PAS4 Flashcards

1
Q

What is the aim of research?

A

Develop new treatments and ; information to benefit people.

Research is hypothesis driven. We collect data as evidence. You can never disprove any hypothesis.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Describe pre-clinical research?

A

Basic or bench research.

Laboratories: invertebrates, invitro and animal experimentation. Underpins clinical and healthcare research.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Describe clinical Healthcare research?

A

Human participants, patients & healthy volunteers. Study of illness and health.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What does bench to bedside mean?

A

Translates findings pre-clinical research into new treatments and information to benefit people.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Quantitative research?

A

Measure numerical data in small group of people; specific study design, analyse, generalise findings to population.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Qualitative research

A

Understanding underlying reasons, opinions and motivations; non numerical data.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Give characteristics of good quantitative research?

A

Well defined study aim: research question.
Study is well designed.
Consideration data collection and minimising biases.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Describe types of quantitative study designs.

A

Observational Designs: No intervention (record behaviour, attitudes, and symptoms-naturalistic).Investigating associations. Eg, cross sectional studies, cohort studies.

Experimental designs: (Factorial designs)
Researcher controls or introduces factor:
-effects of different diets on weight of mice;
-effectiveness of new antidepressant drug.
Record effects of intervention: Investigate sources variability. Eg) trials.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What is a sample used for

A

Represents population, used to make inferences about population. It is not practical to include entire population.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Describe the different types of bias possible

A

Selection bias: systematic difference between population and sample.
Non-response Bias: systematic difference between non responders and responders (volunteers). Difference between people who respond to bias and people who don’t. If people do not respond to questionaire, that is non response bias.
Response bias: when there is a systematic difference between what has been said/stated and the truth.
Assessor bias: Systematic difference between assessor measurement of
participant & “truth”

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Define generalisation?

A

Inferences about population based on sample.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Define sample estimates?

A

Estimate population value(s). Values we get from the study. We use the sample estimates to predict the population values.
We can increase sample estimate by increasing sample size.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Define population values?

A

Population parameters, they are fixed. They are known, that is why we are taking a sample to try and estimate them.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What is a statistical population?

A

Not Restricted geographically (locally). The statistical population is infinite. But you can use sample from UK, to predict what is happening in population. Can be restricted by time (/)-peoples behaviour might change in time, eg in 5 years.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Describe the different types of sampling errors as a result of sampling?

A

Sampling error is the distance in magnitude betwen sample estimate and population parameter.
Sample estimate may not equal population parameter. If we don’t know population parameter, we don’t cannot predict how close our sample estimates are to the population parameter. Cannot quantify; estimate from single sample (theoretical concept)
Reduce: Increase in sample size. use
confidence intervals to Predicting uncertainty.
For example, a population has different ethinicities, different work, but in our sample we have only selected people from some ethnicities, not all, so we have already immediately introduced selection bias.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What are the methods of sampling?

A
For (simple) random sampling:
Sampling frame (list) for population.
Every member has equal probability of selection; Representative sample (large enough);
It is never feasible though. Cost and time? Theoretical concept. 

For convenience sampling: Convenience Sampling: Participants convenient to access. e.g. Single hospital or clinic;
But is that simple clinic Representative of population. It introduces Selection bias and you get Volunteer bias. People have asked to be in study. Diff in people in volunteer and diff in people who don’t.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

How do we make sample more representative of a population?

A

Use greater than 1 hospital or clinic, so sample is more representative of population.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

Describe different types of biases and effects

A

Response Bias:
 Particular problem: Self-report outcomes.
 Systematic difference between participant response & “truth”.
Assessor Bias:
 Systematic difference between assessor measurement of participant & “truth”.
Controlling: Difficult to remove only minimise.
 Experimental Designs: Aspects of methodological designs.  Observational Designs: Harder to control.
Hawthorne Effect: Change in participants’ behavior due to attention received in study.
 Change in behaviour afterwards?

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

Describe types of hypotheses

A

Research: Hypotheses driven.
Research Hypothesis: Initiates the research.  Typically based on anecdotal evidence;
 “Believe dietary protein affects weight gain in mice”.  Objective evidence required.
 Undertake research; Collect data as evidence.
Statistical Hypotheses (Traditional) (Future lecture)
Null: No difference exists between factor levels in outcome; Alternative: Difference exists between factor levels in outcome; Data (evidence): Lend support to Null or Alternative.
 Cannot (dis)prove a hypothesis;
 Philosophy: Based on sampling.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

Describe study design

A

Sample: Representative of population.
 Biases & Effects: Awareness; if possible minimise.
 Study Design:
 Observational versus Experimental  Association versus Causation.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

What is the golden triad of moral philosophy? or What are the 3 main theories of modern philosophy?

