Medical Videos ppt and Lecture Notes: Clinical Trials

Showing posts with label Clinical Trials. Show all posts

10 February 2012

Psoriasis Clinical Trials

Current / Recent Psoriasis Clinical Trials. Click title to view trial details.

21 July 2011

Clinical Trial Presentations - Agreement, GCP, Data Safety, Design Analysis, Standard Terminology

Clinical Trial Agreements, Institute for Clinical Research, Weill Medical College of Cornell University
http://www.med.cornell.edu/octa/documents/ppt/cta_presentation.ppt

Introduction to Clinical Trials
http://www.biostat.wisc.edu/Courses/542lectures2007/03-design.ppt

Clinical Trial Process: An Overview by John O. Naim
http://oric.research.wvu.edu/r/download/6881

Understanding Clinical Trials , Developed by Sara Back
http://www.hawaii.edu/hivandaids/Understanding%20Clinical%20Trials.ppt

Knowledge Acquisition for Clinical-Trial Selection
by: Savvas Nikiforou, Eugene Fink, Lawrence O. Hall, Dmitry B. Goldgof, Jeffrey P. Krischer
http://www.cs.cmu.edu/~eugene/research/talks/trial-knowledge.ppt

Good Clinical Practice Standards
http://www.research.drexel.edu/forms/compliance/irb/good_clinical_practice.ppt

Data and Safety Monitoring in Clinical Trials by Harvey Murff
http://www.mc.vanderbilt.edu/gcrc/workshop_files/2004-10-08.ppt

Design and Analysis of Group Sequential Clinical Trials and Software Development by
Shuangge Ma, Michael R. Kosorok, Thomas D. Cook
http://www.bios.unc.edu/%7Ekosorok/clinicaltrial/doc/ENAR.ppt

CDISC Standard Controlled Terminology across the Clinical Trial Continuum by Bron W. Kisler
http://pathcuric1.swmed.edu/Research/haglerdocs/Kisler_OCI_Work_Group_CDISC_Terminology_2Aug2007.ppt

How To Design a Clinical Trial: Overview Experiment Design & Clinical Trial Design
http://www.owlnet.rice.edu/~bioe301/kortum/class/students/hw/archives/2006/Project.ppt

20 July 2011

How to write a clinical trial protocol

How to write a study protocol
http://www.nci.cu.edu.eg/lectures/monday2006/23-4/How%20to%20Write%20a%20Protocol.pdf

Clinical Research Protocol from University of University of Pennsylvania
http://www.med.upenn.edu/ohr/docs/ProtocolTemp.doc

Clinical Research Protocol Guidelines from University of University of Pennsylvania
http://www.med.upenn.edu/ohr/docs/ProtocolTemp_guidelines.doc

Professional Development: How to Write A Research Proposal (Protocol)
by Egyptian Group for Surgical Science and Research
www.ess-eg.org/pages/groups/surgical/publications/1-how.pdf
Understanding Clinical Trials
http://clinicaltrials.gov/ct2/info/understand#Q01

A Collaborative Clinical Trial Protocol Writing System by
Chunhua Weng M.S., David W. McDonald Ph.D., John H. Gennari Ph.D. ,University of Washington
http://faculty.washington.edu/gennari/papers/chunhua-2-18-medinfo.pdf

Writing the research protocol - WHO Publication
http://whqlibdoc.who.int/emro/2004/9290213639_chap5.pdf

Writing a Study Protocol by Auckland District Health Board, Newzealand
http://www.adhb.govt.nz/researchoffice/Research-Resources/Study%20Protocol%20guide%20%20final%20vs%207%20Oct%2009.doc

Reviewing A Clinical Trial Protocol
http://www.crossover-cri.com/files/media/files/dd998638000ef1c55902847a2e12b2b2/COCRQ2011Apr.pdf

Investigational Plan – Feasibility Study
http://www.o3is.pitt.edu/documents/IDETemplateInvestigationalPlanFeasibility.doc

How to Write a Successful Clinical Research Proposal
http://www.fp7ireland.com/cms/Documents/Webinear%20%20How%20to%20write%20a%20successful%20Clinical%20Research%20Proposal_1264.pdf

Guidelines for Researchers beginning a research study
http://www.sld.cu/galerias/pdf/sitios/revsalud/guidelines_for_observational_studies.pdf

30 December 2009

Medical Epidemiology Clinical Trials

A clinical trial is
* A cohort study
* A prospective study
* An interventional study
* An experiment
* A controlled study

The Structure of a Clinical Trial
Various Aspects Are Standardized and Protocol-based
* Subject selection (who are these people?!)
* Subject assignment
* H & P data
* Therapeutic intervention
* Lab calibration
* Outcome evaluation

Subject Selection
* Adequate number of subjects
* Adequate number of expected endpoints
* Easy to follow-up
* Willing to participate (give consent)
* Eligibility (criteria)
* Efficacy Versus Effectiveness
* Internal Validity (validity) versus External Validity (generalizability)

Phases
* Phase I: find toxic dose
* Phase II: no controls
* Phase III: RCT
* Phase IV: Post marketing?

