions received and subsequent outcomes
What is the difference between a prospective and retrospective cohort study?
Prospective - recruits participants before
Retrospective - subjects from past records describing interventions received
What are case-control studies?
Observational study to find the possible cause of a disease/condition
Researcher looks for aspects of lives that differ to see what has caused the condition
Why are case-controlled studies used?
Compares groups of patients who have the disease with a group of people without but with similar characteristics (unrelated from condition)
What is a cross-sectional study?
A ‘snap-shot’ observation of a set of people at 1 time
Describe a variable not measuring it
Why are cross-sectional studies used?
Public health research uses this to assess exposure and a disease and compare the rates of disease and symptoms of an exposed and unexposed group
What are the advantages and disadvantages of cross-sectional studies?
Advantages: cheap, quick, minimal room for error
Disadvantages: Doesn’t help determine cause and effect, report bias is probable (surveys)
What are ecological studies?
Used to understand relationship between outcome and exposure at a population level (population with shared characteristics)
Characteristics include geography, ethnicity, socio-economic status of employment
Why are ecological studies used?
Ecological vs other studies is the group is the unit analysis studied no assumptions about individual study participants
What are the phases of a clinical trial?
Laboratory studies - cell/animal studies
Phase I - Safety of medication on people
Phase II - Safety and effectiveness
Phase III - Safety, effectiveness and dosing
Phase IV - long-term effectiveness vs new treatment to standard treatment
What happens during the laboratory stage of clinical trials?
Basic research, accurately model desired biological effect of a drug predicting treatment outcome in patients and predict ant adverse reactions
Testing: in vitro, in vivo and drug profiling using computer models
What happens during phase I of clinical trials?
Drug/treatment on small group of people for first time
Safety and side effects
Several months
Success around 52%
What happens during phase II of clinical trials?
Larger group of people
Emphasis on effectiveness
Preliminary data whether drug works in people with disease/condition
Last several years (~1-4)
Success around 30%
What happens during phase III of clinical trials?
Large groups of people
More information of safety and effectiveness, different populations and dosages and drug-drug interaction
Information for the drug to be used safely
Success around 58%
What is the FDA approval stage during clinical trials?
New Drug Application (NDA) for treatment to an organisation e.g. FDA
Review results to determine if approves the drug and allow marketing to public
Continue to monitor effects
Success around 25-30%
What happens during phase IV of clinical trials?
After approved by FDA - post-marketing monitoring stage
Available to public
Monitored in large diverse populations
More information of treatment’s benefits and optimal use
What are things to consider when setting up and running a clinical trial?
Ethics
Consent
Controls
Randomisation
Binding
Sample size
Statistics
What is ethics?
It is moral principles that govern a persons behaviour or the conducting of an activty
What are examples of different ethical considerations in research?
Voluntary participation
Confidentiality
Consent
Anonymity
Potential for harm
What is consent?
Informed consent is one of the founding principles of research ethics, so human participants can enter research freely with full information about what it mean for them to take part
Give consent before they enter
How can a researcher ensure the participants are fully informed?
By understanding what the research is and what they are consenting to
Researcher giving sufficient and appropriate information about the trial (information sheets)
Researchers ensures no coercion
Time given for the participant to consider choice and discuss if appropriate
Participant has the right to withdraw at any time
What is bias?
Systematic errors that encourage one outcome over others
Investigators then come to wrong conclusions about the beneficial and harmful effects of interventions
What is the result of bias?
Over-estimation of the effect of treatments
Treatment look better than they really are
Make ineffective treatments look as if they work
What is a control group?
The standard to which comparisons are made in an experiment
Composed of participants who do not receive the experimental treatment
Why are controls used?
To effectively test a treatment in the absence of some absolute or relative measure of success
What are the parameters of control groups?
Ideally they are identical in every way except that the experimental groups are subjected to treatments or interventions with effect
What is randomisation?
