Module 9 Flashcards
What is one defining feature of experimental studies?
Manipulation of tx or exposure
What is the study called when the unit of analysis is the individual?
Randomized clinical trials
What is the study called when the unit of analysis is groups?
Community interventions
Characteristics of epidemiologic experimental studies
Resemble controlled experiments performed in scientific research
Assignment of exposure done randomly by investigator
Best for establishing cause-effect relationships and for evaluating the efficacy of preventive and therapeutic interventions
Characteristics of quasi-experimental experiments
Ranked immediately below controlled experiments in rigor
Investigator is unable to randomly allocate participants to the study conditions (tx or control group)
Because of this, the intervention and control groups may differ in ways other than the presence or absence of the intervention
Clinical trials definition
A planned experiment that assesses the efficacy of a tx or preventative intervention in humans
Randomized control trials are the gold standard to which other studies are compared
Design of a clinical trial
The unit of analysis is the individual
Prospective: follow at least two groups forward in time
-Tx and control groups
-Participants in both groups are enrolled, treated, and followed over the same time period.
Intervention is compared with placebo or usual care
-Investigator controls/manipulates conditions studied
-Investigator assigns exposure (tx) randomly
Outcomes in treated group are compared with outcomes in an equivalent control group
Details about first clinical trial
James Lind in 1747 applied experimental methods to discover that eating citrus fruits was an effective remedy for scurvy among sailors at sea
What makes a randomized clinical trial superior to the other study designs?
The experimental nature
Details about random assignment
Makes intervention and control groups look as similar as possible
Chance is the only factor that determines group assignment
Neither the patient nor the physician know in advance which prevention program or therapy will be assigned
Details about randomization
Purpose is to prevent a form of bias called “confounding bias”
Method of choice for assigning participants to the tx or control conditions of a clinical trial
Guarantees that tx assignment is not based on pt prognostic factors (anything else that may influence the outcome)
Details about quasi-experiment
Concurrent comparison group is allocated by a nonrandom process (convenience sample)
Non-random assignment may cause mixing of the effects of the intervention with differences among the participants of the trial
The tx and control groups may be different in ways extraneous to whether they get the intervention or not (such as age)
What are the two main types of clinical trials?
Prophylactic and therapeutic trials
Prophylactic trial purpose
Evaluates the effectiveness of a substance that is used to prevent dz; it can also form a prevention program. It is a test of a form of primary prevention
Therapeutic trail purpose
Involves the study of curative drugs or a new surgical procedure to improve the pt’s health. It is a test of a form of secondary or tertiary prevention.
Definition of crossover designs
Any change of tx for a pt in a clinical trial involving a switch of study txs
Planned crossovers
A protocol (plan) is developed in advance, and the pt may serve as his/her/their own control
Unplanned crossovers
Exist for various reasons, such as the pt’s request to change tx
Phase I of clinical trial
To learn about the safety of drug, tx, or vaccine.
In adult volunteers (<100 volunteers)
Drug dosage
Side effects
Phase II of clinical trial
To learn if the drug, tx, or vaccine works
Expands testing to a group of 100 to 200 participants (from the source population)
May include a control group
Examine antibody responses and clinical reactions
Phase III of a clinical trial
To learn if the drug, tx, or vaccine is better than usual care
(the main test) assesses the efficacy of the vaccine in the source pop (possibly thousands of participants)
Now must include at least one control group
Goes up for FDA approval
Phase IV of a clinical trial
To learn what else may need to be known
Only after FDA approval
Studies very long term effects in large groups of ppl
What question does efficacy ask?
Can the tx work under ideal conditions?
Established by restricting study to pts who will follow medical advice
What question does effectiveness ask?
Can the tx work under normal (ordinary) conditions?
Established by offering tx to pts and allowing them to decide to accept or reject it
If tx ineffective, could be d/t lack of efficacy or to lack of compliance
Compliance definition
Extent to which pts follow medical advice
Intervenes between an efficacious tx and an effective one
Not just willful neglect of advice
Failure to understand instructions
Failure to keep prescriptions filled
Can limit effectiveness regardless of efficacy
What are the types of bias in clinical trials?
Placebo effect
Hawthorne effect
Interviewer/abstractor bias
Loss to follow-up bias
Placebo effect definition
The effect on pt outcomes (improved or worsened) that may occur d/t the expectation by a pt that a particular intervention will have an effect
Hawthorne effect definition
The process of being observed (or studied) itself brings about behavior change in the participants and influences the results
Interviewer/abstractor bias definition
Occurs when interviewers probe more thoroughly in the tx group than in the controls (or any two comparison groups)
Loss to f/u bias definition
Can occur when many participants are lost to f/u over time and are not included in the analysis of data at the end, and those lost to follow up differ systematically from the ones who are left.
Blinding definition
An attempt to control or prevent some forms of bias in clinical trials
There can be:
Single blinded studies
Double blinded studies
Details about single blinded study
The participants are blinded, but investigators are aware of who is receiving the active tx?
Why blind pts?