Types of Control Groups
* Historical
* Contemporaneous
* Concurrent
* Randomized

Allocating Treatment
* Complete (Simple) randomization
* Restricted randomization

Complete Randomization
* Patients assigned by Identical chance process (but not necessarily in equal numbers)
* Mechanics
* Insures process fairness
* Does not insure balance, especially in small studies.Therefore, may still need statistical adjustment

Randomization
* The only way to deal with unknown confounders.

Philosophy of Randomization
* Why are randomized trials not “epidemiologic” studies?
* Why randomization is so special?
* Has nothing to do with sampling bias.
* Randomization (random allocation) versus random sample.
* Does NOT deal with “chance” as a possible explanation of the difference. To the contrary.
* Can be used to create groups of unequal size.
* Baseline characteristics (table 1).

Allocation Concealment
* Define.
* Why do we need it?
* How is it done?
* Buzz words
* Versus blinding

Buzz Words
* Central (phone) randomization
* Sequentially numbered, opaque, sealed envelopes
* Sealed envelopes from a closed bag
* Numbered or coded bottles or containers

Restricted Randomization
* Stratification
* Blocking (Permuted Block Design)
* Stratified Blocking

Stratified Randomization
* Why

Scheme of stratified randomization
Blocking
* Why?
* Ensures close balance of the numbers in each group at all times during trial.
* How is it done?
* More importantly when stratified.
* Problem If block size is discovered.
* Remedy: more blinding, varying block size, larger blocks.
* Basic, Randomized (random-sized), Stratified

Problems With Concurrent Controls

Use your imagination
Examples
Problems With Contemporaneous Controls
* Regional population differences.
* Regional practice differences.
* Diagnostic variations.
* Referral pattern biases.
* Variations in data collections.

Problems With Historical Controls
* A lot more

Why Do Controls in a Randomized Trial Do So Well ?!
* Volunteerism
* Eligibility
* Placebo effect
* Hawthorne effect
* Regression towards the mean

Placebo Effect
* Placebo can do just about anything (prolong life, cure cancer).
* Improve athletic performance
* Lower T4 count
* Placebo can do just about anything (prolong life, cure cancer).
* Placebo can also cause side effects (nocebo, Wile E Coyote effect).
* Placebo effect is very useful in medicine but in epidemiology it causes problems, so we try to equalize it between the 2 groups.
* We use placebo for other benefits.

Hawthorne Effect
* Hawthorne works of the Western Electric Co. Chicago, IL

Regression Towards the Mean
Course Evaluation Question
Explains difficult material:
* Strongly agree
* Agree
* Neutral
* Disagree
* Strongly disagree
* What difficult material ?

Regression Towards the Mean
Explains difficult material
ATTENTION
CAUTION
DIFFICULT MATERIAL AHEAD!

Regression Towards the Mean

* Example
* Individuals with initially abnormal results tend on average to have more normal (closer to the mean) results later.
* Lab tests, BP etc.
* Recheck before randomization. Run-in period.
* Sophomore slump, medical school, Airforce landing feedback, most dangerous intersections.

Quicken Loans
* Rates this low seldom stay around long and tend to go up quickly and without warning

Why Does Prognosis Improve Over Time ?
1. Initial reports come from referral centers..
2. Publicity
3. Physicians’ awareness
4. Development of a Diagnostic Test
* Allows diagnosis of atypical cases.
* Is an incentive for physicians. It’s more challenging to diagnose difficult cases.
* Physicians with zero diagnostic skill can now diagnose this disease.
* Allows diagnosis of non-cases.
* Allows population based studies.
5. Publicity that a disease is very common relieves clinician from worrying that they may be overdiagnosing it.
6. Placebo effect increases over time. Why?

7. Safer treatment (laparoscopic cholecystectomy) lowers the threshold for doing surgery. So patients having surgery are not as sick as before.

Stage Migration Bias
Will Rogers Effect
8.Improved staging tests cause an apparent improvement of prognosis in every stage.
Stage Migration Bias Will Rogers Effect

“BEFORE-AFTER” STUDY
Mortality by severity level
Severity distribution
Mortality by severity level
Will Rogers Effect
* When subjects with the most severe disease in each stratum are moved to the next (more severe) stratum - for whatever reason - this will cause an apparent improvement of prognosis in every stage.
* Common.
Exclusions
Exclusion Criteria
* Excluded patients are “ineligible”. So, Why the separate category?
* More informative
* Usually very large number.
* Usually underestimates. Real number even bigger. Why?

