Does the FDA consider electronic signatures to be as trustworthy and reliable as handwritten paper signatures?
Yes (although permission to use such
... [Show More] e-sigs has to be approved by the FDA)
Does the FDA consider electronic records that meet requirements to be equivalent to handwritten records ?
Yes
Open system (FDA term)
System access is NOT controlled by people who are responsible for the content of the electronic records in the system. (Like me putting data into CHOP - controlled databases)
Closed system (FDA term)
Environment in which SYSTEM ACCESS is controlled by the same people responsible for the content of the system (I.E. I control the Robotic Database access AND its contents)
What are some FDA Standards to meet when operating a closed record system?
1. Must be able to tell if records have been altered or invalid
2. Must be able to copy records for agency review
3. Protect records throughout retention period
4. Limit system to authorized individuals only
5. Use time-stamped audit trails of modification etc
6. Use operational system checks and restrictions
7. Use authority checks to make sure only authorized individuals are using the system
8. Use device checks to validate data input
9. Make sure those authorized to use system have appropriate training, education, experience
10. Have written policies that deter data falsification
11. Audit and control the maintenance of the actual system
What are some FDA standards to meet when using an Open System?
All those mentioned for the closed system.
1. Document encryption as appropriate
What information should a handwritten SIGNATURE block contain?
1. Printed name of signer
2. Date and Time when signature was executed
3. The MEANING associated with the signature (approval? responsibility? authorship?)
Signature and record linking ?
Signatures must be linked to their respective electronic records to make sure they cannot be copied, falsified, transferred etc.
Do researchers need to request permission from the FDA to use electronic signatures in place of regular signatures?
Yes
What controls should an E-SIGNATURE contain?
Employ at least 2 identification components - such as an identification code AND a password.
Name some CONTROLS for the identification components (i.e. identification code and password) for e-signature?
1. no 2 people should have the same identification controls (password... code)
2. Identification codes and passwords should be periodically checked, revised, etc.
3. Deauthorize lost, stolen, missing codes and passwords
4. Periodically test your devices that generate these codes
Can an informed consent contain exculpatory language?
NO! Cannot say things like "you are waiving your right to damages" etc
When may an experimental drug or device be used on a patient WITHOUT informed consent? ((EMERGENCY USE))
1. the investigator and an independent physician agree that the patient is -life threatening situation
-informed consent cannot be obtained
- there is no time to obtain consent from th esubject's legal representation
-there is no recognized therapy that provides equal or greater likelihood of saving life
- within 5 working days this must be evaluated by another independent physician
-documentation must be submitted to the IRB within 5 working days
-the president can authorize use on the military (lots of information on this military stuff..)
When is it okay to skip informed consent and perform ((EMERGENCY RESEARCH))?
1. Human subjects are in life threatening danger, available treatments are unproven or unsatisfactory, and collection of valid science is needed
2. Obtaining consent is not feasible
-subjects can't consent due to medical state
-can't feasibly get LAR consent in time
-no reasonable way to identify ahead of time individuals who will be eligible for participation
3. Participation holds the prospect of direct benefit to subjects
-animal/preclinical studies support it
-risks are reasonable
4. could not practicably be carried out without waiver of consent
5. OTHER protective measures are in place (counseling, disclosure, disclosure to public, data monitoring committee ETC
Name the 8 elements of INFORMED CONSENT
1. statement of research. purpose of research. duration of participation. procedures involved. identification of all that is experimental.
2. Risks and discomforts
3. Benefits
4. Disclosure of alternatives
5. Confidentiality
6. Compensation if injury
7. Who to contact
8. Statement of voluntariness
ADDITIONAL:
Costs, pregnancy, termination of participation, withdrawal consequences, disclosure of findings, number of subjects in the study.
Clinicaltrials.gov statement.
Short Form consent
In the context of human subjects research, a written document stating that the elements of informed consent required by the Common Rule have been ORALLY presented to and understood by the subject or the subject's legally authorized representative
When can children participate in clinical trials ? (conditions)
1. No more than minimal risk
2. Adequate assent of the child
3. Risk is justified by potential benefit
4. Risk is above minimal, but likely to yield knowledge about a disorder or condition. Not reasonably different from their expected medical course. Assent.