It is the process by which treatments are assigned to participants by chance rather than by choice
Avoids bias in assigning volunteers to get one treatment or another
What are the different types of randomisation?
Simple
Block
Stratified
What is simple randomisation?
Based on a single sequence of random assignments
Maintains complete randomness of the assignment of a subject to a particular group
Most common and basic
What are the advantages and disadvantages of simple randomisation?
Advantages: Simple
Easy to implement
Disadvantages: Could result in unequal number amongst groups
What is block randomisation?
Randomise subjects into groups that result in equal sample sizes
Block size decided by researcher, all possible balanced combinations must be calculated
Blocks randomly chosen to determine patients’ assignment into the groups
What are the advantages and disadvantages of block randomisation?
Advantages: Balance in sample size
Disadvantages: Can predict blocks
Groups may not be comparable in terms of covariates
What is stratified randomisation?
Control and balance covariates
Generates separate block for each combination of covariates subjects assigned appropriate one
After all subjects identified and assigned, simple randomisation is performed within block to assign subjects to group
What are the advantages and disadvantages of stratified randomisation?
Advantages: Simple for small trials
Takes covariates into consideration
Disadvantages: Complicated if many covariates
Subjects have to be identified before assignment (bias)
What is blinding?
Studies designed to prevent members of research team and study participants from influencing results
Allows collection of scientifically accurate data
What are single-blinded studies?
Only the researcher knows treatment or intervention the participant is receiving until the trial is over
What are double-blind studies?
Neither participants or researcher knows which treatment or intervention participants are receiving until clinical trial is over
How can blinding help influence the behaviour of the researchers?
Influence patient management
Decision to withdraw patient from trial
Decision to adjust drug dose
Decision about intensity of therapy
Decision about adjacent therapy
Decision to discharge patient
How can blinding help influence the behaviour of the trial subjects?
Influence compliance with the trial
Influence expectations
Influence assessment of patient reported outcome
Knowledge of treatment group can influence behaviour outcome assessor
Influence assessment of outcome
What is a placebo?
Treatments that look like the real thing but contain no active ingredient
What is the aim of a placebo?
To achieve blinding
What is the placebo effect?
When a persons physical or mental health appears to improve after taking a placebo or dummy treatment
Why are statistics important in clinical trials?
For design, conduct, analysis and reporting
Researchers form reasonable and accurate inference from collected information
No uncertainty
Prevent errors and biases in medical research
What is a hypothesis?
A proposed assumption for a phenomenon that may or may not be true
What is hypothesis testing?
An evaluation done by a researcher to confirm or disprove a hypothesis
What are the different types of hypothesis tests?
T-test
Chi^2
Z-test
What are the 2 different hypothesis the researcher has?
Null and alternative hypothesis
What is the null hypothesis (H0)?
Captures what the current situation is
What is the alternative hypothesis (H1)?
Captures what we want to show by doing the trial
What does hypothesis testing do?
It tests if the hypothesises more probable than the existing hypothesis and assumes the null hypothesis is true until proven that the alternative hypothesis is instead true
What happens if there are too little participants?
Real effect may be missed - indistinguishable from chance variation
If study does not yield useful results, time and money wasted
What happens if there are too many participants?
Smaller trials could reach firm conclusions so no need for participants beyond this
Cost implications
What is the true endpoint of a clinical trial?
A clinically meaningful endpoint that directly measures patients (has treatment worked?)
What is a surrogate endpoint?
A measurement of a specific outcome used in place of another as a predictor to tell if a treatment works
Usually occurs before a true endpoint and yields conclusions bout the effect of treatment on a true endpoint
What is dissemination of results?
Getting the findings of the research to people that can make use of them, maximise benefit of research
What are the principles of good dissemination?
Stakeholder agreement (primary audience, engage with them)
Format (produce targeted outputs in an appropriate format)
Utilise opportunities (established networks, conferences and events)
Context (service context of research)
Timing (not limited to end of study)
What are things to consider during dissemination of results?