Exclusion Criteria
What to watch for
* Patient preference
* Clinician preference
* No reason given

Drop ins and Drop outs
* Define.
* Typical case
* Other

Subjects who drop out of study or change treatment. But available for outcome assessment.
* Intention to treat analysis
* Once randomized always analyzed
* Why ?

1. Change in therapy may be related to outcome or eligibility
2. To get the full benefit of randomization
3. Effectiveness versus efficacy
Five-Year Mortality in Coronary Drug Project
A COHORT STUDY OF RECURRENT MI BY PARTICIPATION IN
A GRADUATED EXERCISE PROGRAM FOLLOWING INTITIAL MI

RECURRENT MI
YES NO TOTAL
PARTICIPATION IN GRADUATED EXERCISE PROGRAM

A RANDOMIZED CLINICAL TRIAL OF ENDURANCE TRAINING FOR PREVENTION OF RECURRENT MI
More on “Intention to Treat”
* Always analyze the results of the subjects according to the group they were randomized to. No exclusions.
* Even if they received no intervention.
* Even if they didn’t have the disease (example).
* The philosophy of “Intention to Treat” analysis
* Addresses the ultimate (and only) question for the clinician: Does prescribing treatment make a difference?
* LDL targets?!

Alternatives to “Intention to Treat” Analysis. (PROBLEMATIC)
* “Per Protocol” analysis.
How is it done?
Problems.
* “As Treated” analysis.
How?
Problems.

“Per Protocol” analysis.
* Censoring data after subjects become non-adherent
* Preserves randomization
* Stops counting events (when? “Carry-over” effect)
* Reduced power

“As Treated” analysis
* Change the treatment arm of the subject as he/she changes exposure
* The follow-up time and the events will be assigned to current exposure
* Retain all events.
* Randomization violated.
* Have to assign “lag-time” (latency) and Carry-over time.

Loss to follow up
Differential vs. Random
+ Compare their baseline variables with the rest of the subjects.
+ Chase a subgroup.
+ Worst case scenario

Objectives of Subgroup Analysis
* Support the main finding
* Check the consistency of main finding
* Address specific concerns re efficacy or safety in specific subgroup

It may also generate hypotheses for future studies. But that is not a reason to do it.

Inappropriate Uses of Subgroup Analysis
* Rescue a negative trial
* Rescue a harmful trial
* Data dredging: find interesting results without a prespecified plan or hypothesis

To Avoid Inappropriate Uses of Subgroup Analysis
* Prespecify analysis plan.
* Prespecify hypotheses to be tested based on prior evidence.
* Plan adequate power in the subgroups
* Avoid the previous pitfalls.

Problems with Subgroup Analysis
* Low power
* Multiplicity
* Test for interaction
* Comparability of the treatment groups maybe compromised
* Over-interpretation

Blinding
* PATIENTS Single blind.
* CLINICAL THERAPISTS usually double blind.
* Double Dummy
* CLINICAL EVALUATORS. Have to specify.
* Subjective vs. objective assessment

DSMB
* Data and Safety Monitoring Board
* Have duty toward:
* Current study participants (ongoing treatment)
* Future participants.
* Enough evidence to change practice
* Enough evidence to withstand criticism. (Unable to randomize afterward).

Multiple looks
* Alpha spending
DSMB
* Data Safety Monitoring Board
* Early Termination rules
* O’Brien-Fleming
* Early vs. late
* Benefit vs. harm (blinding?)
* Multiplicity
* Rules. Scenarios.
CLINICAL TRIALS JARGON
* Consecutive patients (versus a random sample)
* Baseline characteristics of patients (to see if randomization worked)
* Number of subjects and average duration of follow-up
(versus patient years)
* Interim analysis, problems
* Cumulative incidence (versus incidence density)
* Relative risk (Odds Ratio, or Hazard Ratio) (hopefully <1)is:
rate of outcome in a drug group
rate of outcome in a placebo group
* Relative risk reduction (similar to attributable risk %). But here it is 1-RR.
* Absolute difference in risk (ADR)= risk in control group – risk in intervention group (similar to AR) very important, sometimes not reported
* Relative risk reduction versus absolute difference in risk
* Number needed to treat NNT =1/ADR very useful (remember time)

Descriptions of “Trials”
* 34% relative decrease in the incidence of MI. The decrease is statistically significant. The 95% CI ranges from 55% relative decrease to a 9% relative decrease.

* 1.4% decrease in …. (2.5% versus 3.9%). The decrease is statistically significant. The 95% confidence interval ranges from a 2.5% decrease to a ..

