Understanding Phase 2B Clinical Trials

Presented By

Salman Istiak Sabbir

PHA-16021
Presentation Outline
Introduction to clinical trials
Purpose of phase 2b trials
Study design
Patient population
Outcome Measurement
Results
Challenges and limitations
Conclusion
 Introduction to Clinical trials

• Clinical trials are vital research studies that evaluate the safety and efficacy of medical interventions,
including drugs, treatments, and devices. They provide essential data to determine whether a new
intervention is effective and safe for widespread use.
 Purpose of Phase 2b Trials
• Phase 2 trials also known as therapeutic exploratory trials conducted in 100 to 300 patients approximately.
• One of the main goals of phase 2 trials is to determine an appropriate dose and treatment regimen that can be
tested in phase 3 trials. Dose response studies may therefore be carried out and confirmed in the phase 2 trial.
• Phase 2 trials are sometimes further divided into:
Phase 2a
Phase 2
Phase 2b
Phase 2a Phase 2b

• Phase 2a trials mainly all about proof of concept
studies with Maximal tolerated dose (MTD) or a
little bit lower dose.
• Two treatment groups, one group with test drug
and other group with placebo.
• Phase 2b all about dose ranging or dose response
studies with selected doses.
• Dose ranging studies starts here.
• Dose response studies conducted in this phase.

• If no promising effect observed in this trial, • Different methods used to select the test doses
further trials will be stopped. like equal dose phasing or log dose spacing or
using Fibonacci series or by other approaches etc.
 Study Design
• In Phase 2B trials, the study design is carefully crafted to gather reliable and meaningful data on the safety,
efficacy, and optimal use of the investigational product. Here's an overview of the study design elements
typically used in Phase 2B trials:

Randomization Crossover Design

Blinding Data Collection and

Analysis

Control Group
Ethical Considerations

Treatment Arms
 Patient population
• Phase 2B clinical trials, the patient population is carefully selected to ensure that participants meet specific
criteria and are representative of the target population for the investigational product. There are some
exclusion and inclusion criteria of patient population:
• Inclusion criteria are characteristics or conditions that prospective participants must possess to be eligible for
enrollment in the study.
• Exclusion criteria are characteristics or conditions that disqualify prospective participants from enrollment in
the study.

Inclusion criteria
Exclusion criteria
• Age
• Diagnosis • Concomitant Medications
• Disease Severity • Medical Conditions
• Previous Treatment History • Allergies or Sensitivities
• Demographic Factors • Pregnancy or Lactation
• Medical History • Participation in Other Clinical Trials
• Laboratory Values • Psychiatric or Cognitive Impairment
• Substance Abuse
- Inclusion criteria ensure that participants are
representative of the target patient population and - Exclusion criteria help ensure participant safety, minimize
are likely to benefit from the investigational confounding factors, and maintain the integrity of study results.
product.
 Outcome Measurement

• In Phase 2B clinical trials, a variety of primary and secondary outcome measures are used to assess the
efficacy, safety, and other endpoints of the investigational product.

Clinical Endpoints:
Primary Outcome Measures: • Disease Remission
• Efficiency Endpoints • Symptom improvement
• Disease progression
• Safety Endpoints • Treatment response
Secondary outcome measures: Biomarkers
• Inflammatory markers
• Additional Efficiency Endpoints • biomerkers panel
• Additional Safety Endpoints • genetic markers
• imaging biomarkers
• Other Endpoints
Patient-Reported Outcomes (PROs)
• Quality of life
• pain intensity
• functional status
• treatment satisfaction
 Results

• Key findings from Phase 2B trials provide critical insights into the efficacy, safety profiles, and dose-response
relationships of investigational products.
• Some graphs, tables, and charts can effectively illustrate key results from Phase 2B trials:
• Dose response curve
• safety profile table
• Kaplan-Meier survival plot

Treatment Adverse Treatment Severity

Events (AE) Related
Adverse
Events
(TRAE)
Dose A 10(5%) 5(2.5%) Mild
Dose B 15(7.5%) 8(4%) Moderate
Placebo 5(2.5%) - -
 Challenges and Limitations
• Phase 2B clinical trials play a crucial role in the drug development process, but they are not without
challenges and limitations. Here are some common challenges and limitations associated with Phase 2B
trials:
• Despite these challenges and limitations, Phase 2B trials remain a critical stage in the drug development
process, providing valuable insights into the safety, efficacy, and optimal dosing of investigational products.
By addressing these challenges proactively and leveraging innovative approaches, researchers can overcome
obstacles and advance the development of new treatments for patients in need.