A
Virtue ethics (Aristotle-question is what is the right or wrong person to be), eg to be a courageous person, what would this person do in that situation? what is the courageous thing to do (can play both ends).
Consequentialism (John Stewart Mill, the right or wrong thing to do, is that which maximises the good, maximising theory. Think about the consequences of your actions), and about medium and long term actions. 
Deontology: (Emmanuel Camp -the right thing is found in rules and reasons (includes rights/justice))-be honest, looking at the principles. 

Pluralists: bring all these three theories together. They include application of multiple perspectives for thorough analysis of the problem and challenging of assumptions.

These are ways of dealing with values and normative things, rather than descriptive things.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

What is the 4 principles approach?

A

An ethical tool, used to help around scenarios as well as primary principles or theories.
Non Maleficence : no harm
Beneficence : do good
Autonomy : not valuing people’s choices but people’s right to choices
Justice : being fair

The Ethical grid: is also another ethical tool. It is 20 different ideas and concepts that we can take and apply to the case.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

What does process mean?

A

Arguably, the process of doing ethics is as important as the ethical conclusions drawn (esp. for virtue ethicists!)
Process of doing ethics is as imortant as the ethical conclusions drawn (esp for virtue ethicists).
What is this thing called “process”?
….listening, asking questions, critical reflection, deliberately ‘thinking the opposite’, using intuition and emotion, being alert to logic ….etc.

So don’t get too lost in the theory, think also about the way in which you conduct the analysis.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

What is the law and what are the basic distinctions in (UK) law?

A

What is the law?
“the principles and regulations established in a community by some authority and applicable to its people, whether in the form of legislation or customs or policies which is recognised and enforced by judicial decision”

Basic distinctions in (UK) law:
Statute (created by parliamentarians) v Common Law (created by judges).
Criminal v Civil Law

Law and ethics may mismatch: something that is legal may be unethical.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

What is professionalism

A

-maintaining and upholding professional standards.

Most professionals have a set of principles and virtues that they are expected to uphold.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

Why does ethical analysis matter?

A

It is morally important to behave ethically

Maintains reputation &; accountability

Teams function more effectively & inclusively

Enhances productivity, efficiency & morale

Professional regulatory bodies require their members to behave professionally and ethically

The law reflects ethical values and often requires scientists to abide by professional and ethical guidance

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

What is the challenge of doing ethics

A

Limited resources e.g. time, expertise, staff, accountable sources of advice and variable quality. Difficult to make time to have these conversations, who will you talk to.

Integrating ethics into scientific practice so it becomes automatic in decision-making rather than settling for ‘moral mediocrity’

Constructing ethics as ‘hoop jumping’, ‘common sense’, ‘yet more rules’ or ‘irrelevant’

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

What is a variable

A

Azny aspect of an individual / animal / specimen
that is measured like blood pressure, sex, age,
level of C-reactive protein is called a variable
Diff variables give diff data.
• Numerical variables (quantitative)
• Binary or other categorical variables (qualitative)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

How do we summarise numerical data?

A

Perform a frequency distribution:
-this shows the number of people within groups and is usually represented by a histogram.
Height of each bar corresponds to the number of people in group.
There are different shapes of frequency distributions.
-Symmetrical bell shape
-Not symmetrical -long tail to LEFT, left skew/negatively skewed.
-Not symmetrical -long tail to right. -Right skew/positively skewed.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

How can we summarise continuous data

A

If data are Normally distributed… symmetrical …summarise using mean & standard deviation
•Spread: calculate the variance –It is a measure of the variation from the average (i.e. mean) value –Used for symmetric (“normal”) distributions –The standard deviation is the square root of variance

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
31
Q

What values are known for normally distributed data

A

If the data is normally distributed:
68% of all measurements fall within 1standard deviation of mean
95% of all measurements fall within 2 sd of mean

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
32
Q

What is the 95% central reference range?

A
It’s the interval
Mean ± 1.96 x SD
•95% of the data lies between these limits IF
data are Normally distributed
•1.96 often rounded up to 2
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
33
Q

In a positive skew, would the mean be higher or lower than the median?

A

Mean would be greater than the median.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
34
Q

How do you summarise continuous data if it is not normally distributed (symmetrical)?

A

If data are not normally distributed (i.e. are not
symmetrical)…
Median and quantiles
– 3 commonly used
– Median
– Lower quartile
– 25% of data lies at or below lower quartile
– Upper quartile
– 25% of data lies at or above upper quartile
• Other quantiles
–Tertiles : Splits data into 3 equal sized groups
–Quintiles: Splits data into 5 equal sized group
–Could use percentage cut-point e.g. 10% or 90%

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
35
Q

What is the 95% central reference range?