Objective
Audience
Timeline
Resources
Strategy
What are the nuremberg trials?
In 1947 horrendous medical experimentation in Nazi concentration camps - led to the realisation that there was no generally accepted guidelines for medical research
What are the 10 principles of the nuremberg code?
Voluntary consent
Research - good of society
Based on previous knowledge to justify the experiment
Avoids unnecessary physical and mental suffering
Research avoided if suspected that death will occur
Risk mitigated against and proportionate
Adequate facilities
Conducted by qualified persons
Subjects can end experiments - withdrawal
Scientists should not continue if trial is likely to result in injury
What is the Helsinki declaration?
1964 - Guidance for doctors operating in a dual role as clinician and researcher
Revised multiple times
ICH-GCP (international conference for harmonisation - good clinical practice) is routine in the declaration of Helsinki principles
How is a human participant defined?
A living human being
Human beings who have recently died
Foetuses
Embryos
How can human participants be involved in research?
Directly through physical appearance
Indirectly through stored human tissue/bodily fluids or use of human data records
What are the 4 steps of giving informed consent?
1 - giving of information
2 - discussion and clarification and review of information
3 - obtaining written and/or verbal consent
4 - process consent
How are children able to give consent?
Common law - children are below the age of 18
Generally accepted that whilst children of 16 years and over are minors they can give their own consent
Under 16 years often best to gain Childs assent and parent/legal guardian provides informed consent
What is Gilicks competence?
It is the measurement of whether a child is mature enough to give their own consent
What are the parameters for vulnerable adults?
Temporary: unconsciousness/ some mental illnesses
Permanent: genetic/inherited/clinical condition
What are the legal constraints of informed consent for vulnerable adults?
The mental capacity act 2007
Medicines for human use regulations 2004
Common law
What was the HeLa cells case?
Came from Henrietta Lacks (died 1951)
Cells taken from her cervix months before she died
What are HeLa cells?
Cervical Adeno-carcinoma cells
What was the Alder-Hey organ retention scandal?
Pathologist collected organs from very young children at post-mortem examination (1988-1996)
Without asking for permission
~850 body parts collected
Not clear how many samples were used
What is the human tissue act 2004?
A frame work for regulation of storage and use of human tissue from the living, and the removal, storage and use of the tissue and organs from the deceased for specified purposes
What is inducement?
The provision of an incentive to entice a person to carry out an action
What is the Tuskegee Syphilis study?
US public health service between 1932-1972
600 low-income black males recruited
Free medical care, free meals and burial insurance in return for participation
400 had syphilis
Participants monitored for next 40 years
What was wrong with the Tuskegee Syphilis study?
None of participants were treated for syphilis and none were told they had it (effective cure of penicillin found in 1940s)
Prevented participants from accessing syphilis treatment programs available to others in the area
Victims included numerous men in program who died of syphilis and partners contracted disease and children born with congenital syphilis
Why is confidentiality important in clinical trials?
Goes with anonymity when dealing with participant information
Participant in research study has to have confidentiality maintained unless specifically consented to personal details being disclosed
What is general data protection regulation (GDPR)?
Governs protection and control of personal data
Anyone processing personal data must comply
What are the GDPR principles?
Lawfulness, fairness and transparency
Purpose limitation - not used for anything else
Data minimisation
Accuracy - checks in place
Storage limitation - time held
Integrity and confidentiality - safe and secure
The ‘accountability’ principle - principles are followed
What is personal data?
Identifiable data
Confidential information
Sensitive information
Coded data
Linked anonymised
Unlinked anonymised
Data that relates to an individual
Who does GDPR apply to?
Everyone processing personal data
Why is GDPR important?
As it is part of the research process
Carefully considered in advance of a research study, processes in place at stages and after the end of the study to ensure compliance
Recognised that personal data is handled and managing it within the law
ICO now applies large fines to those not complying
What were the regulations of drugs in research before 1960s?
