CCRC NEED TO MASTER

Twenty-six subjects were enrolled in a pneumonia trial. The site received 100 bottles of IP. Each subject received two bottles. Four subjects did not return their trial bottles. How many bottles are available for the CRC to return to the sponsor at the end of the trial? 44 48 92 96

92

What needs reported to the IRB?

*Changes / deviations from protocol due to unforeseen hazard * changes to subject risk * adverse events * new info that may impact subject safety

Purpose of Trial monitoring

*Ensure rights & safety of subjects are protected *Report on accuracy of trial data *Ensure trial is compliant (protocol, GCP, etc)

LARs may sign for a subject if what conditions exist?

-non-therapeutic studies only -low risk to subject - cannot be conducted otherwise -IRB approves it -trial is not illegal by law

Declaration of Helsinki

-principles and duties of physicians -research ethics committee -privacy and confidentiality -scientific requirement and research protocols -informed consent -use of placebo -Dissemination of research

What does the Trial Master File include?

1. Protocol 2. Investigators brochure 3. Sample case report form 4. Contract signed by all parties 5. Sample labels of IP 6. Cv's of relevant staff 7. Financial arrangements 8. Approval to perform the study 9. Information given to trial subjects

What are the standards analyzed during licensure?

1. Safety 2. Purity 3. Potency 4. Stability 5. Product Quality 6. Marketing compliance

Difference between monitor, audit and inspection

Monitoring: done by study team or assigned by sponsor Audit: Conducted by independent person assigned by Sponsor/ CRO. Focus on Compliance and process review. Checked against Regulations and sponsor SOP Inspection: regulatory bodies, focuses on Patient safety and data credibility. Checked against legislation

Vulnerable subjects in order of hierarchy

employees armed forces detainees incurable disease pts homeless*poor those in nursing home minors those unable to give consent

Audits differ from monitoring visits because

monitoring visits assess safety of subjects and day to day data collection & source documents. audits look for compliance with approved protocols

A study to assess spironolactone's efficacy in patients with heart failure is performed 450 patients receive either spironolactone or placebo for two years. Neither the patients nor physicians are aware of who takes the drug or placebo. The study setup described above is most effective in preventing.

observer bias

Who is ultimately responsible for Source Data Verification (SDV)?

the monitor

Who is responsible for the appropriate monitoring of clinical trials?

the sponsor

Notification of Termination of a significant risk trial, report must be submitted to IRB within

within 30 working days sponsor must notify FDA. Final report to FDA and IRB within 6 months.

What to document - destruction of investigational product

• Name of medication • Lot, batch or serial information • Dose • Date destroyed • Quantity destroyed • Means of destruction • Name/title/signature of the person destroying • Name/title/signature of AT LEAST ONE WITNESS

What to document - returning IP

• Name of medication • Lot, batch, or serial information • Dose • Date returned • Quantity returned • Name of the person receiving • Any reason for conflicting information • *Subject calendar to be reviewed

What to document - dispensing IP

• Subject ID • Name of product • Lot, batch or serial information • Dose • Date dispensed • Quantity • Name of the person dispensing

According to ICH Guidelines, the source document should contain which of the following information regarding informed consent? Time the consent form was signed by the subject Date the PI and subject signed the consent form Date and time the consent form was signed by the witness Evidence that the consent form was signed prior to trial-related procedures

Evidence that the consent form was signed prior to trial-related procedures

Required essential documents at completion of trial

*Investigational product accountability at site (ensures products were used appropriate ensures which products were used/returned *device construction list *ID code list *audit certificate *final monitoring report *decoding document returned *final report of trial by PI *clinical study report (interpret trial)

Responsibilities of monitor and what they verify

*Main line of communication b/w investigator & sponsor *Subjects receive direction on product use *drug accountability log *ensure all staff are informed about the trial *report recruitment rate *verify source documents (CRFs match) *patient withdrawal or missed visits are reported on CRFs *missing data or signed edits *monitor reporting of AEs *report on deviations • investigator & site staff qualification • adequacy of resources/facilities • appropriate storage of drug • appropriate use of study drug, by dose and person • compliance to protocol, GCP, SOP, and FDA/OHRP • time of ICF obtained • eligibility of participating subjects

Auditors vs Monitors vs inspectors

*Monitors - address data, storage of drug, & report to sponsor/investigator. They can be internal *Auditors - focused on compliance which is separate from routine monitoring - they should not be part of trial; independent committee reviewing data *Inspectors - IRB or FDA

