6-10
As per US CFR 21 CFR 50, what statement MUST be provided to each clinical trial statement in informed consent documents and processes?
"A description of this clinical trial will be available on http://www.ClinicalTrials.gov as requires by US law. This website will not include information that can identify you. At most, this website will include a summary of the results. You can search this website at any time."
[HIPPA privacy rules] If study involves protected health information and involves consent from a subject, Consent document must contain section entitled... "Will my Health Information
"Will my Health Information be Used During this Study?"
Why might some IP go missing during the course of a clinical trial?
- Subject can lose a pill when they accidentally drop bottle - Pharmacist may incorrectly dispense amount - Coordinator may misplace IP - IP may be stolen from subject's bag
According to Title 21 Part 50, who needs to sign the informed consent doc?
- Subject/representative must sign AND date - Sign and date is one thing - its NOT COMPLETE if no date, has to have BOTH *****Person signing must PERSONALLY DATE -- PI or coordinator cannot date signature for them by LAW
[5 states of a team] Performing
- Team has settled relationships and expectations - Seldom regresses to storming stage - Can successfully complete new tasks and add new team members - Ability to prevent problems, constructive self-change
[Protocol Feasibility ] Critical review of the protocol considerations:
- Therapeutic area - does PI have experience and interest in this? - Investigational product - is this something you think patients need? Need to look at past research - Hypothesis - do the primary and secondary endpoints make sense medically? - Control and experimental groups - Study design - Randomization - Length of study - Sponsor - Evaluate the value of the trial and decide on participation
Pre-trial communication: Kick-off meeting
- W/ monitors and sponsor-level study team prior to start of study - Provide training on GCP and applicable SOPs - Discuss and provide training on project-specific trackers - Establish chain of command and lines of communication - Define data management processes and data flow
Documentation of informed consent as per: Title 21 Part 50
- document by use of written consent form approved by IRB - SIGNED AND DATED by subject or legal rep - Copy given to person signing form
[COV] What is included in the site's final reporting to the IRB?
1. Summary of patient enrollment 2. Safety events 3. Deviations 4. Informs IRB that site is done conducting clinical trial
Given the examples of the inclusion and exclusion criteria, why would we want to exclude a pregnant subject from the trial? Select all that apply. A. A pregnant subject might have complications with their pregnancy while on the IP B. The study team would have to add the fetus to the list of study subjects C. The subject might develop unusual cravings D. Hormones produced during pregnancy could skew lab values
A and D
Performance is dependent on both:
ABILITY and MOTIVATION
Good Documentation Practices (GDP) must be (6):
ALCOAC Attributable Legible Contemporaneous Original Accurate Complete
Whose duty is it to maintain and provide ethical oversight for human research subjects?
ALL clinical researchers
US Title 21 (CFR) parts 11, 50, 54, 56 apply to...
ALL types of IP research in the USA ONLY
__________________ is easier to assess and create - training, etc.
Ability
[Safety Reporting] Define: Adverse event
Any undesirable change in, or worsening from, baseline condition, regardless of causality or severity Anything that worsens the patient regardless of the drug's involvement. Ex. a patient being injured in a MVC is considered an adverse event, since they have been changed since baseline.
[Styles of monitoring] Risk-Based Monitoring (RBM) PURPOSE
As clinical trials increase in size and complexity, cost to monitor effectively increased also. This type of monitoring focuses on the area which pose the greatest risk to patient safety and data integrity
[US Title 45 CFR Part 46D] At certain age __________________ may be required (usually older children)
Assent
When should you obtain informed consent?
BEFORE subjects participate in the study
US Title 21 CFR Part 320
Bioavailability and bioequivalence (generics)
US Title 21 CFR Part 600
Biologics
US Title 45 CFR Part 46C
Biomedical and behavioral research involving prisoners as subjects
Scope Creep
The uncontrolled expansion to product or project scope requirements that were not initially defined without adjustments to time, cost, and resources.
If monitor discovers missing documentation, there is clear indication that additional _____________________ is needed
Training
3 phases of a clinical research project:
Trial initiation Execution Close-out
Building a budget determines the... AND...
True cost of conducting research Establish a foundation to manage funds and plan resources
As per IRB, payment incentive is is __________________________ meaning subjects need to be paid an x amount every visit and not bulk at the front or the end of the study.
prorated
[Declaration of Helsinki Basic Principals] trials should have clearly formulated...
protocols
What is the main goal of the SIV? a. To confirm that the site has everything in order before they enroll study subjects b. To make sure the IP has arrived at the site c. To collect the original copy of the IRB approval letter d. To train the entire study team on GCP
a. To confirm that the site has everything in order before they enroll study subjects
Good team leadership = tapping into _________________ and providing ________________________ that encourage a person to feel motivated
abilities environment
[Nuremberg Code] states that voluntary consent is...
absolutely essential
[HIPPA privacy rules] "Will my Health Information be Used During this Study?" section in the consent document serves as authorization from subjects for researcher to...
access health information
[US Title 21 CFR 50] Investigator is required to give the prospective subject ______________________________________ to decide whether or not to participate w/out ________________________________________
adequate time coercion or undue influence
The informed consent process gives subjects the opportunity to
agree or decline to participate
Informed consent is designed to provide subjects with...
all information - including risks and benefits
ICH E6 (R2) Section 4.8.7
ample time must be provided before informed consent may be obtained
[Nuremberg Code] States that _____________ experimentation should be done before __________________ experimentation ** ALSO a part of US common law**
animal human
[Belmont Report] Publicly funded research should not be conducted on those who
are unlikely to benefit from it
[After the Trial] Must store files for _______________________. CANNOT destroy records until...
at least 2 years The sponsor says you can IN WRITING
Other vulnerable populations includes a broad spectrum of factors that limit someone from acting _________________________
autonomously
[Belmont Report] Respect for persons
autonomy, protection for diminished autonomy
How does the clinical trial monitor ensure compliance with FDA mandated regulation for the control on an IP? a. By providing the site with FDA approved IP accountability logs b. By ensuring that the site is properly trained on the handling of the IP c. By doing and investigational accountability check before the site gets sent the IP d. By not allowing anyone other than the PI to handle the IP at the site
b. By ensuring that the site is properly trained on the handling of the IP
Which of the following does not usually occur until an IMV? a. Getting IRB approval for the study b. Performing data verification c. Determining the previous research experience of the study staff d. Reviewing the qualifications of the PI
b. Performing data verification
US Title 21 CFR 50 outlines the....
general requirements for informed consent
Where does the copy of the signed and dated ICF go?
given to the subject at time of consent
[US Title 45 CFR Part 46C] If conducting research on prisoners, the IRB must
have necessary prisoner-related members (at least 1) - usually former prisoner or warden
[Nuremberg Code] States that degree of risk to subjects should never exceed...
humanitarian importance of the problem
In general the amount of work ___________ throughout the initiation phase and into the execution phase
increases
ICH E6 R2 definition of "Other vulnerable populations"
individuals whose willingness to volunteer participation in a study may be unduly influenced by the expectation (justified or not) of benefits associated with participation or of a retaliatory response of senior members of a hierarchy in case of refusal to participate
[Nuremberg Code] Investigators should be ready to end experiment at any stage if there is cause to believe that continuing the study will result in...
injury or death
[Declaration of Helsinki Basic Principals] Subjects have the right to safeguard their...
integrity
[US Title 21 CFR Part 11] Electric signatures need to maintain the same level of ___________________ as they would in real life paper documents.
integrity (others cannot sign for you)
ICH E6 (R2) Section 4.8 Informed Consent of Trial Subjects - applies to...
international trials
Trial recruitment methods are mainly via the ________________________, BUT, people really want to hear from __________________________ more than anything.
internet and media their primary care physician (second is specialty care physician)
Qualified sites tend to have fewer...
issues
If it wasn't documented...
it didn't happen
IF COI arises, what should happen?
it should be formally disclosed so sponsor and FDA can be made aware
To minimize coercion IRB has to review _______________________________ and
payment amount and process of pay,
Sometimes FDA approval of a product may require _____________________________, or sponsor may decide that they want to conduct these ________________ on their own (same word twice)
post-marketing studies
[Declaration of Helsinki Basic Principals] Hazards of trial must be...
predictable
[Nuremberg Code] Experiments should only be conducted by...
qualified investigators
If medicine is intended to be used in a special population, then...
research MUST be done in this population to make sure it is safe and effective.
