stt520-420: biostatistics analysis dr. cuixian chen chapter 02: introduction to clinical trails...

STT520-420: BIOSTATISTICS ANALYSIS

Dr. Cuixian Chen

Chapter 02: Introduction to Clinical Trails

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Overview

Basic Terminology in Clinical Trials Features of Clinical Trials

ProtocolEthics Protection of Participants Phases of a Study

Randomized Experiment Designs Statistical Analysis in Clinical Trials

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TERMS AND DEFINITIONS IN CLINICAL TRIALS


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General Abbreviations FDA – Food and Drug Administration IRB – Institutional Review Board IND – Investigational New Drug NDA - New drug application AE – Adverse Event SAE – Serious Adverse Events GCP – Good Clinical Practice CTA – Clinical Trial Agreement MTD - Maximum Tolerated Dose DLT - Dose Limiting Toxicity ICH - International Conference on Harmonization SOP - Standard Operating Procedures SE – Side Effect STT520-420

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Control Group

Two groups in an experiment: treatment group and control group.

One group is given the experimental drug or treatment (the experimental group) while the control group is given either standard care and/or a placebo.

The standard by which experimental observations are evaluated

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Placebo

When referring to medicines, placebo is a preparation which is pharmacologically inert but which may have a therapeutically effect based solely on the power of suggestion

It may be administered in any of the ways in which pharmaceutical products are administered An inactive pill, liquid or powder that has

no treatment value The control group will receive the placebo

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Placebo Effects “Inert” substitute for a treatment or intervention “Inert” means the compound has no known activity that

would be expected to affect the outcome In actuality, a placebo effect is a psychosomatic effect

brought about by relief of fears, anxiety or stress because of study participation.

It's not just the little white pill that brings about the effect; it's the additional attention and the belief that your condition might be being treated with a superior new treatment.

All outcomes affected by psychosomatics are prone to placebo effects.

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Blinding, also called masking

If the outcome can conceivably be affected by patient or investigator expectations, then blinding is important.

Helps to protect against bias Reduces the placebo effect psychological benefit Open versus Blinded Clinical Trials

Open Label clinical trials The doctor and patient know which drug or

vaccine is being administered

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Types of Blinding

Single Blinded – the subject does not know if (s)he is in the control (placebo) or the experimental group (drug)

Double Blinded – both the subject and the Principle Investigator (PI) do not know which group the subject is in

Triple Blinded – the subject, the PI and the sponsor do not know to which group the subject is assigned. The statistician can only be partially blinded since he/she has to know which patients are in the same treatment group.

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Blinding Examples

Subject John is enrolled in a trial testing a new drug for cancer. He does not know if he is receiving a placebo or the actual drug. The PI, however, knows that John is receiving the actual drug.

Subject Tom is enrolled in a trial testing a new drug for diabetes prevention. He does not know if he is receiving a placebo or the actual drug. The PI also does not know if Tom is receiving the actual drug or the placebo

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Adverse Event (AE)

An adverse event is any undesirable experience associated with the use of a medical product in a patient

Examples: Death, irreversible damage to liver, nausea

Not always easy to specify in advance because many variables will be measured

May be known adverse effects from earlier trials

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Serious Adverse Event (SAE)

Death Life-threatening (risk of death) Hospitalization Disability Requires further intervention to prevent

additional impairment or disability

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Some Basic Research Terminology Retrospective: Refers to time of data

collection Prospective: Refers to time of data

collection Case Control Study: Persons with disease

& those without are compared Cohort Study: Persons with and/or

without disease are followed over time

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Prospective study

A cohort of individuals are identified who are free of a particular disease under study and data are collected on certain risk factors; i.e. smoking status, drinking status, exposure to contaminants, age, sex, race, etc.

These individuals are then followed forward over some specified period of time to determine whether they get disease or not. The relationships between the probability of getting disease during a certain time period (called incidence of the disease) and the risk factors are then examined.