A

Used a lot in biomedicine • You will see this used as a guide on many biological measures –Its frequently used to express range of expected values from healthy individuals • Other reference ranges are also used for biological data e.g. 90% or 85%

36
Q

Disadvantages of ‘range’

A

• Dependent on outliers • The larger the sample the wider the range • Interquartile range –Less influenced by outliers –Can still vary quite a bit from sample to sample
Many different types of data in biomedicine • How data are summarized or displayed depends on –Type of data –What question is being addressed • The concept of what if “normal” –Clinical meaning of what is expected in healthy patients –Statistical definition based on the distribution of the data –Reference ranges

37
Q

Why do we study samples?

A

Results from sample tells us something about the population of similar individuals

38
Q

What is the population vs sample

A

Studies are generally done on samples from the population –Population of all men 25-29y –Sample of men aged 25-29y • Once we have the results from a study we wish to make inferences (decisions) about the entire population to whom the results from the study might be applicable to.

39
Q

How do we make inferences?

A
  • How was the study designed, conducted, how was the sample selected.
  • were statistical analyses appropriate?
  • what is the estimate of effect?
  • how precise is the estimate?
  • what is the probability that result observed in the study is a fluke? (not real)
40
Q

What is the point estimate of effect?

A

What is the probability that this result could
have arisen by chance, if there were no real
difference in the population.

41
Q

How can we test the null hypothesis

A

An independent samples T-test is used to compare means between 2 independent groups • It takes into account –mean value in each group –number of observations –spread of the data in each group [Standard deviation].

42
Q

What is the link between 95% CI and P values?

A

• If 95%CI contains null effect (i.e. no
association) p will be greater than 0.05
• I If 95%CI excludes null effect (i.e. no
association) p will be less than 0.05

43
Q

Describe the precision of estimate

A

Based on SD, we can calculate a standard error for difference in mean between the 2 groups.

44
Q

What is the link between 95% CI and P values?

A

If 95%CI contains null effect (i.e. no association) p will be greater than 0.05 • I If 95%CI excludes null effect (i.e. no association) p will be less than 0.05

45
Q

Describe the assumptions of t-test

A

Assumptions of t-test • Generally OK for large samples • If sample is small –data needs to be is normally distributed –variances similar in each group (i.e. check SDs are similar) • If sample is small & data is not normally distributed……. –we use a different test …..see flowchart –Interpretation of p value is same

46
Q

What if we have more than 2 groups for t-test

A

Comparison of means from 3 or more groups uses –Analysis of Variance (ANOVA) –Gives p-value only – Does not tell you which groups specifically are different from one another

47
Q

Risk ratio

A

Risk in effected group / risk in control group

48
Q

What is a prospective cohort study?

A

The outcome, occurs after information about the risk factor has been collected.

49
Q

What is the p value?

A

Probability that the result observed (in the
sample) or one even more extreme occurred
by chance if in truth (i.e. in the population)
there is no effect
• OR
• Probability of obtaining a difference as large
(or larger) as that observed if there is really
no difference / association in the population
(from which the sample came)

50
Q

What are clinical implications of values at each end of

confidence Interval?

A

A wide interval is consistent with the two end values
having different clinical implications
• Wide confidence intervals that straddle (include) the
value of “no effect” do not advance our knowledge,
 they usually mean the sample size was too small &
a more precise (bigger) study is needed

51
Q

Meaning of small p value vs large p value

A
• Small p-value
– Unlikely that sample
came from population
where null hypothesis is
true
– Conclude that real
difference exists in
population
• Large p-value
– Likely that sample came
from population where
null hypothesis is true
– Can not conclude that
real difference exists
Remember we have NOT proved that there
is no difference – perhaps sample was too
small to detect potential “real” difference
52
Q

Wide/narrow confidence intervals

A

Narrow CI -> precise estimate

Wide CI -> imprecise estimate

53
Q

Chi squared test

A
Chi squared test is used for
• Data that can be tabulated in terms of counts
• Compares percentages (proportions) between
groups
– Can have more than 2 groups
• The data is in categories e.g:-
– Treated vs. placebo
– Male vs. female
– Drug dose
– Different experimental groups

Assumptions of Chi squared test
• If some cell counts in table are <5 its best to
use an adaptation of Chi squared test called
Fisher’s exact test
– Just mentioning it in case you see it in medical
literature
• Interpretation of p value is exactly same