Sample Size and Outcome measures Interpretations and

Patient Recruitment and endpoints generalizability of events

Heterogeneity of Safety monitoring Regulatory and

patient population and adverse events ethical considerations

Dose selection and Placebo effect and

regimen optimisation blinding
 Conclusions

• Phase 2B trials are pivotal in drug development, offering insights into

efficacy, safety, and dose optimization.
• They validate treatment effectiveness, assess safety profiles, and
establish optimal dose ranges.
• Findings guide decisions for Phase 3 trials, ensuring efficient
progression of promising therapies.
• Crucially, Phase 2B trials strike a balance between risks and benefits,
shaping the trajectory of drug development and eventual patient
care.
 Introduction to Clinical trials

• Clinical trials are vital research studies conducted to assess the safety and
effectiveness of new medical treatments, such as drugs, therapies, or medical
devices.
• While a phase 1 trial may recruit healthy volunteers for determining the maximum
doses and dose ranges that should be administered, phase 2 is more focused on the
therapeutic efficacy in a particular patient population to establish whether or not
the drug may ultimately benefit patients and should be studied in a phase 3 trial.
 Purpose of Phase 2B Trials

***
• Phase 2a trails are critical and most important trials in clinical development of a new drug.
Because important decisions taken here for proceeding the further drug development. Proof of
concept (PoC) studies done here. No efficacy data is not available in humans till this trails. Most
of the drugs, efficacy wise perform well in animals and in non-clinical models but fail to show
efficacy in the humans. So Phase 2a trials are critical. Usually Proof of concept studies conducted
with two treatment groups, one group with test drug other group with placebo. First of all new
drug is tested with a dose of Maximal tolerated dose (MTD) or a dose a bit lower than the MTD.
The selected dose in this phase is as high as possible up to MTD, because to know the best
possible efficacy. If the drug showing promising efficacy in humans with target disease, based on
this proven concept, further trials will be conducted. If no promising effect observed in this trial,
sponsor may stop the investments and man force for this drug tested drug. Further trials will be
stopped.
 Purpose of Phase 2B Trials

Phase 2b trials: Based on proven efficacy from the early phase 2 trials, phase 2b trials conducted. Dose ranging
studies starts here. Now they know the efficacy of a new drug at high dose but they do not the efficacy of other doses
that are lower than the actual effect produced dose. So dose response studies conducted in this phase. Now the question
is, which doses should be selected as test doses other than actual effect produced dose (MTD). Different methods used
to select the test doses like equal dose phasing or log dose spacing or using Fibonacci series or by other suggested
approaches etc. For example effect produced high dose in phase 2a trial is 900mg. By using equal dose spacing
method, calculated medium and low dose will be 600 mg and 300 mg respectively. If we use log dose spacing for high
dose 900 mg we will get medium and low dose as 600 mg and 100 mg respectively. In groups new drug doses tested
with placebo group. Along with these methods some other approaches are also used.

****Equal dose spacing and log dose spacing are two different methods used in various fields, especially in experimental design, pharmacology, and statistics, to
determine the intervals between doses or levels of a variable.
1. Equal Dose Spacing: In this method, doses or levels are spaced equally apart from each other. For example, if you have a range of doses from 1 mg to 10 mg, and
you want to space them equally, you might administer them at intervals of 1 mg (e.g., 1 mg, 2 mg, 3 mg, ..., 10 mg). This method is straightforward and easy to
implement, but it may not be the most efficient way to explore a dose-response relationship, especially if the doses are very large or very small.
2. Log Dose Spacing: In this method, doses or levels are spaced apart logarithmically. This means that each successive dose is a multiple of the previous one by a
constant factor. For example, if you have a range of doses from 1 mg to 1000 mg and you want to space them logarithmically, you might use a logarithmic base of
10, resulting in doses of 1 mg, 10 mg, 100 mg, and 1000 mg. This method is often used when exploring dose-response relationships because it covers a wide range
of doses efficiently, allowing researchers to identify thresholds or saturation points more effectively.
 Study Design

1. *Randomization:*
- Randomization is a fundamental aspect of Phase 2B trials that involves assigning participants to different treatment groups randomly. This
helps ensure that each group is similar in terms of baseline characteristics, minimizing bias and allowing for more robust comparisons between
treatment arms.
- Randomization may be stratified based on factors such as disease severity, age, or previous treatment history to ensure balanced
representation across treatment groups.

2. *Blinding:*
- Blinding, also known as masking, involves withholding information about the assigned treatment from participants, investigators, and/or
outcome assessors. Blinding helps minimize bias and ensures the integrity of the study results.
- In Phase 2B trials, blinding may be single-blind (participants are unaware of their assigned treatment), double-blind (both participants and
investigators are unaware), or even triple-blind (including outcome assessors).

