Lecture 5Objective 14.

Describe the elements of design of experimental studies: clinical trials and community intervention trials. Discuss the advantages and disadvantages of each.

Definition of a clinical trial

• prospective studies in human subjects• compare the outcomes between

intervention groups• one intervention may be a control

group– could be the standard treatment or no

treatment – placebo or sham indicates a treatment

identical to the treatment to be tested in all aspects except with an inert substance.

Phases of Clinical Trials

Preclinical Preclinical Trials I. Determine Maximum Tolerated

Dose II. Evidence of a Response III. Safety, Efficacy (humans)IV. Safety, Acceptability,

Efficacy

Issues in Clinical Trials

• Posing the right question

• Defining the right end points (outcomes)– Multiple end points

• Defining the population who might benefit– Inclusion criteria– Exclusion criteria

Design of Clinical Trials

• Parallel design– Randomized controls– Concurrent controls– Historical controls

• Crossover design

• Factorial design

• Equivalence design

May 1747, Aboard the Salisbury

Intervention over 6 days SampleSize

Recovered

A quart of cider a day 2 0/225 gutts of elixir vitriol (tid) 2 0/22 spoonfuls of vinegar (tid) 2 0/2Sea water one pint per day 2 0/22 oranges and 1 lemon per day 2 2/2*Nutmeg, Garlic and assorted herbs 2 0/2*1 recovery, 1 partial recovery, Lind J. 1753

1954 Field Trial of Poliomyelitis Vaccine (Salk)

Vaccination Status + Study Pop ParalyticCases

Rate*

Vaccinated 200,745 33 16Placebo 201,229 110 55Inc. Vaccine 8,484 2 24Inc. Placebo 8,577 4 47Not Inoculated 330,201 118 36Total 749,236 267 36+ Placebo areas * per 100,000 Francis T et.al. Field Trial ofPoliomyelitis Vaccine University of Michigan, 1957.

Breast Cancer Therapy

Nodes Rx N 5-yr Survival + se

Neg TMSMSM+RTX

362390396

82 + 491 + 292 + 2

Pos TMSMSM+RTX

224242229

66 + 574 + 575 + 5

Fisher B, et.al. NEJM; 1985,312:665-73 TM-Total Mastectomy,SM – Segmental Mastectomy , RTX – Radiation Therapy

PHS Study: Aspirin Arm

End Point Aspirin Placebo RR* P-value

MI Fatal Nonfatal

599

18171

0.250.56

.0006<.00001

STROKE Fatal Nonfatal

674

268

3.01.1

.16

.61PHS Study Group. NEJM 1988;319:262-88 *RRRelative Risk Aspirin/Placebo

AZT in AIDS

Treatment 24 week survival*

AZT 98%Placebo 78%

Fischl M, et.al. NEJM 1987;317:185-91 *P<.001 Trialterminated due to emergence of beneficial arm

Lecture 5Objective 15.Discuss the terms subject selection, exposure allocation, randomization, stratification, self‑selection, systematic assignment, outcome assessment, threats to validity: internal, external

Selection of Subjects

• from population at risk• determined by inclusion and

exclusion criteria (who will benefit or may be harmed

• how are patients ascertained and recruited for study

• referral bias

Assignment of Exposure

• self-selection (doctor selects or patient selects) can lead to bias/confounding

• exposure (treatment) assigned randomly is preferred (data coordinating center or other independent of investigators)

Why Randomize• Treatment groups comparable wr

to risk factors (known and unknown)

• Removes investigator bias in allocation of subjects

• Removes self-selection bias in allocation of subjects

• Guarantees that statistical tests have valid significance levels

Assignment of Exposure

• Simple Randomization

• Blocked Randomization

• Stratified Randomization

• Systematic assignment is not randomization

Temporal Relationship

Investigator (I) to Exposure (E) and Outcome (O)

I E O

| | |

________________________ t

Measurement of Risk and Association

• Risk: Incidence rates (IR) can be cumulative incidence (CI) or incidence density (ID)

• Association: Risk Ratio (RR) or Risk Difference (RD)

Validity• Confounding Bias: possibility

reduced through random assignment of exposure; all minimized by matching, restriction

• Information Bias: prevent by "blinding"; reduce possibility with objective diagnostic criteria

• Selection Bias: very unlikely to occur (prospective study)

Control of Bias in Clinical Trials

• Selection Bias (randomize)

• Observation bias (blind/mask)

• Attrition bias (simple to participate/incentives)

• Compliance bias (simple regimen)

• Drop-in/Drop-out (timing)

Advantages

• can reduce potential of confounding through random assignment of exposure

• can estimate risk using incidence rates

• best design for interpreting causality

Limitations

• not suited for studying harmful exposures, only preventive or therapeutic agents

• difficult to study rare outcomes

• not well suited for studying outcomes with long latent periods

Limitations

• not well suited for studying a particular outcome; best suited for studying exposures

• cannot study traits of subjects that are present at the time of selection (such as age sex, genetic factors)

Ethics in Clinical Trials

• Informed Consent

• Interim Monitoring and Early Termination

• Proper Timing of Trials

Analysis of Data from Clinical Trials

• Intent to Treat

• Control of Confounding

• Subgroup analyses

• Meta-Analysis

Community trials

• assignment of school rooms, towns and cities to the intervention arms rather than individuals.

• COMMIT - Smoking trial• CATCH - Child and Adolescent

Trial for Cardiovascular Health • Fluoridation studies

Evaluating a therapeutic

effectiveness study• Was the study properly conducted?

– Were the entry criteria clearly specified? (evidence entry criteria fulfilled)

– Were the study groups comparable? (potential confounders accounted for? attempts to control confounding?)

– How was compliance assessed?– Did the loss to follow‑up exceed 20%?

Evaluating….

– Was the study blinded?– Were the outcomes clearly

specified? (outcomes clearly specified and accurately measured?)

– Was the study size sufficient to justify the author's conclusions? (if the results were not significant, was the power reported?)

Evaluating...

• What is the "value" of the study?– How were the subjects recruited?– Were the results clinically

significant?– Do the subjects in the study

resemble your patients? (Did the study contain men and women, minorities, elderly?)

Evaluating...

– Could your patients avail themselves of the treatment? (Did the treatment used in the study involve medicines or treatments unavailable to the average patients? Cost? Distance? Side effects?)

Internal Mammary Artery Ligation (IMAL) in Angina

Author Study %Improved

Battezzati (1950) Case Series 95%

Mitchell (1958) Case Series 65%

Cobb (1959)DBRCT

ShamLigation arm

43%32%

Supplemental Ascorbate in Treatment of Cancer

• 100 Treated (began ascorbate treatment)

• 1000 Controls 10 to 1 match (same sex, age, site, histology)

• Average Survival Time– Treated: 210 days– Controls: 50 days

Cameron and Pauling, Proc. Natl Acad. 1976