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Retrospective or Case-Control study Individuals with disease (called cases) and

individuals without disease (called controls) are identified.

Using records or questionnaires the investigators go back in time and ascertain exposure status and risk factors from their past.

Such data are used to estimate the relative risk of developing disease between exposed and un-exposed.

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Terminology (Cont.)

Cross-sectional Study: Presence or absence of exposure to possible risk factor measured at one point in time. Prevalence obtained.

Prevalence: The # of new cases and existing cases during specified time period.

Incidence: The # of NEW cases per unit of a population at risk for disease occurring during stated time period.

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Cross-over Design

PopulationPopulation

SampleSample

InterventionIntervention

RandomizationRandomization

PlaceboPlacebo

WashoutWashout

WashoutWashout

PlaceboPlacebo

InterventionIntervention

OutcomeOutcome OutcomeOutcome

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Observational study vs Experiment Observational study – the investigator observes

individuals and measures variables of interest but does not attempt to influence the response.

Example: Based on observations you make in nature, you suspect that female crickets choose their mates on the basis of their health. Observehealth of male crickets that mated.

Experiment (study) : the investigator observes how a response variable behaves when the researcher manipulates one or more factors.

•Example: Deliberately infect some males with intestinal parasites and see whether females tend to choose healthy rather than ill males.

Observational Studies Correlation vs. Causation Observational studies: Often, the effect of one

variable on another often fail because the explanatory variable is confounded with lurking variables.

1. High cholesterol diet and rectal cancer2. Smoking and breast cancer3. Vasectomy and prostate cancer4. Red meat and colon cancer5. Red meat and breast cancer6. Drinking water frequently and bladder

cancer7. Not consuming olive oil and breast cancer Replication of observational studies may not

overcome confounding and bias

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1992, 1997 Food and Drug Administration Modernization Act

Major drug companies pay a fee of $350,000 when an NDA is submitted. The money is spent to hire a qualified person to review the NDA. Drugs are now approved in less than a year.

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Investigational New Drug (IND) Federal law requires that a drug must have an

approved marketing application prior to being transported or distributed across state lines

When a sponsor screens a new molecule for pharmacological activity and toxicity in animals and wants to test the drugs diagnostic or therapeutic potential on humans At this point, the molecule changes in legal status Under Federal Food, Drug, and Cosmetic Act, it becomes a

new drug subject to regulation

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IND and NDA

IND: Investigational new drug

(device) application Filed prior to beginning clinical trials

NDA: New drug application

Filed after pivotal trials to get drug (device) approval

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Adverse Events

Challenges Long term follow-up versus early

benefit Rare AEs may be seen only with very

large numbers of exposed patients and long term follow-up

Example – COX II inhibitors Vioxx & Celebrex Immediate pain reduction vs longer

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Example: Vioxx Adverse Events

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Example: Vioxx Adverse Events 09/30/2004, Merck voluntarily withdrew Vioxx: concerns about increased risk of heart attack and

stroke associated with long-term, high-dosage use. Merck withdrew the drug after disclosures that it

withheld information about Vioxx's risks from doctors and patients for over five years, resulting in between 88,000 and 140,000 cases of serious heart disease.[2]

Vioxx was one of the most widely used drugs ever to be withdrawn from the market. In the year before withdrawal, Merck had sales revenue of US$2.5 billion from Vioxx.[3]

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http://en.wikipedia.org/wiki/Rofecoxib

Contract Research Organization (CRO) An independent contractor with the sponsor

Assumes one or more obligations of a sponsor Design of protocol Selection or monitoring of investigations Evaluations of reports Preparation of materials to be submitted to the FDA

Are legally liable for the obligations they assume

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Site Management Organization (SMO) Independent contractor with the clinical

investigator Assumes one or more of the regulatory

obligations of the clinical investigator Preparation and maintenance of case histories Ensuring compliance with IRB review Informed consent requirements AE reporting

