Evidence Based Medicine (3&4) Flashcards
1
Q
Hierarchy of evidence
A
- Meta-analysis of RCTs (randomized clinical trials)
- Single large RCT
- Cohort Study
- Case-control study
- Case series
- Expert opinion
2
Q
- Meta-analysis of randomized clinical trials (RCTs)
A
Considered the best evidence and the least biased.
Pool of single large RCTs
3
Q
- Single large RCT
A
This is the second best evidence, only after a large pool of these
4
Q
- Cohort Study
A
(level 2)
Observational study and more biased than RCTs
5
Q
- Case-control study
A
(level 3)
Observational study and more biased than RCTs
6
Q
- Case series
A
(level 4)
Observational study and without a comparison group
7
Q
- Expert opinion
A
The worst type of evidence
8
Q
What are the common pitfalls in the conduct of clinical research
A
- Lack of randomization
- Lack of concealment of randomization
- Lack of blinding
- Wrong intention to treat analysis
- Errors in hypothesis tesgting
9
Q
- Lack of randomization
A
(common pitfalls in the conduct of clinical research)
Randomization is important because:
- it gives every patient an equal probability of being enrolled to either group.
- It is the single most important technique to limit bias in clinical research. Thus, studies that fail to randomize patients introduce an important bias in the measurement of the outcome measure.
10
Q
Why is randomization so important? (1)
A
it gives every patient an equal probability of being enrolled to either group.
11
Q
Why is randomization so important? (2)
A
It is the single most important technique to limit bias in clinical research. Thus, studies that fail to randomize patients introduce an important bias in the measurement of the outcome measure.
12
Q
Concealed randomization ensures that surgeons are unable to ________ the treatment to which their next patient will be allocated.
A
(common pitfalls in the conduct of clinical research)
predict
13
Q
The safest manner in which to limit the occurrence of failed concealment is a _________
A
remote 24-hour telephone randomization service
14
Q
If randomization is concealed, then the physician cannot ______ the patient will be allocated to at the time of patient consent and application of exclusion/inclusion criteria.
A
predict to which treatment
15
Q
Randomization techniques that preserve ________ can include telephone and internet-based randomization.
A
concealment
16
Q
_____ also guards against potential bias in a research study.
A
Blinding
17
Q
While blinding is feasible in most, if not all, drug trials, it is rarely feasible in a ______trial
A
Surgical
18
Q
When ______ is not possible, investigators should take care to ensure _________ assessment of the outcome measures if they require some interpretation (i.e. Radiographic healing of bone, assessment of clinical outcomes, physical examination
A
blinding is not possible; independent
19
Q
When blinding is not possible then researchers should ensure that
A
Independent assessment of the outcome measures if they require some interpretation (i.e. Radiographic healing of bone, assessment of clinical outcomes, physical examination
20
Q
- Lack of concealment of randomization
A
Basically being able to predict what treatment the patient will be allocated to
21
Q
- Lack of blinding
A
Basically knowing and having bias in a surgical study (ex. giving the more sick some treatment to show more improvement)
22
Q
- Wrong intention to treat analysis
A
When some patients undergo the alternative treatment they were not allocated to either by mistake or the result of technical difficulties
23
Q
Even when proper randomization is performed, some patients undergo the alternative treatment they were not allocated to either by mistake or the result of technical difficulties with one treatment
A
This approach seems to be COUNTERINTUITIVE at first glance, it PRESERVES the value of randomization: on average known and unknown prognostic factors will be equally distributed across both treatment groups and therefore the treatment effect will be primarily determined by the assigned treatment.
24
Q
- Errors in hypothesis testing
A
A common pitfall in clinical trials
25
Evidence based medicine is defined as
the conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients.
26
Bias
Any tendency which prevents unprejudiced consideration of a question.
27
When does bias occur?
When systematic error is introduced into sampling or testing by selecting or encouraging one outcome or answer over others.
28
What does bias cause?
E estimates of association to be either larger or smaller than the true association.
In extreme cases, can cause a perceived association which is directly opposite of the true association. (Example: HRT and Heart Disease)
29
1. Preclinical Research
| types of research
The evaluation of potential therapeutic interventions in cells and animals.
All drugs require data from various toxicological preclinical studies to support their potential safety in humans before clinical studies can begin
30
Types of research:
1. Preclinical Research
| 2. Clinical Research
31
2. Clinical Research
The study of human disease, including its prevention, diagnosis and treatment, using human participants, human populations or materials of human origin (mainly involve human participants)
32
Clinical trial
A research study involving HUMAN participants that is designed to answer specific questions about the safety and efficacy of a biomedical INTERVENTION (e.g., drug or device).