IRB / IEC Responsibilities

*Oversee principles of ICH/GCP *Make sure the PI / Co-Is are qualified * Review studies at least once a year

Non-therapeutic trials can be conducted with consent from legal rep IF

*trial objectives cannot be met by personal subject consent low risk trial is not prohibited by law *IRB has approved such inclusion

Required essential documents provided during study

*updates to IB *updates to protocol / CRF, etc *approvals from IRB of updated materials *updates to any procedures / tests / shipping *records of any monitoring visits signed ICFcompleted CRFs, signed & dated*documentation of edited CRFs *source docs for completing CRFs *documentation of AEs/SAEs *subjects screening log *Subject enrollment log *subject ID code list * investigational product accountability *signature sheet (KSP) *record of samples

An IMPARTIAL witness signature is required on ICF when

*using a non-English language short-form ICF *someone who can comprehend the language, but is unable to read, write, talk or who is blind

Principles of ICH E6

- Only if benefits justify the risks - Safety is the concern above everything else - Supported with adequate clinical basis and evidence - Has a clear protocol that is scientifically sound

Financial Disclosures

-Any equity interest in a publicly held company that exceeds $50,000 in value. -Any equity interest in the sponsor of a covered study

which of the following pre-clinical studies must be completed before phase 1 studies can begin in the United States

-Single dose toxicity in two mammalian species.-Safety pharmacology studies to include assessment of effects on vital functions. -Pharmacokinetic studies ( absorption, distribution, metabolism, and excretion) -Repeated dose toxicity studies in two species (one non-rodent) for two to four weeks, providing phase 1 studies will not exceed two weeks. -Local tolerance studies using route of administration relative to propose clinical administration. -In vitro tests for evaluation of mutations and chromosomal damage (genotoxicity) -Carcinogenicity studies (only if there is cause for concern)

what needs to be done before intiation of phase III if pregnant women are used?

-all reproduction toxicity studies -standard genotoxicity tests should be completed

What are the abbreviated requirements for device studies?

-label device -ensure investigators records and make reports -obtain IRB approval -Informed consent -Monitoring of study -refraining from promotion

What reports does the Investigator give to the Sponsor?

1. Progress reports 2. Safety reports 3. Final reports 4. Financial disclosure reports

A CRC has received three subject complaints of localized infection at the venipuncture site. The CRC queries the phlebotomist and discovers that when the first stick is unsuccessful, any additional sticks are done with the same needle. This is in violation of the site's SOPs. Which of the following actions should the CRC take? 1. Suggest review of proper specimen collection for the phlebotomist. 2. Document and report the findings. 3. Inform the IRB/IEC of the situation and the corrective action. 4. Report the incidents to the IDMC/DSMB. 1 and 2 only 1 and 3 only 2 and 4 only 3 and 4 only

1 and 2 only

A potential subject for a trial has been mailed an ICF prior to his screening visit. When the subject arrives at the research department for his screening visit, he states he read the ICF and is ready to do the trial. He does not have the copy of the ICF that was mailed to his home with him. According to the ICH Guidelines, which of the following are the BEST actions for the CRC to take initially? 1. Have the subject sign the ICF. 2. Document that the subject reviewed the ICF at home. 3. Tell the subject to keep the ICF mailed to the home as his copy. 4. Confirm the subject's understanding of the ICF. 1 and 2 only 1 and 4 only 2 and 3 only 3 and 4 only

1 and 4 only

What are the clinical development stages for DEVICES

1) Pilot Study 2) Pivotal Study (only needs to be on 100's, not 1000's of subjects) 3) Post-market studies

A CRA is conducting a close-out visit at a site to review the regulatory documents. The CRC has prepared the following documents to be filed and/or sent to the sponsor: treatment decoding documentation, drug accountability log, subject identification code list, documentation of IP destruction, and final report to the IRB/IEC. Which of the following actions should the CRC perform? 1. Send the treatment decoding documentation to the sponsor. 2. Remove the subject identification code list from the material to be sent to the sponsor. 3. Send copies of the IP destruction forms to the sponsor. 4. Remove the drug accountability log from the material to be sent to the sponsor.

1, 2, & 3

4 components of short form

1. A short form consent document 2. An oral presentation of the required elements of consent 3. An IRB approved written summary of what is to be said 4. A witness must be present

What must INFORMED CONSENT always have?