Not legally liable for the clinical investigator’s obligations they assume

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Contract Concerns (CTA) Complex blend of business, law and

regulation Requires negotiation and time

Publication Intellectual Property Confidentiality Indemnification Subject Injury

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CLINICAL TRIAL PROTOCOL


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Clinical Trial Protocol Definition: A document that describes the

objective(s), design, methodology, statistical considerations, and organization of a clinical trial

Usually gives the background and reason the trial is being conducted, but these could be provided in other documents referenced in the protocol (Investigator’s Brochure)

A study plan on which the clinical trial is based

Describes, among other things, what types of people may participate in the trial; the schedule of tests, procedures, medications, and dosages; and the length of the study

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Clinical Trial Protocol (cont.)

A recipe or blueprint Strict scientific guidelines: --Purpose of study --How many people will participate --Who is eligible to participate --How the study will be carried out --What information will be gathered about

participants --Endpoints

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Purposes of a Protocol

1. To assist investigators in thinking through the research

2. To ensure that both patient and study management are considered at the planning stage

3. To provide a sounding board for external comments

4. To orient the staff for preparation of forms and processing procedures

5. To provide a document which can be used by other investigators who wish to confirm (replicate) the results

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Components of Clinical Trial Protocols http://www.med.upenn.edu/ohr/protocol/sample/sample.html A protocol generally has the following elements: 1. Schema: Depicts the essentials of a study design. [OHR Sample Protocol page 12-13]

2. Objectives: The objectives should be few in number and should be based on specific quantifiable endpoints [OHR Sample Protocol page 7]

3. Project background: This section should give the referenced medical/historical background for therapy of these patients.

[OHR Sample Protocol page 4]

This generally includes(a) standard therapy

(b) predecessor studies (phase I and II if appropriate)

(c) previous or concurrent studies of a similar nature

(d) moral justification of the study

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4. Patient Selection: [OHR Sample Protocol page 8-10]

A clear definition of the patient population to be studied. This should include clear, unambiguous inclusion and exclusion criteria that are verifiable at the time of patient entry. Each item listed should be verified on the study forms.

5. Randomization/Registration Procedures [OHR Sample Protocol page 10-12]s

This section spells out the mechanics of entering a patient into the study 6. Treatment Administration and Patient Management:

[OHR Sample Protocol page 10-12]

How the treatment is to be administered needs to be specified in detail. All practical eventualities should be taken into account, at least, as much as possible. Protocols should not be written with only the study participants in mind. Others may want to replicate this therapy such as community hospitals that were not able to participate in the original study.

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Components of Clinical Trial Protocols (cont.)

7. Study parameters: [OHR Sample Protocol page 13-15]

This section gives the schedule of the required and optional investigations/tests.

8. Statistical Considerations: [OHR Sample Protocol page 13-15]

• Study outline, stratification and randomization

• Sample size criteria: Motivation for the sample size and duration of the trial needs to be given. This can be based on type I and type II error considerations in a hypothesis testing framework or perhaps based on the desired accuracy of a confidence interval.

• Accrual estimates

• Power calculations

• Brief description of the data analysis that will be used

• Interim monitoring plans

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9. Informed Consent: The consent form needs to be included. [OHR Sample Protocol page 20]

(a) an explanation of the procedures to be followed and their purposes

(b) a description of the benefits that might reasonably be expected

(c) a description of the discomforts and risks that could reasonably be expected

(d) a disclosure of any appropriate alternative procedures that might be advantageous

(e) a statement that the subject is at liberty to abstain from participation in the study and is free to withdraw at any time

10. Study Management Policy: [OHR Sample Protocol page 19-20]

This section includes how the study will be organized and managed, when the data will be summarized and the details of manuscript development and publication

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Key Components of Clinical Trial Protocols

Investigating two or more conditions so have two(+) groups• Ex: drug vs. placebo; medicine vs.