[Monitor & Subject Safety] Monitor ensures subject safety by checking that the study has _________________________ to conduct the trial at the site
resources
During the informed consent process, there is a discussion of the individual's
rights as a research subject
[Declaration of Helsinki Basic Principals] Conform to accepted...
scientific principles
[Declaration of Helsinki Basic Principals] Trials should be conducted by...
scientifically qualified persons
Project
sequence of tasks w/ a beginning and end bound by time, resources, and desired results - Have stakeholders with particular expectations - Specific outcomes, goals, - Product exists afterwards
Monitoring is the mandatory function of the ___________________
sponsor
69% of patients never participated in a trial because...
they didn't know they were eligible to participate
US Title 21 CFR Part 814
PMA
[Trial Recruitment Methods] enroll within 60 days = _____% chance of trial success
50
The ICH E6 (R2) 4.8.10 has how many elements for informed consent?
21 Generally stricter than FDA
When assessing a budget and the protocol, it helps to make a ____________________ to outline what happens at each subject visit and what costs are associated
"schedule of events"
How many monitors does a study need?
# may vary depending on study phase, complexity, and centers involved in the trial
Monitor responsibilities (5)
(1) Adhere to sponsor SOPs (2) follow applicable regulations (3) Ensure protocol compliance (4) Perform and submit a monitoring visit report (5) Resolve site findings through follow-up
Monitoring & Study Protocol considerations (4)
(1) Are study related tasks being followed correctly? (2) Have adverse events been documented? (3) Have any SAE's been reported? (4) Have all protocol deviations been reported?
Monitoring & Investigational Product (IP) considerations (4)
(1) Is IP being received on time? (2) Will site run out of IP early? (3) Is IP stored appropriately? (4) Has IP been recovered from all subjects? (5) Has IP expired?
First evidence of consent in clinical research:
(19th cen) Walter Reed's "contracts" for yellow fever trials
IRB responsibilities:
(21 CFR 56.109) 1. Review, approve, require modification or disapprove research documentation, protocol etc. 2. Set standards for informed consent documentation, execution, and content of consent form in accordance w/ CFR 50.25 3. Require documentation of informed consent unless waived - minimal risk 4. Notify investigators in writing of decisions 5. Conduct review AT LEAST annually 6. Observe the informed consent process
[Trial Recruitment Methods] enroll within 30 days = _____% chance of trial success
+90
AE/SAE reporting:
- All AEs must be captures on SOURCE DOCS and SRFs - All SAEs must be IMMEDIATELY REPORTED to the SPONSOR as per protocol requirements - All SAEs must be IMMEDIATELY REPORTED to the IRB as per IRB requirements *GOAL: clinical study is aware of patient health and makes sure patient gets adequate treatment in event of AE/SAE.
Why conduct feasibility assessments?
- Allows for contingency planning - Costs time and money - but it is a wise investment
Reporting Phase & Close-out
- Assure all final reports sent to IRB by sites - Facilitate biostatistical analysis - Generate final Clinical Study Report - Prepare summary of safety and effectiveness - Facilitate regulatory submissions - Device trial: help with 510(k0) or PMA - Drug trial: work on NDA (or BLA for biologic) - Final deliverables given to customer - project documentation delivered t sponsor or filed appropriately - Team wrap-up meeting to evaluate
IRB membership should include:
- At least 5 members - diverse and qualified - At least 1 non-scientist - At least 1 member not affiliated w/ the institution - Members with COI may not participate in initial and continuing review - IRB may invite comments or assistance from specialists
[5 states of a team] Adjourning
- Briefs and shares improved process - Relationships formed continue after team disbands
IRB responsibilities are outlined in what regulatory documents?
21 CFR 56.109
[IMV] How does reviewing site staffing help the sponsor maintain oversight? What would the Monitor look for?
- Changes in site staff should be supported by documented evidence of the change and proof that the individual is qualified by education, training, and experience to conduct the assigned tasks - Monitor would review the DoA log, CV, evidence of training to verify that new staff is qualified, and provide any additional training if needed
[5 states of a team] Storming
- Competitive, defensive, choosing sides - Establish unrealistic goals - Beginning to understand each other
[Post-marketing studies] FDA:
- Continue assessment of safety and efficacy of product - Studies typically done in general patient population
[Post-marketing studies] Sponsor:
- Continue testing safety and efficacy on their own volition - Info about other potential indications for use
Informed consent special considerations: Consenting minors
- IRB must determine provisions needed to solicit assent of child when possible - in addition to parental permission - 45 CFR 46.408 - Need informed consent and Assent if required by IRB - Age and need for pediatric assent is determined by IRB - Assent is defined as a "child's affirmative agreement to participate in research" *** The mere absence of an objection by the child should not be construed as assent
Considerations when estimating the number of potential subjects:
- Inclusion/exclusion criteria - Environmental and seasonal factors - Review available medical and electronic records - Review past subject profiles - Consult w/ colleagues—utilize professional networks - Review previous trial data in similar areas - Is there competition? - might be difficult to recruit subjects if other trials are going on in the area - Why will subjects drop out? - Are the subjects accessible?
Why do you think the site should hold on to all shipping information from the IP?
- Many moving parts to a clinical trial, including logistics of shipping IP - If there is a shipping error, such as temp out of range, incorrect does, having shipping info available would help determine if it was the fault of the carrier or form where the shipment originated
[Post-marketing studies] Doctors:
- May notice AEs related to drug - MedWatch report can be filed - sponsor and FDA will be notified - Allows sponsor to assess if there is a need for additional trials
[During the trial] Subject follow up
- Office visits outside of standard visit schedule - Continued follow-up for long periods of time - Subjects lost to follow up (must continue attempts to find subject)
Who are project managers?
- Often experience CRAs (monitors) very familiar with the clinical trial process - PM normally not their "formal" job title
During the IMV, the Monitor notes that an individual on the study team has performed a task not delegated to them by the PI. Why is this a concern?
- PI is 100% responsible for the conduct of the trial at their site - They can delegate authority for tasks to qualified individuals, but ff someone was not delegated the task, it is a deficit of the PIs oversight - Subjects and data were put at risk as an unqualified person conducted that study task
[5 states of a team] Forming
- Polite stage - Team members introduce - Defines tasks and how they will be accomplished
[US Title 45 CFR Part 46C] Problems with conducting research on prisoners:
- Prisoners have disproportionate rates of infectious disease, substance abuse, and mental illness - Vulnerable to coercion --> do not have the same amount of rights as non-imprisoned patients (MK Ultra studies)
Informed consent special considerations: Non-English speaking or illiterate subjects
- Protocol must reflect methods for assuring full understanding - possible w/ assistance of interpreter or by using translated ICD(s) *** IRB must review and approve any translated copies before being used - Subject signs form they can read, PI reads English version, Translator signs both - fully effective informed consent signatures *** Credentials of translator should be verified and must be provided to IRB
[5 states of a team] Norming
- Reaches consensus on the "to be" process - Beginning to work well together - Can bounce between storming and norming when new issues arise
Pre-trial communication: Investigator meeting
- Review key protocol information - Get consensus among investigators - Ensure PIs understand and accept responsibilities - Establish chain of communication
[SQV Monitor Procedures] Obligations
- Review regulatory documents with PI - Ensure that PI is aware that they are: 1. responsible for everything at site 2. to follow all federal regulations 3. to meet source document requirements
Why is the PI required to be at the site during the COV if all study documentation is complete?
- Sponsor can never assume all documents are in order even at the COV - PIs signature is required on several essential documents --> without it, site cannot be properly closed out - PI needs to be available to answer any final questions, sign required documents, and be made aware of the final status of the trial at their site.
[SIV] Why does the monitor need to re-verify the facility after they already did so at the SQV?
