Investigator Training Clinical trials at Avera
Description: Investigator Training Clinical trials at Avera Research Institute Overview for Investigator Responsibilities 1. Ensure all aspects of a clinical trial are completed per the Investigative Plan 2. Protecting the rights, safety and welfare of
Related Topics
Download Presentation
"Investigator Training Clinical trials at Avera" is the property of its rightful owner. Permission is granted to download and print the materials on this website for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.
Presentation Transcript
slide1. Investigator Training Clinical trials at Avera Research Institute<br>
slide2. Overview for Investigator Responsibilities 1. Ensure all aspects of a clinical trial are completed per the Investigative Plan
2. Protecting the rights, safety and welfare of Subjects
3. Control of investigational agent under investigation<br>
slide3. Supervision of Study Conduct 1. Per Code of Federal Regulation the investigator commits to conduct and supervise the investigative trial
2. The investigator is responsible to assess the study related employees delegated to perform key task and adequately supervise their conduct<br>
slide4. Appropriate Delegation 1. Investigator Needs to complete and show documentation of completion for all trial related medical decision.
Review of screening, medical history and assessment of inclusion/exclusion criteria- this is best documented in a clinical note
Physical Exams- unless state law allows APP
Evaluation and attribution of Adverse events
Assessment of endpoints
Oversight of informed consent process
Oversight and approval of delegation log<br>
slide5. Study Timeline Before the study
Attend and complete necessary trainings (Site Initiation Visit, EDC system, etc.)
Attend a study walkthrough with study staff
Sign the delegation log
During the study
Confirm eligibility of participants after baseline visit
Review labs if needed
Review Adverse Events/Serious Adverse Events if applicable
Attend Monitoring Visits
Typically call in for ~15 minutes. Monitoring visits occur every few weeks during the course of the study.
Attend PI meeting with study lead
15 minutes weekly
After the study
Sign off that all components were completed for the study after study close out<br>
slide6. PI Responsibilities: Additional Resources GCP:
file:///C:/Users/scerkovnik/Downloads/Roles%20&%3B%20Responsibilities.pdf
FDA:
https://www.fda.gov/media/87513/download
Introduction to Clinical Research:
http://compliance.emory.edu/documents/S-I_Responsibilities.pdf
https://www.jefferson.edu/content/dam/university/research/jcri/crf_03_17_pdf/0840_Roles%26Responsibilities.pdf
National Cancer Institute:
http://cancerpreventionnetwork.org/Roster_Forms/ResponsibilitiesOfResearchTeam_May2020.pdf<br>
slide7. Data Sponsor ONLY receives deidentified data
No name, EMR number, or any other PHI should be sent to the sponsor.
If an AE/SAEs or death has occurred, the sponsor may request additional information. Please do not send any materials directly to the sponsor. Report deidentified information in the EDC system.
Sponsor may see identifiable data (IF outlined in contract or other appropriate document) on monitoring visits but NEVER send any identifiable data to the sponsor (email, documents, etc.)
If there are any questions about sharing data, please ask regulatory specialist.<br>
slide8. Documentation - EMR Why do we document in the EMR?
The patient’s EMR is considered a source document. This means research staff will use the EMR to transpose data directly into the EDC.
Research needs documentation on a source document to prove it happened.
Example: informed consent, lab draws, physicals, etc.
How do we utilize quick texts?
Quick texts are to help PIs and Sub-Is efficiently document research activities while including all necessary information
Quick texts can be added from the notes section of a patient’s chart
What should and should not be included?
Include: what happened (include any abnormalities), was anything clinically significant, and is there follow-up if Clinically Significant
Not Included: Review of assessments/labs outside the protocol unless an AE or SAE has occurred<br>
slide9. Documentation – Lab Values All lab values outside the normal range must be deemed clinically significant (CS) or non-clinically significant (NS)
These will be reported on the source document (in EMR or on paper depending on the protocol)
Usually the study’s protocol will say whether or not clinically significant values must also be reported as an Adverse Event (AE)
Note: an AE must be reported as a diagnosis.
Example: High glucose would be reported as “hyperglycemia”<br>
slide10. Clinically Significant An abnormal lab value should be deemed clinically significant if either of the following conditions are met:
The abnormality suggests a disease and/or organ toxicity that is new or has worsened from baseline.
The abnormality is of a degree that requires additional active management, e.g., change of dose, discontinuation of the drug, close observation, more frequent follow-up assessments, or further diagnostic investigation….
