Clinical Studies Flashcards
A ___ is a systematic process that is intended to find out the safety and efficacy of a drug/device in treating/preventing/diagnosing a disease or a medical condition.
Clinical trial
It involves the study of the effect of an investigational drug/any other intervention in a defined population/participant.
Clinical Trial
The new FDA guidelines includes five (5) phases of clinical trials:
Phase 0 (micro-dosing studies)
Phase 1
Phase 2
Phase 3
Phase 4
Phase 0 and phase 2
Exploratory Trial Phases
Phase 1
Non-Therapeutic Phase
Phase 3
Therapeutic Confirmatory Phase
Phase 4
Post-Approval or Post-Marketing Surveillance Phase
Study participants are randomly assigned to a group.
Randomized trial
Both study subjects and the researchers are aware of the drug being tested.
Open-label
In this study, the subject has no idea about the group (test/control) in which they are placed.
Blinded (single-blind)
In this study, the subjects as well as the investigator have no idea about the test/control group
Double-blind
A substance that appears like a drug but has no active moiety.
Placebo
An additional drug apart from the clinical trial drug given to a group of study participants
Add-on
A study being carried out at a particular place/location/center
Single center
A study is being carried out at multiple places/location/carriers
Multi-center
Clinical trials are broadly classified into ___ and ___ .
controlled and uncontrolled trials
The ___ are potentially biased, and the results of such research are not considered as equally as the controlled studies.
Uncontrolled trials
___ are considered the most effective clinical trials wherein the bias is minimized, and the results are considered reliable.
Randomized controlled trials (RCTs)
Randomizations in Clinical Trials (7)
- Simple randomization
- Block randomization
- Stratified randomization
- Co-variate adaptive randomization/minimization
- Randomized by body halves or paired organs (Split body trials)
- Clustered randomization
- Allocation by randomized consent (Zelen trials)
The participants are assigned to a case or a control group based on flipping coin results/computer assignment
Simple randomization
Equal and small groups of both cases and controls
Block randomization
Randomization based on the age of the participant and other covariates
Stratified randomization
Sequential assignment of a new participant into a group based on the covariates
Co-variate adaptive randomization/minimization
One intervention is administered to one-half of the body and the comparator intervention is assigned to another half of the body
Randomization by body halves or paired organs (Split body trials)
Intervention is administered to clusters/groups by randomization to prevent contamination and either active or comparator intervention is administered for each group
Clustered randomization
Patient are allocated to one of the two trial arms
Allocation by randomized consent (Zelen trials)
Clinical research design has two major types that include ___ and
___ .
non-interventional/observational and interventional/experimental studies
The non-interventional studies may have a comparator group (analytical studies like case-control and cohort studies), or without it (descriptive study). The experimental studies may be either randomized or non-randomized.
non-interventional studies
Clinical trial designs are of several types including (7)
- parallel design,
- crossover design,
- factorial design,
- randomized withdrawal approach,
- adaptive design,
- superiority design, and
- non-inferiority design
Types of Trial Designs (5)
Randomized Study:
- Parallel
- Crossover
- Randomized withdrawal approach
Non-randomized Study:
- Factorial
Post-Approval Study:
- Matched pairs
NATURE OF TRIAL STUDY
This is the most frequent design wherein each arm of the study group is allocated a particular treatment (placebo: an inert substance/therapeutic drug).
Parallel
NATURE OF TRIAL STUDY
The patient in this trial gets each drug and the patients serve as a control themselves.
Crossover
NATURE OF TRIAL STUDY
Two or more interventions on the participants and the study can provide information on the interactions.
Factorial
NATURE OF TRIAL STUDY
This study evaluates the time/duration of the drug therapy.
Randomized withdrawal approach
NATURE OF TRIAL STUDY
Recruit patients with the same characteristics.
Matched pairs
DIS/ADVANTAGES OF TRIAL DESIGNS
The placebo arm does not receive the trial drug, so may not get the benefit of it.
Parallel
DIS/ADVANTAGES OF TRIAL DESIGNS
Avoids participant bias in treatment and requires a small sample size. This design is not suitable for research on acute diseases.
Crossover
DIS/ADVANTAGES OF TRIAL DESIGNS
The study is complex.
Factorial
DIS/ADVANTAGES OF TRIAL DESIGNS
The study uses a placebo to understand the efficacy of a drug in treating the disease.
Randomized withdrawal approach
DIS/ADVANTAGES OF TRIAL DESIGNS
Less variability.
