Clinical Trials

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what is evidence based medicine?

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use of current best evidence in making decisions about the care of individual patients

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Steps to providing EBM

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ask - clinical question
acquire (best scientific evidence)
appraise - evaluate evidence
apply
***** - evaluate performance

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practice of EBM

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using... to improve patient outcomes
1. patient's values and expectations
2. individual clinical expertise
3. best available clinical evidence

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Research Methods - approach

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quantitative** vs qualitative
or mixed methods

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quantitative research strategies

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experimental > intervention under control of the researcher
observation > not under control

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study designs in clinical research

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prospective vs retrospective vs cross-sectional

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PROSPECTIVE
1. experimental > randomized or controlled clinical trial
2. analytical > cohort study, comparison groups
3. descriptive > cohort study, single group

RETROSPECTIVE
1. analytical > cohort study, comparison group OR case control
2. descriptive > cohort study, single group
* retro cannot be randomized

CROSS-SECTIONAL > analytical or descriptive

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deciding on type of study

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factors?
- state of current knowledge
- availability of comparison group
- ethics of randomization
- frequency of events
- research question
- feasibility

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What is a clinical trial?

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form of clinical research that evaluates the effects of >1 health-related interventions on health outcomes

- randomized controlled trial is the primary method for evaluating therapeutic interventions

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TCPS2

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tri-council policy statement-2

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Randomized Controlled Trials

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- experimental method
- treatment and control groups are assigned by chance rather than chosen by subject/doctor/researcher > attempts to make both groups the same except for intervention

key features:
- ethics
- randomization
- concealment of allcoation
- blinding
- complete follow-up

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Clinical Drugs Trials - Phases

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1. "first into man" - small number of patients > figuring out safety and doses
2. "proof of principle" > studies involving patients with specific disease, first venture into safety and efficacy
3. large-scale comparative studies > 3a) demonstrative of efficacy and safety; 3b) new indications
4. surveillance and post-marketing studies

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Hierarchy of evidence

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best to least

1. meta-analyses and systematic reviews
2. randomized controlled trials
3. cohort studies (prospective better than retro)
4. case-control studies
5. case reports (write article about somebody with particular side effect); case series (several case reports)
6. editorials, expert opinion (only when there is no other evidence available)

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Makes a good trial

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1. high internal validity
- low systematic error > bias and confounding (systemic deviation from the truth)
2. precision > low random chance error
3. high external validity
- generalizabiltiy > extent in which results can be applied to other individuals or settings > AKA EBM: can this be applied to my patient?

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Strengths of RCT

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- difference at the end = due to intervention >> only study that can prove causality, and not just correlation
- groups similar for known and unknown confounders

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Randomization in RCTs

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randomization > sorting participants > intervention OR control group > outcome

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Randomization

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- allocation of treatment by chance
- reduces SELECTION BIAS
- achieved by random sequence generation, coin toss, computer...always reported in published study

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Allocation Concealment

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- researcher doesn't know the patient that is being recruitment
- not usually described in published papers

Sequentially Numbered Opaque Sealed Envelopes (SNOSE)

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Blinding

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- disguise treatment
- blind to avoid unequal co-intervention in treatment groups and unequal ascertainment of outcome
- look for descriptions in published papers about who was blinded > will affect interpretation

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allocation concealment VS blinding

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AC = blinding before randomization > can always be implemented > aims to prevent selection bias

B = blinding after randomization > goal is to prevent unequal treatment of groups

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cohort

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group of individuals having a statistical factor in common

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Cohort Study
prospective vs restrospective

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proceed from exposure to factor of interest (now or in the past); then FOLLOW FORWARD in time to determine outcome

PROSPECTIVE - start assembling cohort and collects data in the future
RETROSPECTIVE - use existing database to assemble cohort at a time in the past and follow patients forward

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Case Control Study

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- looking backwards
- looks at group with a certain outcome and selects another group without the outcome
- information is compared on whether subjects have been exposed to the treatment

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Cross-sectional study

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looking at now/snap-shot

- examines relationship between outcomes and exposures in a defined population at one particular time

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Following up on RCTs

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- ensure that all participants are accounted for > and if they dropped out, why?

this reduces ATTRITION BIAS (bias arising from exclusion of participants from study groups)
- can look in paper to see who dropped out and reasons

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Patient flow diagram

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assigned for eligibility > patients declined > rest randomized > allocated to 1) intervention or 2) control > numbers tallied for a) died before discharge, b) wished to be excluded, c) lost to follow-up and d) excluded from analysis > reported number of patients analyzed