* 77 persons must be treated for an average of just over 5 years to prevent 1 MI.

Ratings of Trials
(-5=harmful,+5=very effective)

Medical Epidemiology Clinical Trials.ppt

27 September 2009

Planning, Development of Clinical Trials

Planning of Clinical Trials
Development of a Clinical Trial
Idea
Reviews from the experts(Sponsor or CRO)
First planning meeting (basic design features)
Second planning meeting (draft protocol)
Final protocol (ethical and scientific, signed by a statistician)
Evaluation (scientific review, IRB, funding)
Implementation
Final analysis and publication

Evolution of Trial Structure
* Large cooperative trials (multicenter trials)
* High scientific level protocol
* Well-defined administrative structure
* Control of performance at all levels (SOPs)
* Competent biometric advice (ICH E9)
* Careful ethical considerations

Why Multicenter Trials?
* Small but important effect
* Enhance generalizability of the results
* Bring new treatment to the community

Clinical Trial Protocol
* A detailed plan giving instructions to the study investigators(doctors) about the way

to conduct the study.
o Contributors to the protocol development
+ investigators,
+ medical personnel from the Sponsor or delegated CRO
+ representatives from the study monitoring team
+ project statistician

Crucial Roles of Statisticians
* Design (very important!!!)
* Monitoring
* Analysis
* Reporting
* New statistical methodology

Sophisticated Statistical Techniques
* O’Brien and Fleming Boundaries
* Lan & DeMets “Spending function”
* Equivalence testing
* Repeated measures
* Bayesian methods
* Nonlinear random effect modeling

Functions of Clinical Trial Protocol
* Guideline for the conduct of the trial
* Quality control for all aspects of a clinical trial
* To provide guidelines to the monitoring groups such as: IEC / IDMC.
* Written agreement between:
o the investigator
o the participant,
o and the scientific community
* Legal documents for
o FDA and other regulatory bodies
* To procure funding

Duration of Protocol Development
7days-6months!!!
4-50 pages long!!!

Three Fundamental Aspects
* Which patients are eligible
* Which treatment are to be evaluate
* How each patient’s response is to be assessed

Background
* Rationale
* Unpublished work of the investigators
* Pharmacological and toxicity
* Any new and non standard methods

Specific Objectives
* New treatment
* New indication
* Determine the best of a number of standard treatments
* To provide additional data on safety or efficacy

Methods
o Hypothesis
o Patient population (operational definition)
+ Inclusion Criteria
+ Exclusion Criteria
More homogeneous less generalizable!!

Treatment Regimens
Required procedures for treatment administration, including precise rules for does

determinations

Trial Design
Control groups
+ Define and justify the control group
+ Safety consideration of the placebo group
+ Randomization (verifiable method)
# Method used to generate the allocation schedule
# Method of allocation concealment
* Packing number
* Telephone
* Remote data entry
# Timing of assignment
+ Balance on Prognostic Factors
# Stratification
# Minimization
Blinding
+ Mechanism of treatment blinding
+ Single, double, triple, quadruple blinding
+ Assessment of the effectiveness of blinding

Experimental design
+ Parallel designs
+ Cross-over designs
+ Factorial designs
+ Sequential designs

* Patient management guidelines, including specifications for does reductions, treatment

delays and treatment terminations
* Schedules of required clinical tests and assessments

Follow-up phase
* Schedule of submission of required materials and data, including long-term follow-up
* Data and materials submission procedures

Termination
* Procedures for ending patients’ participation in the trial

Study Flow Diagram
* A flowchart describe how patients progress through the trial
o Initial screening
o Randomization
o Planned schedule
o Follow-up visits
o Early termination

Outcome Measures
* Primary end points
Secondary end points

Statistical Issues
* Power analysis justifying sample size requirements
* Interim monitoring and analysis plans
* Planned time and methodology of final analyses e.g. ITT, PP, NNT, CI
* Methods on secondary aims, compare toxicities

Ethics and Safety
* Protection of the trial patient’s right and safety
o How the patient is approached for entry into the trial
o Regulatory obligations, including informed consent and reporting of adverse

events
o Plan and action if a SAE be detacted

Other Topics in a Study Protocol
* Laboratories
* Compliance
o How compliance is monitored
o Methods used to improve compliance
* Organization
o Roles
o Responsibilities
* Budget
* Study Forms (CRFs) and data handling
* Administrative responsibilities

CRF Design
* Identification data
* Research data
* Administrative data
* Regulatory data

Basic Information in CRF
* Consent dates
* Eligibility checklist
* Baseline assessments
* Dosing of study medications ( incl. compliance)
* Concomitant illness
* Safety
* Effectiveness
* Premature termination of study

Administrative Structure of Multicentre Trials
* Steering Committee
o Leadership body of the investigative group
* Data and Safety Monitoring Committee
o Assess the progress, safety and efficacy
o Recommendations about continue, modify or terminate.

