Midterm Flashcards
Describe the drug development process in canada
4 phases of clinical trials
Phase 1: first in-human to evaluate safety and PK/PD
Phase 2: Exploratory, safety and efficacy in individuals with the disease
Phase 3: Confirmational, confirm safety and efficacy on larger scale
Phase 4: monitor safety and efficacy once the drug is on market
Pharmacokinetics vs pharmacodynamics
Pharmacokinetics (ADME)
how our body works on the drug
Absorption
Distribution
Metabolism
Excretion
Pharmacodynamics
how the drug works on our body
Mechanism of drug action
Relationship between drug concentration and effect
Adverse reactions
Approvals needed before initiation of clinical trials and who to get it from
Certificate of approval- USask Research Ethics Board
Letter of authorization- Sask health authority
No Objection Letter- Health Canada
When is a CTA required
Clinical trial application
Clinical trials of a product that is not authorized for sale in Canada
Clinical trials for marketed drugs where the proposed use of the drug is outside the parameters of the Notice of Compliance (NOC) or Drug Identification Number (DIN) application.
All experiments begin with a _________
question
What are outcomes
Specific assessments designed to help inform a given study objective
The success of the study will be based on results from _______
the primary outcome
Describe the steps in creating clinical trials
Question–>Objectives and outcomes–> Primary outcome–> Enrollment–> Randomization–> Allocation concealment–> Blinding –>Control groups –> Finding control group –> placebo controls
Two criteria of enrollment
Inclusion and exclusion criteria
How is randomization accomplished
Stratification
What is allocation concealment
How well you can conceal which group the patient has been randomized to
What are adequate procedures to ensure blinding
should have a matching control, control and intervention should be identical in appearance
What are some complications with blinding
Hard to do when comparing different techniques. Such as injectable vs oral.
Solution: patients who get ablet get placebo injection and vice versa
what group is essential to the scientific process
parallel control group
4 different options for control groups
Placebo
No treatment
Usual care/ standard of care
active treatment
what is the default control group for any RCT
placebo control
Quasi vs true experiment
Quasi: non-random assigning, pre-existing groups that got treatment after the fact, controls are not mandatory
True: Randomly assigned, Treatment designed by the researcher, control is mandatory
What is a prospective study
Almost all clinical trials are prospective
Looks forward
Watches for outcomes such as development of a disease
What is a retrospective study
Looks backwards
Examines past exposure to suspected risk of protection factors in relation to an outcome that is established at the start of the study
When would we use a historical control? What is a historical control
When there is no active control or placebo is unethical or when investigators think all patients should get intervention because it is so good
Outcomes compared to a group of patients retrieved from a database
why not use a historical control
Results are highly dependent on choice of control
subject to considerate bias
Crossover design
In a crossover trial, all of the participants in the trial will be exposed to all of the interventions/controls used in the trial
The advantage of a crossover design is that patients (in theory) serve as their own control
And…patients are able to experience both treatments
Does order matter in crossover design
yes
When should crossover design be used
Diseases that are chronic and stable
Treatments should not result in total cures, but should alleviate the disease
Withdrawal studies
Participants on a particular treatment (e.g., for a chronic disease) are taken off therapy or have the dosage reduced
Objective is to assess response to discontinuation or dose reduction
This design may be used to evaluate duration of benefit of an intervention already known to be useful
Cohort study
Observational
Participants (a cohort) are selected and information is obtained to determine which participants either have: Particular characteristics related to the disease or have been exposed to something that may cause disease
Participants are then followed in time and the incidence of the disease of those exposed is compared to the incidence to those who were not exposed
What kind of study was the framingham
Cohort
A cohort was selected from the city of Framingham, Mass. and followed for decades, tracking cardiovascular outcomes
Data from this trial has been used for years to calculate risk scores for CV disease
And the study is still ongoing…
Advantages and disadvantages of cohort studies
Advantages: Ability to study multiple outcomes for a given exposure
Good for investigating rare exposures
Can calculate rates of disease in exposed and unexposed individuals over time
Disadvantages: Large numbers of subjects are required to study rare exposures
Prospective Cohort Studies:
May be expensive
May require long durations for follow-up
Maintaining follow-up may be difficult
Susceptible to loss to follow-up or withdrawals
Retrospective Cohort Studies:
Susceptible to selection bias
Susceptible to recall bias
Less control over what information is available
Case-control study
compares patients who have a disease or outcome of interest (cases) with Patients who do not have the disease or outcome (controls)
Look back retrospectively to compare how frequently the exposure to a risk factor is present in each group to determine the relationship between the risk factor and the disease.