surgery; low dose vs. high dose Specific inclusion/exclusion criteria Sample size & power calculations potential biases handling of attrition/loss to follow up

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Summary of Clinical Protocol

A study plan on which all clinical trials are based (recipe or blueprint)

Provides background about the trial Describes trial’s design and organization Ensures that trial procedures are

consistently carried out Each study enrolls people who are alike in

key ways

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CLINICAL TRIALS ETHNICS


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Ethics of Clinical Trials: Protection of Participants

3 ethical principles guide clinical research: Respect for Persons: Treatment of person

as autonomous Beneficence: potential conflict between

good of society vs. individual Justice: Treatment of all fairly & all equally

share benefits & risks

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Ethical Norms of Clinical Trials

Sound study designs take into account: Randomization or sharing of risks Proper use of placebo Processes to monitor safety of RX/TX

(prescription) Competent investigators Informed consent Equitable selection of participants Compensation for study related injuries

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Ethical Issues: Protection of Human Subjects

Rely on integrity of Investigator but outside groups also have oversight

Participants’ rights protected by Institutional Review Boards [IRBs]

o An IRB is defined as: "any board, committee or other group formally designated by an institution to review, to approve the initiation of, and to conduct periodic review of biomedical research involving human subjects"

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PROTECTION OF PARTICIPANTS


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Informed Consent

Partly as a result of terrible things done in the name of clinical research, various bodies developed guidelines such as the

Nuremberg Code; Declaration of Helsinki; Belmont Report; And the International Ethical Guidelines for

Biomedical Research Involving Human Subjects [6]. These guidelines lay out standards for informed consent that are commonly followed internationally.

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Hippocratic Oath

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Informed Consent

Form vs process Freely given consent to participate in a

clinical research study No coercion Emphasis on “informed” Obtained prior to enrolling the subject

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Requirements: Lay language Participant must have sufficient time to

consider consenting Reading level Adequate presentation of the facts to the

subject and/or representative

Informed Consent (cont.)

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Protection of Human Subjects Informed consent (21 C.F.R. Part 50)

Ensures voluntary participation Required disclosures:

Risks, benefits, and alternative treatments No contracting out of liability “No more than minimal risk”

“Institutional Review Boards” (IRBs) (21 C.F.R. Part 56) Composed of at least 5 members from the health care

community and public Approve and monitor protocol Authority to approve, require modifications, or

disapprove research

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Protection of Human Subjects(cont.) IRBs should review proposed clinical trial within a

reasonable time IRBs should provide dates for the following

Approval/favorable opinion; Modifications required prior to its approval/favorable

opinion; Disapproval/negative opinion; and Termination/suspension of any prior approval/favorable

opinion

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Types of IRB Review

Full review Complete, initial review of the protocol, drug

brochure, advertisements, IND, etc Continuing Review

Annual required review of the study, progress report, and informed consent form

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Types of IRB Review (cont.) Expedited

Used for research involving not more than minimal risks to the subjects and in which the only involvement of subjects falls within certain categories

Can be utilized for the review of minor revisions that are submitted for a protocol that was previously approved

The Chair of the IRB and/or an experienced reviewer can review and approve the research

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Types of IRB Review (cont.) Exempt Research

Certain types of research, although they involve human subjects, do not require IRB approval Involving normal educational practices Using educational tests Surveys Retrospective collection of data

NOTE** Only the IRB has the right to determine if said research is “exempt”

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Human Subjects’ Protection

IRB responsible for such tasks: Review research to ensure that potential

benefits outweigh risks Develop and issue written procedures Review research for risk/benefit analysis

& proper protection of subjects Issue written notice of

approval/disapproval to the Investigator Review and respond to proposed protocol

changes submitted by the Investigator

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Human Subjects’ Protection

Review reports of deaths, and serious and unexpected adverse events received from the Investigator

Conduct periodic continuing review of the study, study risks, selection of subjects, privacy of subjects, confidentiality of data, and the consent process

