DH308: NIRMAL PUNJABI

DH 308 – Class 3
11th January 2023

Clinical Data
Management
- Nirmal Punjabi, Ph.D.

Welcome to the course. We will start at 11:05 am.

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Today’s Agenda (Class 3)

• Revisit Class 2 Class 3:
• Clinical Trials • Background
• Types • Clinical Trials
• Observative • Phases
• Prospective • Terminology
• Retrospective • Examples
• Intervention / Experimental
• Why?
• Phases
• Phase 0 • Clinical Data
• Phase 1 • Sources
• Types

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Clinical Trials
Background: Phases, Types, ….

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Clinical Trials
• Research involving human subjects.
• “A prospectively planned experiment for the purpose of evaluating
potentially beneficial therapies or treatments”

• Any research:
• that prospectively assigns participants/groups (humans),
• to one or more health related interventions,
• to evaluate the effect on health outcomes.

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Clinical Trials (…)

• Types
• Observative
• Prospective
• Retrospective

• Intervention
• New treatment/medicine/
• New medical device

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Clinical Trials
• Controlled Conditions • Controlled Conditions
• Participants • Site / Location
• Environmental
• Age Group
conditions
• Sex
• Ethnicity
• Types:
• Present Health Status • Single Site
• Diet • Multi-Site
• Medical History • Hospitals
• Regional
• State
• Country

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Clinical Trials
• Controlled Conditions
• Intervention /Therapy
• Investigational Drug

• Control
• Gold standard / Conventional
• Placebo
• No active drug
• Non-interacting substance

11-01-2023 Image Reference: Volkmann et al, 2020. https://doi.org/10.1371/journal.pone.0241497; 7

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Types of Clinical Study Designs

1. Observational Designs

2. Experimental Designs – interventional studies

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Types of Clinical Study Designs

1. Observational Designs
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Types of Observational Studies

• Cohort Studies
• A group of subjects followed over time
• Purpose: Defining the incidence and investigating potential causes of a
condition

• Can be prospective – investigator chooses a sample group and measures

characteristics in each subject over a period of time that might predict
outcomes
• Can be retrospective – same as prospective, except all data collection and
follow-up has happened in the past; only possible if adequate data is available
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Types of Observational Studies

E – Exposure
O – Outcome

Past (xxxx – 2023) Today (2023) Future (2023 – xxxx)

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Types of Observational Studies

• Cross-Sectional Studies
• Similar to cohort studies
• Exception: All the measurements are made at one time point with no follow-up

• Purpose: describing variables and their distribution patterns (prevalence)

• Strength – fast and inexpensive since there is no follow-up or waiting time for
outcome
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Types of Observational Studies

• Case-Control Studies
• Two groups of people examined for the same outcome
• Group 1 – “cases” or a population of people with a certain disease
• Group 2 – “controls” or a population of people without that same disease

• Purpose: compare prevalence of risk factor(s) in subjects with the disease

(cases) versus subjects without the disease (controls)
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Types of Study Designs

1. Experimental Designs
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Experimental Studies
• These studies evaluate the effects of an intervention
• Types of interventions:
• Behavior modification (Eg.: A walking program to improve weight loss)
• Drug (Eg.: A new investigational drug or studying a drug for off-label use)
• Device (Eg.: A new investigational stent)

• Strength/Benefits: Can demonstrate causality and provides better

control on biases.
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Phases of Experimental Studies / Clinical Trials

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Phases of Experimental Studies / Clinical Trials

• Phase – 0 / Early phase - 1
• First testing on human.
• Purpose: To check for any serious effects on limited healthy participants and
to get the drug metabolism and pathway in the body.

• Limited number of healthy subjects (n < 15).