33
Clinical trials studies are
intended to discover or verify the clinical, pharmacological or pharmacodynamic effects of a drug, or study the absorption, distribution, metabolism and excretion of a drug.
34
The first "clinical trial"?
: Nebuchadnezzar in the book of Daniel whom ordered to eat meat and wine
35
The first REAL clinical trial?
James Lind and Scurvy Trial
36
James Lind
Is considered the first physician to have conducted a controlled clinical trial of the modern era.
While working as a surgeon on the ship Salisbury, Dr. Lind was appalled by the high mortality from scurvy among the sailors.
37
Drug and device development
1. Starts with extensive preclinical laboratory (one of the research types) research involving experiments in animals and human cells.
38
2. If the preclinical research is ________, the manufacturer requests approval from Health Canada to ______ research in humans.
[Drug and device development]
successful; continue research in humans
39
3. Once approved from Health Canada, a series of ________ is conducted to document the effectiveness (or “efficacy”) and safety of the drug or device.
[Drug and device development]
clinical trials
40
4. The evidence from these trials is used to support the _________ _______ to Health Canada to market the drug in Canada.
[Drug and device development]
manufacturer’s application
41
The four phases of clinical trials of drugs and device development in humans:
Phase I – Human Pharmacology
Phase II – Therapeutic Exploratory
Phase III – Therapeutic Confirmatory
Phase IV – Therapeutic Use
42
Study Objectives of Phase IV – Therapeutic Use
1. Refine understanding of benefit/risk relationship in general or special populations and/or environments
2. Identify less common adverse reactions
3. Refine dosing recommendation
43
Study Examples of Phase IV – Therapeutic Use
1. Comparative effectiveness studies
2. Studies of mortality/morbidity outcomes
3. Studies of additional endpoints
4. Large simple trials
5. Pharmacoeconomic studies
44
Phase IV – Therapeutic Use may also be called
Therapeutic use trials.
45
Phase IV – Therapeutic Use is performed
After the drug has been approved by the regulator for the market.
46
Phase IV – Therapeutic Use includes
safety studies and studies designed to support use under the APPROVED indication, such as mortality and morbidity studies or epidemiological studies.
47
Phase IV – Therapeutic Use is typically related to the approved indication
If a drug that has been approved for marketing is to be investigated for a new indication (i.e., off-label use), then the trials are generally considered phase II or phase III, rather than phase IV trials
48
Phase 4 studies may be “________” initiatives intended to encourage prescription and ______ market share, and these are called seeding trials.
marketing initiatives; expand
49
Seeding trials
are clinical trials, deceptively portrayed as patient studies, which are used to promote [recently approved] drugs…encouraging prescribers to use [them] under the guise of participating as an investigator in a clinical trial.
50
______ departments, rather than _______ research departments, are known to design and conduct these seeding trials.
Marketing ;
| clinical
51
The primary goal of seeding trials
is to expose physicians to a new drug and have them interact with the pharmaceutical company sponsor and its sales representatives, in order to influence prescribing decisions, independent of any findings from the actual study.
52
STEPS was a
seeding trial posing as a legitimate scientific study
53
Study objectives of Phase I – Human Pharmacology
1. Assess tolerance
2. Define/describe pharmacokinetics and pharmacodynamics
3. Explore drug metabolism and drug interactions
4. Estimate activity
54
Study examples of Phase I – Human Pharmacology
1. Dose-tolerance studies
| 2. Single and multiple dose PK and/or PD studies
55
Phase I – Human Pharmacology may be called
human pharmacology trials
56
Phase I – Human Pharmacology involves the ______ introduction of an investigational new drug in humans.
initial
57
These studies in human pharmacology trials (1) are designed to
Determine the metabolism and pharmacologic actions of the drug in humans, the side effects associated with increasing doses, and, if possible, to gain early evidence on effectiveness.
58
Phase I – Human Pharmacology are
typically closely monitored and may be conducted in patients or healthy volunteer participants.
59
Total number if participants in phase 1 human pharmacology
Small (20-80 people)
60
Study objectives of Phase II – Therapeutic Exploratory
1. Explore use for the targeted indication
2. Estimate dosage for subsequent studies
3. Provide basis for confirmatory study design, endpoints, methodologies
61
Study examples of Phase II – Therapeutic Exploratory
1. Earliest trials of relatively short duration in well- defined narrow patient populations, using surrogate or pharmacological endpoints or clinical measures
2. Dose-response exploration studies
62
Phase II – Therapeutic Exploratory may be called
therapeutic exploratory trials.
63
Phase II – Therapeutic Exploratory are conducted to
1. evaluate the effectiveness of the drug for a particular indication(s) in patients with the disease or condition under study and
2. to determine the common short-term side effects and risks associated with the drug.
