Clinical Trials

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

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Urinalysis

METHODS OF URINE COLLECTION

1. Random collection taken at any time of day with no precautions regarding contamination. The sample may be dilute, isotonic, or hypertonic and may contain white cells, bacteria, and squamous epithelium as contaminants. In females, the specimen may cont contain vaginal contaminants such as trichomonads, yeast, and during menses, red cells.
2. Early morning collection of the sample before ingestion of any fluid. This is usually hypertonic and reflects the ability of the kidney to concentrate urine during dehydration which occurs overnight. If all fluid ingestion has been avoided since 6 p.m. the previous day, the specific gravity usually exceeds 1.022 in healthy individuals.
3. Clean-catch, midstream urine specimen collected after cleansing the external urethral meatus. A cotton sponge soaked with benzalkonium hydrochloride is useful and non-irritating for this purpose. A midstream urine is one in which the first half of the bladder urine is discarded and the collection vessel is introduced into the urinary stream to catch the last half. The first half of the stream serves to flush contaminating cells and microbes from the outer urethra prior to collection. This sounds easy, but it isn't (try it yourself before criticizing the patient).
4. Catherization of the bladder through the urethra for urine collection is carried out only in special circumstances, i.e., in a comatose or confused patient. This procedure risks introducing infection and traumatizing the urethra and bladder, thus producing iatrogenic infection or hematuria.
5. Suprapubic transabdominal needle aspiration of the bladder. When done under ideal conditions, this provides the purest sampling of bladder urine. This is a good method for infants and small children.

Full details here

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Clinically Relevant Microbiology Starts at the Source

Clinically Relevant Microbiology Starts at the Source
By: Mike Costello, PhD, MT(ASCP)
ACL Laboratories
Mary Dikeman, MT (ASCP)
Affinity Health System

Program Objectives
* Emphasize that obtaining sensitive and specific microbiology results begins with the patient and not at the door of the microbiology laboratory.
* Accentuate the importance of proper collection and transport of specimens in both local and referral environments
* Stress the importance of timely communication between the Microbiology laboratory and those collecting specimens
* Describe common pitfalls in specimen collection and transport
* Discuss What rules or principles must be followed in order to collect microbiology specimens which will accurately reflect the pathogenesis of the microbiological agent. (Church D. The Seven Principles of Accurate Microbiology Specimen Collection. . Calgary Laboratory Services Microbiology Newsletter. Volume 6, 2005)

Introduction
The practice of sensitive, specific and cost effective clinical microbiology is intimately tied to the submission and proper handling of optimal specimens for analysis. Unfortunately, these aspects of clinical microbiology are not as critically controlled as our laboratory assays. It is our responsibility to educate and notify our healthcare colleagues when specimens arrive at the laboratory that will yield inferior results.

Quality assurance of specimen collection and transport is a never ending battle and requires long term commitment of your time and resources, but the end results are better patient care and a more rewarding experience for those of us who work in the microbiology laboratory.

Principle #1: The specimen must be collected with a minimum of contamination as close to
site of infection as possible

Urine Culture Contamination Rates

* Urine Culture contamination rates (>2 bacteria at >100,000 CFU) should be <20%
o CAP Q-Probe study (Valenstein P Meier F. Urine culture contamination: a College of American Pathologists Q-Probes study of contaminated urine cultures in 906 institutions. Arch Pathol Lab Med. 1998;122:123-129)..
+ 630 participants collected information of 155,037 urine culture specimens; 20.1% were considered contaminated (>2 organisms at >105 CFU)
+ The top 10% of institutions reported a rate of 5.6%. Bottom 10% of institutions reported a contamination rate of 36.8%
+ Males have a lower contamination rate than females (11.2% Vs. 22.8%)
+ ER departments had a contamination rate of 17.8%, sites adjacent to lab had rates of 19.5%, and other sites had rates of 22.1%

Blood Culture
* Two sets of blood cultures should be drawn. Number of sets positive correlates with true sepsis (except for coagulase negative Staph?) (Clin Microbiol. Rev 19:788-802, 2006)
* Catheter drawn blood cultures
o Catheter drawn blood cultures are equally likely to be truly positive (associated with sepsis), but more likely to be colonized (J Clin Microbiol 38:3393, 2001.)
+ One drawn through catheter and other though vein PPV 0f 96%
+ Both drawn from catheter PPV 0f 50%
+ Both drawn through vein PPV of 98%
o Study of positive coagulase negative Staphylococcus cultures and sepsis (Clin Infect Dis. 39:333, 2004.)

