SUPPLMENTAL INFORMATION: CRA Key Things to Remember (Back 01)

Labs completed on patients

ANC: absolute neutrophil count... is a measure of the number white blood cells that fight against infection...ALT..AST..ABC

What is ANC

ANC: absolute neutrophil count... is a measure of the number white blood cells that fight against infection...ALT..AST..ABC

What is ALCOA

Accurate, Legible, Contemporaneous, Original, Attributable.. It is what the FDA expects all data acquired from trials to follow

Name the IRB Approval Documents

Approval for protocol, ICF, any protocol related items, and IB has to be submitted but not approved

What is done during Drug Accountability:

Assess site's drug preparation, dispensing procedures, subject compliance, ensure proper drug storage and log maintenance, account for all supplies (returned or destroyed), check temperature log. Write down Lot # and expiration dates.

Name the 4 Types of Visits

SSV-Qualification Visit assess site's qualification to conduct study, completed once per study SIV-Initiation Visit (training; completed once per study) RMV-Monitoring Visit (review subject charts; completed multiple times during study) COV-Termination Visit (closing the site; completed once per study)

What is the Karnofsky scale?

an assessment tool for functional impairment. It can be used to compare effectiveness of different therapies and to assess how the prognosis in individual patients. In most serious illnesses, the lower the score, the worse the likelihood of survival.

Common SDV findings

corrections made but not signed and dated source documents don't match EDC dose escalations error brief medical history missing reports ineligible handwriting Poor IP accountability AEs not entered Conmeds associated with the AEs not entered

Who is the Project Director

he Clinical Program Director (CPD) is responsible for managing Clinical Operations activities and providing functional supervision for Clinical Operations staff within their assigned Clinical Development Plan (CDP) as determined by the Sr. Director of Clinical Operations.

Who is the Regulatory Coordinator

responsible for the maintenance of all regulatory documents/IRB fillings

ICF components

risk, benefit, visit schedules, compensation, steps of fetal involvement, causes to be terminated

Who is the CRA

they monitor clinical trials. They perform may activities related to clinical research.

Differences in oncology vs other studies

1 More risk based monitor in other non-oncology studies 2 All drugs are pretty much IV for oncology 3 More SAEs in Oncology

RECIST v1 vs v1.1

1- #of lesions assessed has decreased from 10 to 5 2- maximum of 2 lesions per organ 3- confirmation of response is required for trials as a primary endpoint 4- assessment of pathological lymph nodes is now included 5 definition of disease progression has been refined

Documents in Regulatory Binders

1572 DOA\ CV CLIA IRB Approval Documents ICFs Protocol Safety Reports Training Logs Subject Logs Enrollment Logs Monitoring Visit Logs

Creatinine Clearance

A test that helps determine whether the kidneys are functioning normally. Specifically, the test gauges the rate at which a waste, creatinine, is "cleared" from the blood by the kidneys

Name some Imaging for oncology:

CT, MRI, and ultrasound are all imagine that provides the lesions, location, and measurement

Drug Accountability: What should you check?

Check for the expiration date of the unused drug Check the temperature log of where drug is stored Check the site's drug accountability logs

When do you start collecting SAE's

Collect SAE's from the time of consent

Purpose of Phase lll clinical trials

Compare one or more treatments of proven efficacy. Often patients will be randomized between an established 'standard' treatment and a new 'experimental' treatment - it is not known which is the better treatment (Drug vs Placebo)

CRA Duties:

Conduct site mgmt. activities, ensure integrity of data, well-being and safety and subjects, write confirmation/follow up letters. Upload docs into the TMF, review EDC, follow up and resolved open queries. Ensure consistency, prevent fraud, and to make sure adherence to protocol, GCP and SOP

Drug Accountability: What should a CRA NOT do?

DO NOT open any bottles, boxes, or vials that have never been opened.

Phase I: tips about this Phase (oncology)

Duration is shorter Looking for endpoints (dose escalation) Targeting how soon subject progress, only have 30 day survival follow up PK testing, lots of labs drawn Looking for AEs Lots of PK testing is done

purpose of ECOG

Eastern Cooperative Oncology Group: used to grade the performance level of a subject, grade 0-5. Performance status is a scale used to assess how a patient's disease is progressing, assess how the disease affects the daily living abilities of the patient, and determine appropriate treatment and prognosis. 0-5 with 5 being death

What happens If PI leaves sight\study:

Ensure IRB was notified and new PI was assigned ... make sure old PI has stop date on the DOA... New PI has CV, medical license and FDF is obtained and submitted... be sure new PI was trained.

Name some Oncology Drugs

Falsodex (Prostate) Methotrexate (Breast) Docetaxel (Prostate) Darzalex (Myeloma cancer formed by malignant plasma cell...Jannsen) Yondelis (Liposarcoma, cancer in fat cells...Jannsen)

Oncology Terms: Ferile Neoadjuvant Adjuvant Lymphoma

Ferile (high fever), Neoadjuvant (1st step to shrink tumor, chemotherapy/radiation) Adjuvant (surgery followed by chemo or radiotherapy to decrease cancer from returning) Lymphoma (cancer that affects the immune system...Cancer in the lymph nodes. 90% non-hodgkins and 10% hodgkins.