- Sponsor should not assume that everything at the site is the same was as during the SQV. - Visits are often months apart and equipment can break, leases may end, staff may turn over - Missing critical changes can cause costly delays
Nuremberg Code
-Grew out of Nazi physicians who committed "crimes against humanity" - Section on Permissible Medical Experiments - 10 directives for human experimentation - First time creating documents that outline how human research participation should be handled
Project Manager Responsibilities
-Initiates project -Plans project -Executes project -Controls the process -Closes project IPECC
Criteria for IRB approval is outlined in...
21 CFR 56.111
The Sponsor manages...
1 or more projects
A CRO may be dedicated to...
1 project or several smaller ones
[After the Trial] Financial disclosure must be updated through ____________________ post trial
1 year
[Before the trial] What does the site want (4)?
1. A logistically feasible protocol - something realistic 2. Study w/ novel treatment or scientific interest/merit 3. Budget that can cover expenses and turn a profit (need to pay people) 4. A supportive sponsor - training, answering questions, addressing concerns
[During the Trial] IRB Continuing review involves (4)
1. Annual review of STUDY + ALL RELATED ITEMS for continued approval (at least annually) 2. Annual review of ICF for continuing approval (at lease annually) 3. IRB approval for change in study personnel 4. Submission of study protocol deviations and SAEs to IRB as required
IRB Review possible outcomes (4):
1. Approval on first try w/ no changes --> RARE 2. Approval w/ modifications or revisions needed --> need resubmission 3. Study could be tabled for ethical questions or unsound research, protocol or consent forms insufficient, etc. 4. Study could be disapproved if judged to be ethically or scientifically unsound --> RARE BUT POSSIBLE
[COV] Dcoumentation considerations (3):
1. Are all essential documents accounted for and filed correctly? - All required essential documents should be completed and filed securely in the event of FDA inspection - At COV, monitor will verify that site's essential documents are complete, signed by PI, and filed securely 2. Is the site aware of their record keeping responsibilities? 3. Has the final reporting to the IRB been completed? - Site must complete final reporting to IRB in order to completely close out site.
[IMV] Study status considerations (4):
1. Are the site's facilities in working order? - Site must have appropriate equipment - monitor should reverify that nothing has changed in regard to the site facilities 2. Are there any staffing concerns? - Monitor must determine if there are new members of the study team - should reverify documented qualifications and training 3. Is the site meeting their screening and enrollment goals? - Confirmation that timelines are being met - If site is behind, document and report back to sponsor so that sponsor can work with PI to get study back on track --> Delays can be costly o Have issues from previous visits been resolved? 4. Monitor reviews previous reports before each visit - check on any outstanding issues at the site - Confirm that all have been addressed and corrected while on site
What should the PI submit for IRB approval?
1. CV + site demographics 2. Informed consent 3. Recruitment materials 4. Any study related materials seen by the subject
[During the Trial] PI responsibilities in study monitoring process
1. Communication w/ the monitor openly - free flow of info 2. Facilitating monitoring visits 3. Responding to monitor observations (at site level)
US Title 45 CFR 46 - requirements for federally-funded human research
1. Consent forms should begin w/ concise summary of "key information" that should facilitate understanding 2. New requirements for additional consent elements related to use of de-identified information, use of biospecimens, potential for commercial profit, and return of clinically-relevant results 3. 2018 regulations require that certain clinical trial consent forms be posted on a government website (those that are conducted/supported by a federal agency) --> must occur no more than 60 days after last study visit by any subject
Budget development considerations (8):
1. Costs per patient - procedures, materials, recruitment, etc. 2. Time required per patient 3. Items not covered by a 3rd party 4. IRB approval and continuing reviews 4. Translations and other unique study personnel 5. Storage (for paperwork often) 6. Advertising 7. Overhead costs 8. Other services
Protocol feasibility considerations (3):
1. Critical review of the protocol 2. Consider inclusion/exclusion criteria, patient population 3. Identify the experimental procedures
Documents that outline the principals of informed consent (4):
1. Declaration of Helsinki 2. Human Research Subject Protection and Belmont Report 3. US Title 21 CRF part 50, FDA info sheet guidelines 4. ICH E6 (R2) section 4.8 (fundamental and universal)
Sponsors use questionnaires to (4):
1. Determine the site's interest in the study 2. Help the site determine if they are able to participate in the study 3. Collect information for future studies - database 4. Determine if changes need to be made in the study
[Monitoring & Study Protocol ] How does the monitor ensure study related tasks are being followed correctly?
1. Determines who completes study related tasks via documentation 2. Verify the person is a. on the delegation of authority (DoA) log and b. is qualified to conduct that work
[Trial Recruitment Methods] Goal is to enroll within _____ days
30
5 states of a team:
1. Forming 2. Storming 3. Norming 4. Performing 5. Adjourning
[SIV] IP Considerations (5)
1. Has the site received the first shipment of the IP? 2. Monitor can learn a lot about the site from how they handled documentation and storage of the initial IP shipment 3. Has the IP received correctly? - Site is responsible for maintaining all shipping information in the IP binder 4. Was it stored correctly? - IP must be stored as indicated in the protocol - If IP is not stored correctly, it may not work as intended - Could result in putting subjects at unnecessary risk and collecting unreliable data 5. Does the study team need any training? - Monitor will use thorough IP inspection to determine any training deficits and provide training to correct them
[SIV] Monitor Expectations Checklist (5)
1. Have I developed a good relationship with the site? - Monitor who conducts SIV will monitor the same site throughout the trial - Good relationship lays foundation for honest and open communication - ESSENTIAL for proper oversight 2. Have I communicated the sponsor's expectations? - Clear communication of expectations necessary for success of investigation - If site knows what is expected of them, they are more likely to ask necessary questions, further ensuring they will be successful 3. Does the site know how to reach me? - Monitor should confirm number of staff and contact information - Site should always reach out to monitor if they have Qs or need assistance 4. Does the site know when visits will occur? - Verify that site knows when visits will occur - Clearly communicating monitoring time frames is a polite and effective way to ensure applicable members of team are present at each monitoring visit
[HIPPA privacy rules] 3 important features that affect the way clinical research is conducted:
1. Healthcare providers must seek authorization from patients or waivers from IRB to examine medical records - need signed HIPAA authorization 2. De-identified medical information is not protected 3. Patients have the right to access and copy their medical records at any time
[Styles of monitoring: Risk-Based Monitoring (RBM)] Quality Risk Management Plan contains (3):
1. How often monitor goes out on site 2. What specific data to look at 3. What triggers will indicate if site needs additional oversight
Sponsor should clearly express expectations on (4):
1. How to conduct the study 2. How data should be collected 3. How to communicate w/ sponsor 4. How often monitoring will occur
[US Title 45 CFR Part 46B] If pregnancy is coincidental to subject selection, then 2 things must occur:
1. Informed consent w/ statement of potential risks 2. Subjects should inform PI if become pregnant
[IMV] Document review considerations (4):
1. Is the site's regulatory binder up to date? - Review of regulatory binder on each visit - obtain dated signatures to ensure info is contemporaneous - Verify that essential documents are being collected and maintained 2. Are the site's qualifications current? - Monitor should confirm that the PI and team is still qualified - Some licenses and certifications can expire and must be updated to remain qualified to conduct the study 3. Are there any updates to financial disclosures? - May need to update financial disclosure and COIs 4. Does the DoA log reflect who performed study tasks? - Monitor will verify form is up to date and check the people who performed certain tasks against the log
[IMV] IP Accountability considerations (4):
1. Is there enough IP available? - Site must have enough IP to stay on track - Missing doses or delays ins tarting subjects on the IP can alter timelines, produce unreliable data, or harm study subjects 2. Is the staff handling the IP appropriately? - Monitor will inspect IP handling to ensure compliance w/ protocol in how site receives, stores, accounts, dispenses, returns and or disposes of the IP - All steps must be in compliance with the protocol - Deviations can result in harm to subjects, or data that is unreliable 3. Are subjects receiving the correct IP? - Ensure correct dispensation of IP to appropriate subject - Noncompliance here can be harmful to subject and skew any data that was gathered from the subject 4. Is there any IP that needs to be retrieved from study subjects? - Ensure that site has made a reasonable effort to obtain remaining IP at the end of the study or when subjects leave study --> If not done, monitor will ensure site complies
2 Reasons a study may get a bad letter from FDA:
1. Issues with informed consent 2. Failure to maintain appropriate IP accountability
What might the sponsor look for during the Study Initiation Visit (SIV) (4)?