Blood Culture Contamination Rate
By Service Drawing Culture
What is an “Acceptable” Blood Culture Contamination Rate for Your Lab??
Blood Culture Contamination in Pediatric Patients
Young Children and Young Doctors
Inexperienced physician-young child
Inexperienced physician-older child
Experienced physician-younger child
Experienced physician-older child
Predicative Value of a Positive Result
False Positive
True Positive
Variable
Ped Infect Dis. 2006, 25:611-614.

Inexperienced Physicians = Interns and residents in 1st half of training
Experience Physicians = Residents in 2nd half of training and senior physicians
What is an “Acceptable” Blood Culture Contamination Rate for Your Lab??

What is an “acceptable” blood culture contamination rate*?
Berkeris LG, JA Toworek, MK Walsh, PN Valenstein. Trends in Blood Culture Contamination.
Arch Pathol Lab Med 129:1222-1294, 2005

Respiratory Cultures
* Community Acquired Pneumonia – Sputum rejection rate and culture correlation with gram stain
o 54% of all samples were judged to be of good quality.
o Presence of a (predominant morphology) PM on Gram stain was predictive of whether the sputum culture could demonstrate a pathologic organism. In the presence of a positive PM, 86% of cultures yielded a pathologic organism, while a positive culture was obtained in 19.5% of Gram stains without a predominant organism. S. pneumoniae was the most common infection, growing in 55.7% of positive sputum cultures.
o The sensitivity and specificity of finding Gram-positive diplococci for a positive culture of S. pneumoniae were 60% and 97.6%, respectively (Arch Intern Med. 2004;164:1725-1727, 1807-1811)
* Ventilator associated pneumonia (VAP) – appropriate specimen
o Blood cultures highly specific but not sensitive (positive in <10% of VAP)
o Quantitative cultures of lower respiratory tract specimens show a closer clinical correlation than sputum subcultures (Clinical Microbiol. Rev. 19:637-657, 2006.)

Viral Respiratory Cultures – Collect Sample From Site of Infection
How do you know that an adequate
Specimen was submitted for rapid
EIA assays???
Throat swabs are even worse!
Samples for Diagnosis of Viral Respiratory Infections
Lung biopsy
Bronchial alveolar
lavage/wash/brush
Nasopharygeal secretion
Nasopharygeal wash
Induced sputum
Nasopharygeal swab
Nasal wash


Throat swab (adenovirus only)
Saliva
Blood?
Sputum
DFA/EIA
OIA
Culture
LRTC*present
LRTC cells absent
Reagent Cost

Skin and Soft Tissue (Wound) Cultures
* Collect with steel (needle aspirate or scalpel)
* Discourage the use of swabs
* If infection NOT suspected, DON’T culture
* Get infected tissue or body fluid [ discourage swabs! ]
* -use something sharp ( syringe, scalpel, etc )
* -close doesn’t count
* *Don’t culture the surface / get deep infected sample*
* Remove needles / send capped syringe with aspirate
* Share specimen: Microbiology-Surgical Path-Cytology
* ** Label specimen and site accurately
* ** Give appropriate history
(Matkoski C. Sharp SE, Kiska DL. Evaluation of the Q Score and Q234 Systems for cost-effective and clinically relevant interpretation of wound cultures. J Clin Microbiol 2006;44:1869-1872)