64
Phase II – Therapeutic Exploratory are typically conducted in a
Group of patients who are selected by relatively narrow criteria, leading to a relatively HOMOGENOUS population which is closely monitored.
65
Total number of Phase II – Therapeutic Exploratory
Typically consist of a relatively small number of patients – usually no more than several hundred.
66
Study Objectives Phase III – Therapeutic Confirmatory
1. Demonstrate/confirm efficacy
2. Establish safety profile
3. Provide an adequate basis for assessing the benefit/risk relationship to support licensing
4. Establish dose-response relationship
67
Study Examples Phase III – Therapeutic Confirmatory
1. Adequate, and well controlled studies to establish efficacy
2. Randomized parallel dose-response studies
3. Clinical safety studies
4. Studies of mortality/ morbidity outcomes
5. Large simple trials
6. Comparative studies
68
Phase III – Therapeutic Confirmatory may be called
therapeutic confirmatory trials.
69
Phase III – Therapeutic Confirmatory expanded trials are performed ______ preliminary evidence has been obtained suggesting _________ of the drug
After;
| effectiveness
70
Major intentions of Phase III – Therapeutic Confirmatory
1. Intended to gather the additional information to confirm the drug’s effectiveness and safety and to evaluate the overall benefit-risk relationship of the drug.
2. Intended to provide an adequate basis for marketing approval.
71
What kind of study is it? Total number of Phase III – Therapeutic Confirmatory
Typically RANDOMIZED, controlled, multi-centre trials on large participant groups – usually several hundred to several THOUSAND participants.
72
Seeding trials are not _____ but are ______
ILLEGAL BUT ARE UNETHICAL
73
Drug development process timeline:
```
1. Discovery, preclinical testing: lab and animal tests
CTA submission and review
2. Clinical trials: Phase 1, 2, 3
NDS submission and review
3. Post-marketing studies: Phase 4
```
74
1. Discovery preclinical testing
[Drug development process timeline]
3-6 years
75
2. CTA submission and review
[Drug development process timeline]
0.2 years
76
3. Clinical trials
[Drug development process timeline]
6-7 years
77
4. NDS submission and review
[Drug development process timeline]
0.5-2 years
78
5. Post-marketing studies
[Drug development process timeline]
indefinite
79
(1) In Canada, before a clinical trial can begin, the sponsor must submit a ____ _____ _____ ___to Health Canada and receive Health Canada’s approval.
Clinical Trial Application (CTA)
80
(2) After sufficient evidence of safety and efficacy has been obtained through clinical testing, the sponsor completes a ___ ____ _____ ____ to apply for Health Canada’s authorization to market the drug in Canada.
New Drug Submission (NDS)
81
It can take as long as __ ____ to develop a new drug
15 years
82
Patents last __ ____, but there is an _ year market exclusivity granted for "innovative" drugs
20 years;
8-year market exclusivity granted for “innovative” drugs
83
Sponsor
The individual, company, institution or organization that takes responsibility for the initiation and management of a clinical study and compliance with applicable regulations.
84
Industry-Sponsored Research
Documents the safety and effectiveness of drugs and medical devices intended for the market.
85
Investigator-Initiated Research
Research that is initiated, managed and conducted by an investigator (“sponsor-investigator”).
An investigator conducting an investigator-initiated clinical trial has the SAME regulatory responsibilities as does a pharmaceutical company.
86
The two kinds of sponsorships
- Industry-sponsored research
| - Investigator-initiated research
87
An investigator conducting an __________ clinical trial has the SAME regulatory responsibilities as does a pharmaceutical company.
investigator-initiated
88
Canadian Regulations
Researchers conducting clinical trials must comply with:
1. Food and Drugs Act
2. Food and Drug Regulations
Division 5: clinical trials
3. Medical Devices Regulations
89
Give authority to _________ to regulate drugs and medical devices.
Health Canada
90
The regulations define requirements for obtaining ______ to _____ drugs and medical devices in Canada
And they spell out sponsors’ and investigators’ obligations in the conduct of clinical trials.
approval;
| market
91
Regulatory Agencies
Health Canada
U.S. Food and Drug Administration (FDA)
European Medicines Agency (EMA)
92
Guideline for Good Clinical Practice (GCP)
International standard for the conduct of clinical trials
93
GCP (guideline for good clinical practice) provides assurance that:
1. The data submitted to regulators (e.g., Health Canada) with applications to market new drugs are credible and accurate, and
2. The rights, integrity, and privacy of clinical trial participants are protected.
94
Food and Drug Regulations require adherence to _____
ICH GCP
| Pharmaceuticals for Human Use and (guideline for good clinical practice
95
GCP was created by the
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)