Therefore, a clinically significant lab value is one that indicates a new disease process, an exacerbation or worsening of an existing condition, or requires further action(s) to be taken.
Link to an ACRP article: https://acrpnet.org/2019/02/12/opinion-appreciating-a-clinical-approach-to-the-evaluation-of-nonserious-laboratory-adverse-events/<br>
slide11. Examples of CS vs NS In a study for diabetic patients
Subject has a blood glucose of 220 mg/dL
Not Significant
Subject has a Hb of 3 g/dL
Clinically Significant – could be sign of a new condition or worsening of health
Action: Retest? Contact PCP? Contact Patient? Report as AE?
In a study for COVID+ patients
Subject has high LDH, troponin, Ferritin, D-dimer CPK, & CRP values
Not Significant - this is expected with disease progression
Subject has an low GFR
Significant – could be sign of kidney failure
Action: Retest? Contact PCP? Contact Patient? Report as AE?<br>
slide12. Adverse Events (AE)& Serious Adverse Events (SAE) An AE is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and that does not necessarily have a casual relationship with this treatment.
A physical event (e.g., a rash).
A psychological event (e.g., depressed mood).
A laboratory event (e.g., elevated blood sugar).
An increase in the severity or frequency of a pre-existing symptom or condition (e.g., increased pain in a painful tooth)
A SAE is any AE that in the opinion of the Investigator or Sponsor results in:
Death or is life-threatening (immediate risk of death)
Hospitalization or prolongation of existing hospitalization
Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions (aka disability)
Congenital anomaly / birth defect<br>
slide13. AE/SAE Steps General: follow the protocol for specific steps that are required for the study
Reporting of AE/SAE is typically within 24 hours of discovery
PI needs to determine diagnosis, severity, expectedness, relatedness, and needs to create a narrative for the event (see next slides for each step)
Research staff are available to help determine steps that need to be taken for reporting:
Contacting the sponsor if needed
Contacting the medical monitor for the study if needed
Determining what forms need to be filled out
Filling out necessary forms
Meeting with the PI to review the forms for accuracy and make needed updates
Having the PI sign off on the forms
Submitting the forms to the necessary entities (sponsor, safety board, etc.) deemed in the protocol
Entering data into the EDC systems (PI typically needs to sign off in the EDC system once this is done)<br>
slide14. Classifying AEs: Severity (non-healthy participants) Each protocol will have a specific guide they require to be followed for grading and reporting a diagnosis
Grade 1 Mild;
asymptomatic or mild symptoms; clinical or diagnostic observations only; no intervention indicated
Grade 2 Moderate;
minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL
Grade 3 Severe or medically significant but not immediately life threatening;
hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL
Grade 4 Life-threatening consequences;
urgent intervention indicated.
Grade 5 Death related to AE.<br>
slide15. AE Severity Grading Scales DAIDS (used for allegories and infectious disease): https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf
NCI (used for oncology): https://evs.nci.nih.gov/ftp1/CTCAE/About.html
DMID (infectious disease): https://www.niaid.nih.gov/sites/default/files/dmidadulttox.pdf
Ask the study’s sponsor, which severity scale to use. The sponsor may not be following a particular scale. The scales are guides developed by the FDA but not required. Check the protocol to see if a severity scales is provided.<br>
slide16. Classifying AEs: Expectedness Unexpected
nature or severity of the event is not consistent with information about the condition under study or intervention in the protocol, consent form, product brochure, or investigator brochure
Expected
event is known to be associated with the intervention or condition under study.
Additional Info:
To be reported to the FDA an AE must be Serious, Unexpected, and a Suspected Adverse Reaction.
Please see link drug toxicity guide: https://www.fda.gov/media/73679/download<br>
slide17. Classifying AEs: Relatedness Definitely Related:
The adverse event is clearly related to the investigational agent/procedure – i.e. an event that follows a reasonable temporal sequence from administration of the study intervention, follows a known or expected response pattern to the suspected intervention, that is confirmed by improvement on stopping and reappearance of the event on repeated exposure and that could not be reasonably explained by the known characteristics of the subject’s clinical state.
Possibly Related:
An adverse event that follows a reasonable temporal sequence from administration of the study intervention follows a known or expected response pattern to the suspected intervention, but that could readily have been produced by a number of other factors.