1. Make sure that the facility can conduct the study tasks 2. Facility has all the necessary documentation in place 3. Look at how the site has handled the IP since its arrival 4. Ensure that the study team understands their obligations when collecting data from protected subjects
Who should be present at the IMV?
1. Monitor 2. PI 3. Clinical Research Coordinator 4. Site personnel (Optional -- Needed only at request of the monitor to follow up)
Who should be present at the COV?
1. Monitor - Verifies that site documentation and data are complete 2. PI - Must be at COV to ensure oversight 3. Clinical Research Coordinator - facilitates the tasks of the COV 4. Site personnel (Optional - May only be needed if questions arise)
Who should be present at the SQV (4):
1. Monitor - conducts visit on behalf of sponsor 2. PI - responsible for everything that happens at the site 3. Clinical Research Coordinator - ensure clinical investigation runs smoothly 4. Anyone performing study tasks, and will be listed on the Delegation of Authority Log (DoA)
COV occurs when... Site checklist (5):
1. Study visits complete 2. All study subjects off of IP 3. Data has been collected 4. Data queries answered 5. AEs and SAEs resolved
Reasons for IRB review delay:
1. Submitting incomplete application 2. Not crosschecking information on consent form vs protocol 3. Proof-reading
Process of monitor securing compliance from the site
1. Monitor IDs ISSUE 2. Monitor INFORMS PI + SPONSOR 3. ROOT CAUSE ANALYSIS performed - Uses a series of questions to discover where the cause of deviation originated from 4. PI given chance to CORRECT ISSUE - Site must document they trained study team members on whatever topic will alleviate the issue that caused deviation 5. If continued noncompliance... sponsor terminates the site 6. SPONSOR REPORTS site termination to regulatory authorities (FDA
Who should be preset at the SIV (4)?
1. Monitor: represent sponsor 2. PI - responsible for everything that happens at site level 3. Clinical Research Coordinator - make sure everything runs smoothly at site; needs to be there to understand entire process 4. Site personnel - perform study tasks and need to make sure they know exactly what they need to do and when they need to do it
Before the site can enroll study patients they must (4):
1. Must send copy of IRB approval letter to sponsor 2. Receive first shipment of IP from sponsor 3. Already have made necessary preparations at site to conduct clinical investigation 4. Sponsor will send representative, usually monitor, to verify that site is ready to receive subjects (SIV)
Key elements of recruitment materials (direct advertisements) (6):
1. Name + addresses of the clinical investigator and/or research facility 2. Condition under study and/or the purpose of the research 3. Summary form of the eligibility criteria 4. Brief list of participation benefits 5. Time or other commitment required of the subjects 6. Location of the research + the person or office for further contact
Styles of monitoring (4):
1. On-site monitoring 2. Remote monitoring 3. Centralized monitoring 4. Risk-based monitoring (RBM)
When determining the feasibility of a trial what 3 things should be considered?
1. Operational and logistical factors - looking at protocol 2. Should be able to recruit required number of subjects in set time frame (demonstrate, based on retrospective data) 3. Complexity of the trial - how involved is it
[SQV Monitor Procedures: Verification] What must the Monitor verify (4)?
1. PI qualifications - Are they sufficient to conduct study? - Ensure PI is familiar with type or research being done 2. Administration - Assess site SOPs - See if site has adequate processes in place to collect/maintain the required essential documents for the study 3. Study staff member qualifications - documented training*, CVs - Verify site has appropriate staffing to handle workload associated with study *Depending on protocol, training may be given to site staff after SQV to ensure they can perform study tasks 4. Facility equipment - Ensure sufficient space, equipment, supplies** needed to perform the required work with accuracy, efficiency, and timeliness - Verify ability of site's lab to conduct study procedures if required by sponsor **In some circumstances, sponsor may need to provide site with special equipment to conduct investigation
PI Requirements (8):
1. PROTECT the rights, safety, and welfare of subjects (really everybody is responsible for this) 2. Ensure staff is QUALIFIED and well-trained 3. Follow protocol/COMPLIANCE 4. Control IP 5. Obtain INFORMED CONSENT 6. Maintain RECORDS - if it wasn't documented, it didn't happen 7. Report FINDINGS (data, but also safety) 8. Permit MONITORING and auditing by the sponsor, IRB, and authorities PQC IPIC RF M
Why it is important to have the right sites conduct the right studies (3)?
1. Patient and subject rights, safety, health 2. Cost - operational - Sponsors upfront costs - Site has costs in the qualification visit, investigator meeting/training, IRB submissions, etc. - Additional hidden costs 3. Cost - opportunistic - Every day in delay from the market, sponsor may lose an estimated $8 million
[US Title 21 CFR Part 11] Electric file needs to be (2):
1. Protected 2. able to document changes (what was done, and when it was done) --> document, track acknowledge
[Before the trial] What does the sponsor want (4)?
1. Quality sites - will do quality research efficiently, for reasonable cost 2. Quick, clean data 3. Enrollment goals met 4. Cost w/in budget
SIV Monitor responsibilities (4):
1. Re-verification 2. IP follow-up 3. Reestablish expectations 4. Training
Benefits of E-consent (6):
1. Reduces/eliminates lost/misplaced forms 2. No missed sections 3. Precise version control 4. Access limited to appropriate personnel 5. Can be repository for other subject info 6. Sharing/storage flexibility
8 Basic elements of informed consent (FDA)
1. Research 2. Foreseeable Risks 3. Benefits 4. Alternative procedures 5. Confidentiality 6. Compensation 7. Contacts · PI + IRB contact (for questions about rights) 8. Voluntary
[Belmont Report] 3 basic principals
1. Respect for persons 2. Beneficence 3. Justice
Strategies to ensure Informed Consent process comprehension
1. Review consent form carefully - pausing to allow time to process information 2. Ask subject if they have any questions 3. Ask subject to verify understanding 4. Consider a comprehension quiz 5. Personally meet w/ subject to review consent if obtained by PI 6. Provide supplemental study information - must be IRB approved 7. Consider ongoing assessments to assure subject understands
Criteria for IRB approval
1. Risks to subjects MINIMIZED 2. Risk-benefit is REASONABLE 3. Subject selection is EQUITABLE 4. Informed consent will be SOUGHT and DOCUMENTED 5. Adequate SAFETY MONITORING 6. Patient PRIVACY and CONFIDENTIALITY protected
Process of creating the ICF
1. Sponsor or PI/site will draft document 2. Sponsor approves first draft -- May go through revision cycle before site and sponsor agree on draft 3. Site sends it to IRB for approval 4. RB may want revisions and send back for update 5. Before site sends back to IRB, MUST submit for approval by SPONSOR again FIRST, THEN can resubmit for final IRB approval 6. After sponsor approves revisions, Site sends revised ICF to IRB 7. IRB approves 8. Site sends approved documentation to sponsor ---> File letter and copy of approved document template goes 9. Sponsor stores documentation in investigator's study files
Site Qualification Visit (SQV): 3 goals
1. Sponsors first step into deciding WHICH SITES will PARTICIPATE in clinical investigation 2. VERIFIES that SITE is CAPABLE of fulfilling obligations of study 3. Ensure SITE and SPONSOR are in AGREEMENT with study process
Compared to FDA requirements, ICH requires the following additional elements in the ICF (5)
1. Trial treatment(s) and probability for random assignment to treatment 2. Subjects responsibilities (what is expected of them for participation) 3. Alternative procedures or course of treatment available to subject, and their important potential benefits and risks 4. Anticipated prorated payment to subject, if any, for participation 5. Monitors, auditors, IRB, and regulatory authorities will have direct access to subject's original medical records for verification of clinical trial procedures w/out violating the confidentiality of subject
During a trial, what regulatory and ethical compliance documents must be met at all times (6)?