Things to consider when soliciting ASSENT
Age, maturity, mental capacity
When is ASSENT NOT REQUIRED?
Children cannot be reasonably consulted in this case. Benefit is so great. Minimal risk. Could not practicably be carried out without the waiver.
When can WARDS be included?
related to their status as wards, conducted in a setting (school) where most are not wards, advocate has experience to act in the best interest of the child (cannot be associated with study team)
Within how many days can emergency use of a test article be reported to the IRB?
5
Do IRBs need to register with the federal government?
Yes! Every IRB that reviews clinical investigations must register under HHS
How many members are required to be on an IRB?
5 members, with varying backgrounds to promote complete and adequate review of researchj
Do the members of an IRB have to represent adequate diversity of backgrounds, race, vulnerability?
Yes
Each IRB shall include atleast 1 _________ and atleast one _______ (3 categories)
Scientific member and non scientific member.
Institution affiliated and NON institution affiliated
Man and Woman
Do a majority of IRB members need to be present when reviewing protocols?
I think so. And you definitely need one nonscientific person.
Does an IRB have to write out its reasons for not approving an IRB?
Yes. It must allow the investigators appropriate response.
Does an IRB have to do a yearly continuing review?
Review of research at intervals appropriate to the degree of risk, not less than once per year (I suppose this could mean modifications like CHOP)
When can an IRB use an expedited review method?
Research is no more than minimal risk OR minor changes to previously approved research
What criteria must be met for an IRB to approve a study?
-Risks are MINIMIZED
-Risks are reasonable in proportion to benefits
-Selection of subjects is equitable
-Informed consent will be sought
-Informed consent will be appropriately documented
-Data will be monitored for subject safety
-Adequate provisions to protect privacy and confidentiality
-Additional safeguards are in place for vulnerable subjects
-All research is in complianace with FDA part 50, subpart D
Can an IRB suspend or terminate research?
Yes. If unanticipated harm, or if researchers are not following IRB requirements
How long are IRB records required to be maintained after completion of a study?
3 years (and accessible!). FDA can shut it down if IRBs are not keeping records appropriately
Are there a lot of required documentations and records by the IRB?
Yes. Lots of written procedures, must keep copies of meeting minutes, copies of correspondance, research proposals etc. Everything needs to be documented!
Does the FDA have the power to shut down, stop studies, etc if an IRB is not operating in compliance?
Yes! Can full on disqualify if they repeatedly dont comply.
When does a research drug need an IND?
If it can't be legally marketed or shipped, it needs an IND. If you're hoping for a label change or a new indication for use, it needs an IND.
When does a research drug NOT need an IND?
It is already legally able to be marketed. Your research doesn't aim to change label or current use. If it doesn't increase risk, or go in unstudied populations etc.
Do you need an IND for a placebo drug?
NO
Do you need an IND for a UNLABELED indication of an approved product?
No, and this is confusing to me.
Do investigational new drugs need to be clearly labeled as such?
Yes
Can sponsors charge for an investigational drug?
Yes, but it has to be regulated and approved by the FDA. And they need to show proof that its efficacious. Also, the cost of the drug must be burdensome on the sponsor in order for them to charge for it.
What are the three phases of investigational drug studies? Describe and provide average # of subjects.
Phase 1 - initial introduction of IND into humans. Determine metabolism and pharmacologic actions, pharmacokinetics. 20-80 subjects.
Phase 2 - Controlled clinical study to evaluate effectiveness for a particular indication. Determine short term side effects and risks. Several hundred subjects.
Phase 3 - Gather additional information about safety and efficacy, needed to evaluate overall benefit-risk ratio. Hundreds to thousands of subjects.
What does an Investigator's Brochure contain?
Drug substance, formula, structural formula. summary of animal data, summary of any human data. Pharmacokinetics in animals/humans. Summary of safety and efficacy, risks and side effects (to the extent known)
Is an IND application brief?
No it needs a billion and one things, like a grant but way worse. Summarizing the state of the union on this drug across time and nations
How does an SAE differ from an AE?
SAE contains death, life-threatening state, inpatient hospitalization (or prolongation thereof), incapacity, birth defect.
Do researchers need to submit annual reports updating the FDA on their IND?
YES! lots of details needed.
How soon after an IND is submitted can investigators begin their studies?
30 days
What is a "clinical hold" in regard to an IND?