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historical documents

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1. hippocratic oath > earliest known code of medical ethics (5th century BC) > "first do no harm"
2. nuremberg code - "voluntary consent" > US report post-Nazi
3. declaration of Helsinki > world medical association (1964) > cornerstone for research ethics
4. Belmont report > National Commission for the protection of Human Subjects of Biomedical and Behavioural Research > summarizes ethics for research with human subjects > "respect, beneficence, justice"

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General Requirements for RCTs - lecture 8

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medically, scientifically and ethically justifiable
- appropriate treatment and comparison groups
- benefit vs risk
- compatibility with health care needs
- sufficient sample size to find a difference
- reasonable doubt about efficacy

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responsible conducts of research

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- ethics/human subjects protection
- accountability of researchers

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rules and regulations of clinical research

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REGULATIONS : Health Canada Food and Drug Regulations for Clinical Trials

Guidelines
- Tri-council Policy Statement-2 (TCPS2) - ethical conduct for research involving humans (Canada)
- International Conference on Harmonization of pharmaceuticals for human use Good Clinical Practice (ICH-GCP) guidelines

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Drug Approval process in Canada

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approvals based on drug's safety, efficacy and quality

1. Therapeutic Products Directorate (TPD) > reviews trials for pharmaceuticals and medical devices
2. Biologics and Genetic Therapies Directorate (BGTD) > reviews trials for biologics and radiopharmaceutics
3. Natural Health Product Directorate (NHPD) > reviews trials for natural health products

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Clinical Trials

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- investigation of drug for use in humans that involve human subjects > intended to verify clinical, pharmacological or pharmacodynamic effects
- Phase 1, 2, 3 studies involving human subjects must be reviewed and approved by Health Canada
- in Canada, all studies must follow ICH-GCP guidelines as well as be reviewed by Research Ethics Board (REB) > who follows TCPS2

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ICH-GCP

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2 important elements
1. patient safety
2. study credibility

standard for clinical trials that provides assurance that data and reported results are credible , while keeping the integrity and confidentiality of study subject are protected

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Research Ethics Board (REB)

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- independent peer review body
- >5 members, both medical and lay
- reviews protocol to ensure safety and well-being of subjects
- research begins AFTER APPROVAL is granted
- usually more than one institution involved

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TCPS2

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core principles
1. respect for persons - autonomy, informed consent > subject voluntarily confirms willingness to participate ; may be delegated to an authorized third party (ex. parent for child)
2. concern for welfare - beneficence, maximum benefit/minimum risk
3. justice - fairness

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threats to voluntary participation

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1. undue influence > from a person of authority
2. coercion > involving harm or punishment
3. incentives > not the same as compensation/reimbursement

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Capacity (research)

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participants must understand information about the research and appreciate the consequence of their decision to participate
"assent" obtained for children

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Stopping or withdrawing from study

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1. researchers may stop a study if it doesn't meet safety/efficacy rules
2. researchers may pull participant > worsening health, better therapy available, non-adherence
3. participant removes themselves

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research without consent

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allowed !
- involves no more than minimal risk
- impossible to carry out research with consent
- won't affect person's welfare
- not a therapeutic intervention
- consent is obtained later, if appropriate

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concern for welfare

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research risks
1. physiological > ex side effects
2. psychological > ex stress
3. social > ex embarrassment
4. economic > ex monetary

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privacy and confidentiality

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privacy risks related to being able to identify participants and associated potential harms

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clinical equipoise

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genuine uncertainty exists on the part of the relevant expert community about what therapy or therapies are most effect for a given condition

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placebo controlled trials

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ethically acceptable if...
- used to establish the efficacy or safety of the intervention
- doesn't compromise safety/health of patient
- compelling scientific justification

placebos used when...
- no established effective therapies
- doubt about benefit of available therapies
- add-on trial
- patients have provided refusal of effective therapy and withholding therapy will not cause serious/irreversible harm
- patients resistant to available therapies due to treatment/medical history

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potential conflict of interest by being a clinician-researcher?

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yes!
responsibility of health care provider is patient VS researcher's is research

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clinical trial registration

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public registries to provide a record of ongoing clinical trials
intended to increase transparency and accountability

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Adverse events

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- untoward medical occurrence in patient or subject
- does not necessarily need to have a casual relationship with treatment or usage
- includes adverse reactions which are noxious and unintended response to a medicinal product or to a medical or surgical device

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serious adverse event + reporting

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SERIOUS ADVERSE EVENT
- is life threatening or results in death
- results in persistent or significant disability/incapacity
- is a congenital anomaly or birth defect
- results in hospitalization

REPORTING
- reporting requirements will vary by local research ethics board and regulatory authority

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adverse drug reaction

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ADR is a type of adverse event with a reasonable possibility of being related to the treatment

