21 CRF 50: Protection Of Human Subjects

Question 1

What authority does the President have regarding waiving the prior consent requirement for the administration of an investigational new drug to a member of the armed forces? What are the specific grounds on which the President may grant such a waiver?

Answer 1

The President has the authority to remove the requirement for informed consent for a member of the armed forces that is involved in military operations.

The president can grant this waiver IF:
1) is not not feasible to obtain consent from te subject
2) it is in the best interest of the country to use the investigational product
3) it is in the best interest of the subject

Question 2

In what situation, does the investigator have the authority to make determinations about the use of a test article without informed consent? What is the subsequent requirement for the review and evaluation of these determinations?

Answer 2

The investigator has the authority to administer an investigational test article in a life threatening situation where there isn’t enough time for the investigator and a physician to satisfy the 4 criteria.

The investigator must have a physician (not related to the study) assess the use of the test article within 5 days AND submit this to the IRB within 5 days

Question 3

According to the 21 CFR part 50, what are the 4 exceptions for not obtaining informed consent for a test article?

Answer 3

1. Life threatening situation - an independent physician and the investigator can verify 4 criteria
2. Life threatening situation - investigator does not have time to meet the criteria for #1, but they believe that immediate use of test IP will preserve a person’s life. Requires review within 5 days of use by independent doctor
3. The US president can waive the need for informed consent for armed forces involved in a military operation
4. Physician and investigator can verify criteria for an in vitro diagnostic device

Question 4

What are the criteria that both the investigator and an independent physician must certify in writing to waive the need for informed consent for a test article?

Answer 4

1. There is no alternative method that provides equal or improved likelihood to save the subject’s life
2. There isn’t enough time to obtain consent from legal representative
3. The subject cannot communicate consent or it is not ethical for them to (e.g. if they are in an incapacitated state)
4. It is a life-threatening situation

Question 5

How does the information provided in 21 CFR 50 about exceptions for informed consent relate to the ability of the IRB to not require consent? Explain the key concepts and considerations that connect these sections, emphasizing their significance in the context of clinical investigations and the waiver of informed consent.

Answer 5

The IRB has the ability to waive consent for the following two situations:
1) the test article poses no more than minimal risk and in non-research situations, you would normally not need written informed consent
2) the exceptions for informed consent in emergency research are met

Meanwhile, the section 50 provides two sets of criteria and scenarios in which the FDA or the Secretary of Human Health Services may approve exceptions of obtaining informed consent.

The FDA has the authority to approve the exception from general informed consent regulations for research that meets 1 of 4 criteria.

Meanwhile, the secretary of HHS has the authority to approve exception of obtaining informed consent for emergency research.

Question 6

What is one situation where the IRB may approve a study to not obtain informed consent?
Highlight the key criteria that the IRB, along with a licensed physician, needs to consider and document in such cases.

Answer 6

As part of their review process, the IRB may approve a study to not obtain informed consent in emergency research situations if the IRB finds the following criteria:

1. The subject is in a life threatening situation, the alternative methods are not good enough and it is the only way to obtain information about the safety and efficacy of the product
2. Obtaining informed consent is not feasible
3. The product may actually have a direct benefit to the subject
4. The investigation’s informed consent, ICF process and proposed information that they will share with the research participant meets the regulations.
5. The investigators have a plan to attempt to contact the legal representatives of the subjects within the treatment window BEFORE proceeding without consent
6. Safeguards are in place to protect the welfare of participants
7. The research cannot be done without the waiver

Question 7

How does the concept of “Prospect of Direct Benefit” play a crucial role in allowing an exception from informed consent requirements for emergency research? Explain the factors that the IRB must consider regarding the potential benefits to subjects, particularly those facing life-threatening situations, and how these considerations are linked to ethical and scientific standards.

Answer 7

The prospect of direct benefit is one of the criteria that an IRB must ensure that an investigational trial meets in order to approve a waiver of consent.

The factors that must be considered that make this concept true are:
1. The subject is in a life threatening condition
2. Mice and lab studies support the potential benefit of the investigational drug
3. The risks of the investigational drug are reasonable when compared to the risks of the medical condition and the risks/benefits of standard of care (if there are any)

Question 8

Per the CFR, outline the basic elements of informed consent that must be provided to each research subject.

Answer 8

1. Telling the participant that the study involves research, description of what they will be asked to do, duration of study, purpose of research and significance
2. Description of risks and discomforts
3. Explanation of voluntary nature of research and lack of consequences if they choose to withdraw
4. Efforts implemented to protect their privacy and confidentiality
5. Benefits (if applicable)
6. Mention of alternative treatments that can be done instead of the proposed treatment
7. Contact information for pertinent study personnel and IRB
8. If > minimal risk, description of compensation or treatment if an injury occurs

Question 9

Per the CFR, what are the additional components that may be provided to research participants as part of Informed consent?

Answer 9

1. Cost of participating in the research
2. Consequences of withdrawing from the research study
3. Situations where the investigators might withdraw research participants from research studies
4. The total number of anticipated participants that will be part of the study
5. A statement that there might be risks in which the investigators are not privy to (unforeseeable)
6. A statement about if anything in the study changes that may affect their willingness to participate, the pts will know

Question 10

Which studies are required to be registered to clinicaltrials.gov? How must this information be shared with participants?

Answer 10

Any applicable clinical trials are required to register.

In the informed consent form and during the process, a participant will be made known that a description of the clinical trial will be uploaded to clinicaltrials.gov per US law and that no personal information will be disclosed, at most it will be results

Question 11

Regarding the informed consent requirements, what is explicitly stated in the ICH(?) regulations?
a) They preempt all applicable laws.
b) They will not limit the authority of physicians in emergency medical care.
c) They are intended to provide exhaustive details.
d) They apply only to federally funded studies.

