Clinical Studies Flashcards by ANGELO KEANE CABIGON

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

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It involves the study of the effect of an investigational drug/any other intervention in a defined population/participant.

Clinical Trial

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The new FDA guidelines includes five (5) phases of clinical trials:

Phase 0 (micro-dosing studies)
Phase 1
Phase 2
Phase 3
Phase 4

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Phase 0 and phase 2

Exploratory Trial Phases

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Phase 1

Non-Therapeutic Phase

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Phase 3

Therapeutic Confirmatory Phase

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Phase 4

Post-Approval or Post-Marketing Surveillance Phase

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Study participants are randomly assigned to a group.

Randomized trial

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Both study subjects and the researchers are aware of the drug being tested.

Open-label

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In this study, the subject has no idea about the group (test/control) in which they are placed.

Blinded (single-blind)

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In this study, the subjects as well as the investigator have no idea about the test/control group

Double-blind

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A substance that appears like a drug but has no active moiety.

Placebo

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An additional drug apart from the clinical trial drug given to a group of study participants

Add-on

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A study being carried out at a particular place/location/center

Single center

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A study is being carried out at multiple places/location/carriers

Multi-center

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Clinical trials are broadly classified into ___ and ___ .

controlled and uncontrolled trials

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The ___ are potentially biased, and the results of such research are not considered as equally as the controlled studies.

Uncontrolled trials

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___ are considered the most effective clinical trials wherein the bias is minimized, and the results are considered reliable.

Randomized controlled trials (RCTs)

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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)

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The participants are assigned to a case or a control group based on flipping coin results/computer assignment

Simple randomization

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Equal and small groups of both cases and controls

Block randomization

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Randomization based on the age of the participant and other covariates

Stratified randomization

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Sequential assignment of a new participant into a group based on the covariates

Co-variate adaptive randomization/minimization

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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)

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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)