Matched pairs
PRINCIPLES OF CLINICAL TRIALS
___ is the most frequently performed clinical research. This type of research is undertaken to analyze the presence or absence of a disease/condition, potential risk factors, and prevalence and incidence rates in a defined population.
Observational research using a cross-sectional study design
PRINCIPLES OF CLINICAL TRIALS
Clinical trials may be ___ type depending on the type of intervention
therapeutic or non-therapeutic
The ___ of clinical trial uses a drug that may be beneficial to the patient. Whereas in a ___ , the participant does not benefit from the drug.
therapeutic type;
non-therapeutic clinical trial
The ___ provide additional knowledge of the drug for future improvements.
non-therapeutic trials
PREPARING A CLINICAL TRIAL
The clinical trial process involves ___ , ___ , and ___ . It also includes data management and the monitoring of clinical trial site activities.
protocol development;
designing a case record/report form (CRF);
functioning of institutional review boards (IRBs)
PREPARING A CLINICAL TRIAL
The ___ is the most significant document in a clinical study. It contains the information collected by the investigator
about each subject participating in a clinical study/trial.
Case Record/Report Form (CRF)
PREPARING A CLINICAL TRIAL
The clinical study is conducted by a ___ or ___ .
Sponsor or a Clinical Research Organization (CRO)
PREPARING A CLINICAL TRIAL
A ___ , ___ , and ___ assume significance while planning a clinical trial. What, when, how, and who are planned ___ the initiation of a study trial.
perfect protocol;
time limits;
regulatory requirements;
before
PREPARING A CLINICAL TRIAL
The two most important points to consider before the initiation of the clinical trial include ___ , if there is a need, then ___ .
- whether there is a need for a clinical trial;
- one must make sure that the study design and methodology are strong for the results to be reliable to the people
CLINICAL TRIAL PHASES
Examines too low (1/100th) concentrations (micro-dosing) of the drug for less time. Study the
pharmacokinetics and determine the dose for phase I studies.
Phase 0 (Safety Assessment)
CLINICAL TRIAL PHASES
Phase 0 (Safety Assessments) studies the ___ and determine the ___ for phase I studies.
pharmacokinetics; dose
CLINICAL TRIAL PHASES
Around <50 healthy subjects are recruited.
Phase 1
CLINICAL TRIAL PHASES
Establishes a ___ ,
and the ___ . Examines the
___ and ___ .
safe dose range and maximum tolerated dose;
pharmacokinetic and pharmacodynamic effects
CLINICAL TRIAL PHASES
Phase 1 are usually ___ studies.
single-center
CLINICAL TRIAL PHASES
Phase 1a
Single ascending dose (SAD) and Maximum tolerated dose (MTD)
CLINICAL TRIAL PHASES
Phase 1a
Duration of ___ to ___ depending on the trial and includes ___ groups of ___ participants.
one week to several months;
6-8 groups of 3-6 participants
CLINICAL TRIAL PHASES
Phase 1b ___ and the dose is gradually ___.
Multiple ascending doses (MAD);
narrowed down
CLINICAL TRIAL PHASES
Phase 1b consists of ___ groups with ___ individuals each.
3 groups of 8 individuals each.
CLINICAL TRIAL PHASES
Recruiting around 5-100 patients of either sex.
Phase 2
CLINICAL TRIAL PHASES
Examines the ___ and the
___ on patients. It decides
the therapeutic regimen and drug-drug interactions.
effective dosage and the therapeutic effects
CLINICAL TRIAL PHASES
Phase 2 are usually ___ studies.
Multicenter
CLINICAL TRIAL PHASES
Decides the drug dosage, includes 20-30 patients, and takes up to weeks/months.
Phase 2a
CLINICAL TRIAL PHASES
Studies dose response relationship, drug-drug interactions, and comparison with a placebo.
Phase 2b
CLINICAL TRIAL PHASES
More than 300 patients (up to 3000) of either sex are recruited in this study and are multicentric trials.
Phase 3
CLINICAL TRIAL PHASES
___ examines the efficacy and the safety of the drug. Comparison of the test drug with the placebo/standard drug.
Premarketing phase
CLINICAL TRIAL PHASES
Adverse drug reactions/adverse
events are noted. Initiate the process of NDA with appropriate regulatory agencies like the FDA.
Phase 3
CLINICAL TRIAL PHASES
Adverse drug reactions/adverse
events are noted. Initiate the process of NDA with appropriate regulatory agencies like the FDA.