1. US Title 21 2. US Title 45 Part 46 3. ICH E6 (R2) guidelines 4. IRB requirements 5. Declaration of Helsinki 6. Belmont Report
What CANNOT be said in recruitment material:
1. Undue coercion 2. Promises of certainty of cure beyond what is outlined in consent 3. "IP is safe/effective" for claim under investigation 4." IP is superior or equivalent to another treatment 5. "new treatment", "new medication", "new drug" - without explaining IP is investigational 6. "free medical treatment" 7. Emphasizing that you will be paid at the end of the study - you an say it, but it shouldn't be heavily emphasized - and its called "reimbursement", and it should be "prorated"
Additional elements of informed consent
1. Unforeseeable risks 2. Termination circumstances - Circumstances in which a PI can terminate a subject against subject's wishes 3. Additional costs 4. Withdrawal consequences and procedures 5. New findings 6. Number of subjects - Why? Subject should be able to use that info to make a better decision
SQV Monitor Procedures (3):
1. Verification 2. Review obligations 3. Q&A
[Styles of monitoring] On-site monitoring
1. Visit site based on SCHEDULE defined by sponsor ahead of time in the monitoring plan 2. Validate proper INFORMED CONSENT was obtained from each subject - **otherwise monitor CANNOT LEGALLY VIEW DATA (1st thing to do at site) 3. Check that case report forms match source documents - ensure 100% SOURCE DOCUMENT VERIFICATION (SDV) 4. DOCUMENT accuracy and completion is checked + adherence to study protocol 5. Assess IP ACCOUNTABILITY + evaluate investigator oversight 6. After monitor has completed visit, REPORT FINDINGS back to sponsor
[COV] IP reconciliation considerations (3):
1. Was IP dispensed properly throughout the trial? - Monitor will recheck that IP was dispensed to correct subject - should be no more IP still in circulation at time of COV - Any IP still in possession by study subjects must be returned 2. Are all accountability logs for the IP complete and accurate? - Gaps in accountability log for the IP should be resolved in lost or missing IP 3. Return or confirm disposal of IP. - Remaining IP must be returned to sponsor or disposed of according to protocol
[IMV] Data review considerations (4):
1. Was the proper informed consent obtained? - MUST have proper informed consent signed copy of HIPPA in order for monitor to review subject's medical history, CRF. 2. Was the subject screening done properly? - Monitor will review subjects' files to confirm site only enrolled subjects who met inclusion/exclusion criteria --> Ensures safety of subjects and quality data 3. Are subjects receiving appropriate care? - PI must ensure subjects receive care for any SAEs that arise as a result of trial participation and document proof of care (monitor will review documentation) 4. Are there any incidents of discordant data? - Monitor will compare info on source documents to the data entered on the CRF
[COV] Study Data considerations (3):
1. Were there any incidents of discordant data? - Monitor will reverify all source documents against CRFs - correct any discrepancies before site can be closed 2. Are all informed consent forms signed by all subjects that participated? - Monitor will reverify that each subject has proper signed informed consent in file once last time - If there is not documented consent for a subject, their data cannot be used. - Have all data queries been resolved? 3. Site and monitor actively track and respond to queries throughout study, and resolution is confirmed at COV.
The ICF document serves 2 main purposes:
1. written source of info pertaining to the research for the subject to reference 2. Documented proof that the process of consent occurred
US legislation did not mention requirement informed consent until ______ with the ___________________________________
1972 Kefauver-Harris Amendments
Belmont Report
1979 US ethical principles and guidelines for the protection of human subjects of research - internationally recognized
[Regulations for computerized systems] When did the first regulation appear? What was it?
1997 21 CFR Part 11 electronic signatures for research records - Address issues for quality, security, and integrity of data that the FDA will accept as an equivalent to paper records
When did the FDA establish guidance for computerized systems? When was it reorganized?
1999, 2007
At COV, Monitor should reiterate that site is to retail all required records for AT LEAST ____ years following _____________________________. If drug is not approved for market, or application is not filed, site will retain the required records for a period of at least ___ years after ___________________________________.
2 marketing action 2 investigation is discontinued
Good Clinical Practice (GCP)
A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials "The rules of research" (ICH E6 R2) - Protects patients - Provides a framework for research *** Ignorance is not a defense in the eyes of the court!!! - Includes ethics, federal law, state law, guidance documents provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected.
The study decided to broaden the inclusion/exclusion criteria to increase the allowable aldosterone level in a study. The next step the CRC should take is: A. Notify the IRB of the change B. Revise the ICF C. Contact previously ineligible patients D. Document the change in existing subjects' CRFs
A. Notify the IRB of the change
[Monitoring & Study Protocol] What is an adverse event and why does the monitor need to be sure it is documented?
Adverse event can be a physical, psychological, lab value, or increase in severity or frequency of a preexisting condition. Monitor MUST verify that all events are appropriately documented to HELP ASSESS SAFETY of the IP
According to the FDA, ______________________ is the start of the informed consent process
Advertising
[Regulations for computerized systems] What was published in 2002?
EMEA's notes for Guidance on GCP -- established requirements for eCRF
[After the Trial] Monitor conducts a ________
COV
Why is it important that the monitor recheck documentation during the COV?
COV is last time monitor will be at site - final opportunity to lay eyes on source documents - If there are open queries or unchecked source documents at end of COV, quality of data is put into questions --> Could be very costly to sponsor and could damage reputation of clinical site
US Title 45 CFR Part 46D
Children involved as research subjects
How often IMVs are conducted are outlined in the _______________________. The number of IMVs is determined by __________ and ___________________ of study
Clinical Monitoring Plan (CMP) Risk Complexity
[Belmont Report] clinical practice vs research
Clinical Practice: Interventions designed to enhance the well-being of the individual Research: Any activity designated to test a hypothesis
Purpose of Close out visit (COV)
Close out site, prepare data for regulatory submission and publication
US Title 45 CFR Part 46 is covered under... and applies to...
Common Law FEDERALLY-FUNDED research ** regardless, nearly all research follows common law anway
Feasibility assessments take into account the practical aspects of....
Conducting and managing a trial ex. Can a sufficient number of subjects be recruited in the set time frame for the set budget?
[Declaration of Helsinki Basic Principals] ___________________ or _____________ should not be present
Conflict of interest or duress
[During the trial] Importance of subject screening and enrollment
Continued screening and enrollment activities occur in addition to routine daily activities
Building a budget is ....
Contractually REQUIRED
21 CFR 312.61
Control of the Investigational Drug - Can only give drug to someone who is in the study - NOT to anyone not authorized to receive it - Inclusion/exclusion criteria is important here
PI should complete ____________________ line next to their signature line when appropriate
Date
[Styles of monitoring: Risk-Based Monitoring (RBM)] Risk Indicators
Define when a risk is detrimental to subject safety and data integrity and prompts action from sponsor
[Monitoring & Investigational Product] Why is it important for a monitor to ensure IP is received on time?
Delays are costly to study since timeline gets pushed back
What is the DoA log?
Delegation of Authority Log states which members of the study team the PI has authorized to perform certain tasks
ALL ___________________ advertising must be reviewed and approved by the FDA and IRB
Direct Targeted group is the patient/subject. Very specific, about particular study/recruitment requirements.
Direct vs non-direct advertisement
Direct: targeted to patients: Non-direct: something like a "dear Dr. X letter...." like a soliciting request that the patient themselves will not see, general discussion about research topic, publicity intended for other audiences like investors, Posting studying on clinicaltrials.gov
[Belmont Report] Beneficence
Do no harm maximize benefit, minimize harm
Contents of regulatory binder
Documentation of all study relate info 1. Source documents: everything written recorded (2 times) 2. all study-related communication for all study personnel
[Monitor & Subject Safety] Monitor ensures subject safety by checking that the study has __________________________ qualifications. Examples?
Documented. Examples: CVs, training records for all members of team)
[Regulations for computerized systems] What was published in 2010?