Case-control vs cohort studies
Unlike cohort studies, case-control studies identify subjects by outcome status at the outset of the investigation.
Selecting the appropriate group of controls can be one of the most demanding aspects of a case-control study (e.g., should be from same source population).
Individual matching may be used, whereby each case is individually paired with a control subject with respect to the background variables (e.g., age, sex
advantages and disadvantages of case-control studies
Advantages: Relatively quick to conduct
When a condition is uncommon can produce a lot of information from relatively few subjects
Relatively inexpensive
Existing records can be used
Disadvantages: Susceptible to recall bias
Difficult to validate information
Selection of an appropriate control group may be difficult
Individual matching can be time-consuming and expensive
Case series
Case series are a group or series of case reports involving patients who were given similar treatment.
Reports of case series usually contain detailed information about the individual patients.
This includes demographic information (for example, age, gender, ethnic origin) and information on diagnosis, treatment, response to treatment, and follow-up after treatment.
Size can range from two or three cases to hundreds or even thousands.
Advantages and disadvantages of case series
Advantage: can provide important initial indication of treatment efficacy, can describe the natural history of a condition or the recovery and complication rates after a treatment
Disadvantage: no control group
Characteristics of a good case series
Clearly defined question
Well-described study population
Well-described intervention
Use of validated outcome measures
Appropriate statistical analyses
Well-described results
Discussion/conclusions supported by data
Funding source acknowledged
Why are clinical trials important
Well designed and conducted clinical trials yield reliable results and help ensure participant safety.
Poorly designed clinical trials waste resources and have the potential to put participant’s safety at risk.
principles of GCP are designed to:
Be flexible and apply to a broad range of trials
Encourage consideration and planning
Be considerate of the factors relevant to ensuring a trials quality
What are the 3 regulatory bodies
Therapeutic products directorate
Biologics and genetic therapies directorate
Natural and non-prescription health products directorate
what does TPD, BGTD, and NNHPD regulate
Therapeutic Products Directorate (TPD) ensures that the pharmaceutical drugs and medical devices offered for sale in Canada are safe, effective and of high quality
The Biologics and Genetics Therapies Directorate (BGTD) ensures that the biological or radiopharmaceutical drug and medical device combinations offered for sale in Canada are safe, effective and of high quality
Natural and Non-prescription Health Products Directorate (NNHPD) falls under the Natural Health Products Regulations of the Food and Drugs Act. These Regulations came into effect on January 1, 2004
what is a nutraceutical
a product isolated or purified from foods that is generally sold in medicinal forms not usually associated with food”
What is a research ethics board
an independent committee made up of medical and non-medical professionals, such as scientists, physicians and community advocates, that serves to ensure that a clinical trial is ethical
When is a REB required
a) research involving living human participants
b) research involving human biological materials, embryos, fetuses, fetal tissue, reproductive materials, and stem cells. Derived from living and deceased individuals
When is research exempted from REB review
- REB review is not required when it relies exclusively on information that is in the public domain
- Observation of people in public places
- research relying exclusively on secondary use of anonymous information or anonymous human biological materials
- Quality assurance and quality improvement studies
- Creative practice activities
Three core principles
Respect for persons
Concern for welfare
justice
What is respect for persons
Autonomy: ability to make their own decision, being well informed
Protection of individuals with developing, impaired or diminished autonomy: researchers must seek consent from an authorized third party
Consent is the key aspect of the “respect for persons” core principle
Participant autonomy and informed consent
What is concern for welfare
Welfare of a person: quality of a persons life
Determinants of welfare: Housing, employment, security, family life
Concern for welfare: Concern for privacy, for minimizing harm
Minimizing risk/harm
what is justice
Participants must be treated fairly, equal distribution of research benefits as well as burden, Awareness of participant vulnerabilities, recruitment based on inclusion/ exclusion criteria
Inclusion/exclusion of participants, equitable distributions of risk and reward
T/F Consent is an ongoing process
true
8 requirements of consent
- freely given by participant or proxy if they lack the capacity
- Easily understandable
- on-going
- Precede data collection
- No undue influence or coercion
- Incentives cannot be coercive (not enough money to cloud judgment)
- If participant lacks the capacity to decide, they need to get an authorized third party
- consent must be documented
When can consent be waived in research (4 reasons)
No more than minimal risk
Could not be carried out otherwise
If the waiver will not adversely affect the subjects
Subjects will be provided with additional information
When can consent be waived in individual medical emergencies (5 reasons)
Needs immediate intervention
No standard effective treatment, or research offers direct benefit when compared to standard care
Participant is unconscious or lacks capacity
Authorization by a third party cannot be secured in time
What was TGN1412
Humanized monoclonal antibody originally intended to treat leukemia and rheumatoid arthritis.