54
Q

How does drug development occur

A

The whole process takes an average of 12 years. It all starts from pre-clinical testing (in petri dish, in vitro, test tube…etc).
Work done, mostly in academic department universities: are research and development labs in industry, that develop and try and investigate new mechanisms to understand disease.
Once this new mechanism of disease has been discovered, then a new target, for treating the new condition comes about. New target: new receptor/enzyme. Pharmaceutical companies try to screen drugs that can hit this target. The companies contain big banks of drugs, which are basically screened on specific assays and gains the target. Once the drugs have been screened, then, you get certain hits, and those hits are then tested in animal models-mice, then non human primates.
So you test a potential hit for the target development and then you assess the safety of drugs on animal models, and you also assess the efficacy of the drug. Eg, develop a model and see if it is able to work, eg reduce depression, or for lowering blood pressure. Model is based on what you are testing. If drug approves to be safe and efficaous, then you start doing clinical trials, with humans.
It takes a long period of time to develop into clinical trials. If all the drugs are successful and drug is proved to be safe and efficacious, then it gets submitted to the FDA or mhra, which are regulatory authorities, which allow it to be licensed. Once it is licenced then GPs can prescribe it to patients.
However the safety of the drug doesn’t stop there. There is also post markets surveillance of the drug where the drug is actually monitored after it has been licenced.
This 12 year of duration of development of drugs, a lot of things can go wrong. Drugs can get knocked o=down, because of toxicity, lack of efficacy-lose a lot of money,

55
Q

What are controlled clinical trials

A

A clinical trial is a series of tests that scientists need to
conduct when they come up with new ideas for new drugs,
new medical procedures, or medical devices. Medicines and
Healthcare products Regulatory Agency (MHRA) of the
United Kingdom (UK) and the Food and Drug Administration
(FDA) of the United States of America (US) are the regulatory
authorities which approve drugs or devices or claims made
by pharmaceutical companies

clinical trials, not always drug development, but also new medical procedures and devices, eg a bionic arm or foot.
-we conduct clinical trials for these as well.
Different countries have different regulatory authorities-Medicins and Healthcare Products Regulatory Agency (MHRA for UK,) and Food and Drug administration (FDA) of the US.
For a drug to be licenced it needs to bbe approved by these companies.

56
Q

Describe the overview of clinical trial development

A

Starts from pre-clinical trial, testing of drugs either in vitro or in vivo.
Once the drug has been tested and found to be safe and efficacious, then it goes to a Phase 1 clinical trial.
Phase 1 clinical trial, assesses usually the safety of the drug. It is usually conducted on healthy volunteers (~20-80 people).
If this drug proves to be safe, then you go to a phase 2 clinical trial, where you assess the safety and the efficacy of the drug, in a patient population (disease population). So not healthy volunteers anymore, but people who suffer from a particular condition. There are more people involved in this clinical trial, (100-300 people). If this still shows drug is safe, then you go to phase 3 clinical trial.
Phase 3 clinical trial involves more people 1000-3000 people. You also assess efficacy and safety of the drug. If phase 3 clinical trial is successful, then the pharmaceutical companies will submit a portfolio to the MHRA or FDA, and the mhra will either apprve it, or they will decline it, or they will ask for ammendemts (more experimentatous, more clinical trials). But once it is approved, then doctors are able to licence it and prescribe it as they wish.
But things do not stop here. –phase 4
Phase 4 clinical trial is about surveillance of the drug, post marketing. Companies are obliged to monitor the safety of the drug. They have to contact the GPs, contact the community, and find out any adverse effects, any interactions with other drugs.

57
Q

How long does each phase in a clinical trial take?

A

Pre- clinical development, could take between 1-5 years. It depends on the disorder.
Phase 1 clinical trial takes about 6-12 months, on development.
Phase 2 clinical trial, takes maximum 3 years.
Phase 3 is much longer because you have more people involved (takes upto 5/6 years)
Phase 4 clinical trial is ongoing, so they are long, long periods of time.

58
Q

Phase 1 of clinial trial development

A

Phase 1
So once a drug has been tested on animal models, and it has proved to be safe and efficacious, then it is tested in humans for the first time. This is phase 1.
The aim of phase 1 clinical trial, is to assess the safety of the drug, and its tolerated dose (how much of dose of drug is tolerated by the healthy volunteer).
It also aims to see if pharmacokinetics differs form animal to man. Pharmacokinetics, are drug metabolism of the drug. This has been assessed in animal models, but it also has to be assessed in humans because they could be completely different. P450 enzymes involved in metabolising of drugs, could be completely different in terms of affinity for drug, in humans, compared to animal models.
This phase 1 also predicts any predictable toxicity. It is important to capture this earlier rather than later (saves money).