1. A statement that the study involves research, it is an experiment, the purpose of the research, trial duration 2. Description of risks to the subject 3. Description of benefits 4. Disclosure of alternatives 5. How confidentiality will be maintained, who has access to direct records, and note that FDA can see records 6. Compensation if any, available medical treatments if injury and how to find additional info 7. Contact information for questions 8. Statement that participation is voluntary, that refusal will lead to no loss of benefits, and can discontinue participation with no penalty Also: *Treatments/Procedures *randomization aspect if applicable *Subject responsibilities *New information will be made available to subject *Involuntary termination *Subjects to be enrolled

Sponsor/Investigator agreement should contain

1. Agreement to comply w/ GCP (adhere to protocol & IRB) 2. Agree to comply with data recording 3. Agree to permit monitoring 4. Agree to retain documents for specified length of time *Agreement should be signed by both parties

Investigator Responsibilities

1. Conducting a clinical trial at their site 2. Adhering to SOPs, protocol and regulations 3. Human subject protection 4. Ensures IRB review 5. Obtains informed consent 6. Case history, case report forms, etc. 7. Record retention- at least 2 years 8. Control and disposition of investigational product 9. Reports to sponsor Also: *Maintain delegation long *Ensure staff are trained/informed about the protocol (give delegated tasks, but not assign) * Ascertain reason study participant withdraws consent while respecting their privacy & rights *Document & explain any deviations from approved protocol * Process protocol amendments according to GCP

What are the 3 primary criticisms of standard phase I design?

1. Doesn't target a particular probability of DLT to be associated with the MTD 2. The MTD definition is unnecessarily imprecise 3. Dose Escalation is unnecessarily slow

Documents collected during SIV?

1. FDA 1572 Form 2. Financial disclosures 3. protocol and signature 4. DOA log and sit training log 5. Training certificate and medical licenses of personnel 6. IRB application and approval

4 types of Expedited Review

1. Fast track designation (FT) 2. Breakthrough therapy design (BT) 3. Accelerated Approval (AA) 4. Priority review designation (PR)

Grounds for putting a Phase 1 trial on hold

1. Human subjects are or would be at an increased risk 2. Investigators are not qualified 3. The Investigators brochure is wrong 4. IND does not contain enough info about the risks 5. Study for a life threatening disease that includes both genders but trial excludes based on gender

Protocol amendments should be submitted to

1. IRB 2. Sponsor 3. Regulatory Authority

What do the IRB check?

1. Informed Consent 2. Risk/If meets minimal risk 3. Risks are reasonable in comparison to the benefits to the subjects 4. Selection of subjects is reasonable 5. If vulnerable groups need additional safeguarding

List of documents during Site Closeout Visit:

1. Inventory Log 2. On site destruction form 3. IRB IEC final report 4. Accountability Log 5. Duty delegation log and site training log 6. Shipping record

Information Needed from Investigator prior to Clinical Trial Participation

1. Investigator Statement (Form 1572) 2. CV 3. Signed Protocol 4. Financial Disclosure

Sponsor Responsibilities

1. Maintain an effective IND or IDE 2. Ensure studies are conducted according to the general investigative plan and protocols 3. AE Reporting 4. Investigator/site selection 5. Provide IB , protocol, SOP 6. Ensure proper monitoring (medical monitor, DSMB, on-site monitoring) 7. Manufacture and label drug/device 8. Promptly inform PI's and FDA of significant new AE's or risks 9. Act on investigator non-compliance 10. Notification of premature termination or suspension 11. Quality Assurance/Quality Control 12. Trial and data management 13. Allocation of duties and functions 14. Auditing 15. Investigational product

Nuremberg Code 10 Elements

1. Voluntary consent 2. The intervention should benefit society, be unable to be done any other way and not designed at random 3. Based on previous science and evidence 4. Minimal risk involved 5. Experiments should not risk death unless the investigator is also part of the participants 6. The benefits should outweigh the risks 7. Preparations should be done to minimize risks and death 8. Should be conducted on by qualified investigators 9. Subjects should be able to leave at any point 10. The experiment must be stopped if increased risk of death is realized

4 Types of Clinical Outcome Assessments

1. clinician-reported outcome (ClinRO) 2. observer-reported outcome (ObsRO) 3. patient-reported outcome (PRO) 4. performance outcome (PerfO)