Phase 4
CLINICAL TRIAL PHASES
MTD
SAD
MAD
Maximum Tolerated Dose;
Single Ascending Doses;
Multiple Ascending Doses
PHASE 1 CLINICAL TRIALS
Phase I trials typically start with a very low dose of the investigational product and gradually increase the dose in a controlled manner.
Dose Escalation
PHASE 1 CLINICAL TRIALS
Participants are closely monitored for any adverse events or side effects, and the dose is adjusted accordingly.
Safety Monitoring
PHASE 1 CLINICAL TRIALS
The trial aims to identify the ___ , which is the highest dose that can be safely administered without causing unacceptable side effects
Maximum Tolerated Dose (MTD)
PHASE 2 CLINICAL TRIALS
Determine if the drug shows promising results in treating the target condition.
Efficacy Evaluation
PHASE 2 CLINICAL TRIALS
Monitor and assess potential side effects and risks associated with the treatment.
Safety Profile
PHASE 2 CLINICAL TRIALS
Identify the optimal dosage that balances effectiveness and safety for patients.
Dose Optimization
STUDY DESIGN AND METHODOLOGY
Create a detailed plan outlining study procedures, endpoints, and statistical methods.
Protocol Development
STUDY DESIGN AND METHODOLOGY
Assign participants to treatment groups to minimize bias and ensure statistical validity.
Randomization
STUDY DESIGN AND METHODOLOGY
Implement single or double blinding to prevent bias in data collection and analysis.
Blinding
PATIENT POPULATION AND RECRUITMENT
Specific disease characteristics, age range, and health status for eligibility.
Inclusion Criteria
PATIENT POPULATION AND RECRUITMENT
Conditions or factors that could interfere with the study or patient safety
Exclusion Criteria
PATIENT POPULATION AND RECRUITMENT
Outreach through healthcare
providers, patient advocacy groups, and targeted advertising
Recruitment Strategies
EFFICACY ENDPOINTS AND ASSESSMENTS
Main outcome measure, such as tumor size reduction or symptom improvement.
Primary Endpoint
EFFICACY ENDPOINTS AND ASSESSMENTS
Additional measures to support primary endpoint and gather more data.
Secondary Endpoints
EFFICACY ENDPOINTS AND ASSESSMENTS
Biological indicators used to
track treatment response and
disease progression.
Biomarkers
EFFICACY ENDPOINTS AND ASSESSMENTS
Patient-reported outcomes to assess overall well-being and treatment impact.
Quality of Life
SAFETY MONITORING AND DATA COLLECTION
Systematic documentation of any
unexpected medical occurrences during the trial.
Adverse Event Reporting
SAFETY MONITORING AND DATA COLLECTION
Regular checks of blood pressure, heart rate, and other essential health indicators.
Vital Signs Monitoring
SAFETY MONITORING AND DATA COLLECTION
Periodic blood work and other diagnostic tests to assess organ function.
Laboratory Tests
PHASE 3 CLINICAL TRIALS
Involves hundreds to thousands of patients across multiple centers.
Large-Scale Testing
PHASE 3 CLINICAL TRIALS
Often compares new treatment to current standard of care or placebo.
Comparative Studies
PHASE 3 CLINICAL TRIALS
Monitors for side effects and evaluates long-term efficacy.
Long-Term Effects
PHASE 3 CLINICAL TRIALS
Monitors for side effects and
evaluates long-term efficacy.
Regulatory Submission
Phase 3 Trial Design and Enrollment (4)
- Protocol Development
- Patient Recruitment
- Randomization
- Treatment Administration
PHASE 3 TRIAL DESIGN AND ENROLLMENT
Detailed plan outlining trial objectives, design, and methods
Protocol Development
PHASE 3 TRIAL DESIGN AND ENROLLMENT
Rigorous screening process to ensure eligible participants.
Patient Recruitment
PHASE 3 TRIAL DESIGN AND ENROLLMENT
Patients randomly assigned to treatment or control groups.
Randomization
PHASE 3 TRIAL DESIGN AND ENROLLMENT
Strict adherence to protocol for dosing and follow-up.
Treatment Administration
Regulatory Approval Process for Phase 3: (4)
- Pre-NDA Meeting
- NDA Submission
- FDA Review
- Advisory Committee
REGULATORY APPROVAL PROCESS FOR PHASE 3
Discussion with regulatory agency about submission requirements
Pre-NDA Meeting
REGULATORY APPROVAL PROCESS FOR PHASE 3
Comprehensive application including all clinical and non-clinical data.