Not Related:
The adverse event is clearly not related to the investigational agent/procedure - i.e. another cause of the event is most plausible; and/or a clinically plausible temporal sequence is inconsistent with the onset of the event and the study intervention and/or a causal relationship is considered biologically implausible.<br>
slide18. Tips for Writing an SAE Narrative Peer ICH E3 Guidelines, a narrative should include the following:
The nature, intensity, and outcome of the event
The clinical course leading to the event
An indication of timing relevant to study drug administration
Relevant laboratory measures
Action taken with the study drug (and timing) in relation to the event
Treatment or intervention
Postmortem findings (if applicable)
Investigator's and sponsor's (if appropriate) opinion on causality.
Link for more help: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5950607/<br>
slide19. Guidelines for Blinded Trials Please be sure to never put yourself in a position where you could be unblinded.
Only the unblinded pharmacist should handle IP and accountability logs
If the unblinded pharmacist has a question about shipments or IP, they need to contact the Unblinded CRA directly. Do not cc blinded staff or PI.
In a single blinded trial – do not reveal to the patient which arm they received
Do not treat subjects differently or report AE/SAEs based on whether you suspect they received IP vs placebo<br>
slide20. Protecting Rights, Safety and Welfare of Study Subjects Provide appropriate referral and medical care for all patients on study.
Have a back up for medical questions when the investigator is out of office.<br>
slide21. Submitting Critical Study Reports Must submit and report to Sponsor and IRB
Any serious unanticipated adverse event-(Within 10 days)
Progress Report at least year(may be sooner if IRB/sponsor require earlier)
Any Major deviation made to protect the life or well-being of a subject in an emergency(report due within 5 working days)
Planned(non-emergent) protocol deviation requires sponsor approval. Certain approvals that impact scientific soundness or patient safety may also require IRB and FDA approval.
Any use of investigational agent with obtaining informed consent(Due with 5 working days)
A final report after completion is due with 3 months.
Change in PI must be reported to sponsor with 5 days of change.<br>
slide22. Conflict and Promotion 1. Cannot reflect the agent as approved therapy. Cannot reflect the device as safe or effective.
2. Cannot charge patient for the investigational product.
3. Must report any conflict with regards to sponsor company ownership, payment, and intellectual property per institutional and federal standards. Any mitigation of conflict of interest must be followed during study conduct.<br>
slide23. Insider Trading Insider training is the illegal practice of trading on the stock exchange to one’s own advantage through access to confidential information.
Avoid:
trading individuals stocks within the area of research in which you are involved with or have been apprised of confidential information not related to research you are involved with
telling friends and family members confidential information that the public does not have access to
making stock or trading recommendations based upon confidential or non-public information
If you have any questions regarding conflict of interest or insider trading, please contact human resources.<br>
slide24. Thank you<br>
slide2. Overview for Investigator Responsibilities 1. Ensure all aspects of a clinical trial are completed per the Investigative Plan
2. Protecting the rights, safety and welfare of Subjects
3. Control of investigational agent under investigation<br>
slide3. Supervision of Study Conduct 1. Per Code of Federal Regulation the investigator commits to conduct and supervise the investigative trial
2. The investigator is responsible to assess the study related employees delegated to perform key task and adequately supervise their conduct<br>
slide4. Appropriate Delegation 1. Investigator Needs to complete and show documentation of completion for all trial related medical decision.
Review of screening, medical history and assessment of inclusion/exclusion criteria- this is best documented in a clinical note
Physical Exams- unless state law allows APP
Evaluation and attribution of Adverse events
Assessment of endpoints
Oversight of informed consent process
Oversight and approval of delegation log<br>
slide5. Study Timeline Before the study
Attend and complete necessary trainings (Site Initiation Visit, EDC system, etc.)
Attend a study walkthrough with study staff
Sign the delegation log
During the study
Confirm eligibility of participants after baseline visit
Review labs if needed
Review Adverse Events/Serious Adverse Events if applicable
Attend Monitoring Visits
Typically call in for ~15 minutes. Monitoring visits occur every few weeks during the course of the study.
Attend PI meeting with study lead
15 minutes weekly
After the study
Sign off that all components were completed for the study after study close out<br>
slide6. PI Responsibilities: Additional Resources GCP:
file:///C:/Users/scerkovnik/Downloads/Roles%20&%3B%20Responsibilities.pdf
FDA:
https://www.fda.gov/media/87513/download
Introduction to Clinical Research:
http://compliance.emory.edu/documents/S-I_Responsibilities.pdf
https://www.jefferson.edu/content/dam/university/research/jcri/crf_03_17_pdf/0840_Roles%26Responsibilities.pdf
National Cancer Institute:
http://cancerpreventionnetwork.org/Roster_Forms/ResponsibilitiesOfResearchTeam_May2020.pdf<br>
slide7. Data Sponsor ONLY receives deidentified data
No name, EMR number, or any other PHI should be sent to the sponsor.