Study Chairman
* Chair steering committee
* Responsible for the overall project
* Overseeing the design and conduct of the trial
* Implementation of SOPs and good clinical practices
* Compliance with international and local regulations.

Coordinating Centre
o Training
o Registration
o Randomization
o Supplying
o Collecting and processing CRFs
o Coordination of accrual sites
o Auditing study sites
o Regulatory reporting

Statistical Centre
o Data entry and processing
o Ongoing monitoring of toxicity data
o Periodical interim analysis of study endpoints
o Final data analyses
o Preparation abstract and manuscripts

Central Laboratory

Other Major Personnel
* Trial statistician
* Clinical research associate
* Data manager
* Randomization specialist
* Quality assurance officer
* Computer support personnel
* Resource Centre Directors
* Training directors
* Field site personnel
* Independent Data Monitoring Committee

Field Site Personnel
* Investigator/Study coordinator
* Research Nurse/
o Participants accrual
o Intervention
o Primary data collection
o Follow-up

Standard Operating Procedures (SOPs)
* To ensure that the specific tasks in the trial are carried out in a consistent manner.
* Topics for SOPs for Investigators:

General Topics
* General quality assurance
* Quality control procedures
* Research personnel qualifications
* Clinical audit
* Regulatory authority inspections

Ethics
* Initial and continuing review by ethics committees
* Informed consent
* Consent forms and information sheets

Study Setup
* Review of:
o investigator brochures
o Protocols
o Protocol amendments
o CRFs
o agreements (e.g. responsibility, financial, confidential, insurance/indemnity

agreement)

Monitoring and Initial Data Review:
* Monitoring visits
* Source data verification
* Data query

Management of Study Medications and Clinical Laboratory Samples:
* Shipment
* Receipt
* Control at study sites
* Dispensing inventory
* Compliance with use of study medication
* Randomization procedures
* Clinical laboratory samples

Safety Event Reporting
* Definitions
* Recording and reporting AEs
* Recording and reporting AEs to ethics committees;

Closing The Study
* Review of clinical study reports
* Premature termination or suspension
* Archiving

Some Important ICH Guidelines
* E2A Clinical Safety Data Management: Definitions and Standards for Expedited Reporting
* E3 Structure and Content of Clinical Study Report (1995)
* E6 Good Clinical Practice (1996)
* E7 Clinical Trials in Special Populations: Geriatrics (1993)
* E8 General Consideration for Clinical Trials (1997)
* E9 Statistical Principles for Clinical Trials (1998)
* E10 Choice of Control Group in Clinical Trials (TBI)
o ICH home page: http://www.ifpma.org/ich1.html
o FDA guidelines: http://www.fda.gov/cder/regulatory/default.htm

Federal Office for Human Research Protections (OHRP)
* OHRP is responsible for monitoring subject protections at more than 4,000 HHS

(Department of Health and Human Services) funded universities, hospitals and other research

institutions.

Investigational Melanoma Vaccine Research Study (MV)- Oklahoma Case
* OHRP Halts Human Research at University of Oklahoma for Subject Protection Violations
* Suspension Date: June 29 2000
* Suspension of 75 federally funded clinical trials performed though the Tulsa campus

Major OHRP Findings:
* MV failure to meet GMP
* allowed for potential subject exposure to bacterial and viral infections.
* 26 of 96 subjects (vaccine arm) died.
* Investigators failed to ensure that risks to subjects were minimized.

Major OHRP Findings:
* Incomplete informed consent documents
o the purpose of the study
o Procedures
o Foreseeable risks and discomforts
o Any expected benefit from study participation
o Overstated the benefits of the study as capable of preventing the recurrence of

melanoma or reducing existing tumor mass
* IRB failure to meet its federal regulatory obligations.
* Implemented substantive changes to the study without obtaining IRB approval.
* Failure to adhere to the protocol inclusion/exclusion criteria.
* Recruited 96 patients with IRB approved size <=40.
* Directly ship study vaccine to some subject’s homes for self-administration.

Actions Taken
* Independent accreditation of a newly formed Tulsa IRB
* Require that sponsor use DSMB as a condition for approval;
* Mandatory certification in human subject protection for those involved in the conduct

of clinical studies
* Educational program specially for clinical investigators, research staffs and IRB

members

Consequences
* Director of the Office of Research resigned
* Chair of IRB retired
* PI (Former Vice Chairman of the University’s dept. of Surgery) has been relieved of

all his administrative duty at the University, which in process of terminating his

appointment as a tenured faculty member.
* Federal lawsuit against
o study’s PI,
o its corporate co-sponsor
o and its IRB members,
* Violations of
o human subject protection regulations,
o international recognized ethical standards for research conduct
o and civil rights laws.

