L11: Clinical trials part 2

Question 1

phase 2

Answer 1

Phase 2 study: general principles
* Short and small-size trials compared to Phase 3

• Endpoints:
  Traditionally: tumor response (complete response, partial response, stable disease or progressive disease) - Binary for objective tumour response (ORR)
  Progression-free survival (PFS) at a fixed point in time
  Toxicity (e.g. grade 3 toxicities over treatment period)
  And time-to-event endpoint (PFS, overall survival OS)
  Combining activity and toxicity

Question 2

one or two-stage designs?

Answer 2

One or two-stage designs
Two-stage allow early stopping if insufficient activity

Single arm or randomized
Choosing primary endpoints for phase 2 studies

appropriate primary endpoint: —-> response —-> monotherapy (single arm), combination (randomised design)

PFS: randomised or single arm

phase 2 is either single arm or randomised. randomised can be non or comparative. comparative: either ‘selection’ pick the winner, randomised discontinuation, randomised phase 2 —> open level or blinded

non c—> reference arm
So in phase 2 you can do just a new drug n tis own and just see what the response rate it but its difficult to compare because e.g: if drug did better than chemo, but since every patient is different you cannot directly say this drug is better than chemo. Whereas if you do a randomised trial you can compare them. But you need more patients, more mone,y mote time.

Question 3

phase 3 trial

Answer 3

• confirmatory trial to investigate the comparative effectiveness of a new treatment as compared to standard of care, in some cases, placebo or best supportive care, investigator choice.
  controlled, randomised, multicentre
  large effort/investment: must have decent signal
  for drugs: may lead to marketing approval
  if positive, should be practice changing.

Question 4

randomised controlled CT

Answer 4

Controlled clinical trial= a clinical study that includes. the comparison (control) group recieves a placebo, another treatment, or no treatment ar all.
randomised ct= a study in which the participants are assigned by chance to separate groups that compare different treatments, neither the researchers nor participants can choose which grop, using chance to assign people to groups means that groups will be similar and that the treatments they recieve can be compared objectively. at the time of the trial it is not known which treatment is best. it is the patient;s choice to be in a randomised trial.

why randomise? to ensure that the two groups of patients are comparable in terms of both known and unknown prognostic factors (on average a large number of patients). to be able to attribute differences in effects to the differences in treatment.

Question 5

randomised double blind placebo controlled trial

Answer 5

Single-blind vs double-blind
Single blind: when the patient is ‘blind to’ or doesn’t know which treatment he/she is assigned
Double blind: when the patient and the investigator are both ‘blind to’ or do not know which treatment the patient is assigned to

Placebo
It is a treatment which is specifically designed to have no real effect
The purpose of the placebo group is to account for the placebo effect, that is, effects from treatment that do not depend on the assigned interventional treatment itself
Placebo effects could result from knowing one is receiving a treatment, attention from health care professionals, and the expectations of a treatment’s effectiveness etc, e.g. pain could improve due to placebo effect
Without a placebo group to compare against, it may not be possible to know whether the interventional treatment itself had any effect in certain situation e.g. pain or depression scores could improve with placebo effect
Placebo needs to be packaged/mimicked/given in the same way as the interventional treatment to avoid the patients and/or investigators from guessing which treatment arm the patients are assigned to
For example, the same coloured pills (as the interventional treatment) that contain only sugar with no active drugs or a medical device that is not actually turned on

Randomized double-blind place controlled trial
The “Gold Standard” in intervention based studies but may not be practical as it increases the complexicity and the costs of the trials significantly

Question 6

stratification/minimisation

Answer 6

• randomisation ensures a comparable distribution of known and unknown prognostic factors on average over a large number of patients.
  in a trial of limited sample size, there is no garuntee that there would not be imbalances in important prognostic factors (like center or stage or WHO PS), just by (lack of) chance
  resulting in severe bias
  —> stratificarion or minimisation can be used to enforce the balance of the groups for known important prognostic factors
  method: to use a separate randomisation list for each (combination of) level (s) of stratification factor(s). problem: when there are many stratification factors, the number of lists becomes large, with few patients in each and the overall imbalance in treatment may be large.

Question 7

minimisation

Answer 7

the minimisation technique is an algorithm that balances treatments over several prognostic factors. it requires central randomisation. unlike the tratified randomisation, the minimisation balances the treatments over each stratification factor separtely (and not for each combination of the prognostic factors). it minimises the overall imbalance between the treatments. many variations exist.

Question 8

endpoints

Answer 8

‘the primary outcome measure in definitive trials should be a clinical event relevant to the patient’
or an endpoint that measures directly how a patient feels, functions or survives.
‘functions’ refers to the activities of daily living (not e.g organ function).
endpoint considerations: reliability of observation (similar questions as for assays).

Overall survival (OS) is a direct and true clinical efficacy measure and has been the gold standard endpoint for
randomized phase 3 trial (other endpoints such as PFS and DFS are indirect surrogate measures)

Progression-free survival (PFS) is a surrogate endpoint widely used for overall survival (OS) in oncology

In the UK, a clinically and statistically significant improvement in overall survival compared to existing therapy is
often required for approval of a new drug use in the NHS

Question 9

phase 4 trials

Answer 9

Post market surveillance

Conducted after the drug is aproved and marketed/available

The main objective of the phase 4 trial is to check the drug’s performance in real life scenarios:

• to study the long-term risks and benefits of using the drug

and to discover any rare side effects

and to see the difference in real life compared to the strict criteria applied in clinical trial

Question 10

window of opportunity (woO) trials

Answer 10

Window of opportunity studies are trials in which patients receive one or more new compounds between their cancer diagnosis and standard treatment (mainly surgery)
Patients usually haven’t received any cancer treatment before the trial
Tumor biopsies before and after the investigational treatment are collected for translational research, usually pharmacodynamics markers, e.g. changes in proliferation marker ki67 before and after treatments
Functional pre- and post-treatment imaging may be incorporated into the study (e.g. PET-CT)
The investigational treatment is kept short to avoid delaying standard treatment (e.g. 7 to 10 days of treatment before surgery)
Window of opportunity trials may expedite drug development, improve our understanding of pharmacodynamic parameters, and help to identify biomarkers for better patient selection
However, they have major drawbacks including potential safety and logistical issues, delayed standard treatment, and a probable lack of patient benefit.