If an AE/SAEs or death has occurred, the sponsor may request additional information. Please do not send any materials directly to the sponsor. Report deidentified information in the EDC system.
Sponsor may see identifiable data (IF outlined in contract or other appropriate document) on monitoring visits but NEVER send any identifiable data to the sponsor (email, documents, etc.)
If there are any questions about sharing data, please ask regulatory specialist.<br>
slide8. Documentation - EMR Why do we document in the EMR?
The patient’s EMR is considered a source document. This means research staff will use the EMR to transpose data directly into the EDC.
Research needs documentation on a source document to prove it happened.
Example: informed consent, lab draws, physicals, etc.
How do we utilize quick texts?
Quick texts are to help PIs and Sub-Is efficiently document research activities while including all necessary information
Quick texts can be added from the notes section of a patient’s chart
What should and should not be included?
Include: what happened (include any abnormalities), was anything clinically significant, and is there follow-up if Clinically Significant
Not Included: Review of assessments/labs outside the protocol unless an AE or SAE has occurred<br>
slide9. Documentation – Lab Values All lab values outside the normal range must be deemed clinically significant (CS) or non-clinically significant (NS)
These will be reported on the source document (in EMR or on paper depending on the protocol)
Usually the study’s protocol will say whether or not clinically significant values must also be reported as an Adverse Event (AE)
Note: an AE must be reported as a diagnosis.
Example: High glucose would be reported as “hyperglycemia”<br>
slide10. Clinically Significant An abnormal lab value should be deemed clinically significant if either of the following conditions are met:
The abnormality suggests a disease and/or organ toxicity that is new or has worsened from baseline.
The abnormality is of a degree that requires additional active management, e.g., change of dose, discontinuation of the drug, close observation, more frequent follow-up assessments, or further diagnostic investigation….
Therefore, a clinically significant lab value is one that indicates a new disease process, an exacerbation or worsening of an existing condition, or requires further action(s) to be taken.
Link to an ACRP article: https://acrpnet.org/2019/02/12/opinion-appreciating-a-clinical-approach-to-the-evaluation-of-nonserious-laboratory-adverse-events/<br>
slide11. Examples of CS vs NS In a study for diabetic patients
Subject has a blood glucose of 220 mg/dL
Not Significant
Subject has a Hb of 3 g/dL
Clinically Significant – could be sign of a new condition or worsening of health
Action: Retest? Contact PCP? Contact Patient? Report as AE?
In a study for COVID+ patients
Subject has high LDH, troponin, Ferritin, D-dimer CPK, & CRP values
Not Significant - this is expected with disease progression
Subject has an low GFR
Significant – could be sign of kidney failure
Action: Retest? Contact PCP? Contact Patient? Report as AE?<br>
slide12. Adverse Events (AE)& Serious Adverse Events (SAE) An AE is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and that does not necessarily have a casual relationship with this treatment.
A physical event (e.g., a rash).
A psychological event (e.g., depressed mood).
A laboratory event (e.g., elevated blood sugar).
An increase in the severity or frequency of a pre-existing symptom or condition (e.g., increased pain in a painful tooth)
A SAE is any AE that in the opinion of the Investigator or Sponsor results in:
Death or is life-threatening (immediate risk of death)
Hospitalization or prolongation of existing hospitalization
Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions (aka disability)
Congenital anomaly / birth defect<br>
slide13. AE/SAE Steps General: follow the protocol for specific steps that are required for the study
Reporting of AE/SAE is typically within 24 hours of discovery
PI needs to determine diagnosis, severity, expectedness, relatedness, and needs to create a narrative for the event (see next slides for each step)
Research staff are available to help determine steps that need to be taken for reporting:
Contacting the sponsor if needed
Contacting the medical monitor for the study if needed
Determining what forms need to be filled out
Filling out necessary forms
Meeting with the PI to review the forms for accuracy and make needed updates
Having the PI sign off on the forms
Submitting the forms to the necessary entities (sponsor, safety board, etc.) deemed in the protocol
Entering data into the EDC systems (PI typically needs to sign off in the EDC system once this is done)<br>
slide14. Classifying AEs: Severity (non-healthy participants) Each protocol will have a specific guide they require to be followed for grading and reporting a diagnosis
Grade 1 Mild;
asymptomatic or mild symptoms; clinical or diagnostic observations only; no intervention indicated
Grade 2 Moderate;
minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL
Grade 3 Severe or medically significant but not immediately life threatening;
hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL
Grade 4 Life-threatening consequences;
urgent intervention indicated.