IRB Responsibilities (continued):

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Historical Minute:10 Key Points

Voluntary informed consent

Experiment must be for the good of society, & results not obtainable by other means

Experiment should be based upon prior animal studies

Physical & mental suffering & injury should be avoided No expectation that death/disabling injury will occur from

the experiment Risk vs. benefit Protect subjects against injury, disability, or death Only scientifically qualified persons to be involved Subject can terminate her/his involvement

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Historical Minute: Origin of IRBs & Human Subject Codes Since 1947, additional subject protection

requirements developed & implemented Latest additions: Year 2000 - President

Clinton & DHHS Secretary Shalala announced additional study requirements related to:

informed consent training req. adverse events

conflict of interest civil monetary penalties

improved monitoring of Phase I & II trials

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Informed Consent:A Part of Human Subject Protection

Objectives of Informed Consent

To Ensure: Voluntariness Comprehension Information

To Demonstrate That: Person freely gave consent to participate Consent given by a competent person Person has been given all information Person knows this is research – not treatment

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Components of Informed Consent

Must Include the Following Information: Why research being done? What researchers want to accomplish What will be done and for how long Risks & benefits of trial Other treatments available Can withdraw from trial whenever desire Compensation for unexpected injuries

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Vulnerable Populations

Groups thought not to have autonomy to give informed consent:• children• mentally impaired, individuals with dementia• Prisoners

OR

Who may be unduly influenced to participate:• students• subordinates• pregnant women (actually, the fetuses)• patients (care-giver vs. researcher)

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Vulnerable Populations

To safe guard these groups, special requirements such as:

Only parent can consent for minor Consents must be in subject’s native

lang. Prisoners: only some types of research

allowed

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Inclusion in Clinical Trials

NIH Revitalization Act of 1993: Guidelines that require inclusion of women & minorities in clinical studies

New guidelines stipulate that:o Women & minorities are to be included in all

human subject researcho They are to be included in Phase III trials to

allow sufficient power to note differenceso Cost cannot be a barriero Outreach activities must take place to

include & follow these groups

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Inclusion in Clinical Trials

Historically women were excluded if of reproductive age (ages 18-45)

Fear of harm to potential unborn child In essence, excluded MAJORITY of women New guidelines eliminates this stipulation

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Issues in Clinical Trials:Use of Placebo Trials

On international realm, 1999 “Declaration of Helsinki” revised to address use of placebos:

Placebos not ethical in virtually all studies that involve diseases with PROVEN tx

Remain ethical in trials where no proven tx Revisions due to controversy over use of

placebos in attempting to find easy/cheap way to reduce HIV perinatal transmission

1998 study in Ivory Coast, Uganda, & Thailand: HIV+ pregnant women given either placebo or shorter course of AZT

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Participation in Clinical Trials

Why Some Participate: Give back to society Exhausted all other

txs Health care services Payment &

incentives Support Others??

Why Some Do Not? Mistrust of studies Do not want to be

“guinea pig” Do not meet criteria Cannot give up time

for study visits Barriers: lang.,

distance

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Taking Part in Research Studies:Questions to Ask

What is study about?

What are the goals?

Study sponsor? Participant input

into protocols? Inclusion criteria? Benefits & risks

Is there an incentive? How protected from

harm? What is required: #

study visit & what occurs?

What happens after study is over?

How results will be disseminated?

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The Impact of Studies

Other clinical trials have not been as successful for a variety of reasons:

Medications did not work as in laboratory Loss to Follow-Up of too many patients Harmful substance Unethical & poorly conducted study (Ex:

Tuskegee Study & recent Gene Replacement Study)

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Summary

Clinical trials often yield important results that affect health and well being

Must follow guidelines & protocol Must ensure well-being of participant Clinical trials are susceptible to human

error either on part of investigator or patient

Research is soft science

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stt520-420: biostatistics analysis dr. cuixian chen chapter 02: introduction to clinical trails...

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