Arshdeep Ethics

Question 1

What are the 3 regulatory bodies?

Answer 1

Therapeutic products directorate (TPD)
Biologics and genetic therapies directorate (BGTD)
Natural and non-prescription health products directorate (NNHPD)

Question 2

what does TPD, BGTD, and NNHPD regulate

Answer 2

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) regulates non-prescription and disinfectant drugs, in addition to natural health products

Question 3

what is a nutraceutical

Answer 3

a product isolated or purified from foods that is generally sold in medicinal forms not usually associated with food”

Question 4

What is a research ethics board

Answer 4

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

Question 5

When is a REB required

Answer 5

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

Question 6

5 things

When is research exempted from REB review

Answer 6

1. REB review is not required when it relies exclusively on information that is in the public domain
2. Observation of people in public places (no intervention or expectation of privacy)
3. research relying exclusively on secondary use of anonymous information or anonymous human biological materials
4. Quality assurance and quality improvement studies
5. Creative practice activities

Question 7

Three core principles

Answer 7

Respect for persons
Concern for welfare
justice

Question 8

What is respect for persons

Answer 8

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

Question 9

What is concern for welfare

Answer 9

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

Question 10

what is justice

Answer 10

Justice: Participants must be treated fairly and equitably
Equity: equal distribution of research benefits as well as burden, Awareness of participant vulnerabilities
recruitment based on inclusion/ exclusion criteria

Inclusion/exclusion of participants, equitable distribution of risk and benefits

Question 11

T/F Consent is an ongoing process

Answer 11

true

Question 12

8 requirements of consent

Answer 12

PONTIFIED
1. freely given by participant or proxy if they lack the capacity
2. Easily understandable
3. on-going
4. Precede data collection
5. No undue influence or coercion
6. Incentives cannot be coercive (not enough money to cloud judgment)
7. If participant lacks the capacity to decide, they need to get an authorized third party
8. consent must be documented

Question 13

When can consent be waived in research (4 reasons)

Answer 13

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

Question 14

When can consent be waived in individual medical emergencies (5 reasons)

Answer 14

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

Question 15

What was TGN1412? Which core principle was wrong?

Answer 15

Humanized monoclonal antibody originally intended to treat leukemia and rheumatoid arthritis. TGN1412 directly triggers T-cell activation and proliferation. This circumvents the need for an antigen-dependent signal.
showed no evidence of toxicity in non-human primates
In phase I clinical trials every patient that received it developed severe allergy-like reactions resulting in hospitalization
Reactions were caused by a cytokine storm
Differences in T-cell reactivity between humans and non-human primates contributed to ineffective pre-clinical toxicity screening

Respect for persons

Question 16

4 lessons learned from TGN 1412

Answer 16

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

Question 17

6

What must an acceptable plan for monitoring safety include

Answer 17

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

Question 18

Study-wide stopping rules identify when a study should cease due to evidence that (3 things)

Answer 18

A condition is more or less efficacious
A conditions is more or less safe
The study is futile: data is unreliable

Question 19

What is MTD, MABEL, and NOAEL

Answer 19

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

Question 20

What were the 4 things wrong with TGN1412

Answer 20

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

Question 21

What was BIA 10-2474? What were the chief ethical issues? What roles were violated?

Answer 21

Physicians continued running a trial after a participant was sent to the hospital. The study was not cancelled until the patient went into a coma. Several more participants fell ill.
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

Question 22

What are the goals and chief concern of phase (First in man) clinical trial

Answer 22

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 safety concern

Safety and tolerability

Question 23

Goal and chief concern of phase II clinical trial

Answer 23

Therapeutic exploratorial trials
Goal: does the treatment work, determines if there is any biological activity or effect in a small number of volunteers with the disease of interest
Concerns: Participants may be financially impacted by their health condition which may be coercive, Circumstances (such as chronic pain) may affects the patient’s perception of risk and rewards

Question 24

Goal and chief concern of phase III clinical trial

Answer 24

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 benefits relative to the standard options so it should be clear whether treatment will continue after study

Question 25

Goal and chief concern of phase IV clinical trial

Answer 25

Goal: Effectiveness and long-term safety of the approved drug are monitored after market release
concern: Trials should be undertaken for true scientific purposes without external motivations, sponsors pay a per capita fee which may sway investigators

Question 26

Why was BIA 10-2474 important

Answer 26

highlighted importance of consent and stopping rules

Question 27

Articles 4.1-4.7 of who acceptable inclusion/exclusion (4.1)

Answer 27

4.1 Culture, spoken language, religion, race, sexual orientation, ethnicity, disability, gender, age or linguistic proficiency should NOT be grounds for exclusion
Valid reasons must be provided for exclusion of any of the above. Study recruitment should aim to be inclusive of all members of society

Question 28

Articles 4.1-4.7 of who acceptable inclusion/exclusion (4.2-4.6)

Answer 28

Question 29

Articles 4.1-4.7 of who acceptable inclusion/exclusion (4.7)

Answer 29

Question 30

Consent process falls under the purview of which core principles

Answer 30

Respect for persons
Concern for welfare

Question 31

T/F One role of a Research Ethics Board (REB) is to ensure that there is true, voluntary consent

Answer 31

True

Question 32

14 required elements in a consent form

Answer 32

a. Information that the individual is being invited to participate in a research project

b. A statement of the research purpose in plain language

c. The identity of the researcher, as well as the funder or sponsor

d. The expected duration of the study and the nature of participation, a description of the research procedures, and an explanation of the responsibilities of the participant

e. A description of all reasonably foreseeable risks and potential benefits

f. An assurance that prospective participants:
* are under no obligation to participate and are free to withdraw at any time without penalty
* will be given information that is relevant to their decision to continue or withdraw from participation
* will be given information on their right to request the withdrawal of data or human biological materials, including any limitations on the feasibility of that withdrawal
g. Information concerning the presence of any conflicts of interest on the part of the researchers

h. The measures to be undertaken for dissemination of research results and whether participants will be identified

i. The identity and contact information of a qualified representative who can explain the scientific or scholarly aspects of the research to participants

j. The identity and contact information of the appropriate individual(s) outside of the research team whom participants may contact regarding possible ethical issues in the research

k. An indication of what information will be collected about participants and for what purposes

l. information about the payment of any incentives for participation or reimbursement for participation-related expenses and/or injury

m. A statement that participants have not waived any legal rights

n. Information on stopping rules and when researchers may remove participants from the trial

Question 33

What are the principles of fairness and equity for

Answer 33

Ensures individuals are not excluded for reasons unrelated to the research question

Question 34

What is the safety margin

Answer 34

Margin between the intended therapeutic range and highest dose causing no serious adverse effects

Question 35

To balance risk and potential benefit, researchers and REVs must have mechanisms to…

Answer 35

Stop all or part of the study due to evidence of greater than expected harms or greater than expected benefits in any of the study outcomes

Remove individual participants from the study for their own safety

Question 36

3 things

The consent and recruitment process must be followed as dictated by the REB:

Answer 36

The consent process must be followed as dictated by the REB
A proper consent form must be used, as previously discussed
Appropriate inclusion and exclusion principles must be applied during participant recruitment
Recruitment must NOT be coercive