• Exposure to low & non‐toxic doses of the drug for a limited duration (≤ 7 days)
• Provide human PK/PD data.
• Pharmacokinetic : Absorption, Distribution, Metabolism, and excretion
• Pharmacodynamic: Biological processes respond to impacted by drug
• No therapeutic benefit to the participants.
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Phases of Experimental Studies / Clinical Trials

• Phase – 1
• “First in human” studies of a drug /regimen.
• Few patients/participants required (n<30).
• Primary aim is to assess the drug safety/toxicity.
• Along with biological and pharmacological effects.
• Usually conducted in health patients

• Outcome measures:
• Dose limiting toxicity (DLT)
• Minimum acceptable dose for generating response
• Maximum tolerated dose (MTD)
• Maximum allowable dose with manageable side-effects.
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Phases of Experimental Studies / Clinical Trials

• Phase – 1
• Dosage selection
• Based on data from pre-clinical animal experiments.
• Tested on atleast two mammalian species.
• Starting dose is 1/3rd or 1/6th of the lowest toxic dose.
• Subsequent dose : Fibonacci sequence, logarithmic scale.

• Phase 1A: Single ascending dose trials (Common)

• Phase 1B: Multiple ascending dose trials
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Phases of Experimental Studies / Clinical Trials

• Phase – 2
• To look at efficacy of drugs on the participants
• Usually done in comparison with a control group

• Single-arm
• The baseline or historical data acts as control.
• ‘Before’ v/s ‘after’

• Multi-arm / Controlled
• Comparison with Gold-standard treatment and/or placebo
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Phases of Experimental Studies / Clinical Trials

• Phase – 3
• To look at efficacy of drugs on the participants in a large and diverse group.
• More participants
• In-combination with other drugs
• Different dosages
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Phases of Experimental Studies / Clinical Trials

• Phase – 4
• To look at long-term efficacy and safety after approval.
• Post-market monitoring
• Failure to meet the safety criteria:
• Can lead to recall of drugs approval / medical devices / implants
• Examples:
• Rofecoxib drug: Non-steroidal anti-inflammatory drug (NSAID)
• Approved in US in May 1999
• Treat Osteoarthritis, Rhuematoid arthritis, Migraine, Dysmenorrhea
• Recall in September 2004
• Increases risk of Heart Attack and Stroke (~1,00,000 cases)
• J&J Acetabular Hip Implant
• Launched in 2004
• Recalled in August 2010 due to implant failure
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Terminologies in Clinical Trials

• Randomized • Open Trial / Open - label
• All eligible participants are randomly
allocated • Opposite to Blinding
• Non-Randomized • Especially seen in Cancer/fatal
• Decided by researcher disease treatment

• Blinding / Masking
• Hiding the information about the • Controlled
intervention to avoid bias • Some other intervention acting as
• Single-blind control
• The participants
• Gold-standard
• Double blind
• Participants and Researchers • Placebo
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Terminologies in Clinical Trials

• Single Center Trial • Study Group / Treatment Group /
• Single Site Arm
• The group getting intervention /
active treatment
• Multi Center Trial
• Multi-site
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Phases of Experimental Studies / Clinical Trials

Phase 1 Phase 2 Phase 3 Phase 4
No. of 15-30 <100 100 to Several
Participants thousands hundreds to
several
thousands

Purpose First in Determine Compare Post –market

humans efficacy new agent Long-term
Find safe with safety and
dose standard efficacy
treatment
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Phases of Experimental Studies / Clinical Trials

• Phase I:
Unblinded studies of a small number of healthy volunteers to test safety of
treatment (can sometimes use people with the disease)
• Phase II:
Randomized studies of relatively small number of people with the disease to test
dose ranges and/or efficacy of treatment
• Phase III:
Randomized studies of large number of people with the disease to test efficacy of
treatment on pre-selected outcomes
• Phase IV:
Large experimental studies or observational studies conducted after treatment has
been approved by the FDA to assess performance of treatment (called Post-Market
Studies)
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Phases of Experimental Studies / Clinical Trials

Overall theme of various phases

Efficacy Safety Efficacy Long-Term

& Safety Safety &
Efficacy
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Clinical Data
Types, Information, Source

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Clinical Data Types/Sources

Basic
Parameters

Other
Clinical
Pathology
medical
instruments
Data Tests

Source

Medical
Imaging

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Clinical Data Types/Sources

• High Density Data

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Image Reference: www.brainkart.com; www.liftl.com