Primary questions to ask PI

How many subjects can you enroll during the enrollment period? How many Subjects can you screen once activated?

What are the circumstances when Phase I will use real patients

However, there are circumstances when real patients are used, such as patients who have terminal cancer or HIV and the treatment is likely to make healthy individuals.

When Reviewing a chart for eligibility

I look at the pathology report which provides diagnosis and staging of the cancer IB: Investigational Brochure...includes clinical data and non-clinical data relevant to the investigation product in human subjects (Safety profile) ..example: the side effects and info from past studies

When are Trip Reports to be completed?

they are to be completed after all site visits (ALL VISIT TYPES)

Expiration docs to review

IRB approval letter, IRB membership list, PI ML, site personnel ML, CLIA

Name the Systems used

Impact Harmony for CTMS...MediData Rave for EDC... IVRS: IcoPhone and Iview...CTCAE using version 4.3

Risk Based Monitoring (limited experience)

Include a mix of centralized and on-site monitoring practices. Identify critical data and processes to be monitored. Determines risk assessment. Determines monitoring plan. Identify critical data and processes, then perform a risk assessment to identify and understand the risk that could affect the collection of critical data or the performance of critical processes, and then develop a monitoring plan that focuses on the monitoring plan that focuses on the important and likely risks to critical data and process... Low, moderate, or high risk

Key Points of the Protocol: Inclusion/Exclusion Criteria

Inclusion criteria are characteristics that the prospective subjects must have if they are to be included in the study. While exclusion criteria are those characteristics that disqualify prospective subjects from inclusion in the study

Drug Accountability

Inventorying how much drug is at the site

Non-target:

Lesion that is not being measured on the Baseline Scan.

Phase 4

Made it to Market

Activities During Site Visit

Must Sign Visit Log Collect Delegation of Authority Log Review how source docs maintained in subject chart Review EDC/Schedule of Events/Assessments Appropriate tools (eg, eCRG, TMF reports) effectively utilized to document needed clarifications and changes to the CRF/DCFs/eCRF and Essential Documents Arrangements made for retrieval of paper CRFs or finalization of eCRFs (eg Investigator e-signature) Source documentation review conducted (including informed consents) per sponsor SDV plan Verify access to all original site source documents (subject research chart); determine if the site is utilizing Electronic Medical Records (EMR) Adverse Events and Serious Adverse Events reviewed and reported to sponsor and IRB/IEC and filed appropriately Verify PI\Sub-I assessment of SAE/AE data log, causality and relationship to IP in the source documents/ensure evidence of NCS or CS Patient eligibility All SAE source documentation, causality and relationship to IP in the source documents Actions needed for unreported Serious Adverse Events identified Source document deficiencies identified (such as protocol defined requirements, AE causality, lab review, and SAE site notifications) and discussed with the investigator Protocol deviations, violations or exceptions noted appropriately per sponsor process and escalation process reviewed Review lab requisition in subject charts Open action items reviewed, closed and/or addressed during the visit and updates documented Next monitoring visit tentatively scheduled per monitoring plan and documented per sponsor practice

Describe the Pharmacist & Site Manager role related to CRA

Often the role of pharmacist in clinical research is somewhat limited to drug management, but it should be recognized that the clinical trials pharmacist has an in-depth knowledge of pharmacotherapy and study protocol and is capable of providing comprehensive clinical services for study participants.

Most challenging about oncology

Overwhelming amount of SAEs either not logged or not graded because sites tend to not answer safety queries in a timely fashion and sometimes it takes sites a long time to submit all of the required documentation from a SAE b/c the subject may have went to another facility aside from the site's hospital. So the site has to wait to receive the necessary documentation to be sent to the safety dept. Additionally, the lengthy medical history review of subjects for the 1st time.

Things found in Form 1572:

PI name, address of site, facility where research is being conducted, IRB info, title of the study, informs investigator of their obligations and obtains investigators commitment to follow FDA regulations.

who is the Principal Investigator

Primary Physician at the site that oversees all study-related tasks. He/she can delegate responsibilities among the site staff.

Test done on Prostrate:

Prostrate specific Antigen (PSA) (Genetic Markers)

What does the IRB approve?

Protocol Acknowledgement of the Investigator Brochure (IB) ICF (Informed Consent Form)

Recruitment for Phase I is for

Recruitment for Phase I trials are usually from patients for whom no other effective therapy is known. (Is it safe?) Phase i trials most often include healthy volunteers.

Who is the Study Coordinator

Responsible for scheduling site visits, may enter data, orders and confirms study drug, maintains regulatory binder.