showed no evidence of toxicity in non-human primates
Every patient that received it developed severe allergy-like reactions resulting in hospitalization
This resulted in a cytokine storm
failed to uphold the respect for persons because patients were not well-informed
4 lessons learned from TGN 1412
animal data doesn’t always predict human response
Guidelines for phase I clinical trials were revised to improve safety
A rigorous, fair and transparent consent process is of the utmost importance
Incentivization must not unduly influence the decision-making of the patient
What must an acceptable plan for monitoring safety include
how participant safety will be monitored
What actions will be taken in the event that the safety of a participant is compromised
How the efficacy of the intervention will be monitored
What action swill be taken if the efficacy is greater than expected
Criteria by which participants may be removed
Study-wide stopping rules
Study-wide stopping rules identify when a study should cease due to evidence that (3 things)
A condition is more or less efficacious
A conditions is more or less safe
The study is futile: data is unreliable
What is MTD, MABEL, and NOAEL
MTD: maximum tolerated dose, highest dose that does not cause unacceptable side effects
MABEL: Minimal anticipated biological effect level, lowest animal dose required to produce pharmacological activity
NOAEL: Non-observed adverse effects level, highest dose at which there is no observed adverse effect in animal
What were the 4 things wrong with TGN1412
Did not sufficiently inform participants
failed to disclose the degree of uncertainty
Coercive financial incentive
Participants were not well educated on the nature of the study or mechanism
What were the ethical issues of BIA 10-2474
Physicians continued running a trial after a participant was sent to the hospital
Participants were not informed of the acute symptoms of the hospitalized patient
Physicians did not wait to determine the full scope of the adverse effects of the hospitalized participant.
respect for persons and concern for welfare were violated
What are the goals and chief concern of phase I clinical trial
Phase 1: is the treatment safe, estimates safety and tolerability and establish the recommended dose for phase II trials.
Concerns: little to no experience regarding the drug and its effects, combination of clinical risk and uncertain benefit raises concern
Goal and chief concern of phase II clinical trial
Goal: does the treatment work, determines if there is an effect in a small number of volunteers
Concerns: Participants may be financially impacted by their health condition which may be coercive, Circumstances may affects the patient’s perception of risk and rewards
Goal and chief concern of phase III clinical trial
Goal: is it better than the current standard therapeutics, effectiveness and safety are compared to current standard
Concern: Care of patients should not be compromised by the assignment to an experimental group, drug may provide additional benefit relative to the standard options so patients should continue to receive adequate treatment following the study
Goal and chief concern of phase IV clinical trial
Goal: Effectiveness and long-term safety are monitored over a large number of participants
concern: Trials should be undertaken for true scientific purposes without external motivations, sponsors pay a per capita fee which may sway investigators
Why was BIA 10-2474 important
highlighted importance of consent and stopping rules
what is the ISO definition of quality
Degree to which a set of inherent characteristics fulfills requirements
definition of quality of care
the degree to which health services for individuals and populations increase the likelihood of a desired health outcome
Definition of medical error
failure of a planned action to be completed as intended or the use of wrong plan to achieve an aim
definition of an adverse event
an undesired outcome resulting from medical management rather than underlying condition of the patient
Definition of patient safety
freedom from accidental injury
what is the magnitutde of health care
44,000-98,000 hospital deaths in the US per year
Canada: one in eight affected by an adverse event
Human errors will occur between 1/1000 and 1/5000 events, and this will increase in stressful situations
What are system errors
flaws in the systems and processes that contribute to most mistakes
what is the swiss cheese model of accidents
When the different slices of swiss cheese incidentally line up, it will lead to an accident even though it is improbable
what is the blunt and sharp end model
The blunt end refers to the many layers of the health care system not in direct contact with patients, but which influence the personnel and equipment at the sharp end that come into contact with patients.