Controlled Clinical Trial
A Journal
* An official journal for the Society for Clinical Trials
* The first issue was published in the May of 1980.
* Aim and scope:
o Basic Design
o Operating features
o Organization
o Analysis

Other Useful Journals
* Applied Clinical Trials
* Statistical Methods in Medical Research
* Statistics in Medicine
* Biometrics

Statistical Principles for Clinical Trials ICH E9
* Considerations for overall clinical development
* Trial design considerations
* Trial conduct considerations
* Data analysis considerations
* Evaluation of safety and Tolerability
* Reporting

Scope of Trials (ICH E9)
* Population
* Primary and Secondary Variables
* Composite variables
* Global Assessment variables
* Multiple Primary Variables
* Surrogate Variables
* Categorized Variables

Design Techniques to Avoid Bias (ICH E9)
* Blinding
* Randomization

Trial Design Considerations (ICH E9)

* Design Configuration
* Parallel Group Design
* Cross-over Design
* Factorial Design
* Mulitcentre Trials

Trial Design Considerations (ICH E9)

* Type of Comparison
o Trials to show superiority
o Trials to show Equivalence or Non-inferiority
o Trials to show Does-response Relationship
* Group sequential designs
* Sample Size
* Data capture and Processing

Trial Conduct Considerations
(ICH E9)
* Trial Monitoring and Interim Analysis
* Changes in Inclusion and Exclusion Criteria
* Accrual Rates
* Sample Size Adjustment
* Interim Analysis and Early stopping
* Role of IDMC

Data Analysis Considerations
(ICH E9)
* Prespecification of the Analysis
* Analysis Sets
o Full Analysis Set
o Per Protocol Set
o Roles of the Different Analysis Sets
* Missing Values and Outliers

Data Analysis Considerations
(ICH E9)
* Data Transformation
* Estimation, CIs and Hypothesis Testing
* Adjustment of Significance and Confidence Levels
* Subgroups, Interactions and Covariates
* Integrity Data and Computer Software Validity

Planning, Development of Clinical Trials.ppt

A Randomized Clinical Trial to Prevent Type 2 Diabetes

A Randomized Clinical Trial to Prevent Type 2 Diabetes in Persons at High Risk

The DPP Research Group
Institutions and Investigators
Abbas Kitabchi
U. of Tennessee

Steven Kahn
U. of Washington
Edward Horton
Joslin Diabetes Center

Richard Hamman
U. of Colorado Health Sciences Center

Steven Haffner
U. of Texas Health Science Center and many others

* There is a long period of glucose intolerance that precedes the development of

diabetes
* Screening tests can identify persons at high risk
* There are safe, potentially effective interventions that can address modifiable risk

factors

Feasibility of Preventing
Type 2 Diabetes

Modifiable Risk Factors for
Type 2 Diabetes
* Obesity
* Body fat distribution
* Physical inactivity
* Elevated fasting and 2 hr glucose levels
* To prevent or delay the development of type 2 diabetes in persons with impaired

glucose tolerance (IGT)

DPP Primary Goal
DPP Secondary Goals
* Reduce cardiovascular disease (CVD) events
* Reduce CVD risk factors
* Reduce atherosclerosis

Study Design
* 3-group randomized clinical trial
* 27 clinical sites
* Standardized across clinics:
o Common protocol and procedures manual
o Staff training
o Data quality control program
Eligibility Criteria
Screening and Recruitment
Step 1 screening
Step 2 OGTT
Step 3 start run-in
Step 4 randomization
Number of participants
Step 3 end run-in

The DPP Research Group, Controlled Clin Trials (in press)
Study Interventions
Eligible participants
Randomized
Standard lifestyle recommendations
Intensive Metformin Placebo
Lifestyle
Primary Outcome: Diabetes

* Annual fasting plasma glucose (FPG) and 75 gm Oral Glucose Tolerance Test
o FPG > 126 mg/dL (7.0 mmol/L) or
o 2-hr > 200 mg/dL (11.0 mmol/L),
o Either confirmed with repeat test
* Semi-annual FPG
o > 126 mg/dL, confirmed

Lifestyle Intervention
An intensive program with the following specific goals:
* > 7% loss of body weight and maintenance of weight loss
o Dietary fat goal -- <25% of calories from fat
o Calorie intake goal -- 1200-1800 kcal/day
* > 150 minutes per week of physical activity

Lifestyle Intervention Structure
* 16 session core curriculum (over 24 weeks)
* Long-term maintenance program
* Supervised by a case manager
* Access to lifestyle support staff
o Dietitian
o Behavior counselor
o Exercise specialist