Principle #2: A specimen must be collected at the optimal time(s) in order to recover the pathogen(s) of interest
Principle #3: A sufficient quantity of the specimen must be obtained to perform the requested tests
Blood Cultures
* Volume of blood drawn is the single most important factor influencing sensitivity. A single set for an adult blood culture consists of one aerobic and one anaerobic bottle. Optimally 10 mL of blood should be inoculated into each bottle. Volume of blood for a pediatric culture can be related to the infants weight
* Solitary blood cultures should be less than 5% (Arch Pathol Lab Med. 2001 125:1290-1294)
* If only enough blood can be drawn for one bottle, inoculate the aerobic bottle.
o 644 positive blood cultures, 59.8% from both bottles, 29.8% from aerobic bottle only and 10.4% from anaerobic bottle only (J Infect Chemother 9:227, 2003).
Pediatric Blood Cultures - Volume
Surgical Specimens (Other Shared Specimens)
TISSUE
FLUID
Specimen size of pea or larger
Divide
Anaerobic transport tube
Hold
upright,
uncap,
insert specimen and recap
Anaerobic
Culture
and stain

COLLECTION AND HANDLING OF OPERATING ROOM SPECIMENS FOR MICROBIOLOGY
Acceptable Specimens For Anaerobic Culture

Principle #4: Appropriate collection devices and specimen containers must be used to ensure recovery of all organisms
Recovery of Anaerobic Bacteria Placed in in Aerobic/Anaerobic Transport Media
CVP = Copan Vi-Pak Amies Agar Gel collection and transport swabs
SSS = Starplex StarSwab II,
PAC = BBL Port-A-Cult

How Does Transport Time Affect Yields?
J Clin Microbiol. 2001:39 377-380

Suggested Transport Media – General Comments

Principle #5: Collect all microbiology test samples prior to the institution of antibiotics
Principle #6: The specimen container must be properly labeled and sealed prior to transport
Principle #7: Minimize transport time or maximize transport media. There is always some loss of viability during transport
Minimize transport time and maximize use of transport media as much as possible
Environmentally Fragile Organisms
QA monitor??
Principle #8: Special handling/Collection instruction must be followed
* First, communicate with those that are doing collections.
* Collection instructions are written and available.
* Get involved with nursing orientation/education days and ask to have the instructions given out; poster board learning; quiz or competencies.
* Talk to providers when there are problems with specimen collection; they sometimes do not know they could do it better.


Principle #9: Improper specimen Collected for Ordered Test

Criteria For Rejection of Microbiological Specimens
* Criteria for rejection must be readily available and laboratory specific
* Unlabeled or improperly labeled specimen
* Prolonged storage or transport
* Improper or damaged container
* Specimen received in fixative
* Oropharyngeal contaminated sputum
* Duplicate specimens stools, sputum) within a 24 hour period. Exceptions cleared by the laboratory
* Specimens unsuitable for culture request (anaerobic culture from not acceptable source, urine from Foley catheter)
* Dry Swab
* 24-hr collection of urine or sputum for AFB or fungal culture
* Other criteria specific to your laboratory

Cultures That Should Include a Gram Stain
* CSF or sterile body fluid (cytospin)
* Eye
* Purulent discharge
* Sputum or transtracheal aspirate
* All surgical specimens
* Tissue
* Urethral exudates (male only, intracellular gonococcus))
* Vaginal specimens
* Wounds

Summary
* Publish specific rules for specimen collection
o There will be exceptions!
+ Make physician or healthcare provider aware of implications of culturing suboptimal specimens
* Communicate, communicate, communicate!
o Real time feedback
o Contact the health care worker who collected the suboptimal specimen

References

* Clinical Microbiology Procedures Handbook. 2nd Edition. . HD Isenberg ed. ASM. Cumitechs. ASM Press. Wash. DC.
* Manual of Clinical Microbiology, 9th Edition. ASM Press. Wash. DC. 2007.Miller MJ.
* A Guide To Specimen Management in Clinical Microbiology. ASM Press. Wash. DC. 1999.

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