Not necessary to show that drug actually worked against what it worked against
Bring a drug to market if you had a good theory that it might work against a disease
What was the thalidomide scandal?
Developed as sickness tablet
Given for morning sickness during first trimester of pregnancy in 1950s and early 60s
Resulted in thousands of children being born with severe congenital abnormalities
Highlighted insufficient safe guards in relations to ways efficacy and toxicity of drugs were accessed before they were put on the market
What is the medicines act?
Developed in 1968
Merged a number of pervious medical regulations
Provides a broad legal standard on the manufacture and supply of medicines related to general practice
Necessity of clinical trials and scientific evidence to inform on the safety and efficacy of medication
Looks at the effects of drugs or possible toxicity of drugs in relations to females who are pregnant and the foetus and the future development of the child
What are the 3 main classifications of the medicines act?
Prescription only, pharmacy and general medication
Who is the clinical trials legislation under?
Medicines for human use regulations 2004
What is the UK policy framework for health and social care research?
Developed in 2018
Designed to set principles of good practice across all areas of health and social care research in the UK
Applies to organisation and individuals that have responsibilities for health and social care research
Includes funders, sponsors, researchers and employers, research sites and care providers
What are the principles that apply to all health and social care research?
Safety
Competence
Scientific and ethical conduct
Patient, service user and public involvement
Integrity, quality and transparency
Protocol
Legality
Benefits and risks
Approval
Information about the research
Accessible findings
Choice
Insurance and indemnity
Respect for privacy
Compliance
What are the principles that apply to interventional health and social care research?
Justified intervention
Ongoing provision of treatment
Integrity of the care record
Duty of care
What is the Northwick Park incident?
London 2006
Healthy male volunteers
Antibody drug TGN 1412
Would be used in rheumatoid arthritis and other autoimmune disorders
First human trial to test for safety
Managed by TeGenero of Wurzburg, Germany
What was the response to TGN 1412?
1 hour - Excruciating headaches, shivering, back pain, gut pain, diarrhoea, swelling and nausea
4 hours - fevers, flushed, BP drops dangerously low, hearts race, blood tests show lymphocytes and monocytes vanishing fast
5 hours - one fighting for breath, lung pain, steroids and others to ease inflammation
12 hours - ICU on ventilator, all taken to ICU
24 hours - 2 ventilators, 4 need support
48 hours - 4 start to recover 6 begin to suffer multi-organ failure and attached to kidney machines
What are UK research ethics committees for?
Ensure dignity, rights, safety and well-being are protected
Reducing risk associated with research
Patient participants - UK research ethics committee
Non-patient participants - university ethics committee
What are the different meta-ethical theories?
Moral absolutism/dogmatism - I know that X is right or wrong (anyone disagreeing is wrong)
Moral relativism - Statement X is right or wrong is synonymous with the statement that an agent approves or disapproves of X
Pyrrhonian moral scepticism - I believe that X is right or wrong
What are tools of the ethics trade?
Logic
Analogies
Avoiding slippery slope arguments
Why is ethics needed subjectively?
Subjective aspect:
To justify behaviours
Explain why behaviour is (un)acceptable - relate actions to principles
theory account of which principles should be followed and how to balance
Why is ethics needed objectively?
Objective aspect:
Many (or all) things deserve moral consideration
What are formal ethical theories?
About the sorts of abstract principles and values that should matter
What are material ethical theories (axiologies)?
About the concrete things/entities that should matter
What are examples of formal ethical theories?
Principlism - autonomy (e.g. biomedical research), beneficence (doing good), non-maleficence (doing some harm, trying to prevent it), justice
Consequentialism - can be bad if ill intention
Deontology - blind eye to consequence (careless)
Virtue ethics - cultivate virtues (high moral standard) and right actions follow
Care ethics - caring personalities
What is the connection between axiologies and ontologies?