Issued by the FDA to delay a proposed clinical investigation or to suspend an ongoing investigation. This means no new subjects can be recruited.
Why might a clinical hold be issued?
unreasonable risk is posed to human subjects, investigators are not qualified, brochure is misleading, IND is not sufficient, reproductive toxicity, etc. OR approved for marketing by another study. OR shown to be ineffective.
Can the FDA terminate an IND?
Yes, for mostly the same reasons why they would impose a clinical hold
Can an IND be deemed "inactive" but not "terminated"?
Yes. if no subjects are entered for 2 years or more, or if on clinical hold for 1 year, the IND can be placed on inactive status.
Does the FDA spell out suggested meetings as well as dispute resolution for sponsors and investigators?
Yes
Who is ultimately responsible for the proper conduct of a study?
Sponsor. They select monitors and investigators.
Do investigators need to supply sponsors with a whole host of information, kind of like a grant application?
Yes
Who receives the investigator's brochure?
Every participating clinical investigator
How long does a sponsor need to keep records after a marketing application for a drug is approved?
2 years
Can FDA inspect whenever they want?
Yes i think so
What are the responsibilities of the investigator?
Uphold their investigator's agreement and conduct study according to plan. Obtain informed consent.
What type of records to investigators need to keep, and for how long after marketing approval?
Disposition of drug records, case histories. For 2 years.
Who submits annual reports to FDA, the investigator or the sponsor?
The sponsor.
Who submits reports of SAEs, and to whom?
The investigators report to the sponsor, and also to the IRB i think
Can a clinical investigator be disqualified? Why might that be the case?
Yes - if repeatedly or deliberately failed to comply with subparts, agreements etc, or falsified any information.
Is there a different set of regulations when it comes to life-threatening / debilitating diseases for which no good alternatives exist?
Yes, evaluate the risk-benefit ratio differently
Can drugs be imported and exported for clinical trials?
Yes, under specified circumstances and with proper review etc.
Can the FDA "rely" on an "external" FDA in a multi-national trial?
Yes - you can accept foreign IND's if they were conducted under GCP etc, if the FDA can validate the data, and also need to submit lots of regulatory stuff.
Is an IND application automatically public knowledge?
No, it can be if investigator's want it to be.
expanded access
The use of an investigational new drug (IND) outside of a clinical trial by patients with serious or life-threatening conditions who do not meet the enrollment criteria for the clinical trial in progress. Requires an application.
Can a special access be granted for small patient populations, i.e. orphan drugs, orphan conditions?
Yes - special considerations.
Do the policies of devices largely mirror the policies for investigational new drugs?
Yes, mirrored closely
Federal Regulations Part 45/46
Protection of Human Subjects - Protection of Public Welfare
Federal Regulations Part 21
Electronic Records, Human Subjects (50), IRB, IND, Investigational Devices
04955D
auth code smh
What types ofhuman subjects research could be considered exempt from human subjects review/regulation?
Schools, educational tests, unidentifiable subjects, benign behavioral interventions, secondary research, public services research,
expedited review
a review of study proposals that pose minimal risk to subjects; one or two IRB members participate
What are requirements for waiver of informed consent?
Minimal risk, and could not be practicably be carried out without the waiver
When may fetuses or pregnant women be included in research?
-pregnant animals and non pregnant people have already been assessed for risk
-risk to fetus/pregnant women is less than direct benefit
-there is minimal risk to woman and fetus
-this biological knowledge can be obtained by no other means
If benefit is EXCLUSIVE to the fetus, with no benefit to the pregnant woman, who needs to consent?
woman and father (there are exceptions for rape, artificial insemination, death/disability, and unavailability)
If there is no risk/benefit for the fetus, only a potential risk/benefit for mom, who needs to consent?
pregnant woman only
Are there protections for coerced abortion for research?
Yes. You cannot compensate for a terminated pregnancy.The individuals doing the research cannot determine the viability of pregnancies or timing of terminations.
When can nonviable and questionably viable neonates be included in research?
preclinical/clinical studies have been conducted.
-researchers have no role in determining viability
-research enhances possibility of survival
-biomedical knowledge cannot be obtained ANY other way
If Nonviable neonates are included in research... what are some protections that limit the research that can be done on them?
