PHC 502 Midterm Dr Wen lecture Clinical Study Design & Biomarkers + Ch 6

What is a randomized control trial (RCT)?

A prospective longitudinal study in which patients are randomly assigned to treatment groups

Why would you run a randomized controlled trial?

• Produce comparable groups

• Distribution of groups should be unbiased with respect to prognosis and responsiveness to treatment

• Treatment is not determined by the investigators, the clinicians, or the participants

• The measured/unmeasured and known/unknown prognostic factors + other characteristics of the participants at the time of randomization will be (on avg) evenly distributed/balanced

Why is blinding done in clinical trials? Describe the types of blinding

To eliminate bias

1. Single blind

   • Only the researcher doing the study knows which treatment or intervention the participant is receiving until the trial is over

2. Double blind

   • Neither participants nor researchers know which treatment/intervention participants are receiving until the clinical trial is over

3. Triple blind

   • The study participants, the researchers, and the data analysts do not know which group received treatment

Describe the study design for randomized controlled trials (RCT)

List advantages of RCT

• Efficient for investigating causality

  • “cause” precedes the “effect”

• Possible confounding factors are balanced

• Randomization facilitates simple statistical analysis

• Practical way to minimize several sources of bias

  • Selection bias

Disadvantages of RCT

• Can be long and/or expensive

• Requires rigorous control of the allocation/group distribution process

• Not ideal for rare conditions or problems with a long latency

• Generalizability

• Volunteer issues

Define the term biomarker

• A laboratory measurement that reflects the activity of a disease process and directly relates to clinical outcomes

• A characteristic that is objectively measured and evaluated as an indicator of normal biologic or pathogenic processes, or pharmacological responses to a therapeutic intervention

List examples of biomarkers

• Blood pressure

• Cholesterol

• Fasting glucose

• Total lipids & lipid fractions

• CD4 count

• Tumor size

• RNA viral load

• Positron Emission Tomography (PET)

• Magnetic resonance imaging (MRI)

What is a prognostic biomarker? Give an example

A biomarker used to identify the likelihood of a clinical event, disease recurrence, or progression in patients who have the disease/medical condition of interest

Ex: PSA level, PIK3CA mutation status

What is a predictive biomarker?

A biomarker that is a pre-treatment measurement used to characterize the patient’s disease in order to determine whether the patient is a good candidate for a treatment

Is this biomarker predictive, prognostic, or both? Explain

prognostic

• Biomarker + have a better survival rate than biomarker - regardless of treatment

Not predictive because the treatment effect is the same for biomarker - and biomarker +

Is this biomarker predictive, prognostic, or both? Explain

Predictive

• Only a treatment effect for biomarker +, no treatment effect for biomarker -

  • Treatment effect quality differs between groups

Not prognostic because the untreated biomarker + have the same survival rate as untreated biomarker -

Is this biomarker predictive, prognostic, or both? Explain

Both prognostic and predictive

• Predictive

  • Treatment effect is different for biomarker + and - groups

• Prognostic

  • Biomarker + patients have improved survival compared with biomarker - patients, independent of treatment group

What are some reasons why biomarkers may be used in clinical trials?

• Replace a distal endpoint with a proximal one

  • Can be measured earlier

  • Can be measured more easily or frequently

  • Can be measured with higher precision, or less subject to competing risks

• May be less affected by other treatment modalities

• Reduced sample size requirements

• Possibility of faster decision making

How can the use of biomarkers increase ROI?

• Quantitative correlation with disease progression

• Use of biomarkers in early phases of drug development can be used to obtain info early or to choose study cohort

• Can reduce the time and expense of drug development

How can biomarkers be used in clinical practice?

• Can be diagnostic, prognostic, predictive, or companion

• Can be used to screen for diseases in the general population

• Can be used to screen for diseases in the at risk population

• Can diagnose symptomatic patients

• Can be used to divide patient populations to prescribe drug treatment

• Can be used to determine drug efficacy

• Can be used to determine drug side effects and toxicity

What clinical study designs use biomarkers?

• Biomarker stratified designs

• Targeted (enrichment) designs

• Biomarker-strategy designs

Describe biomarker-stratified clinical trial designs

• Treatment options are given at random regardless of biomarker status

• Analysis plan is centered on testing the dependence of treatment effect on biomarker status

Describe targeted (enrichment) clinical trial designs

• Treatment eligibility is restricted to patients considered “most likely” to benefit from the experimental drug

Describe biomarker-strategy clinical trial designs

• Patients are randomly assigned to an experimental treatment that uses the biomarker to determine if they get the treatment

What is the fast track program intended for?