-Pts try to get well/please physicians
-Minimize potential bias from a placebo effect
-Placebos improve comparability of tx groups in terms of compliance and f/u
How placebo is carried out in clinical trials
Pill of same size, color, shape as tx
Sham operation (anesthesia and incision)
Double blind study definition
Neither the participants nor the investigators know who is receiving the active tx
Benefits of double blind study
Best way to avoid unconscious bias
-Physicians don’t know which pt is taking the placebo and which pt is taking the drug
-Assessors of outcome are not the treating doctors and are not told which tx was used
Problems with blinding
For non-drug studies such as those involving behavior changes or surgery, it may be impossible or unethical to blind
It may also be problematic to blind in drug studies where a tx has characteristic side effects
Loss to follow up bias details
A common problem in clinical trials and cohort studies, increasingly so in cohorts with longer f/u times
Can bias the results, if the percentage lost to f/u is large, and those lost to f/u are different from those who remain with respect to the outcomes being measured
Reasons for loss to f/u
Refusal to participate
Unable to locate
Unable to be interviewed
Death
Clinical endpoint details
In a clinical trial, the outcomes are referred to as clinical endpoints
May include incidence rates of dz, death rates, recovery rates, reoccurrence rates, or increased survival time
Outcomes must be measured in a comparable manner in the intervention and control groups
Exposure definition
The experimental tx or intervention that has been assigned to one group
Relative risk definition
The ratio of the incidence of the clinical endpoint (or outcome) in the exposed or tx group to the incidence of the clinical endpoint in the non-exposed or placebo group
Relative risk formula
Relative risk= incidence (or mortality) rate in the treated/incidence (or mortality) rate in the controls
[a/(a +b)]/[c/(c+d)]
Precise interpretation statement for relative risk
The exposed or tx group were RR times as likely as the non-exposed or placebo group to develop the dz, die, or recover
Sample of Nazi medical experiments that were not ethical
Twin and genetic experiment (of 1500 sets of twins, only 100 remained alive)
Spotted fever experiments
- >90% died
-Injected with the dz agent and then experimental “cures” tested
Similar experiments with yellow fever, smallpox, typhus, TB
Seawater experiments (given seawater to drink)
Freezing and hypothermia experiments
Sterilization experiments
Others
Principles of the Nuremberg code of 1949
Human subject should provide voluntary consent and know the risks of participation
The experimental results must be for the greater good of experimentation
Experiment should be based on previous animal experimentation
Experiment should avoid unnecessary physical/mental suffering
No experiments should be conducted if it is believed to cause death/disability
Benefits must always outweigh risks
Adequate facilities should be used to protect subjects
Experiment should be conducted only by qualified scientists
Subject should always be at liberty to stop at any time
Scientist in charge must be prepared to terminate the experiment when injury, disability, or death is likely to occur
Tuskegee Syphilis Study (1932-72) and the Belmont Report (1979)
Respect for persons: protect the autonomy of all ppl, treat them with courtesy and respect, allow for informed consent, be truthful and conduct no deception
Beneficence: follow philosophy of “do no harm”, while maximizing benefits to research project and minimizing risks to participants
Justice: fair and equal distribution of costs and benefits to potential research participants
Ethical aspects of human experimentation
Informed and voluntary consent
Withholding beneficial tx from control group
-Crossover designs are used as a solution
Monitoring for harmful SEs in tx group
-Can be circumvented using animals
Deciding when to withdraw an individual pt
Deciding when to stop the entire study
-Depends on degree of uncertainty
Vulnerable groups
-Children
-Prisoners
-Intellectually challenged
-Poor, homeless
What must be true to ethically continue a trial?
Benefits must always outweigh the risks
There must still be uncertainty about the effects of the tx
Advantages of clinical trials
Most scientifically rigorous design for evaluating the effect of a single, controlled exposure or intervention
Ability to randomize reduces the likelihood that groups will differ significantly on factors other than the tx, that may influence the results, such as age.
Less potential for bias than observational studies
The best of all studies for establishing cause and effect (causality)
Reproducible
Provide the greatest control over:
-The amt of exposure
-The timing and frequency of exposure
-The period of observation
Limitations of clinical trials
Ethical considerations may limit:
-Selection of participants
-Generalizability of results
-Type of exposures studied: not for harmful exposures
Applicable only to certain types of research questions, at a particular stage of knowledge about the problem
Expensive
Complex planning
Adherence to protocol is difficult to enforce
-Compliance issues
Artificial setting
Generalizability may be limited
Group assignments in Lind clinical trial
Each group had 2 people who already had scurvy
1: A quart of cider daily
2: An unspecified elixir 3 times/day
3: Seawater
4: Garlic, mustard, horseradish
5: Spoonful of vinegar
6: 2 oranges and a lemon daily
In six days, only group 2 was fit for duty
What are the two types of interventional studies?
Randomized control clinical trials
Community interventions
What are multi-center trials?
Results from several researchers are pooled.
Are multi-center trials randomized control trials or community interventions? Why?
Randomized control trials because the unit of analysis is the individual