Cannot artificially maintain a heartbeat or vitals
-cannot TERMINATE the heartbeat or respiration/ vitals
-No additional risk to the neonate
-biomedical knowledge cannot be obtained any other way
For a nonviable neonate, who needs to consent?
Both parents (exceptions for unavailability, rape, incest etc)
IRB rules when prison research is involved
majority of the IRB members can have no relation to the prisoners.
A prisoner or prisoner representative with appropriate background must serve
Name some protections against coercion in prison research
Cannot affect his/her parole status. Cannot give advantages or compensation that would coerce. Subject selection must be equitable/random.
When can research include prisoners?
If it is RELEVANT to incarcerated peoples.
Does the FDA define the term children in terms of years?
No. A child is someone who cannot legally consent to treatments or procedures in research (defined locally)
Describe some instances when children MAY be included in research.
-Minimal risk
-risk is small in comparison to direct anticipated benefit
-NO OTHER WAY of obtaining this information
-appropriate preclinical trials
-yield knowledge about a disease or condition
-adequate assent/consent in place
When is assent not needed?
-Children are incapacitated/not sound to assent
-Benefit is so great to the child
-minimal risk
Are there instances in which both parents need to consent for a child to participate in research?
YES. I suppose more than minimal risk? of course, there are exceptions
Are there exceptions for parental consent when a child is neglected or abused?
Yes
When can WARDS be included in research?
If the research is directly related to their status as wards. If they are part of a big group... like a (non-ward) school, where excluded them would be inappropriate
What government office do IRBs register under?
OHRP (office of human research protections)
When an IRB submits appropriate information to OHRP and is registered, how long is their registration active for?
3 years
FDA Notice Of Inspection (482)
An FDA Inspector presents this form which details rights, policies etc when they arrive on-site to Inspect an organization
FDA Inspectional Observations (483)
Lists (negative) observations during an inspection. A copy has to be given to organization. This form should include recommended corrective action. The action CAN be taken immediately with the inspector.
FDA Statement of Investigator (1572)
Provided to Sponsor. This is the "Investigator's Agreement" that they will uphold stated practices and communications and record keeping. The investigator also submits qualification information about themselves.
FDA Certification - Financial Interests/Arrangements of Clinical Investigators (3454)
This is the form that certifies that investigators have NO financial conflict of interests exist. Certified!
FDA Disclosure - Financial Interests/Arrangements of Clinical Investigators (3455)
If financial conflicts of interest exist, use this form to DISCLOSE Them! Attach the details of the conflict to this form.
FDA Voluntary Reporting of AEs and Product Problems (3500)
voluntary reporting of Aes, probems, use errors. These are less serious AEs
FDA Mandatory Reporting for use by User-Facilities, Distributors, Manufacturers (3500A)
3500A is MANDATORY and includes details of serious AEs that led to death or serious injury
Which FDA reporting form can also be used by patients?
3500 (not life threatening)
Quick Overview: BELMONT REPORT (year and summary)
The Belmont Report is a summary of the agreements about ethics of human research from the Commission that was created by the 1974 National Research Act. These deliberations occurred in 1976.
Quick Overview: NUREMBURG CODE
A set of 10 ethical principles for human experimentation. Developed in 1947 as a result of trials held in Nuremburg, Germany for medical personnel involved in the Nazi biomedical experimentation/torture/murder in concentration camps.
Quick Overview: DECLARATION OF HELSINKI
A set of ethical principles for medical research on human subjects originally set forth in 1964. Developed by the WORLD MEDICAL ASSOCIATION (WMA)
Quick Overview: ICH HARMONISED GUIDELINE FOR GCP
GCP is international guidelines for conduct of TRIALS. Developed by an international health council in 1990s to harmonize international guidelines that were already put forth. Meant to faciliate clinical trials internationally, especially between US, EU, Japan, and Switzerland.
It serves to both protect subjects AND to assure data quality / good practice.
Quick Overview: Paperwork reduction act of 1995
The purpose was to reduce the Burden of paperwork held by the public (or people involved in trials). Basically, before you have people fill out forms... it HAS to be approved by Office of Management and Budget.
Why is the Belmont report such named?
The Commission created by the National Research Act held its deliberations at the Belmont Conference Center of the Smithsonian.