EMA reflection paper on Expectations for Electronic Source Data and Data Transcribed to Electronic Data Collection Tools in Clinical Trials
[US Title 21 CFR 50] An investigator may not involve a human being in a study unless there is ___________________ informed consent obtained
Effective NOTE: effective isn't defined
What is EDC and eCRF? What is the purpose?
Electronic Data Capture (EDC) Electronic Case Report Forms (eCRF) - Databases for collection of clinical data in clinical trials - Replaces need for paper Case Report Forms - Allows instant access to data for monitors, sponsor, data management, etc. --> Sponsor can make faster adjustments if AEs occur-- decreasing subject risk more quickly
What is HER?
Electronic Health Records
What are ePRO and eDiaries?
Electronic Patient Reported Outcomes (ePRO) Electronic Diaries (eDiaries) Provide patients with tech to document outcomes, help with compliance - Transmits data daily, and is more accurate--> allows for researchers to find out about AEs in real time rather than next time subject visits (how it worked in the past)
What is eSource?
Electronic Source (eSource) - Information entered in one place - Direct entry of trial data - Eliminates need for transcription from source documents or medial record
Documentation is becoming more electronic via _______________________________________
Electronic health records
US Title 21 CFR Part 11
Electronic records, electronic signatures
Monitor ensures subject safety by making sure only ____________________ individuals are enrolled in the study. How?
Eligible How: Check medical records to ensure subjects meet entry criteria defined by inclusion/exclusion criteria in study protocol
What is the PRIMARY task during the SIV?
Ensure site understands WHY the DATA being collected is IMPORTANT to the OUTCOME of the study + TRAINING on following protocol (GCP)
[Monitoring & Study Protocol] Sites are expected to report what types of SAEs?
Expected and unexpected SAEs
TRUE OR FALSE Information about site termination cannot be shared to other sponsors
FALSE Information about the termination CAN also be shared to other sponsors
If the _____________ identifies an issue during site inspection, consequences will most likely be more severe than if it were found by the ________________________
FDA sponsor monitor
[Regulations for computerized systems] What was published in 2013?
FDA Guidance: Electronic Source Data for Clinical Trials
IMVs are required by
FDA and ICHE6
[GDP: ALCOAC] Complete
Monitor verifies that all entries for study data are complete - Complete, verifiable, reliable? - Compliant with regulations and record keeping? - Any unexplained blank spots on forms?
US Title 21 CFR Part 54
Financial Disclosure by Clinical Investigators
Monitor IP Obligations to reinforce during SIV (7)
HRSADD 1. Proper HANDLING of IP important to outcome of clinical investigation 2. RECEIPT- retain the shipping information 3. STORAGE - follow storage direction from protocol 4. ACCOUNTABILITY - Compare how much IP is present vs what is expected 5. DISPENSATION- Give correct IP to each subject 6. ORDERING - Confirm site knows how to reorder IP 7. DISPOSAL/RETURN- Verify that team knows when to dispose or return IP at key stages in investigation
Most IRBs will require trials to use _________ requirements for informed consent since it is more comprehensive
ICH
Documentation of informed consent as per: ICH E6 (R2) 4.8.8 and ICH E6 (R2) 4.8.11
ICH E6 (R2) 4.8.8 Written consent form SIGNED AND DATED by subject or legal rep AND person who conducted the informed consent discussion ICH E6 (R2) 4.8.11 Subject/representative should receive copy of signed and dated informed consent form before participation in the trial
[Regulations for computerized systems] What regulatory even occurred in 2016?
ICH E6 (R2) addressed use of electronic systems in clinical trials
What regulatory documents provide information on IRB membership?
ICH E6 3.2.1 21 CFR 56.107
What section of IHC E6 states that a site "should be able to recruit required number of subjects in set time frame "
ICH E6 4.2.1
Monitoring is required by:
ICH, GCP, FDA law
US Title 21 CFR Part 812
IDE
In the event that a subject's informed consent form is not signed, what should the monitor assume about whether or not informed consent was obtained?
IF IT WASN'T DOCUMENTED, IT DIDN'T HAPPEN - Monitor should assume informed consent discussion never occurred - They may NOT look at the subject's information and MUST inform PI so the error can be rectified ASAP **** This is a CRITICAL deviation from protocol and threat to human subject protection --> WILL require notification of the IRB
US Title 21 CFR Part 312
IND
[GDP: ALCOAC] Contemporaneous
Monitor verifies that evidence/results are being recorded at same time they are being observed - Does each recorded entry have dates indicating when data was entered? - Does the handwriting look as if it were signed before/after the info was recorded?
Planned advertising is part of _______________ IRB review.
INITIAL (pre-approval)
[Monitoring & Investigational Product] Why is it important for a monitor to ensure IP has been recovered from all subjects?
IP not yet FDA approved -- subjects at risk if they are using it not as directed outside of the terms of the study. Monitor also must be able to account for every single dose of IP at all times.
[After the Trial] Who should be notified of study closure?
IRB
[US Title 45 CFR Part 46D] What entity decides whether a pediatric subjects needs to provide assent or not, and if so, at what age?
IRB
_________ may require additional signatories, on trial to trial basis
IRB
___________ is required to review and approve all human research
IRB
For a PI and site to get study approval, what regulating body must approve it?
IRB approval
What is the difference between submissions for [IRB review and acknowledgment] vs [IRB approval]?
IRB approval: for protocol, informed consent form, ethics, - things that IRB has the ability to approve IRB acknowledge: investigator's/safety reports, adverse events - things that IRB may not have the ability to approve but can acknowledge (i.e. investigational brochure is a lot of science info, not IRB's wheelhouse so they just acknowledge)
advertisements must be ____________________________ before they can be used
IRB approved
Why is it important for theMonitor to point out and work to solve any discrepancies in the data?
If discrepancies are not resolved, then that incorrect data that will be used to determine if a drug can be marketed INAPPROPRIATELY
What's wrong with enrolling a subject in a study if they are not eligible?
If subject who does not meet requirements is enrolled, subject's safety and data integrity is compromised
Why might it be necessary for site to have the dates of when the monitor will be on site for a visit?
In even that monitor arrives and neither PI nor coordinator is there, monitor will not be able to gather adequate information and insight to properly oversee the investigation
What is one of the main issues found with investigational product management?
Inadequate receipt/recording/log of drug issuance/use by the (ultimate responsibility of PI, task may be delegated to someone else)
Who are monitors?
Individual selected by the sponsor -- their "eyes and ears" Responsibilities delegated to them to meet regulatory requirements of clinical trial oversight
[Monitoring & Investigational Product] Why is it important for a monitor to ensure site does not run out of IP
Monitor verifies there is enough IP to last until next shipment in case there isn't enough -- catch this as early as possible to mitigate chance of delays related to IP
What is the most important document of clinical research?
Informed Consent Form
[Declaration of Helsinki Basic Principals] .... should be obtained
Informed consent
[Monitor & Subject Safety] Monitor ensures subject safety by checking ______________ _______________ form
Informed consent
Subject's _______________ must appear on each page if required by _____
Initials IRB
US Title 21 CFR Part 56
Institutional Review Board - Checks and balance in research - 3rd party review board - each institute has their own that they need approval in before they can conduct a study
Define IRB/IEC
Institutional review board/Independent ethics committee group of people responsible for reviewing and approving biomedical research involving humans Safeguards the rights and welfare of human research subjects
Roles of project manager:
Interpersonal: manages people, should be able to work w/ diverse groups to create a unified team Decisional: can make important decisions on their own, allocates resources properly Informational: maintains open communication, willing to speak w/ individuals on the quality of their work
[IP Management] 21 CFR 312.62
Investigator Record-keeping and Record Retention - Tracking of everything very carefully - Maintain adequate records - Return of all unused drugs and supplies or otherwise provide for destruction of unused supply
[Monitoring & Investigational Product] Why is it important for a monitor to ensure IP has not expired?
It is important to catch exp. date early - otherwise there can be delays in IP shipping process. If subject takes expired IP, they could be at risk.
[Monitoring & Investigational Product] Site accidentally received IP for a different study and nobody at site caught it. How do you think monitory might catch problem?