NDA Submission
REGULATORY APPROVAL PROCESS FOR PHASE 3
Thorough evaluation of submitted data by expert panels.
FDA Review
REGULATORY APPROVAL PROCESS FOR PHASE 3
Public meeting to discuss benefits and risks of the new treatment.
Advisory Committee
All clinical trials conducted worldwide are posted in this website:
https://clinicaltrials.gov/
Among the most significant aspects of a clinical trial is the ___ . An ** is a systematic process of evaluating the clinical trial operations at the site. The ** ensures that the clinical trial process is conducted according to the protocol, and predefined quality system procedures, following GCP guidelines, and according to the requirements of
regulatory authorities.
Audit
The ___ are supposed to be independent and work without the involvement of the sponsors, CROs, or personnel at the trial site. The summary report of the observations of the inspectors is performed using various forms.
Auditors
FDA Audit Inspection Forms (Number) [4]
- 483
- 482
- 1571
- 1572
FDA AUDIT INSPECTION FORMS
List of objectionable conditions/processes prepared by the FDA investigator and submitted to the auditee at the end of the inspection
483
FDA AUDIT INSPECTION FORMS
The auditors submit their identity proofs and notice of inspections to the clinical investigators and later document their observations
482
FDA AUDIT INSPECTION FORMS
This document details the fact that the clinical trial is not initiated before 30 days of submitting the IND to the FDA for approval. The form confirms that the IRB complies with 21 CFR Part 56. The form details the agreement to follow regulatory requirements and names all the individuals who monitor the conduct and progress of the study and evaluate the safety of the clinical trial.
1571
FDA AUDIT INSPECTION FORMS
This form details the fact that the study is conducted after ethics approval ensures that the study is carried out according to protocol, informed consent, and IRB approval.
1572
The NDA Submission and Review Timeline: (3)
- NDA Submission
- FDA Review
- FDA Approval
THE NDA SUBMISSION AND REVIEW TIMELINE
The completed NDA is filed with the FDA for review.
NDA Submission
THE NDA SUBMISSION AND REVIEW TIMELINE
The FDA has 10 months to review the NDA and make a decision.
FDA Review
THE NDA SUBMISSION AND REVIEW TIMELINE
If approved, the drug can be marketed and sold in the United
States
FDA Approval
PHASE 4 CLINICAL TRIALS
Continuous tracking of adverse events in real-world settings.
Safety Monitoring
PHASE 4 CLINICAL TRIALS
Additional research to confirm
long-term benefits and risks
Efficacy Studies
PHASE 4 CLINICAL TRIALS
Assessing treatment effects in
diverse patient groups.
Population Impact
PHASE 4 CLINICAL TRIALS
Evaluating economic impacts of the new treatment.
Cost-Effectiveness
KEY DIFFERENCES BETWEEN IND AND NDA
Focus
Safety and feasibility of new drug
candidates.
IND
KEY DIFFERENCES BETWEEN IND AND NDA
Focus
Comprehensive evaluation of
efficacy and safety.
NDA
KEY DIFFERENCES BETWEEN IND AND NDA
Timing
Preclinical to early clinical trials.
IND
KEY DIFFERENCES BETWEEN IND AND NDA
Timing
Late-stage clinical trials and
manufacturing data.
NDA
KEY DIFFERENCES BETWEEN IND AND NDA
Review Process
30-day FDA review.
IND
KEY DIFFERENCES BETWEEN IND AND NDA
Review Process
10-month comprehensive FDA
review.
NDA
STRATEGIES FOR SUCCESSFUL NDA SUBMISSION
Maintain open dialogue with the FDA throughout the NDA process.
Effective Communication
STRATEGIES FOR SUCCESSFUL NDA SUBMISSION
Ensure comprehensive and well organized clinical trial data in the NDA.
Robust Data
STRATEGIES FOR SUCCESSFUL NDA SUBMISSION
Develop a detailed timeline and strategy for NDA preparation and submission.
Meticulous Planning
STRATEGIES FOR SUCCESSFUL NDA SUBMISSION
Adhere strictly to all FDA guidelines and regulations throughout the process.
Regulatory Compliance
“I get to be a part of the advancement of science and healthcare. I love getting to learn something new every day!”
Madison Smith (Clinical Research Coordinator Artemis Institute for Clinical Research)