2 principles of trial design

1. has to protect subjects 2. has to have a scientific approach

Categories of Research Involving Children

1. no more than minimal risk 2. prospect of direct benefit for the individual subject 3. likely to yield generalizable knowledge about the subjects disorder or condition 4. Not otherwise approvable, but represents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children

Studies eligible for EXPEDITED REVIEW

1.Research activities that present no more than minimal risk to human subjects 2. Research on drugs for which an IND is not required 3. Research on medical devices for which IDE is not required 4. Collection of blood samples by finger stick, heel stick, ear stick, or venipuncture following max collections 5. Prospective collection of biological specimens for research purposes by noninvasive means (includes hair and PLACENTA) 6. Collection of data through noninvasive procedures (not involving general anesthesia or sedation) routinely employed in clinical practice, EXCLUDING procedures involving x-rays or microwaves.But INCLUDES MRI's and US 7. Retrospective and Prospective chart review only 8. Collection of data from voice, video, digital, or image recordings made for research purposes.

what fraction of experimental drugs pass phase 1 and 2 testing?

1/3

Days the investigator has to report UADE to the sponsor, IRB, and FDA

10 working days

The trough blood level for a once-daily drug should be drawn how long after the last dose? Immediately 4 hours 12 hours 24 hours

24 hours

How many days do you have to report a protocol deviation?

5 days

A subject is issued 120 tablets and is instructed to take 2 tablets 4 times a day. He returns 88 tablets on the morning of day 9 fasting for laboratory tests. What percent compliant is he? 50% 64% 78% 100%

50% If he was 100% compliant he'd have gone through 72 pills. By being 50% compliant he want through 36 pills and 120-36 is roughly 84

Notification of Completion. For non significant risk trial, report must be submitted to IRB within

6 months

FWA

A contract between the institution and the federal government to ensure the protection of human subjects PIs ensure this is current before starting, updated every 5 years FWA can be used IN LIEU OF the IRB ROSTER if it is not provided

The pediatric population represents a vulnerable subgroup. Therefore, special measures are needed to protect the rights of pediatric study participants and to shield them from undue risk. Which of the following should be taken into consideration? Select all that apply Recruitment Consent and assent Minimizing risk Minimizing distress

ALL!

The day before a CRA is to conduct an initiation visit, the CRC realizes that the IRB/IEC approval letter has not yet been obtained. Which of the following should the CRC do FIRST? Request an expedited IRB/IEC review. Reschedule the initiation visit. Call the IRB/IEC to check the status of the letter. Call the sponsor to have the files checked.

Call the IRB/IEC to check the status of the letter.

Type I error

Error made by wrongly rejecting a true null hypothesis.. If the null hypothesis is that the sample should be negative, a type I error will generate a false positive result

20. All of the following are regulatory documents EXCEPT Informed consent. Protocol signature page. Laboratory certification. Confidentiality agreement.

Confidentiality agreement.

During the monitoring visit, a CRA discusses the following queries with the CRC: - dates of the subject visits recorded as month/day/year instead of day/month/year - subjects' identification numbers are missing lead-in zeros - weights are recorded as pounds instead of kilograms - discrepancies in the two subjects' visit dates between source data and CRF entries. Which of the following actions should the CRC take? Direct the subinvestigator to correct the CRFs. Correct errors on the CRFs as discovered. Resolve discrepancies with the PI. Send the unedited CRFs to data management.

Correct errors on the CRFs as discovered.

Type II error

Error made by wrongly accepting a false null hypothesis If the null hypothesis is that the sample should be negative, a type II error will generate a false negative result

Which of the following brought increased public attention to the problems with the IRB system?

Death of Jesse Gelsinger (Although all of these are related to the problems with the IRB system, the death of Jesse Gelsinger was what received public attention.)

What 3 principles governing the good & ethical phase 1 study?

Efficiency Ethical Conduct Safety

What are the principles of ICH E6 GCP?