Who is the Data Coordinator

Responsible for timely entry of data and query resolution

ISF- Regulatory Review

Retrieve regulatory tracker ISF reviewed and reconciled with the TMF Essential Documents collected and routed to the sponsor appropriately Delegation of Authority Log and site training documentation forms reviewed and verified Gaps or delays noted in reporting expedited Serious-Unexpected ADRs (IND Safety Letters, CIOMs, reports, SUSAR) by the investigator to IRB/IEC, if required

IP - Investigational Product

Review and collect temp logs, accountability logs, disposition of Investigational Product Verified that IP storage continues to be secure and maintained per study requirements IP dispensing and return reviewed, verified against CRFs, source documentation and if applicable, study specific, electronic drug accountability system, and any discrepancies documented Verified that all IP dosing was calculated and administered according to protocol Confirm subject IP compliance was calculated and documented

purpose of Phase I clinical trials

Tests new types of treatment and aim to define a safe dose that will be used for further studies. This is usually the first testing of a treatment on humans after extensive laboratory work.

How long would the site have to inform the Sponsor in case of an SAE

Site to inform Sponsor within 24 hours of finding out and notify IRB (different timelines for some IRBs)

Prep for Visit

Site visit scheduled, confirmed and documented per requirements for the program and/or monitoring plan (confirmation letter, updated on relevant team calendars/CTMS system) Confirm Access to required locations, source documents and CRFs for the visit. Obtained/reviewed Essential Document, IP and /or CRF tracking or reports, if applicable/available Obtained appropriate forms/supplies to conduct visit (transmittal forms, drug return labels, tape) Previous visit report reviewed (to determine if any outstanding issues still need to be resolved)

RECIST

Stable, no change in tumor.. Progressive, 30% increase in tumor Complete response, 30% decrease in tumor Partial response..20% decrease in tumor

TMF

System where all site's essential regulatory documents are housed for the company; the system is an exact replica of the regulatory binder that is kept at each individual site. Only accessed by study team.

EDC

System where data is entered, and queries and resolved by the site. CRA Sdv's data, generates queries, and runs data reports (i.e. number of open queries, how many pages require SDV, number of missing subject visits) in this system. Accessed by site and study team.

CTMS

System where monitors complete Trip Reports, enter protocol deviations, follow-up/action items, and where the site information is listed for all studies and sites. Only accessed by the study team

IVRS/IWRS

System where subject randomization numbers are provided to the site, drug is ordered and drug shipments is confirmed, and where sites will enter subject visits and discontinue subjects Reports are run in this system to determine how much drug has been shipped to the site, if the site confirmed drug shipment and subject visit management. Accessed by site and study team.

Two categories for lesions

Target, measurable lesion that is being targeted... Non-target, lesion that is not being measured

Antitumor in Phase ll clinical trials

Test the anti cancer effects of the new treatment, and include very detailed toxicity investigations. If there is effective antitumor activity, it may be incorporated in future phase lll study. (Does it work in humans)

Two purposes of the 1572

Two Purposes: 1 to provide the sponsor with information about the investigator's qualifications and the clinical site that will enable the sponsor to establish and document that the investigator is qualified and the site is and appropriate location at which to conduct the clinical investigation, and 2 to inform the investigator of his/her obligations and obtain the investigator's commitment to follow pertinent FDA regulations

Name some Drugs given before chemo

Zolfram (nausea), Perkiset (Anxiety), Oxycodone (pain)

When are Confirmation Letters to be sent?

they are to be sent to all sites prior to the visit (ALL VISIT TYPES)

Common AEs in Oncology

low hemoglobin, diarrhea, vomiting, trouble breathing, painful urination, nausea, constipation, fever

Target:

measurable lesion that is being targeted on the Baseline Scan.

When are Follow-Up letters to be sent?

must be sent to all sites after the visit (ALL VISIT TYPES)

Name some Common Conmeds Drugs used

osycotten, oxycodone, IBprofuen, sulfate (constipation),

Who is the CRA Lead/Trial Manager

oversees entire study, and CRA escalates issues to this person. The lead reviews and approves Trip Reports.

Risk Based Monitoring -Critical examples

verification that informed consent was obtained appropriately adherence to protocol eligibility criteria designed to exclude individuals for whom the Investigational product may be less safe than the protocol intended and to include only subjects from the targeted study population for whom the test article is most appropriate Procedures for documenting appropriate accountability and administration of the investigational product (eg, ensuring the integrity of randomization at the site level) Conduct and documentation of procedures and assessments related to - study endpoints- protocol-required safety assessments - avaluating, documenting, and reporting serious adverse events and unanticipated adverse device effects, subject deatshs, and withdrawals, especially when a withdrawal may be related to an adverse events

Before scheduling a Qualification visit, what must happen with a CDA

when does must a CDA need to be signed by the site.

Baseline scans will have

will have Target Lesions and may have non target lesions... I will compare those scans to the new scans to see if tumor decrease or increased Take longest diameter of the lesions... 4.5 x 2.3 = 23MM DIVIDE by base line scan, subtract by 1 then multiply by 100