Please name the 3 Broad Sections of the Belmont Report
1. Boundaries between Practice and Research
2. Basic Ethical Principles (there are 3)
3. Applications (there are 3)
What are the 3 basic ethical principles outlined in the belmont report?
Respect for Persons, Beneficence, and Justice
What are the 3 "Applications" Outlined in the Belmont report?
Informed Consent
Assessment of Risk and Benefits
Selection of Subjects
How does the Belmont report distinguish between Practice and Research?
Practice: Interventions SOLELY designed to benefit and individual, already have a reasonable expectation of success.
Research: an activity to test a hypothesis, develop generalizable knowledge. Formal protocol and procedures defined.
respect for persons
treating persons as autonomous agents and protecting those with diminished autonomy (relates to children, prisoners, mental disability, respect for peoples opinions and judgements)
Beneficence (Definition)
Maximize possible benefits and minimize possible harms.
Belmont Report: Justice
fair balance between those who participate and those who benefit. (good distribution of BURDENS vs. Benefits)
you can't study prisoners to benefit larger society (and other examples)
What are the 3 important elements of informed consent, as outlined in the Belmont Report applications?
Information, Comprehension, Voluntariness
Describe the differences in information, comprehension, voluntariness
Information is WHAT is presented. Comprehension is HOW it is presented (time, organization, layman's terms, simple english). Voluntariness is freedom from coercion and influence (like from powerful people/power imbalance/threats)
How should selection of subjects be systematically approached?
Adults before children, capable before incapable, free before unfree etc. Free from social, racial cultural biases.
Why is the Nuremburg Code such named?
Came about from the trials held in Nuremburg Germany to prosecute unethical human experimentation in concentration camps
Describe (in brief) the 10 principles set forth by the Nuremburg Code
1. Voluntary Consent of the subject
2. Fruitful results unprocurable by other methods
3. Based on animal results and natural history
4. Avoid ALL unnecessary suffering
5. Cannot conduct study in which death or disability will reasonably occur
6. Degree of risk should NEVER outweigh societal benefit
7. Proper preparations and adequate facilities to protect subjects
8. Only conducted by scientifically qualified persons with the highest skill and care
9. Human subjects must be at liberty to bring the experimentation on them to an end
10. Investigator must terminate any experiment when he has probably cause to believe death, injury, or disability is likely
Please order dec of helsinki, belmont report, and nuremburg code in chronological order
1. Nuremburg code (40s)
2. Dec of Helsinki (60s)
3. Belmont report (70s)
Who is the target audience of the Declaration of Helsinki?
Physicians
Loosely describe the contents of the declaration of helsinki
Contains a lot of information that the other reports have. Principles of consent, investigator qualification, use of placebo, post-trial provisions, honestly kind of all over the place. Protection of vulnerable subjects, etc.
Contrast an adverse drug reaction with an adverse event
AEs don't have to be related to the drug/intervention. For ADRs, there is some possibility they are related.
Please name the 9 sections of the ICH GCP
1. Definitions
2. 10 original Principles of GCP
3. IRB
4. Investigator
5. Sponsor
6. Protocol
7. Investigator's Brochure
8. Essential Documents for clinical trials
9. Paperwork Reduction Act
Please name the 10 Principles of GCP (can include amendments)
1. Conducted according to Dec of Helsinki ethics
2. Risks must be in proportion to benefit
3. Wellbeing of individual subjects is more important than anything
4. Information (clin and non-clin) on an investigational product must be thorough
5. Scientifically sound protocol
6. Approved by IRB
7. Investigators must be QUALIFIED
8. Every individual involved in a trial must be QUALIFIED
9. CONSENT
10. Accurate reporting, interpretation, and verification of data are crucial
11. Confidentiality protected
12. Good Manufacturing Practice for drugs/devices
13. SYSTEMS in place to assure quality and safety
Is the IRB responsible for reviewing investigator qualifications?
Apparently, yes. Along with research procedures.
Are prorated compensation models more ethical than entire completion models?
Yes! Good to know! Can't unduly coerce them to remain in the study
Name 4 categories of EVENTS that require submission to the IRB
1. Protocol Deviations or Changes
2. Changes that increase risk
3. all Adverse Drug Reactions that are SERIOUS and UNEXPECTED
4. New information that may affect subjects/trial [Show Less]