FDA Regulations Require that Investigator Reports to Sponsor: 1. safety occurrences 2. protocol deviations 3. progress reports 4. final report and financial disclosure report What are the principles of ICH E6 GCP? 1. CTs conducted in accordance to Declaration of Helsinki 2. Foreseeable risks should be weighed the anticipated benefit. 3. Rights, safety and well-being of the subjects should prevail over interests of science and society. 4. Non-clinical and clinical information on IP should support proposed CT. 5. Must be scientifically sound and clearly described in detailed protocol. 6. Must be in compliance as approved by IRB/IEC 7. Medical care given to patients must be provided by a qualified physician/dentist. 8. All individuals involved in conducting a trial must be qualified by education, training and experience. 9. ICF must be obtained before CT participation. 10. All CT information should be recorded, handled and stored that allows accurate reporting, interpretation and verification. 11. Confidentiality of records that could identify subjects should be protected. 12. IP should be manufactured, handles and stored in accordance to GMP and protocol. 13. Systems with procedures that assures the quality of every aspect of the trial should be implemented.

18. During a respiratory trial, a subject calls the CRC 1 week before his next scheduled trial visit and reports upper respiratory symptoms and a pea-sized lump in his neck. Which of the following should the CRC do FIRST? Inform the sponsor's medical monitor of the situation. Instruct the subject to contact his primary care physician. Have the subject come to the site for an interim assessment. Cancel the scheduled follow-up visit until symptoms resolve.

Have the subject come to the site for an interim assessment.

Required essential documents provided before study starts

IB signed protocol & amendments *CRFS *ICF *ads to promote study *financial aspects of study *agreements (signed) *Approved by IRB study material *Composition of IRB *Signed CVs of PIs *Storing & Handling of device/drug *shipping information *Emergency decoding procedures for blinded study *Master randomization list * Pre-trial monitoring report

A subject has signed the informed consent form for a hypertension trial. All screening procedures and the physical examination have been completed. The CRC is ready to dispense the single-blind placebo to the subject who asks, "Is that the sugar pill that I read about in that form I signed?" Which of the following should the CRC tell the subject? Only the physician knows what medication you are taking at this time. I don't know what you are taking at this time since the trial is blinded. Yes. Remember everybody has to take the placebo for some time during the trial. It might be the placebo, but we will be checking your blood pressure every week.

It might be the placebo, but we will be checking your blood pressure every week.

A sponsor has supplied all sites with digital thermometers for a vaccine trial. At one site, the CRC notices that 10 of 30 subjects have recorded consistently low temperature readings in their diaries for the first 7 days of the trial. Upon review with the subjects, there were no related complaints. Which of the following should be the CRC's FIRST action? Notify the sponsor. Contact the manufacturer. Inform the remaining 20 subjects. Replace existing thermometers with an alternate model.

Notify the sponsor. the sponsor is responsible for maintaining quality assurance and control

If a sponsor's attempts to secure compliance have failed, and the monitoring/auditing identifies serious and/or persistent noncompliance on the part of an investigator or institution, the sponsor should implement which of the following actions? Select all that apply Promptly notify the regulatory authority(ies) Develop a corrective action plan Reeducate the investigator by a total review of the protocol and required procedures Terminate the investigator's/institution's participation in the trial

Promptly notify the regulatory authority(ies) Terminate the investigator's/institution's participation in the trial

Serious vs Severe events

Severe = degree of event (mild/moderate, etc) Serious = overall event outcome; dictates regulatory documentation & reporting

The DSMB has prematurely terminated a trial evaluating an investigational pain medication that is taken one caplet orally b.i.d. for chronic hip pain. Subjects are allowed to take one extra caplet per day. Subjects receive a sufficient quantity of IP for 14 days plus two additional doses. Which of the following represents a drug accountability issue? Subject A returns 24 pills after 10 days on trial. Subject B returns 12 pills after 8 days on the trial. Subject C returns 29 pills after 5 days on the trial. Subject D returns 42 pills after 1 day on the trial.

Subject B returns 12 pills after 8 days on the trial. Should have between 2-29 pills left

With expedited IND applications, what is a Fast Track Designation?

There is a serious condition AND data demonstrates potential to address unmet medical need This allows expedited development and review by the FDA. Also allows for rolling review, and submitting chunks of data at a time

With expedited IND applications, what is Breakthrough Therapy?

There is a serious condition AND data indicates that the drug demonstrates substantial improvement over available therapy on one or more clinically significant endpoints

Peak

Varies, but usually around 30 mins to several hours after dosing, depends on administration

Which of the following would require prior consent when screening a subject? Subject demographics Relevant medical history Washout from medication Routine diagnostic lab tests

Washout from medication

Advocate

a witness assigned as a monitor to attest to consenting process

Double Dummy

both groups of patients in a placebo controlled study take the placebo