common lab medicine errors
sample collection, handling/storage
sample preparation
misinterpretation
interference
instrumentation
communication
inter oberver variability
What stage do most errors happen in clinical laboratories
pre-analytical
Laboratory-clinical interface errors
Inappropriate test request
Inappropriate test interpretation
inappropriate test utilization
What is disclosure
A part of informed consent that enhances patient decision making
Open communication with patient about error is not seen as common practice
consequences of the failure to disclose
Broken trust
ethical challenge
financial factor
General considerations in laboratory stydies in disease
S ubjective
O bjective
A ssesment
P lan
how should clinicians think of tests
as components of a strategy for solving patient’s problems
Serum vs plasma
presence of fibrinogen in plasma
no delay is necessary in obtaining plasma prior to centrifugation
Usually a greater volume of plasma than serum
types of tests
Physiological function
markers
Screening
lab testing definitions of precision vs accuracy
Precision: reproducibility of replicate anlysis
Accuracy- relationship of result obtained to correct or try value
inter-individual biologic variability
race, gender, age, body size
Intra-individual biologic variability
Diurnal variation
circadian
menstrual cycle
seasonal
aging
Preanalytic causes of variability
Food intake
exercise
drug therapy
analytical and postanalytical causes of variability
analyticial: inaccuracy, imprecision
post-analytical: transcription errors
sensitivity, specificity, prevalence, positive predictive value, negative predictive value
sensitivity: frequency of correct result in patient with disease
specificity: frequency of correct result in health patient
Prevalence: frequency of disease in total subjects examined
+ value: percent of positive results that are positive
- value: percent of negatives that are true negatives
how to calculate sensitivity, specificity, positive predictive value and negative predictive value
Sensitivity= TP/(TP +FN) x 100, True positive/ all sick subjects
Specificity= TN/(TN + FP) x 100, True neg/ all disease free
+= TP/(TP+FP) x 100
-= TN/(TN+FN) x 100
explain the steps invoovled in ordering clinical tests and list 5 potential errors that may occur
MD writes order: inappropriate test, Handwriting not legible, request on wrong form, wrong patient ID
Nurse reviews
Clerk writes requisition: form lost or delayed, wrong plate used
Lab prepares tube
Phlebotomist draws blood: wrong patient, sample hemolysis, inadequate volume, tourniquet on too long, blood diluted with IV fluid, wrong time
Specimen collection, transport and storage
four commonly used collection tube types
Red: no additive/ may contain serum separator, used for general biochemistry
Dark blue: No additive/ used for serum, for trace metal analysis, general biochemistry
Dark Brown: Heparin added, for trace metal in whole blood (zinc, cadmium, lead), general biochemistry
Green top: Heparin added, 0.2mg/ml, antithrombin preventing clotting, general biochemistry
what is evidence based clinical medicine
A set of procedures, pre-appraised resources and information tools to assist practitioners to apply evidence from research in the care of individual patients
a combination of individual expertise, best external evidence, and patient values. Application of best evidence and clinical expertise to make the best decisions regarding a patient’s care while respecting their values.
problem with the traditional approach
only as good as the expert, may be affect be biases
clinical: dramatic experiences may influence the practice patterns
Three components of EBCM
Individual’s expertise, best external evidence, patient values and expectations
how is evidence based lab medicine different from evidence based clinical medicine
lab: integration of basic science, technical performance and clinical need for patient decision making. EBLM involves population based data to define clinical assay performance for an individual patient. Using the current best evidence in making well-informed decisions
EBCM focuses on treatment and intervention
EBLM focuses on gathering information for making well-informed decisions
three components of EBLM
Individual expertise, best evidence, patient decision
clinicians expectations from a biomarker/test
Define a disease and potentially reflect on the underlying etiology that can be targeted for therapy
how to structure a question
population, intervention, comparison, outcome
Steps in the EBM process (6)
- start with the patient, a clinical problem will arise
- the question, construct a question
- The Resource, select resources and conduct a search
- The evaluation, Appraise the evidence for validity and usefulness
- The Patietn, return to patient and integrate evidence with clinical expertise
- Self-evaluation, evaluate your performance with the patient
What is EBLM
Evidence based laboratory medicine integrates into clinical decion-making the best available research evidence for the use of laboratory tests or procedures with clinical expertise and experience of the physician, and the needs, expectations and concerns of the patient, in order to improve the outcome of patients
5 components of a clinical trial
Objective
Enrollment
Randomization
Blinding
Control groups