Grade 5 Death related to AE.<br>
slide15. AE Severity Grading Scales DAIDS (used for allegories and infectious disease): https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf
NCI (used for oncology): https://evs.nci.nih.gov/ftp1/CTCAE/About.html
DMID (infectious disease): https://www.niaid.nih.gov/sites/default/files/dmidadulttox.pdf
Ask the study’s sponsor, which severity scale to use. The sponsor may not be following a particular scale. The scales are guides developed by the FDA but not required. Check the protocol to see if a severity scales is provided.<br>
slide16. Classifying AEs: Expectedness Unexpected
nature or severity of the event is not consistent with information about the condition under study or intervention in the protocol, consent form, product brochure, or investigator brochure
Expected
event is known to be associated with the intervention or condition under study.
Additional Info:
To be reported to the FDA an AE must be Serious, Unexpected, and a Suspected Adverse Reaction.
Please see link drug toxicity guide: https://www.fda.gov/media/73679/download<br>
slide17. Classifying AEs: Relatedness Definitely Related:
The adverse event is clearly related to the investigational agent/procedure – i.e. an event that follows a reasonable temporal sequence from administration of the study intervention, follows a known or expected response pattern to the suspected intervention, that is confirmed by improvement on stopping and reappearance of the event on repeated exposure and that could not be reasonably explained by the known characteristics of the subject’s clinical state.
Possibly Related:
An adverse event that follows a reasonable temporal sequence from administration of the study intervention follows a known or expected response pattern to the suspected intervention, but that could readily have been produced by a number of other factors.
Not Related:
The adverse event is clearly not related to the investigational agent/procedure - i.e. another cause of the event is most plausible; and/or a clinically plausible temporal sequence is inconsistent with the onset of the event and the study intervention and/or a causal relationship is considered biologically implausible.<br>
slide18. Tips for Writing an SAE Narrative Peer ICH E3 Guidelines, a narrative should include the following:
The nature, intensity, and outcome of the event
The clinical course leading to the event
An indication of timing relevant to study drug administration
Relevant laboratory measures
Action taken with the study drug (and timing) in relation to the event
Treatment or intervention
Postmortem findings (if applicable)
Investigator's and sponsor's (if appropriate) opinion on causality.
Link for more help: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5950607/<br>
slide19. Guidelines for Blinded Trials Please be sure to never put yourself in a position where you could be unblinded.
Only the unblinded pharmacist should handle IP and accountability logs
If the unblinded pharmacist has a question about shipments or IP, they need to contact the Unblinded CRA directly. Do not cc blinded staff or PI.
In a single blinded trial – do not reveal to the patient which arm they received
Do not treat subjects differently or report AE/SAEs based on whether you suspect they received IP vs placebo<br>
slide20. Protecting Rights, Safety and Welfare of Study Subjects Provide appropriate referral and medical care for all patients on study.
Have a back up for medical questions when the investigator is out of office.<br>
slide21. Submitting Critical Study Reports Must submit and report to Sponsor and IRB
Any serious unanticipated adverse event-(Within 10 days)
Progress Report at least year(may be sooner if IRB/sponsor require earlier)
Any Major deviation made to protect the life or well-being of a subject in an emergency(report due within 5 working days)
Planned(non-emergent) protocol deviation requires sponsor approval. Certain approvals that impact scientific soundness or patient safety may also require IRB and FDA approval.
Any use of investigational agent with obtaining informed consent(Due with 5 working days)
A final report after completion is due with 3 months.
Change in PI must be reported to sponsor with 5 days of change.<br>
slide22. Conflict and Promotion 1. Cannot reflect the agent as approved therapy. Cannot reflect the device as safe or effective.
2. Cannot charge patient for the investigational product.
3. Must report any conflict with regards to sponsor company ownership, payment, and intellectual property per institutional and federal standards. Any mitigation of conflict of interest must be followed during study conduct.<br>
slide23. Insider Trading Insider training is the illegal practice of trading on the stock exchange to one’s own advantage through access to confidential information.
Avoid:
trading individuals stocks within the area of research in which you are involved with or have been apprised of confidential information not related to research you are involved with
telling friends and family members confidential information that the public does not have access to
making stock or trading recommendations based upon confidential or non-public information
If you have any questions regarding conflict of interest or insider trading, please contact human resources.<br>
slide24. Thank you<br>