Which of these is also right if you change the answer?

Answer 11

Answer is b.

Answer a would be right if it stated that it does NOT preempt all applicable laws about information that must be provided during informed consent.

Question 12

What are the two acceptable formats for the consent form, as outlined in 21 CRF 50?

Answer 12

1. A written informed consent document that includes all of the required information listed in that section in addition to any state/local/federal regulations. The form must be signed by the subject or representative and the person obtaining consent
2. Short form consent form with a statement that the required elements of informed consent were discussed via an oral presentation. A summary must accompany the oral presentation to the subject or their representative.

Question 13

Describe the procedure for using a short form consent form. Who has to be present? Who signs what? What documents is each individual receiving?

Answer 13

The short form consent form can be used in lieu of a written consent form. The short form has to include a statement that the participant/legal representative received an oral presentation outlining all of the elements per the regulations of consent forms. A summary (IRB approved) is given to the participant which provides them with an overview of presentation.

A witness has to be present for the oral presentation. They have to sign both the short form and the summary.

The participant only has to sign the short form consent form and they are given the summary and short form to keep.

The person obtaining consent only signs the summary.

Question 14

Under what circumstances may an IRB approve a clinical investigation NOT involving greater than minimal risk with children?

Answer 14

1. If the investigation causes no more than minimal risk to CHILDREN (e.g. Bloom)
2. If the investigation has a plan to obtain assent from children and permission from their parents (if applicable)

Question 15

When does an IRB approve of clinical investigations that involve children with more than minimal risk, provided there is a prospect of direct benefit to individual subjects? (Per CFR)

Answer 15

1. If the risk is justified by the proposed benefit
2. If the benefit:risk ratio is at least similar to that of alternate methods/therapies
3. If the investigation has a plan to obtain assent from children and permission from adults

Question 16

Per the CFR, what conditions must be met for a clinical investigation involving children with more than minimal risk, where there is no prospect of direct benefit to individual subjects, to be approved?

Answer 16

1. The increase above no more than minimal risk must be minor
2. The procedures/interventions that children experience must be similar enough to what they have to or will have to do because of their condition
3. There is a process in place to obtain assent from children and permission from parents
4. The findings will be able to be generalized and will be vital in understanding and addressing the disorder/condition

Question 17

If an IRB believes that a clinical investigation involving children doesn’t meet the specified criteria, under what conditions can it proceed? (CRF)

Answer 17

1. the IRB believes that the findings from the investigation will yield important information that could improve the understanding, prevention and treatment of an existing condition that affects children’s health
2. The commissioner of the FDA confirms either of the following:
   A) that the study does meet criteria’s 1-3 (goes against the IRB opinion)
   B) the following conditions are met:
   i) othe findings from the investigation have the potential to yield very important results that could improve the health of children (same as the IRB criteria)
   ii)the study will operate under ethical conditions
   iii) the study has a plan to obtain assent from children and permission from parents

Question 18

What responsibility does an IRB have concerning clinical investigations involving children?
a) It only oversees investigations with minimal risk
b) It must review and approve investigations that meet specified criteria
c) It is not involved in clinical investigations with children
d) It focuses on investigations presenting direct benefit to individual subjects

Answer 18

Answer is B

Question 19

What responsibility does an IRB have regarding soliciting the assent of children and permission from parents/guardians in clinical investigations? (7) per CFR

Answer 19

1. If the IRB deems that assent is needed, then they need to ensure that the study has a plan to obtain assent from children.
2. Decide if assent is needed from all of the potentially eligible children or specific children by considering their age, maturity and mental state
3. The IRB can decide to waive the requirement for assent
4. The IRB must require that parents/guardians also provide their permission
5. The IRB can determine that assent is not necessary
6. Determine how the assent is documented
7. Determine how the permission from parents is documented

Question 20

Under what circumstances can the IRB waive the assent requirement, even if technically the subjects could provide assent? (Per CFR part 50)

Answer 20

1. The study causes no more than minimal risk
2. The rights and welfare of the children are protected
3. Need to a waiver for the study to function
4. If aplicable, subjects will be provided with additional information

Question 21

How does the IRB determine parental permission for children involved in clinical studies? (CFR). (Hint, think of situations when 1 vs 2 parents are needed)

Answer 21

Parental permission is a requirement for children involved in clinical studies.
1 parent is needed if the study is no more than minimal risk OR the study is greater than minimal risk but has a benefit
2 parents are needed if the study causes greater than minimal risk and there is no potential for direct benefit OR the study does not meet the criteria to have children involved, but it is found that the findings will improve the understanding, prevention and treatment of diseases that affect children

Question 22

In what circumstances can children who are wards of the State be included in clinical investigations approved?

Answer 22

1. If the study is specific to wards
2. If the study takes place in the setting of the wards (prison, foster care, camps, hospitals)

Question 23

If a study is approved to function in a ward, what other IRB requirement must be met before the study can proceed?

Answer 23

There must be an available advocate in the ward.

Question 24

What is a ward?

Answer 24

A ward is a child that is placed in the legal custody of the state/institution/hospital/etc.

Question 25

According to the CFR, what is the dentition of life threatening?

Answer 25

Life threatening situation is when a disease or condition is likely going to end in death, unless the course of the disease is successfully treated. It does not have to be immediate death (e.g. cancer, ALS, etc). It also includes severe and irreversible deliberating conditions/diseases (e.g paralysis, losing one’s sight, stroke)