L11: Clinical trials Flashcards
what are clinical trials?
Clinical trials are studies conducted with patients
* Generally designed to confirm the safety and effectiveness of a new promising treatment
* Also evaluate and optimize different therapeutic approaches including surgery, radiation therapy and combinations of approved drugs + other targets e.g. QoL, better diagnostic tests
target of a clinical trial?
treatment: improve treatment (superiority)decrease morbidity/side effects (non-inferiority)
screening: test the best way to detect certain diseases or health conditions w(when the disease is not suspected)
diagnostic: find better tests of procedures to aid in the diagnosis of a certain suspected disease or condition
quality of life: explore ways to improve comfort and thee quality of life
patients and clinical trials
Patients
Self interest: Trial as a ‘last chance’ treatment, getting access to a treatment that would not otherwise be available.
Community: A way of ‘giving something back’, while hoping that some benefit will come to them personally – and without too much risk from unpleasant side-effects.
Clinical trialists
Understand disease and treatments
Improve patient care
Gather data and samples for further developments (diagnostic
tests, biomarkers …)
→ Investigator(s): Surgeon, medical and clinical oncologists, physicians
Involvement from others: Radiologists, Pathologists, Pharmacologists, Translational research scientists, Statisticians, Data managers, Trial coordinators…
declaration of helsinki?
declaration of Helsinki
It is an international standard for the conduct of clinical research adopted by International Conference on Harmonization (ICH) Good Clinical Practice standards
It was developed originally in 1964 for the medical community by the World Medical association (WMA), which was established in 1947 to handle the growing concern of unethical medical practice which became more apparent during and after World War II
It is regarded as the cornerstone document on human research ethics
Prior to 1947 Nuremberg Code, there was no accepted code of conduct governing the ethical aspect of human research
It has undergon six modifications
GCP is now the standard
basic principles:
1/ to conform to accepted scientific principles
2. design formulated in experimental protocol and reviewed by IEC
3. CONDUCTED BY QUALIFIED AND TRAINS PERSONS
4.improtance in proportion to inherent risk
5. assessment of risks vs benefits
6. safeguard subject’s integrity (privacy)
7. abstain unless hazards are predictable
8. preserve accuracy when publishing
9. aqequaltley inform right to withdraw
10. obtain true informed consent in writing
11/ reliance on legal guardian
12. state compliance wit declaration
steps in clinical development program?
tests in lab (and animals)
phase 0, phase 1 (20-80), phase 2 (100-300): exploratory trials ‘trials to learn’
phase 3 (1000-3000)
FDA APPROVAL
THEN phase 4 (1000+) confirmatory trials
from objectives to sample size
objectives can be primary or secondary leading to primary or secondary endpoints. Primary endpoint is our primary objective which is the most important as you need to calculate sample size based on your primary endpoint so you need to define it. so this allows you to design and sample size.
primary; prespecified outcome that directly addresses the hypothesis of the trial. the basis of trial designs, including patient enrollment
key secondary endpoints are examined if the primary endpoint is prove. sample size may or may not be sufficient to reach statistical significance. interpret with caution. statistical results are not typically presented. When a trial has failed it has not met primary endpoint and not shown statistically significant. So its important to pre-sepecifiedd hypothesis, have the primary endpoint and calculate sample size.
post hoc analysis—> tertiary endpoint and exploratory endpoints
phase 0 trials?
Phase 0 study helps to speed up and streamline the drug approval process:
find out if the drugs do what they are expected to do
use only a few small doses of a new drug in a few people + for a short time
Test whether the drug reaches the tumour, how the drug acts in the human body, and how cancer cells in the human body respond to the drug
Might need extra tests such as biopsies, and blood samples to confirm the effects of drugs
Don’t usually benefit patients since drug doses are low but also minimal risk
Not a required part of testing a new drug
phase 1 trials?
Phase 1 trial : typically where a new drug is entering a human for testing.
Phase I studies are done to find the highest dose of the new treatment that can be given safely without causing severe side effects
Primary endpoints: Maximum tolerated dose (MTD) and/or recommended phase 2 dose (R2PD)
Needs to define dose-limiting toxicities (DLT), e.g. excess toxicities compared to standard
Define a critera. For example if a drug gave patuents nausea, vomitting result, life threatening complication th\t is not acceptible: your DLT
Various designs including:
3+3 (classic) (3 patient + 3 patient. Given low dose to 3 patients to see if they react, not effect, if patients do not have dlt move onto next dose, give to 3 more patients) tthere are variations within 3 +3 the atd is basically variable within patients The crm is same but is a continuous model. Sometimes when you do 3 patients and move on they suddently have side effect. So idea for crm is that it is continulosuly motiered, s soon as you have a dlt you feedback to the model so readjusting it?
ATD: accelerated titration design
CRM – continuous reassessment model
3+3, ATD and CRM
3+3: three patient cohort enrolled for starting dose level
if 0/3 DLTs, proceed to next dose
if 1/3 DLTs expand 3 additional patients
if 2/3 DLTs in initial or 2/6 DLTs in expanded cohort, MAD reached. go back down dose level for MTD
PROS: straightforward to conceptualise and implement. - limited statistical support needed
cons: conservative dose escalation, potential for any patients to be treated at subtherapeutic doses
ATD: Single patient cohorts with dose escalation if no moderate toxicity or aDLTs encountered. once moderate toxicity encourted switch to 3+3 design
PROS: rapid dose escalation in the initial phase with conservative strategy with toxicity encountete d
consL lacks granularity to explore narrow therapeutic index drugs
CRM: initial dose toxicity curve specified (skeleton)
patient toxicity data updates the curve shape
next dose picked based on updated model
PROS: Aggressive dose escalation/ allows skipping of dose levels/ all patients contribute to dose-toxicity model
consL needs intensive biostatistical support
phase1
Phase 1 trials: other therapeutic intent
Although the primary endpoint for Phase I studies are to find the maximum tolerated dose (MTD) or recommended phase 2 dose (R2PD), the secondary endpoint could include therapeutic endpoints:
survival. response rates, safety, biomarkers, dosing