The Core Curriculum
* 16 session course conducted over 24 weeks
* Education and training in diet and exercise methods and behavior modification skills
* Emphasis on:
o Self monitoring techniques
o Problem solving
o Individualizing programs
o Self esteem, empowerment, and social support
o Frequent contact with case manager and DPP support staff

Post Core Program
* Self-monitoring and other behavioral strategies
* Monthly visits
o Must be seen in person at least every two months
* Supervised exercise sessions offered
* Periodic group classes and motivational campaigns
* Tool box strategies
o Provide exercise videotapes, pedometers
o Enroll in health club or cooking class

DPP Study Interventions:
Criteria for Drug Treatment
* Efficacy
* Safety
* Tolerability - minimal side effects
* Acceptability - dose frequency
Metformin- 850 mg per day escalating after
4 weeks to 850 mg twice per day
Placebo- Metformin placebo adjusted in
parallel with active drugs

Interventions:
Medications
DPP Population
Retention and Participation
Lifestyle Intervention: Physical Activity Results
Mean Change in Leisure Physical Activity
Placebo
Metformin
Lifestyle
Effect of Treatment on Incidence of Diabetes
Diabetes Incidence Rates by Age
Diabetes Incidence Rates by Ethnicity
Diabetes Incidence Rates by BMI
Body Mass Index (kg/m2)
Diabetes Incidence Rates by Fasting Glucose
Fasting Plasma Glucose: mg/dl (mmol/l)
Diabetes Incidence Rates by 2-hr Glucose
2-Hour Plasma Glucose (mg/dl)
Consistency of Treatment Effects
Normal Fasting Glucose
Placebo Metformin Lifestyle
Summary-1
* Both interventions were well accepted and safe
* Intensive lifestyle resulted in weight loss and increased activity level for the

duration of the study

Summary-2
* Both interventions were effective in men and women and all ethnic groups
* Intensive lifestyle intervention was effective in all age groups, including those > 60 years of age

Summary-3
* Intensive lifestyle intervention reduced the development of diabetes by 58%
* Metformin reduced the development of diabetes by 31%
* Lifestyle was more effective than metformin

Lipids by Sex and Ethnicity

A Randomized Clinical Trial to Prevent Type 2 Diabetes.ppt

Clinical Trials and Research

Clinical Trials and Research
A Guide for Community Advisory Board Members
Participant Manual

This teaching tool was developed by the François-Xavier Bagnoud Center at the University of Medicine and Dentistry of New Jersey, with the support of the Pediatric AIDS Clinical Trials Group.

Excerpts from this publication may be freely reproduced or adapted with acknowledgement of the source, provided the material reproduced is for non-profit distribution.

PACTG Global Training Initiative

Glossary
* Clinical Trial: A way to test new medications
* Eligibility: Deciding if a person is qualified to join a clinical trial
* Phases: Stages
* Placebo: Dummy tablet
* Protocol: A written plan for the clinical trial
* Study sample: People to be studied in the clinical trial
* Volunteers: People willing to join the trial

What is a Clinical Trial?
Identify a health question.
Develop a plan.
Enroll volunteers and follow the plan.
Study the information collected.
Share the results with others.
Improve treatment.

Example of a Research Question
* Is Medicine A more effective for preventing mother-to-child transmission than
Medicine B?
Medicine “B”
Medicine “A”

Phases of Clinical Trials

Phase I:Safety(15–30 people)

Phase II:Safety and Effectiveness(Fewer than 100 people)

Phase III:
Effectiveness compared to standard of care; Safety(More than 100 to a few thousand)

Structure of a Simple Trial Comparing Two Treatments
Randomisation
Investigational Group
Control Group
Ethics Committees
* The ethics committee reviews a protocol before the study is allowed to start. Their job is to ensure that the risks of being in the study are not greater than the potential benefit.

Informed Consent
* To make informed decisions, patients need to hear and understand specific information about the research.

* Purpose
* Medicine to be studied
* Procedures and schedule
* Risks
* Potential benefits
* Alternatives to participation
* Confidentiality
* Participation in clinical trials is always voluntary.

No, thank you, I’d rather not participate.
Yes, I would like to participate.

Research Protocol
How
Why
Where
When
What
Who

Protocol
Objectives: Clear and Specific Statements
* Which medicine is more effective in reducing mother-to-child transmission of HIV—Medicine “A” or Medicine “B”?

Medicine “B”
Medicine “A”

Eligibility
* Who may participate in this study
* Who may not (X) participate in this study

Data Safety and Monitoring Boards (DSMB)
* The job of the DSMB is to monitor the study for any problems with the safety or effectiveness of the medicines.

Safety
* A protocol must describe known risks or side effects and exactly what will be done to protect and monitor patients.