To facilitate the development and expedite the review of new drugs that are

• intended to treat serious or life-threatening conditions

• demonstrate the potential to address unmet medical conditions

Define a surrogate endpoint

A laboratory or physical sign that is used in therapeutic trials as a substitute for a clinically meaningful endpoint that is a direct measure of how a patient feels, functions, or survives and that is expected to predict the effect of the therapy

• Can be used to assess the benefit of/harm from a therapeutic agent

List:

• Surrogate endpoints

• The disease it’s indicated for

• Clinical endpoints

1. Disease: Hypertension

   • Surrogate endpoints/biomarkers: Blood pressure

   • Clinical endpoints: Stroke

2. Disease: Dyslipidemia

   • Surrogate endpoints/biomarkers: Cholesterol, LDL

   • Clinical endpoints: Coronary artery disease

3. Disease: Diabetes

   1. Surrogate endpoints/biomarkers: Glycosylated hemoglobin (HbA1c)

   2. Clinical endpoints: Retinopathy, nephropathy, neuropathy, heart disease

4. Disease: Glaucoma

   1. Surrogate endpoints/biomarkers: Intraocular pressure

   2. Clinical endpoints: Loss of vision

5. Disease: Cancer

   1. Surrogate endpoints/biomarkers: Tumor shrinkage, response rate

   2. Clinical endpoints: Progression-free survival, overall survival

What classifies a biomarker as a surrogate endpoint?

• If it is expected to predict clinical benefit/harm/lack of benefit or harm based on epidemiologic, therapeutic, pathophysiologic, or other scientific evidence

  • A correlate of the true clinical outcome

  • Treatment effect on the surrogate should capture the full effect of treatment on the clinical endpoint

List advantages of using surrogate endpoints in clinical trials

• Efficient and improved design of trials

• Improved understanding of drug effects

  • Subgroup differences

  • Dose and dose interval

  • Effects over time

  • Withdrawal

  • Pharmacodynamic effects

• Efficacy in new settings (e.g. pediatric)

• Support for results of clinical trials

List disadvantages of using surrogate endpoints in clinical trials

• Not a true clinical outcome

• Lack of long term stability

• Evaluation of biomarkers as surrogate endpoints could be challenging

How many phases of clinical trials are there? Describe each

There are four phases

1. Phase I

   • Safety study

   • Open labeled

   • 20-80 subjects

2. Phase II

   • Safety and efficacy studies

   • Randomized and double-blinded

   • 50-500 subjects

3. Phase II

   • Continued safety and efficacy studies

   • Randomized and double-blinded

   • 100s-1000s of subjects, multisite

4. Phase IV

   • Post marketing approval to monitor drug safety and efficacy at large

What are the “seven ethical requirements” in clinical research

Requirements that must be considered to minimize potential exploitation of human subjects

• Social value

• Scientific validity

• Fair subject selection

• Informed consent

• Favorable risk-benefit ratio

• Independent review

• Respect for human subjects

Describe the social value requirement within the seven ethical requirements

Ensures that the clinical trial is justified on the basis of scientific research and will result in improvements in health or advancement of scientific knowledge

• Resources aren’t directed at nonmeaningful clinical research

• Human subjects are not being exploited

Describe the scientific validity requirement within the seven ethical requirements

• The clinical trial should be conducted methodically with clear objectives and outcomes that are statistically verifiable

• Trial should not be biased

• Trial should be able to be executed without unreasonable caveats and conditions

Describe the fair subject selection requirement within the seven ethical requirements

• Based on scientific objectives

  • Not on:

    • Privilege

    • Vulnerability

    • Connivence

• Inclusion and exclusion criteria must be designed to satisfy scientific basis

• Must be documented evidence to support the choice of selection criteria

Describe the informed consent requirement within the seven ethical requirements

• Subjects must be informed about the aims, methods, risks, and benefits of the trial

• Availability of alternatives should be explained to the subjects

• Subjects should not be pressured into enrolling into the trial

  • Voluntary enrollment

  • Can exit at any time without duress or penalty

• For young/incapacitated people. proxy decisions must be obtained

Describe the favorable risk-benefit ratio requirement within the seven ethical requirements

• Whenever possible subjects should be exposed to minimal risk and maximal benefit

• Risk-benefit ratio should be based on proven scientific data at preclinical stage

• Clinical trial should not be conducted if there is doubt about the risk-benefit ratio

Describe the independent review requirement within the seven ethical requirements

• A third party assesses the clinical trial to avoid conflict of interest

• Oversee the welfare of subjects and to ensure that the trial is conducted in accordance w the study being put forward

Describe the respect for human subjects requirement within the seven ethical requirements

• Subjects should be protected

• New developments in the trial (risks or benefits) must be relayed to the subjects without prejudice

  • Subject’s decisions should be honored

• Trial outcomes must be communicated to subjects promptly and without bias

What is an adaptive clinical trial? (FDA definition)

A study that includes a prospectively planned opportunity for modification of one or more specified aspects of the study design and hypotheses based on analysis of data (usually interim data) from subjects in the study

According to FDA guidelines, an adaptive clinical trial can involve what?

• Interim evaluations to stop or to adjust patient accrual

• Interim evaluations to assess stopping the trial for early success, futility, or harm

• Reversing the hypothesis of noninferiority to superiority or vice versa

• Dropping a certain study group(s) or doses, or adjusting doses

• Modification of the randomization rate to increase the probability that a patient is allocated to the most appropriate group(s)

What is a meta analysis

A statistical approach that analyzes the combined results from multiple independent clinical studies

What are the advantages of meta-analysis

Can provide

• Generalization of results to a larger population

• Improvement to accuracy of results

• Quantification to inconsistences of results