So phase 1 clinical trials, are done predominantly on healthy volunteers. First in man. Not people with diseases, but with healthy volunteers- with 1 exception. This exception is if you develop an anti cancer drug, which you know has a particular toxicity. Then you know it would be unethical to test healthy volunteers. So if you know a drug will cause a toxicity, then do not test on healthy volunteers. Women of child bearing age and children are not involved in phase 1 clinical trials (as you do not know the full effects of the drug).
Phase 1 clinical trial Methods
You use a small group of healthy volunteers. You start with a small dose of drugsand you gradually increase it until you find that there are some adverse effects, then you stop. Once you find the tolerable and safe dose,you then test that dose in a bigger group (50-75 people).
You do not need any blinding for this trial, as it is conducted by clinical pharmacologists (medics). You only need a single centre, you do not need a single centre trial. The success rate is quite high (70% succeed) and then it is continued to a phase 2 clinical trial.

59
Q

phase 2 of clinical trial development

A

Phase 2 clinical trial is called first in patient trial. Assess the efficacy and safety of drugs in patients, not healthy volunteers. This happens in 2 phases. In the first phase, you assess the safety of the drug, as well as the efficacy of the drug, in 20-200 patients. So you look at potential benefits, efficacy, and if any adverse effects.
You can also establish the effective dose you need, balancing the adverse effects, and the efficacy of the drugs (dose). These trials are single blind, so only the patient knows what they are taking, but not the experimenter. The experimenter is blind to what the patient is taking. Once dose is established, and placebo compared to drug, you go and do a late phase clinical trial.
Late phase clinical trial are double blind, where experimenter and patient do not know what they are taking. It happens in a bigger population (50-500 people) and you usually compare drug X with placebo, but you also compare to the gold standard drug. Eg, if developing, a new anti-depressant drug, you ompare to gold standard anti depressant drug. This allows a head head comparison. Eg, if anti-hypertensive drug, you compare to ACE inhibitors.
Outcomes you get from it involve safety, efficacy, pharmacokinetics, pharmacodynamics, establishing overdose etc. Unlike phase 1 clinical trials, phase 2 clinical trials success rate is much lower (35%). Why?
-beccause of toxicity, adverse effects, and reduced/low efficacy, or no better than normal drugs which are available in the market.

60
Q

Phase 3 of a clinical trial

A

If drug is still successful, it moves onto phase 3. Phase 3, much bigger scale, 250-1000 PATIENTS. These trials, are however randomised. Why randomised? Because it avoids bias. They are randomised controlled trials by definition. They are usually performed by clinicians in the hospital, and they are run, in multicentres. This produces a larger amount of people. You randomly allocate one cohort with placebo, other with drug and other with a gold standard drug. All of these are blind.
You investigate efficacy of drug, you also investigate any adverse effects as well. The statistics are extremely rigorous. This is because next stage is application of FDA or MHRA. If you submit and it is not rigorous, you can get sued etc. It takes upto 5 years, and the success rate is not great.

61
Q

Phase 3 clinical trial

A

If a pharmaceutical company performed phase 3 clinical trial, and found that it was seen as more efficacious than gold standard, then it goes to a phase 4 clinical trial. Before this happens, you submit to FDA, OR MHRA, and if they approve it (not straight away) then drug is released, and licenced and GP can then prescribe it. This is when the phase 4 clinical trial begins. So this is when pharmaceutical companies will have the duty of pharmacovigilance. This is monitoring any potential adverse effects to the whole public, So they contact GP surgery, go to patients, to get information of drug-drug interactions, or any rare adverse events. But even on the benefits of the drug, Eg this new antidepressant drug can solve problem of anxiety etc. This then causes a new indication of drug, and then you can re-purpose it for different disease. This is good, as there are many drugs which can be repurposed for diff conditions.
Is it possible that drugs go to phase 4 and still fail? Yes.
The remobant story. Developed by a bog French pharmaceutical company.Following phase 4 post marketing surveillance, it appared that some people were suffering from severe depression, anxiety, suicide, because of the drug.This then had to be withdawn, took a lot of money, and reputation went down.