3. *Control Groups:*
- Phase 2B trials often include one or more control groups to provide a basis for comparison against the investigational treatment. Control
groups may receive a placebo (inactive treatment) or standard-of-care treatment.
- Placebo-controlled trials are commonly used in Phase 2B trials to assess the specific effects of the investigational product compared to no
treatment or placebo.
- Active-controlled trials compare the investigational product to an existing treatment to demonstrate superiority, non-inferiority, or equivalence.
 Study Design
4. *Treatment Arms:*
- Phase 2B trials may include multiple treatment arms to evaluate different doses, dosing regimens, or formulations of the
investigational product.
- Each treatment arm receives a specific intervention, and participants are randomized to these arms to compare outcomes
across different treatment groups.

5. *Crossover Design (Optional):*

- In some Phase 2B trials, a crossover design may be used, where participants receive multiple treatments in a sequential order.
This design helps minimize inter-subject variability and may increase statistical power.

6. *Data Collection and Analysis:* - Data collection in Phase 2B trials is conducted according to a pre-defined protocol, with
rigorous monitoring and quality control measures in place. Statistical analysis is used to analyze the collected data, comparing
treatment groups and assessing safety and efficacy outcomes. Results are interpreted in the context of the trial's objectives and
endpoints.

7. *Ethical Considerations:* - Phase 2B trials adhere to ethical principles outlined in international guidelines and regulatory
requirements. These principles include obtaining informed consent from participants, ensuring participant safety, and maintaining
confidentiality of participant data.
Patient population

• Common inclusion criteria may include:

• - Age: Specific age range or age groups targeted by the study.
• - Diagnosis: Patients diagnosed with the target disease or condition being studied.
• - Disease Severity: Severity level of the disease or specific disease stage.
• - Previous Treatment History: Treatment-naïve patients or those who have failed previous therapies.
• - Demographic Factors: Gender, ethnicity, and other demographic characteristics relevant to the study
objectives.
• - Medical History: Absence of certain medical conditions or presence of specific comorbidities.
• - Laboratory Values: Normal range or specific laboratory values required for enrollment.
• - Inclusion criteria ensure that participants are representative of the target patient population and are likely
to benefit from the investigational product.
Outcome measurements
• Primary Outcome Measures:
• 1. **Efficacy Endpoints:**
• - Clinical Response: Improvement in symptoms or disease severity based on predefined criteria or clinical
assessments.
• - Disease Progression: Slowing or halting the progression of the disease compared to baseline measurements.
• - Biomarker Response: Changes in biomarker levels indicative of treatment efficacy or disease activity.
• - Treatment Success: Achievement of predefined treatment goals or milestones.
• 2. **Safety Endpoints:**
• - Adverse Events: Incidence and severity of adverse events associated with the investigational product.
• - Safety Profile: Assessment of safety parameters, including laboratory tests, vital signs, and physical
examinations.
• - Tolerability: Participant’s ability to tolerate the treatment without significant discomfort or adverse reactions.
Outcome measurements
• Secondary Outcome Measures:**
• 1. **Additional Efficacy Endpoints:**
• - Symptom Relief: Reduction in specific symptoms or disease-related complaints.
• - Quality of Life: Improvement in overall quality of life as assessed by validated questionnaires or scales.
• - Functional Status: Enhancement of functional abilities or performance in daily activities.
• - Disease Remission: Achievement of disease remission or resolution based on objective criteria.
• 2. **Additional Safety Endpoints:**
• - Long-Term Safety: Evaluation of safety over an extended treatment duration or follow-up period.
• - Serious Adverse Events: Incidence and severity of serious adverse events requiring medical intervention or hospitalization.
• - Withdrawal Due to Adverse Events: Participant withdrawal from the study due to intolerable side effects or safety concerns.
• 3. **Other Endpoints:**
• - Pharmacokinetic Parameters: Assessment of drug absorption, distribution, metabolism, and excretion.
• - Pharmacodynamic Effects: Evaluation of drug effects on target biomarkers or physiological processes.
• - Health Economics Outcomes: Cost-effectiveness analysis or economic impact assessments associated with treatment.
Outcome measurements
• Clinical Endpoints:
• 1. Disease Remission:
• - Complete resolution of disease symptoms or activity, often assessed using standardized criteria or scoring
systems.
• 2. Symptom Improvement:
• - Reduction in specific disease symptoms or severity, such as pain intensity, fatigue, or inflammation.
• 3. **Disease Progression:**
• - Slowing or halting the progression of the disease compared to baseline measurements, assessed through
clinical assessments or imaging studies.
• 4. **Treatment Response:**
• - Positive response to treatment based on predefined criteria, such as improvement in disease activity
scores or reduction in lesion size.
Outcome measurements
Biomarkers:
1. Inflammatory Markers:
- Levels of inflammatory markers such as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), or pro-
inflammatory cytokines.
2. Biomarker Panels:
- Combination of biomarkers associated with disease activity, treatment response, or prognosis, assessed using
multiplex assays or profiling techniques.
3. Genetic Markers:
- Genetic variants or mutations associated with disease susceptibility, progression, or response to treatment,
identified through genetic testing or sequencing.
4. **Imaging Biomarkers:
- Quantitative measures derived from imaging modalities such as MRI, CT scans, or PET scans, indicating
changes in disease status or treatment response.
Outcome measurements
• Patient-Reported Outcomes (PROs):
• 1. Quality of Life (QoL):
• - Assessment of overall quality of life, including physical, emotional, and social well-being, using validated
questionnaires or scales such as the SF-36 or EQ-5D.
• 2. **Pain Intensity:
• - Patient-reported assessment of pain severity or intensity using visual analog scales (VAS) or numerical rating scales
(NRS).
• 3. **Functional Status:**
• - Measurement of functional abilities or limitations related to daily activities, mobility, or performance using
standardized instruments like the Health Assessment Questionnaire (HAQ) or the Karnofsky Performance Status Scale.
• 4. **Treatment Satisfaction:**
• - Patient-reported satisfaction with treatment efficacy, tolerability, convenience, or side effects, assessed through
structured surveys or interviews.
•
 Results

