L3b- Clinical Trials Phases And Ethics

Question 1

What are the main objectives of clinical trials for new drugs (although can be for diagnostics aswell)

Answer 1

Determine safety and efficacy in patients

Determine if this drug is more effective than current treatments based on side effects and outcome/impact

Question 2

What do the in vivo preclinical studies eg on mouse models give info on which is better than the in vitro clonogenic assay techniques

Answer 2

Show the impact on 3d model on disease progression/inhibition eg does it reduce tumour size or cause cytotoxicity

Also gives info on dosing and potential toxicities prior to phase 1

Question 3

What sort of considerations when designing trial make it good/ likely to answer the hypothesis

Answer 3

Appropriate:
patient number, controls, measure of impact - eg overall survival , statistical power

Question 4

Why is the ageing population likely directing the design of clinical trials

Answer 4

Diseases such as az becoming more prominent with lack of current treatment

Question 5

How can the control arm differ between types of clinical trials

Answer 5

Likely that in many they will be given a placebo or no treatment if they do not have a serious condition

In for example cancer trials this is not ethical so given the current treatment instead for comparison

Question 6

Which two principles in clinical trials removes bias that impacts outcome

Answer 6

Randomisation
And
Blindness

Question 7

Example: patients with later stage disease have been put into control groups more than early. Early stage have been put on the new treatment. How is this an issue without randomisation

Answer 7

No idea whether the longer survival of the patients is because they were early stage or if the drug had worked/had an impact.
Disease stage in this case is a confounding factor!

Question 8

What 3 types of blinding is there

Answer 8

Single (patient only)
Double - patient and doctor
Triple - researcher too

Question 9

Why would single blindness potentially still have bias in terms of reported side effects (no blindness means more reporting of toxicities in experimental group?)

Answer 9

Could potentially have monitored the placebo group much less which is biased

Question 10

What are the major objectives of phase 1

Answer 10

Determine safety in humans/ toxicities

Determine dose MTD (max tolerated dose)

Determine best route of admin

Pk and Pd insights

Question 11

What is the population in phase 1 usually

Answer 11

Small group of healthy patients

Question 12

When does this differ

Answer 12

In cancer trials they use patients in which no drug has worked. Because chemo drugs are too toxic for healthy

Question 13

Explain the 3+3 dose escalation model to determine MTD from observing dose-limiting toxicities (DLT) aka ADR

Answer 13

3 patients are enrolled into a starting dose
If non have dlt then go onto next
If 2+ have dlt then means the dose below is the mtd
If 1 has a dlt then you enroll 3 more into same dose
If none of the new 3 have dlt go onto next dose
If 2/6 have dlt then the dose below is the MTD

Question 14

What sort of measures can be done eg if testing hypertensive drug to predict efficacy

Answer 14

Blood pressure measurement

Question 15

What do monitoring blood drug levels give insight to

Answer 15

Pharmacokinetics (ADME)- what the body does to the drug

More Pk tests done like eliminate rate, distribution etc

Question 16

What sort of pharmacodynamic tests can be done (drug effect on body)

Answer 16

Any toxicities?

Measure the target inhibition eg enzyme activity - is it working on correct target?

Question 17

What is often the only difference between 1 and phase 2 particularly for cancer trials

Answer 17

Larger group of usually 40-100

For cancer trials by this point you narrow it down to only 1 cancer type group which differs to phase 1 with multiple

Question 18

How large is the sample usually in phase 3

Answer 18

200+

Question 19

What is the trial called in phase 3 which now compares this drug to current treatment

Answer 19

Superiority trial

Question 20

What is phase 4

Answer 20

After fda approval and marketing

Monitor long term side effects and also identify any potential drug resistance

Question 21

When interpreting data, what is it called when you weigh out side effects with efficacy in the superiority trial

Answer 21

Risk benefit ratio

Question 22

7 ethical considerations

Question 23

1. Collaborative partnership

Answer 23

Ensures the clinical research is in the interest of the communities health problems and they would benefit

Also ensures communities can be involved in planning and conducting or overseeing the clinical research

Question 24

2. Social value

Answer 24

Research must lead to improving health or knowledge to
Ppts, the community and worldwide

Question 25

3. Scientific validity

Answer 25

Research must be conducted in which a conclusion can be drawn- reliable and valid data Need to ensure target validation/ preclinical studies show some target and efficacy No non-representative studies, studies with bias, lack of instruments or statistical power , studies with low participation

Question 26

4. Fair subject selection

Answer 26

Ppts should not be enrolled due to privilege eg from upper class/westernised and white countries or are readily available Ie cannot exclude based on non scientific reason Should be selected based on the purpose of the study, generalisability can be enhanced later

Question 27

5. Favourable benefit risk ratio

Answer 27

Must evaluate likelihood and magnitude of harm Should have mechanisms to reduce risks including additional diagnostic tests If benefits outweigh then go forward with research

Question 28

6. Independent review

Answer 28

Because of researchers conflict of interest, an independent review panel with ethics committee must be involved in design to reduce bias and minimises these conflicts

Question 29

7. Informed consent

Answer 29

Provide info leaflet which is reviewed by the research ethics committee Has info on: Who can and cannot take part The treatment What will happen Potential risks and benefits Funding and researcher info

Question 30

Why is competence an issue of consent also understanding/ comprehension by subject , give another example

Answer 30

Some participants are not able to sign agreement if they have difficulties or are children Have guardian sign it Ppts may not comprehend or understand which needs to be considered Also some info may not be disclosed to the participant

Question 31

Where are research ethic committees often based (overlook design with the independent review panel)

Answer 31

Local hospitals formed by local health professionals, lawyers and patients or members of public

Question 32

What does the MHRA do

Answer 32

Needs to approve all clinical trials that happen for medicines