62
Q

Who participates in a clinical trial

A

Who participates in clinical trial? You obviously need patients and healthy volunteers-for phase 1.
You also need a team, consisting of a clinical pharmacologist (esp if it is phase 1). You need a clinical investigator, clinician (someone who can prescribe the drugs). You also need a clinician, someone who can prescribe drugs. You also need a researcher-someone who will carry out the trial as you go along. You also need a coordinator-a primary investigator, who will be co-ordinating the trial. This person will be making sure that the management of the different people is done properly. They will also make sure that they talk to the research ethics committee, the regulatory board etc. Different instituitions are involved. So they have the primary responsibility for the management of carrying out the trial-coordinate it.
You also need the instituition-where the trial will take place, that could be an acadaemia, or a hospital (mostly). It is very important to have the research ethics committee, or the institutional ethical committee. The role of the R.E.C (OR IF TRIAL TAKES PLACE IN nhs, IT WOUld be the NHS research ethics committee) is to supervise and monitor every step in this trial, but to safeguard the welfare and the rights of the participants. So tHese people will look at protocol, scrutinize it, see what each participant will go through, in terms of whether they are going through a lot of different procedures, is it ethical to go through all these proecdures, they will see how much money you give them for compensation, and whether it is enough. So they will scrutinize it all, and scrutinize the design of the study as well. They can stop the trial from happening (if unethical). Or they can give ammendments for you to do.
Who is involved in this ethics committee? –Usually medics, GPS, researchers, scientists, but also members of community, eg local policeman, postman. They can give advice on what they think about clinical trial-maybe it is not needed.
Sponsor-another important member for clinical trial. The sponsor is the ultimate responsible person for the trial. This is ultimately the pharmaceutical company-as they have the money to sponsor the trial, or it could be a medical research council. It could be a university etc. So the sponsors pay for all the expenses of the trial (phase 3 requires large amount). It is responsible for the appointment of investigators. Investigators will have to be competent. They are also responsible for shipping all drugs to the trial. These are drugs, so they have to be shipped from where they are made into where it is needed. They are also responsible for filing all papers, and legal documents, to regulate the authorities, eg for going to MHRA, and submitting all the documents.
Finaly we have the regulatory authorities –MHRA, FDA. They are responsible for the outcome of trial. They are who can allow you to go ahead.

63
Q

Describe a clinical trial protocol

A

When you do a clinical trial, you submit a protocol. The protocol is the master document of the clinical trial and you have to follow it by word. You have to follow it really strictly, and if you don’t, you have to tell your regulatory authorities. Because if you do not tell your regulatory authorities and you find out about it, you are in really big trouble, including imprisonment.
Protocol has a title, eg. randomised control trial to assess efficacy of oxytocin to treat heroin addicts.
It has an introduction: including what pre-clinical work has been done, and what clinical work has been done before you came to this phase 2/3 clinical trial. All documentation has to be there. You need to give the rationale, why the clinical trial is needed: it is needed because of all this pre-clinical work, it’s safe because of this etc. Phase 1 clinical pharmacology showed that…etc. All this has to be in introduction.
You also need to state the primary and secondary objectives-important part of document. Primary objective: 1 or 2, eg objective is to test the efficacy of oxytocin on drug relapse. Secondary objectives: could be many different objectives, eg. Efficacy of oxytocin to treat opoid dependent related anxiety, depression, social anxiety etc. It is very important to have this written in stone. Not only written in stone, but it is also publishe before trial begins. This is important, because many before pharmaceutical companies tested drug, and primary objective found wasn’t significant, but 20 other objectives were significant, so they presented secondary objective as the primary objective to the FDA. This was unethical, and not proper practice. So now, you have to submit before, before trial starts.
It is also important because you hold statistics and power calculations. Power calculations are what you do to find out how many people you need on the trial to get a statistical difference, if there is one. And all this is done, based on the primary objective, not secondary, so it is properly powered.
You also need to tell us about the design in the protocol. What type of study is it, is it observational study, or is it interventional study. What are the recruitment criteria: every clinical trial has exclusion and inclusion criteria. So you are either included or not. Eg, are you going to allow everybody from age 18-100 or are you restricting to a certain age group, females, males etc. So need to think about inclusion criterias but also exclusion criterias, eg smokers (are excluded in many trials).
Randomisation criteria also needed to avoid bias.
Sample size, how many do you need. All based on power calculations. Finally, you need to have a clear, identified how you will analyse data.
-eg P test.
Then you need a bibliography.
These are all very important and you need to stick to this design of protocol. If you do not stick to it, you need to back to ethics committee, Or MHRA and say I need ammendments (take 2 months).

64
Q

What are the different types of designs for a clinical trial

A
  1. Observational trials
    -cohort studies, where groups of subjects are followed over period od times. This is an observational trial.
    -you can define the incidence, and investigate the potential cause, but it doesn’t give you any information about the real cause. There is no real causality, based on this conventional trial.
    -eg assessing the effect of transitioning from heavy smoking to e-cigarrettes, does it change cravings, anxiety, depression.
    When they were smoking, EEG measurements etc.
    Then they were transtioned to E-cigareetes use, did same measurements post switching to E –cigarrette use. So following up on these peopleover a period of diff time points.
    -this is a prospective observational trial, because we investigate the chosen sample group, and measure characteristically each sample over period of time.
    Then the retrospective observational trial, is where the trial or the study has already been done, or the study has already been done, but you go back to it and study a specific time point. Those trials have problems, Benefits are that It is cheap because do not have to spend money to conduct trial, but you need other good data available.
    So these are observational study designs.
  2. Another TYPE of study designs are experimental designs-interventional studies. These studies are when you have a group, and you intervene. You intervene by giving a drug or a placebo, or you can intervene with behaviour intervention, such as exercise.
    So anything which causes intervenience, or it can be using a device.
    These are interventional studies, they allow you to really investigate causality (cannot do in observational studies).
65
Q

wHAT kind of interventional studies are available?