Which things deserve moral consideration, how much moral significance we should attribute to them related to actions
How we value things (ontologies)
What are examples of axiologies?
Strong speciesism - only human beings matter
Weak speciesism - other entities matter
Animal egalitarianism - treat animals the same
Radical biocentrism - all living things treat the same
Ecocentrism - kill humans to make the ecosystem better
Which ontologies has western philosophy been dominated by?
Mechanistic materialism
Dualism
What is mechanistic materialism?
Ontology that realist is composed of bits of stuff that act in a machine-like fashion
What happens in mechanistic materialism?
Mental phenomena should be explained entirely in terms of the material components that constitute them
Material components do not possess any mental properties
What views does mechanistic materialism accept?
Determinism - the view that all events are determined by causes that lack free will
How can mechanistic behaviour be determined?
Externally by the Great Builder of the machine
By aimless forces
What is dualism?
The view that reality is composed of two fundamentally distinct things: things with minds and things that lack minds
What is panexperientialism?
The ideology that all real individuals collect an experience and there is a mindfulness of molecules and atoms
What are aggregates or true/compound individuals?
Individuals that are not experiencing subjects but they have experiencing subjects within it
When was the rise of animal ethics?
1966 - moral philosophers started questioning the use of animals in research
Who started questioning animal ethics and why?
Tom Regan, 1985 - viewing animals as resources
Marti Kheel, 1989 - feelings of connection with other forms of life
Peter Singer, 1990 - equal consideration of interests, speciesism
What is speciesism?
It regards the way people treat different species and the values or rights to beings on the basis of their biological species
What were different researchers’ opinions on speciesism?
Nathan Nobis 2011 - Biological humanity has nothing to do with morals
Richard Haynes 2008 - Benefits of animal used outweighs costs to animal
Mary Midgley 1983 - Relative disregard of other creatures and emotional preference for own species over others
Why is it problematic for the legal and advisory documents of the use of animals in research to be drawn up by scientists?
As they are primarily using the animals
Many prefer self-regulation, forecloses external scrutiny
Are they experts in ethical relevance of animal welfare
What is the law on using nonhuman animals for biomedical science?
Animal Act 1986 - applied to any living vertebrate other than man and any living cephalopod from the stage of development when:
Mammal, bird/reptile 2/3 of gestation/incubation period
Capable of independent feeding
What does the Animal Act 1986 apply to?
Scientific procedures - cause harm, suffering, pain or distress more than the insertion of a hypodermic needle
What are the 3 R’s that laws defend?
Replacement, reduction and refinement
What do the 3 R’s mean?
Replacement - substitution for conscious living higher animals of insentient material
Reduction - reduction in numbers of animals used to obtain information
Refinement - decrease in incidence and severity of inhumane procedures applied to animals still being used
What is required by the ASPA to conduct animal research?
Obtains personal licence
Project licence is obtained for projects
Place of research has certificate, minimum of 3 named people:
Certificate holder
Veterinary surgeon
Animal welfare and care officer
Licences from home office and visits for inspection
What are AWERBs?
Animal welfare and ethical review body
What are alternatives to nonhuman animal research?
Micro-dosing (nano-range)
Observational studies
Randomised controlled trials
Use of human tissues, cells and genes
Computer testing
What are the methods of biomedical research?
Using (parts of) biological organisms to identify the causes of health and illness
What is clinical equipoise?
It is the balance of interest
e.g. uncertainty which trial is better or just as good as the other
What is the Freedom of Information Act?
2000 - promote openness by public authorities, public have statutory right of access to information held by public authorities
Anonymised information disclosed
What are different examples of scientific misconduct?
Falsification - changing data
Fabrication - making up results
Plagiarism
Self-plagiarism - extracts from own previous work
Gift authorship - recognised as author/co-author in spite of making minor contributions
Why is the opinion of ethics concerning animals important?
