Clinical Trials And Drug Deveolpment Flashcards
Steps to drug approval
1) animal testing
2) IND application
3) phase 1
- consists of 20-80 people
- emphasis on total safety of the drug And the ADRs of a drug
4) phase 2
- consists of 100s of patients
- emphasis on total effectiveness and comparing it to usually a placebo
5) phase 3
- consists of 1000s of patients
- emphasis on safety and effectiveness Again and finding therapeutic doseages
6) review meeting
7) NDA application
8 and 9) application reviewed (60 days)
10) drug labeling
11) facility inspection
12) drug is approved
What is phase 4
Occurs after approval of the drug.
Constitution of monitoring safety issues after drugs are on the market (used to detect serious ADRs that were not able to be detected in phase 2/3)
Randomized controlled trials
Special class of clinical trials
Subjects are randomly allocated to a group of either a placebo or actual treatment
Similar to phase 2 except eliminates selection bias and is better at making the research more ethical
Types of dose trials
Dose- escalation
- increasing dose from small to large to try and find the maximum tolerated dose
Dose-finding
- titrates dose up or down to find optimum dose based on pre-set criteria
Dose-ranging
- compares set of pre-specified dose groups
How many successful pivotal studies are required to be approved before the FDA says there is a clear and positive benefit/risk ratio?
2
Specifics of phase 1
Dose usually begins at a dose that is believed to be safe (10x lower than in animal models)
Enroll small group of subjects who receive the same dose
Enroll another group and give them a slightly higher dose
This is continued until one group starts to experience serious ADRs (this is the maximum tolerated dose)
- these often are used to test life-threatening diseases*
Details of phase 2 studies
Usually studies 2 doses of a drug to determine the best dose to use in phase 3
Used to approve a drug being evaluated for a new patient population
Details of phase 3 studying
Generally studies a single dose vs the control dose
this is usually the most expensive phase
Generally requires dozens of hundreds of enrolling sites to do properly
These are also adaptive trials and have the highest rates of shutting down if efficacy is not shown or harm is present
Details of phase 4 studies
Post-marketing studies which focus to learn more about an already approved and marketed drug
- are often called post-marketing surveillance studies*
- used to verify safety, tolerability and effectiveness of a market drug
- also used to determine ADRs that couldn’t be determined from phase 1 studies due to low population size
45 CFR 46
Common rule
Requires that research involving human subjects is to be reviewed and approved by a review committee as long as it is funded or regulated by the federal government
IRB is tasked to protecting the rights and welfare of the human research subjects
Design configuration parallel
Each subject is randomized to one of the treatments
Subjects are randomized to each treatment groups and receive identical care
Design configuration crossover
Each subject is randomized to a sequence of treatments
Each subject in each specific treatment receives all treatments, but in different order
Introduces possibility of carryover effect
Design configuration: factorial design
A subtype of parallel design in which each subject is randomized to a combination of two or more concurrent treatments
Multicenter trials
Centers that are used for enrollment of large trials
Take out an additional variable of bias or patient population being different.
Parametric and non parametric tests for each clinical trial design
Single dose group, EOS measurements
1) parametric test = 1-sample t-test
2) nonparametric test = wilcoxon signed rank
Single dose group, baseline and EOS measurements
1) parametric test = paired t-test
2) nonparametric test = wilcoxon signed rank
Two dose groups
1) parametric test = 2-sample t-test
2) nonparametric = wilcoxon rank sum
More than two dose groups
1) parametric test = ANOVA
2) nonparametric test = Kruskal-Wallis