A

Parallel designs are intervemtional studies, where you have 2 or 3 arms to your investigation, one group of patients take placebo, another group takes treatment and final group takes gold standard treatment. This is called parallel design.
Then we have other types of designs for interventional studies, eg cross over designs, which are more complicated. Cross over designs are designs, where the comparison of treatments and placebo, are made in the same subjects, eg if you have one group, and you expose them to a placebo, for a period of time (2-3 weeks), then group has a wash out period for 1-2 weeks. Then they cross over to the cross over to the active treatment (your drug). So they cross over. You then have another cohort which starts with your drug X for a period of 2 weeks, you wash out, and then you cross over to a placebo. The advantage of this, is that it allows each subject to be a control, so that the treatments can be assessed in each subjects individually.
So you can compare the active treatment, to the placebo, in the same subject. What is the advantage here? You eliminiate interpatient variation, so your error bars are really small. This has an impact on your study sample, you do not need lots of people in the cohort. This is a great advantage of carrying out parallel drug testing.
But they also have disadvantages. Disadvantage of cross over design, is that there is potential for carry over effects, sequence effects etc. These all need to be considered. Eg, if you are on this arm of the cross over design, and you are on this treatment, this treatment, whatever the effect is, could be carried over, to the placebo, and this will become a problem. So this needs to be considered, so although there is a wash out period, there can be a residual effect carrying on. Also, these designs are longer, have a longer duration, than the parallel designs. And the start is much more complicated. So there are disadvantages for this cross over design.

66
Q

What happens before a study even starts?

A

do a study for a clinical trial, you also need money. You then try to find out how much it will cost, need a budget. You then review the protocol, and the institution reviews the protocol, and you submit the protocol in the grand applications. Eg, you submit the grand applications to get money to do trial, you then submit the protocol to ethics review committees, and the MHRA, to then get approval. Hopefully, all these committees, get approval, and then if you get the money, and everything is approved, then you have to hire stuff, make sure monitoring equipment is there, shipments of the drug takes place, source the proper documents, training records, and buy all equipment that you need. Only then, you can start the study.

67
Q

wHAT DO you do after your study idea has been approved?

A

So once study is approved, then you run your study. First thing you need to do, when you run your study, is that you need to recruit patients. So you use posters, social media, newspaper etc.
Once recruit, you need to screen these people (inclusion/exclusion criteria), do you want pregnant or smoking? You go through criteria, if they are eligible, you keep them.
You then need to give them information about the study, benefits and risks. You then tell them, that if they complete study, then they can withdraw whenever they want. There is no obligation to be on study. Once they have understood it, then you sign the informed consent. The informed consent is important, because they consent to carry out the study. They consent they have understood what is needed for them, what kind of procedures/protocols are involved. That they can withdraw whenever they want. This is very important.
Once they sign their informed consent, they are randomised. Somebody else not part of the study will randomise it, or a computer, no one is able to see until the end of the study. It is also blinding.
Once they are randomised and you give drug A and drug B to the appropriate person, then you start the protocol. A researcher comes in, various visits. They visit for a period of time, and they take measurements, blood urine, tests, biopsies scan etc. So they carry out the protocol. Any deviations have to be communicated to the sponsor and ethics research committee. If you find out that there are adverse events during the trial, you have to report them, even if it has nothing to do with the drug per say.
The drug then needs to be stored at particular conditions, usually it is in a fridge, if it is temperature sensitive. This is important, because not only do you have to store the drug in the fridge, but you have to monitor the temperature. Everyday, you have to monitor how much temperature there is. Because if you do not, this can affect the efficacy of the drug.
Then you need to pay the subject. Then you need to enter the data in a spreadsheet (electronic) and then after all this, study closure, you do the statistics, and then you publish the data.

68
Q

Why are ethics so important

A

The reason, is because the participants need to be treated with respect. They shouldn’t be harmed in any way and they need to be fully informed about what is being done to them. The reason for this is because of big scandals that have happened in that past.

69
Q

What is the Nuremberg code of practice?

A

Eveyrone in clinical trial should provide informed consent (except if you are severely disabled, then next of kin can give). Research should be based on prior animal work (need tohave a rationale for it). Risks should be justified by anticipated benefits. So you balance it if you think it will be more benefial than not.
Only QUALITIFIED scientists can conduct research. Physical and mental suffering must be avoided. No research where death/severe injury is expected. These are very important codes of practice.
Everyone involved in clinical trial, shoul be doing clinical study, according to good clinical practice.
GCP is gold standard of how clinical trials should be done. It is full of diff principles and ways to be conducting the trial. Standard for the design, how it should be conducted, monitored, analysed, confidentiality (cannot tell who is on trial) and anonymity. Also data protection, you cannot have data of people lying around.
This is all part of good clinical practice. It has to be dictated. Anyone who doesn’t do things based on gcp will get in trouble.