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research misconduct

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1. plagiarism - misrepresenting someone else's work as one's own
2. fabrication - report measurements that have not been performed
3. falsification - ignore or change relevant data that contract reported findings

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Clinical trial protocol / research plan

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1. research problem - background and significance
- area of concern
2. research question - objective/hypothesis
- what?
- primary questions = focus of the study
- secondary questions = add valuable information

3. design - structure and procedures
4. statistical issues - sample size, analytical approach

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elements of the research question

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PICOT
population
intervention
comparison
outcome
timeframe

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null hypothesis (for superiority trials)

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superiority trials - when you test whether a drug is better than another drug

null hypothesis has to be a testable statement > there is no difference in whatever is being tested

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Alternative/Study hypothesis

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opposite of a null hypothesis

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hypothesis testing
superiority vs equivalence vs non-inferiority

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1. superiority - intended to determine that new treatment is better than control
2. equivalence - new and control treatment are therapeutically similar
3. non-inferiority - new is no worse than the comparison

WHEN CHOOSING...
- consider effective treatment and ethics of placebo-controlled trial
- pharmacological profile and other factors (ex. convenience, cost,...)

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Trial designs - participants

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when choosing...
1. selection criteria - what kinds of pts are best suited for research question
2. sampling procedure - process of picking subgroup to be part of study

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Sampling the target population

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target population > all members of particular group that results are intended to be generalized to
study sample > subset of popn included in study

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selection/admission criteria

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1. ethical rationale > don't want to deny treatment of impose contraindicated treatment

2. scientific rationale > must fulfill same admission criteria to optimize study results

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Inclusion criteria to maximize

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- rates of outcomes
- likely benefit of intervention
- generalizability
- ease of recruitment

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exclusion criteria to minimize

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- harm
- ineffectiveness
- non-adherence
- loss to follow-up
- practical problems

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what is a "representative sample"

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sample that is similar to popn on all charateristics

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Sampling methods

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1. probability/random > all members of popn have equal chance > rarely done
simple - each individual is randomly chosen
stratified - popn divided into homogenous subgroups before simple sampling is applied
cluster - relatively homogenous group by dividing popn up and selecting one of these groups

2. non-probability / non-random
systematic - ordering popn and then selecting members at regular intervals
convenience - patients selected because of convenience
purposive - patients selected based on a variety of criteria

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Selection / sampling bias

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1. individuals have unequal chance of being selected
2. intervention and comparison group differ from each other

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Trial Design - exposure to intervention (4)

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parallel - each subject just receives one of the treatments - each subject receives all treatments
cross-over
cluster - groups of subjects (rather than individuals) are randomized to interventions
factorial

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Longitudinal study

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follows subjects forwards over time

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Sample size - based on number of participants

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1. fixed size - prior sample size calculatio
2. mega trial - large sample
3. sequential - variable size
4. N-of-1 - single subject

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allocation ratio

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ratio of participants in each intervention group

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interventions

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1. intervention/treatment/experimental group
2. comparator/control > intervention can only be measured against an alternative

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choice of intervention

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1. generalizability - feasibility
2. complexity - incorporation of clinical decision-making
3. strength - reasonably affects outcome

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choice of comparison to intervention

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1. placebo
2. active/positive control
3. same intervention, diff regimen
4. absence of treatment
4. standard care control

1, 4 - negative control

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head to head VS add on

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1. head to head - comparing active treatments
2. add-on - comparing the effect of adding on an active treatment

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allocation methods + randomization methods

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1. randomization - chance > key of RCT
2. quasi-pseudo-randomization

RANDOMIZATION METHODS
1. simple - all subjects are randomized
2. blocked - randomize subjects within a block
3. stratified - randomize subgroups sharing similar characteristics
4. cluster - randomly allocate group rather than individuals (ex hospital)

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blinded studies

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blinding methods
1. 1 or more groups don't have knowledge of treatment assignment
2. open trial - all participants and investigators are aware of treatment assignment

blinding is important to minimize risk that groups are treated differently during trial or that outcomes are reported differently
- intended to reduce bias after randomization

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measurement bias

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1. performance bias - systematic differences between groups not due to intervention
2. contamination bias - control group gets the intervention
3. co-intervention bias - treatments other than intervention applied unequally
4. detection bias - outcomes assessed unequally due to preconceived notions

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types of outcomes

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1. primary and secondary (ex. death, disease, pain...)
- easy to observe
- free of measurement error
- clinically relevant
- chosen before starting the study
- can be observed independent of treatment assignment
2. Composite outcome
- a few outcomes adding together
3. Surrogate outcome
- associated with relevant clinical outcome, but by myself it doesn't matter

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outcome evaluation

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1. efficacy/explanatory/fastidious
2. effectiveness/management/pragmatic