• some graphs, tables, and charts can effectively illustrate key results from Phase 2B trials:
• 1. **Dose-Response Curve:
• 2. Safety profile table
• 3. Kaplan survival plot**
• - A dose-response curve visually depicts the relationship between different doses of the investigational product and
the corresponding efficacy outcomes or adverse events. The curve can be plotted using a line graph, with doses on
the x-axis and efficacy or safety measures on the y-axis.
• 2. **Safety Profile Table:**
• - A safety profile table summarizes the incidence and severity of adverse events (AEs) and treatment-related
adverse events (TRAEs) observed in each treatment group. The table provides a concise overview of safety findings,
including the frequency of specific AEs and their relationship to the investigational product.
• 3. **Kaplan-Meier Survival Plot:**
• - A Kaplan-Meier survival plot illustrates the probability of survival or time-to-event outcomes over the study
duration for different treatment groups. This plot can be used to compare survival curves between treatment arms
and assess differences in efficacy endpoints such as progression-free survival or overall survival.
Challenges and limitations
• 1. **Sample Size and Patient Recruitment:** - Recruiting a sufficient number of participants for Phase
2B trials can be challenging, especially if the target patient population is limited or the eligibility criteria
are strict. Delays in patient recruitment can prolong the trial timeline and increase costs.
• 2. **Heterogeneity of Patient Population:** - Phase 2B trials often enroll a diverse patient population,
which can lead to heterogeneity in treatment responses. Variability in patient characteristics, disease
severity, and previous treatment history may affect the interpretation of study results and complicate
data analysis.
• 3. **Dose Selection and Regimen Optimization:** - Identifying the optimal dose range and dosing
regimen for the investigational product is a key objective of Phase 2B trials. However, determining the
right balance between efficacy and safety can be challenging, and dose-response relationships may not
always be linear.
• 4. Outcome Measures and Endpoints:** - Selecting appropriate outcome measures and endpoints to
assess the safety and efficacy of the investigational product can be challenging. Choosing clinically
relevant endpoints that capture meaningful treatment effects while minimizing bias and variability is
essential but may require trade-offs.
Challenges and limitations

• 5. **Placebo Effect and Blinding:** - Placebo-controlled trials are commonly used in Phase 2B trials to assess
the specific effects of the investigational product. However, placebo effects can influence patient-reported
outcomes and subjective endpoints, potentially confounding study results. Maintaining blinding and minimizing
bias are critical but may be challenging in practice.
• 6. **Safety Monitoring and Adverse Events:** - Phase 2B trials involve monitoring participant safety and
assessing adverse events associated with the investigational product. Detecting rare or unexpected adverse
events requires robust safety monitoring protocols and may necessitate post-marketing surveillance to fully
evaluate safety risks.
• 7. **Interpretation and Generalizability of Results:** - Interpreting study results from Phase 2B trials requires
careful consideration of study design, patient population characteristics, and statistical analysis methods.
Extrapolating findings to broader patient populations or real-world settings may be limited by the specific
context of the trial.
• 8. **Regulatory and Ethical Considerations:** - Phase 2B trials are subject to regulatory requirements and
ethical considerations governing the conduct of clinical research. Compliance with regulatory standards,
obtaining informed consent from participants, and addressing ethical concerns are essential but may pose
logistical challenges.