70
Q

Examples of ethical tools

A

4 principles approach
Ethical grid

Used to help us with scenarios as well as ethical principles and theories

71
Q

Examples of ethical tools

A

4 principles approach
Ethical grid

Used to help us with scenarios as well as ethical principles and theories

72
Q

Ways we can get sample estimate close to population paramater

A

Increase the sample size.

73
Q

What are the 2 types of research?

A
Pre clinical (basic/bench research): in labs, in vitro or animal experiments. 
Clinical: patients and healthy people. It is the study of illnesses and how to help people remain well.
74
Q

what types of sampling are more representative of a population?

A

Multicentre and convenience sampling are more representative of the population.

75
Q

What are biases

A

Systematic differences between what is recorded and the truth.

76
Q

What is the Hawthorne effect|?

A

Change in participants behaviour due to attention received in study. Eg, if stressed, behaviour will start to effect the animals.

77
Q

Why is it difficult to know how well sample estimates predict population parameter?

A

Because we do not know what these population parameters are, hence we do not know how well samples are representative to the population parameter.

78
Q

What are the different types of hypotheses

A

Statistical Hypotheses (Traditional) (Future lecture)
Null: No difference exists between factor levels in outcome;
Alternative: Difference exists between factor levels in outcome;

79
Q

Controlling

A

Difficult to remove, we can only minimise. in EXPERIMENTAL studies by aspects of methodological design, whereas observational studies are harder to control.

80
Q

What is ethics

A

Ethics is a branch of humanity and philosophy.

81
Q

what are factual scientists?

A

Do the science, focusing on facts and forget the ethics.

82
Q

Why should scientists take ethics into account?

A

Scientists are citizens like everybody else. Part of a social project that is funded by citizens. Hence they should engage with certain ethics, which might mean they do not choose to do some research.

83
Q

What are the ethical issues related to stem cell research?

A

Dignity, sanctity of life, utilitarian arguments for/against, duty to protect the vulnerable but also duty to advance scientific knowledge, human rights (embryos, scientists, patients)
(think about this in conjunction with the theories there previously are: deontology(rights/rules, what does the law say for that country), consequentialism (long term/short term outcome), virtue ethics-(being good person).
-playing god.
-murder against embryo
-there is risk to commercial exploitation,
-can lead to reproductive cloning
For:
-alleviate human suffering
-embryo will be destroyed anyway, so why can we not use it for research
-cells are produced in a petri dish, not cloning.
Against:
Stem cells are potentially human, innocent lives. But this research can lead to curing many diseases.
In most countries, women can be paid to donate eggs to infertile couples, but many ethicists, lawyers and women’s rights activists feel that women should not be compensated for donating eggs for research. Other ethicists, lawyers and women’s rights activists feel that they should, at least to compensate for time lost from work and other costs to them.

Research that is being carried out, has major implications for lots of different ethical ideas and theories. But the work often has significant issues for society.

Virtue ethics: what would a good scientist do
Consequentialist: will think about the potential treatments that can be made.
Deontologist: will look at law, is it allowed in the country or not,

84
Q

What is criminal law? What is civill law

A

Criminal law: the way the state interacts with individual citizens. It is the state that will punish you if you commit crime.
Civil law: managing relationships between different individuals.
For scientists, statute and civil law is relevant.
For health care professionals: statute, common and civil law is relevant.

Criminal acts are considered offences.
The state has responsibility for crime prevention, for bringing culprits to justice.
Civil law is to protect individuals against one another by specifying rights and duties of individuals.

85
Q

What is the role of a regulatory body?

A

A regulatory body will place down expectations of you.
The general idea is that scientists or nurses or physiotherapists are a body or group, and professions are regulated, and those regulators generally come out with a set of views, of what they think a member of profession ought to be, and how they ought to behave.
Most professions have a set of principles and virtues, that they are expected to uphold.
Professional guidance usually comes from a professional body: general medical council, general healthcare council or from institutes, eg institute of biomedical sciences.

86
Q

what are reference ranges

A

So reference ranges only apply to continuous, quantitative data on a scale, where one interval change has meaning, because it has units. It follows a symmetrical, capital and normal distribution.
It doesn’t apply to all data, percentages, proportions, rates, categories of grades of a disease, or immune standard deviation. Grade of 1-10 is not continuous: a grade has an interval, but going on a grading scale from 1 to 2 isn’t the same as 2 to 3, so it is not on an accurate scale.