For:
Ethical concerns (public concern and animal welfare concerns)
Scientific concerns
Institutional/professional requirements
Legal requirements
What is absolute dominion?
It is the belief that all animal experiments are justified and humans have a higher status than animals so it is okay to use them
What is the absolute dominion view for why animals are necessary for research?
Animals are good models
Fundamental for research as they are used as a legal requirement before drugs are released
Needed to model complex organisation and processes
Alternatives are currently insufficient
How does drug safety govern the use of animals?
It is needed to identify any problems or side effects
Involves: in-vitro and in-vivo screens and a relatively small number of animals (100s)
Only then are they given to many people and animals (could be unwell and/or taking other drugs)
What is abolition?
Animal experiments are morally wrong
What is the abolition view for why animals are unnecessary for research?
Medical advances using:
human-based research
public health measures
population studies
Viable alternatives useful:
computer models & analysis
use of non-animal tests
alternative medicine
Money better spent on prevention not cures
How can misleading experiments be detrimental?
If tested in these species that would they be used in humans
penicillin is lethal in guinea pigs
paracetamol is lethal in cats
Damaging in humans: thalidomide
Tested in rodents which are tetragenic (has no effect)
What is the ‘troubled’ middle of animal experiments?
Some animal experiments are justified
Reduce pain and suffering experienced
Why are the 3 R’s important?
Because it forms a basis for all legislation covering experimental animals
requires alternatives to be considered and evidence provided
forms heart of Ethical Review Process
When will an animal procedure be regulated?
If it causes:
death, disease and injury
physiological and psychological stress
discomfort and disturbance to normal health
anaesthetic or analgesic admin for scientific purpose
What is the animal regulation threshold?
A procedure that causes pain, suffering or lasting harm equivalent to or higher than that caused by insertion of a hypodermic needle for the purpose of research
What are the protected species?
Living vertebrates and cephalopods
Foetal, larval and embryonic forms included:
mammals, birds and reptiles (2/3 through gestation)
fish, amphibians and cephalopods (independent feeding)
Special protection: dogs, cats, horses and non-human primates
What are the ASPA controls?
Purpose of research via project licence (PPL)
People conducting research via personal licence (PPL)
Places that research is done via establishment licence (EL)
Consider licence applications, give advice and provides codes of practice
Enforcement via inspectorate
What are named people required for animal research?
Establishment licence holder (ELh) - responsibility for compliance with ASPA
Veterinary surgeon (NVS) - advises welfare, health and vet medicines
Animal care and welfare officer (NACWO) - care and welfare of all animals
Information officer (NIO) - PILs and PPLs have access to current information
Training and competency officer (NTCO) - PILs properly trained, supervised and competent and record it
What is AWERB?
Animal Welfare Ethics Review Body
What do AWERB do?
Review applications before submission
(cost/benefit and justification, 3 R’s, non-animal approaches used first)
Full implementation of ASPA
Provide advice and guidance on animal health and welfare
Support NACWOs and NVS
What is the utilitarian principle?
Greatest good for the least harm assuming animal research is justified
Benefits of research must be greater than the costs
How do cost/benefit analysis’s work in theory?
Assigns values to costs (animal interests) and a value to the benefits (research value)
What are the 5 pillars?
Honesty, fairness, accountability, transparency and responsibility
What is auto plagiarism?
Using the same piece of work previously submitted and submitting it again to get 2 lots of credit
What is a main example of scientific fraud?
Like Andrew Wakefield and his claims on the MMR vaccine causing autism which was then taken down as there was insufficient evidence towards the claims
What is retraction?
Removal of a paper from the ‘system’ after fraud or honest error has been detected
What is social capital?
Form of economic and cultural capital in which social networks are central, transactions marked by reciprocity, trust and cooperation, market agents produce goods and services not for themselves but for common good
What are the pros and cons to open science?
Pros: open, funders and public see what you are doing, peer reviewed
Cons: ownership, early data, risk of scoop, funders see what you are doing, not peer review