Schedule of Events
* To evaluate the effect of the medicine on their health, all patients in a trial have certain tests or procedures at regularly scheduled intervals.
Endpoints
* An endpoint is what researchers will measure to evaluate the results of a new medicine.
CAB: Part of the Research Team

* CAB members and volunteers who join clinical trials are part of the team dedicated to finding better ways to prevent and treat HIV.

How Have Clinical Trials Helped People with HIV?
* Clinical trials are critical in the effort to find better ways to treat HIV and AIDS.

How Have Clinical Trials Helped People with HIV?
* Antiretroviral medicines can greatly reduce the chance an infant will be HIV-infected during or after birth.

How Have Clinical Trials Helped People with HIV?
* They have greatly decreased sickness and death among patients who receive antiretroviral medicine.

Clinical Trials and Research.ppt

Clinical Trials

Clinical Trials

The Way We Make Progress Against Disease

What Are Clinical Trials?
* Research studies involving people
* Try to answer scientific questions and find better ways to prevent, diagnose, or treat disease
Why Are Clinical Trials Important?

* Clinical trials translate results of basic scientific research into better ways to prevent, diagnose, or treat disease

* The more people take part, the faster we can:
- Answer critical research questions
- Find better treatments and ways to prevent disease

Do Many People Take Part in Clinical Trials?

* Few people participate
What Are the Different Types of Clinical Trials?
* Treatment
* Prevention
* Early detection/screening
* Diagnostic
* Quality of life/supportive care

Treatment Trials
* What new treatments can help people with a particular disease?
* What is the most effective treatment for people with that disease?

Clinical Trial Phases
Phase 1 trials
* How does the agent affect the human body?
* What dosage is safe?

Phase 2 trials
* Does the agent or intervention have an effect on the disease?

Phase 3 trials
* Is the new agent or intervention (or new use of a treatment) better than the standard?
* Participants have an equal chance to be assigned to one of two or more groups

Randomized Trials
Participants have an equal chance to be assigned to one of two or more groups:
* One gets the most widely accepted treatment (standard treatment)
* The other gets the new treatment being tested, which researchers hope and have reason to believe will be better than the standard treatment

Randomization
Why is Randomization Important?
* So all groups are as alike as possible
* Provides the best way to prove the effectiveness of a new agent or intervention

Treatment Trials
* What new treatments can help people with a particular disease?
* What is the most of effective treatment for people with that disease?

Placebos are almost never used:
* Placebos are used only when no standard treatment exists
* Patients are told of this possibility before deciding to take part

Prevention Trials
* Evaluate the effectiveness of ways to reduce the risk of a particular disease
* Enroll healthy people at high risk for developing that disease

Prevention Trials
* Action studies (“doing something”)
* Agent studies (“taking something”)—also called “chemoprevention studies”

Chemoprevention Trials
* Phase 3 chemoprevention trials compare a promising new agent with either a:
--Standard agent
--Placebo

Clinical Trial Protocol
* 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

Benefits of Participation
Possible benefits:
* Patients will receive, at a minimum, the best standard treatment (if one exists)
* If the new treatment or intervention is proven to work, patients may be among the first to benefit
* Patients have a chance to help others and improve patient care

Risks of Participation
Possible risks:
* New treatments or interventions under study are not always better than, or even as good as, standard care
* Even if a new treatment has benefits, it may not work for every patient
* Health insurance and managed care providers do not always cover clinical trials

Patient Protection
* There have, unfortunately, been past abuses in patient protection
* Federal regulations ensure that people are told about the benefits, risks, and purpose of research before they agree to participate

How Are Patients’ Rights Protected?
* Informed consent
* Scientific review
* Institutional review boards (IRBs)
* Data safety and monitoring boards (DSMBs)
Informed Consent:
o Purpose
o Procedures
o Potential risks and benefits
o Individual rights
* Scientific review
* Institutional review boards (IRBs) are required by federal law for trials that are:

--Federally funded
--Subject to FDA regulation
Data and safety monitoring boards:
* Ensure that risks are minimized
* Ensure data integrity
* Stop a trial if safety concerns arise or objectives have been met

Why Do So Few People Participate in Clinical Trials?
Sometimes patients:
* Don’t know about clinical trials
* Don’t have access to clinical trials
* May be afraid or suspicious of research
* Can’t afford to participate
* May not want to go against health care provider’s wishes
Why Do So Few People Participate in Clinical Trials?
Health care providers might:
* Lack awareness of appropriate clinical trials
* Be unwilling to “lose control” of a person’s care
* Believe that standard therapy is best
* Be concerned that clinical trials add administrative burdens

Where to Find Clinical
Trial Information

Clinical Trials.ppt

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