Monitor will catch discrepancy by visually inspecting IP at Site Initiation Visit (SIV) Monitor MUST lay eyes upon IP at each visit to catch issues like this
[Styles of monitoring] Risk-Based Monitoring (RBM) ROLE of MONITOR
Monitor will develop markers to alert the sponsor when there is an indication or risk. Risk indicators + Actions sponsor takes are compiled into Quality Risk Management Plan.
[GDP: ALCOAC] Legible
Monitory must be able to easily understand what has been written in "wet ink" and documented on appropriate form - Can I read it? - Is the info recorded on the appropriate form?
US Title 21 CFR Part 601
Licensing (for biologics)
Declaration of Helsinki is a "______________________________" that provides guidance to _____________________________________ in medical research involving ________________________________
Living document physicians and other participants Human subjects
[Styles of monitoring] Centralized monitoring & benefits
Looks at data all across sites to determine if the gathered data is reliable or unreliable Uses teams to distinguish between reliable and unreliable data Ex. Data managers, biostatisticians, monitor - Benefits: 1. Can complement, and potentially reduces the number of monitoring visits 2. Uses the information from all sites to determine additional monitoring needs, INCREASES EFFICIENCY of monitoring
US Title 21 CFR Part 860
Medical Device Classification Procedures
[GDP: ALCOAC] Accurate
Monitor checks that data was recorded accurately - Was data recorded and reported without error? - Is there discordant data recorded elsewhere?
[GDP: ALCOAC] Attributable
Monitor inspects many documents throughout life of study. Should be able to easily ascertain: - Who created record? - When was it created? - If changed, who changed it and why?
[GDP: ALCOAC] Original
Monitor inspects study records to verify that they are original - Was it photocopied?
[Monitoring & Investigational Product] Why is it important for a monitor to ensure site stores IP appropriately?
Monitor needs to verify storage as per study protocol because incorrect storage of IP can affect integrity of product
[SQV Monitor Procedures] Q&A
Monitor should ask if site has any questions for the sponsor before they are approved for the study Considerations: - Discuss unique challenges site may have - Any questions related to study protocol - Verify responsibilities PURPOSE: Gives monitor more resources to determine if the site is qualified
[Styles of monitoring] Remote monitoring
More often used now that technology has evolved. Can check that data is consistent, complete, and ID any unusual distributions of data in real time - Helps ID higher risk sites faster & target them for additional monitoring 1. Site submits data via Electronic Data Capture (EDC) or electronic trial master file eTMF 2. Monitor verifies incoming data remotely 3. Monitor checks for unusual data 4. Monitor follows up w/ site
Study on E-consent
More time spent reviewing eICF (22.7 min) compared to paper ICF (13.2 min) 1st test for memory of topics/content on consent form --> eConsent had better retention compared to paper ICF 2nd go around at later date --> Again, eConsent had higher retention of info compared to paper ICF
US Title 21 CFR Part 314
NDA
What happened in 1974 regarding informed consent?
National research Act + The Common Rule
What should you NEVER do with ICF documentation and wHY?
Never back date anything In US , informed consent fraud is a felony
If obtaining Informed consent on same day as subject beings trial, what should be done?
Note should be made in medical record that subject was approached for consent before participating in the trial Can even provide time stamp on ICF
Source Documentation + CRF completion: Old vs New procedure
OLD 1. Complete source in real time 2. Complete CRF soon after Try not to fall behind.... NEW 1. eSource has Source and CRF 2. Enter info into same place timely completion, easier to achieve
Informed consent is an _____________________________ between the investigator and the subject
ONGOING EXCHANGE
[Monitoring & Study Protocol] Timeline/process for reporting SAEs varies based on:
ORE Outcome of event Relationship of event to IP Expectedness of event
US Title 21 CFR Part 330
OTC products
When can a market application be generated? Who completes the application? What exactly does it entail? Who is the application submitted to for review?
Once study close out has occurred at all trial sites. SPONSOR can analyze data and generate a clinical study report --> put data together from all sites to compile the clinical study report Study report will be used to determine how the product is to be labeled and what information must be provided to consumers Sponsor can seek approval by submitting a marketing application to FDA for review
US Title 21 CFR Part 316
Orphan Drugs
Original signed form should be maintained in the __________________
PI's files
Pros/Cons of eDiaries?
PROS - Self-reported data from the subject - Gives day to day information - Required information is gathered for the FDA - Improves data collection and compliance - Accelerates data lock (can be done as early as 1 day after Last Pt Last visit, LPLV) - Completed in "real" time - Has automatic reminders - Neater entries - More accurate information collected - true patient experience CONS - devices do get stolen, even with lock security --> lost in gear is costly.
[SQV] Site Questionnaire: Purpose and Considerations
PURPOSE: determine if sponsor should pursue this as a potential investigational site; Determine site's interest in conducting this study. CONSIDERATIONS - Can they recruit subjects at the rate the study requires? - Do they have the resources to conduct the study according to protocol? - Are there any staffing concerns - Is the facility currently conducting other studies? - Is the site close to the target patient population? - Can subjects get to the site easily? - Does the PI have experience in the therapeutic area? - Was the site ever shut down during a different study?
Compliance rates of eDIARY vs Paper
Paper: 90% reported compliance; 11% actually complied Electronic: 90% reported compliance; 94% actually complied
[US Title 45 CFR Part 46D] Who provides consent?
Parents/legal guardians provide CONSENT - but children should be informed at age-appropriate level of understanding Parent/guardian giving consent should be of sound decision-making state, may need consent of both parents
US Title 21 CFR 50.24 - Exception from Informed Consent Requirements for Emergency Research
Patient has: - life threatening conditioning AND - is unable to communicate AND - no time to obtain consent AND - no alternative treatment is available that provides greater chance of saving life, THEN emergency treatment can be provided (very uncommon) How it works: - Based on physician's judgement - Second opinion REQUIRED from another physician - IRB approves as allowable and requires notification - When they are able to get informed consent—you must get it --> If the patient doesn't want to continue, then you have to stop whatever it was you were giving them
Project management
Planning, organizing, leading and controlling resources to meet a specific goal
US Title 45 CFR Part 46B
Pregnant women, human fetuses and neonates involved in research
Informed consent is a __________________
Process
US Title 45 CFR Part 46
Protection of Human Subjects
US Title 21 CFR Part 50
Protection of Human Subjects - ALL about INFORMED CONSENT --> what document should look like, how it should be delivered -- as a process.
US Title 45 CFR Part 46A
Protection of human subjects
[Monitoring & Study Protocol] What is the purpose of SAE reporting?
Purpose of SAE reporting is to ensure that parties involved in clinical trial are aware of significant risks to subject safely and health
Which aspect of the project triable is not usually compromised?
Quality Project will be quick and expensive or long and cheap
What is the project triangle?
Quality, Time, Cost CANNOT HAVE ALL 3- MUST compromise 1
[During the trial] Importance of public awareness and perception during the trial
RETENTION IS VERY IMPORTANT - Getting subjects enrolled is one of the hardest things to do in clinical research - A lot of study subjects lost from the beginning to the end of study completion
When determining budget costs, the site should...
Read the protocol carefully - NEED to understand the costs associated with these terms
As part of sponsor oversight, Project managers are in charge of the clinical study and manage _______________ to meet _________________
Resources Goals
The PI is 100% _________________ for properly conducting the research study at the investigational site
Responsible
Two levels of execution phase of a project:
Site and Sponsor level
[US Title 45 CFR Part 46D] Children are NOT...
Small adults - different metabolism, body composition, etc.
What happened in 1966 regarding informed consent?
Specific requirements for informed consent outlined in Surgeon General's policy
Monitor is the communication link between the _______ and _______
Sponsor and PI
What can the sponsor do after FDA marketing approval?
Sponsor can produce and sell product after FDA approval
How should a sponsor handle a site that consistently does not manage the IP according to the protocol?
Sponsor has duty to secure IP management compliance at site - They can help site implement a Corrective and Prevention Action Plan (CAPA) to fix issues - If non-compliance continues, they sponsor may shut down study at site and report site to regulatory authorities
Purpose of Interim Monitoring Visit:
Sponsor required to monitor progress of investigation THROUGHOUT the entire investiation
[SQV] Preliminary Screening
Sponsor's analysis of its own databases and 3rd party databases to find sites that are available and meet requirements to conduct the investigation Considerations: - Have they conducted research before? - Have we worked w/ them before?
[After the Trial] PI must submit Final report to _______________ and _______
Sponsor, IRB
____________ is a key aspect to the success of a trial
Study Staff
According to o ICH E6 (R2), who needs to sign the informed consent doc?
Subject/representative AND the person who conducted informed consent must sign and date
TRUE or FALSE FDA says eSource can be used as source and CRF
TRUE
True or False: A publication journal CAN reject a paper based on financial disclosure
TRUE
True or False: PIs CAN have a financial interest
TRUE just NEED to disclose it so sponsor can take steps to minimize bias
Effort creep
Takes more effort to get task done than expected
PI can delegate ______ to study related personnel, but NOT __________________
Tasks Responsibility PI is 100% responsible for maintaining compliance at the site
Maintaining compliance is a...
Team effort
Hope Creep
Team member falls behind but does not let manager know bc they hope to catch up (eg. Data entry)
[Monitoring & Study Protocol] Who should protocol deviations be reported to?
The Sponsor
ICEH6 defines monitoring as...
The act of overseeing progress of a clinical trial
Project lifecycle:
The process that the study team follows from start to finish 1. Plan: Where all details of how clinical project will run are determined 2. Execute: longest phase 3. Report: Occurs AFTER trial
What is the most important factor to consider when conducting research with human subjects?
The rights, safety, and well-being of the trial subjects are the most important overall considerations and should prevail over the interests of science and society (!ICH E6) Rights-- being a human being Safety - protect them as much as we can, but can't necessarily guarantee Well-being - physical mental, respect of human and their time
[US Title 45 CFR Part 46C] If a study subject becomes incarcerated during research, what should the PI do?
UNLESS research is for life-saving therapy --> DISCONTINUE RESEARCH W/ SUBJECT
Regulations on exceptions to informed consent
US Title 21 CFR 50.23 - Exception from General Requirements ICH E6 4.8.15 - Exception from Informed Consent Requirements for Emergency Research US Title 21 CFR 50.24 - Exception from Informed Consent Requirements for Emergency Research
What US federal regulation outlines GCP?
US Title 21 Code of Federal Regulations (CFR): Part 11 Part 50 Part 54 Part 56
Where are the are the basic elements of informed consent for FDA outlined?
US title 21 CFR 50.25
[Nuremberg Code] States research must avoid...
Unnecessary physical and mental suffering and injury
[Regulations for computerized systems] What was published in 2016?
Use of Electronic Informed Consent Q&A
Why is it bad to not report SAEs?
When SAE is not reported, sponsor is unable to communicate info to other sites and regulatory authorities - subjects will be as risk
[Monitoring & Study Protocol] What is a protocol deviation?
Whenever study protocol is not followed
Where does a project manager work?
Work under Sponsor company (via a program manager) or are contracted out by sponsor company and work under CRO (Contract research organization)
What entity created and maintains the Declaration of Helsinki?
World Medical Association (WMA)
Qualified sites are more likely to..
be compliant throughout the course of the study
[Belmont Report] Publicly funded research must benefit even those who...
cannot afford the product
[Nuremberg Code] States that human experimentation must yield generalizable knowledge that...
cannot be obtained in another way
[US Title 45 CFR Part 46D] Need to ensure that there is no ______________________ of children
coercion
[Informed consent document - completion guidelines] All blanks must be _____________________
completed
Who needs to consent? If research is directed towards fetus...
consent from BOTH parents required ***UNLESS - father is.. 1. of unsound mind 2. incarcerated OR - pregnancy is from rape/incest
What role do physicians play in the safety and efficacy of a drug after a drug has been approved? a. None, once the drug is approved there is nothing they can do b. The physician can use the drug on themselves to determine if they want their patients to take the drug c. They can refuse to prescribe the drug to their patients d. A physician can report possible adverse events that their patients experience to prompt further review of the drug.
d. A physician can report possible adverse events that their patients experience to prompt further review of the drug.
As trial closes out, amount of work..
decreases
you CAN ___________________ another person
demotivate
[Belmont Report] injustice
denial of entitled benefits OR coercion, manipulation
[US Title 45 CFR Part 46B] Study directed towards pregnancy requires that the IRB...
determines risk to fetus as minimal
P should NOT be mailed to sponsor until __________________________ , after monitor has had opportunity to do final reconciliation of the product against the logs.
end of COV
[Declaration of Helsinki Basic Principals] Protocol should be...
ethical
[US Title 21 CFR 50] Informed consent may NOT include any...
exculpatory language
[US Title 45 CFR Part 46B] Most studies do not intend to involve pregnant women as subjects, so it is standard to require:
female subjects (even male sometimes) to use at least 1 form of birth control
ICH E6 (R2) Section 4.8.6
language must be understandable to subject
[Trial Recruitment Methods] enroll within 60 days = _____% chance of trial success
less than 10
Feasibility assessments are used to determine whether a research study is...
likely to be completed successfully
you CANNOT ______________________ another person
motivate
The program manager manages..
multiple project managers
Building a budget provides information that facilitates...
negotiation (with the sponsor)
ICH E6 (R2) Section 4.8.3
no coercion or undue influence
ICH E6 (R2) Section 4.8.4
no exculpatory language
[Declaration of Helsinki Basic Principals] Results that do not conform should...
not be published
Which of the following should the sponsor assess during the SQV? Select all that apply. o The qualifications of the PI o If the site's equipment meets the needs of the study o If the process the site takes in storing and maintaining study documents is adequate o If the site finished their feasibility questionnaire in the time provided
o The qualifications of the PI o If the site's equipment meets the needs of the study o If the process the site takes in storing and maintaining study documents is adequate
[Declaration of Helsinki Basic Principals] _______________ and ____________ must outweigh the _____________
objectives and benefits risks
[Belmont Report] Justice
obligation to be fair and just in distribution of benefits and burdens of clinical research
Where does the original signed and dated ICF go?
on file at the investigational site in research records
[US Title 45 CFR Part 46B] If a study is directed towards mother's health (and NOT fetus) then consent of... is required
only the MOTHER
[After the Trial] Resolve any...
outstanding issues and queries
Trial participants are ____________________ in the clinical research process and should be treated as such
partners
_____________________ is the biggest hurdle to progressing a study
study startup/enrollment
IP must be on site during SIV so that...
subjects can be enrolled as soon as the monitor leaves
only 7% of Americans report their doctors...
suggested participated in clinical trials
has to mimic...
the paper version exactly
Monitoring is KEY to ensuring:
the rights, safety, and well-being of clinical trial subjects (top priority)
Process of obtaining consent must also be documented in..
the subject's medical records
[COV] Site can only be closed if..
there are no outstanding queries.
Copy of signed consent form must be given to subject/representative at ______________________________
time of consent
[Monitoring & Study Protocol] Monitor must ensure the documentation of all study protocol deviations in a __________________ and __________________ manner, whether ____________________ or ____________________
timely and accurate intentional or accidental
Informed consent recognizes that patients and human subjects share the need to __________________ and make _________________________ decisions
understand autonomous
[US Title 21 CFR 50] Information given to subject shall be in language...
understandable to the patient *Doesn't necessarily say written language..
26% of patients do not know...
where trials are conducted
[Declaration of Helsinki Basic Principals] Subjects must be allowed to
withdraw at any time
[Nuremberg Code] Subjects should always be allowed to
withdraw from experiment
If Informed consent form gets updated, or expires, what should you do?
you MUST get consent again. If the trial is long and consent expires multiple times... you must renew it each time.
Why is there more work in the execution phase?
§ since there are more individuals involved - more tasks being done
[IP Management] 21 CFR 812.110
·Specific Responsibilities of Investigators - Compliance - Supervising device use - Disposing of devices appropriately
